The Ameloblastin extracellular matrix molecule enhances bone fracture resistance and promotes rapid bone fracture healing

PubMed Central

Lu, Xuanyu; Li, Wenjin; Fukumoto, Satoshi; Yamada, Yoshihiko; Evans, Carla; Diekwisch, Thomas G.H.; Luan, Xianghong

2016-01-01

The extracellular matrix (ECM) provides structural support, cell migration anchorage, cell differentiation cues, and fine-tuned cell proliferation signals during all stages of bone fracture healing, including cartilaginous callus formation, callus remodeling, and bony bridging of the fracture gap. In the present study we have defined the role of the extracellular matrix protein ameloblastin (AMBN) in fracture resistance and fracture healing of mouse long bones. To this end, long bones from WT and AMBNΔ5-6 truncation model mice were subjected to biomechanical analysis, fracture healing assays, and stem cell colony formation comparisons. The effect of exogenous AMBN addition to fracture sites was also determined. Our data indicate that lack of a functional AMBN in the bone matrix resulted in 31% decreased femur bone mass and 40% reduced energy to failure. On a cellular level, AMBN function inhibition diminished the proliferative capacity of fracture repair callus cells, as evidenced by a 58% reduction in PCNA and a 40% reduction in Cyclin D1 gene expression, as well as PCNA immunohistochemistry. In terms of fracture healing, AMBN truncation was associated with an enhanced and prolonged chondrogenic phase, resulting in delayed mineralized tissue gene expression and delayed ossification of the fracture repair callus. Underscoring a role of AMBN in fracture healing, there was a 6.9-fold increase in AMBN expression at the fracture site one week after fracture, and distinct AMBN immunolabeling in the fracture gap. Finally, application of exogenous AMBN protein to bone fracture sites accelerated callus formation and bone fracture healing (33% increase in bone volume and 19% increase in bone mineral density), validating the findings of our AMBN loss of function studies. Together, these data demonstrate the functional importance of the AMBN extracellular matrix protein in bone fracture prevention and rapid fracture healing. PMID:26899203

External fixation of tibial pilon fractures and fracture healing.

PubMed

Ristiniemi, Jukka

2007-06-01

Distal tibial fractures are rare and difficult to treat because the bones are subcutaneous. External fixation is commonly used, but the method often results in delayed union. The aim of the present study was to find out the factors that affect fracture union in tibial pilon fractures. For this purpose, prospective data collection of tibial pilon fractures was carried out in 1998-2004, resulting in 159 fractures, of which 83 were treated with external fixation. Additionally, 23 open tibial fractures with significant > 3 cm bone defect that were treated with a staged method in 2000-2004 were retrospectively evaluated. The specific questions to be answered were: What are the risk factors for delayed union associated with two-ring hybrid external fixation? Does human recombinant BMP-7 accelerate healing? What is the role of temporary ankle-spanning external fixation? What is the healing potential of distal tibial bone loss treated with a staged method using antibiotic beads and subsequent autogenous cancellous grafting compared to other locations of the tibia? The following risk factors for delayed healing after external fixation were identified: post-reduction fracture gap of >3 mm and fixation of the associated fibula fracture. Fracture displacement could be better controlled with initial temporary external fixation than with early definitive fixation, but it had no significant effect on healing time, functional outcome or complication rate. Osteoinduction with rhBMP-7 was found to accelerate fracture healing and to shorten the sick leave. A staged method using antibiotic beads and subsequent autogenous cancellous grafting proved to be effective in the treatment of tibial bone loss. Healing potential of the bone loss in distal tibia was at least equally good as in other locations of the tibia.

Effect of healing time on bone-implant contact of orthodontic micro-implants: a histologic study.

PubMed

Ramazanzadeh, Barat Ali; Fatemi, Kazem; Dehghani, Mahboobe; Mohtasham, Nooshin; Jahanbin, Arezoo; Sadeghian, Hamed

2014-01-01

Objectives. This study aimed to evaluate the effect of immediate and delayed loading of orthodontic micro-implants on bone-implant contact. Materials and Methods. Sixty four micro-implants were implanted in dog's jaw bone. The micro-implants were divided into loaded and unloaded (control) groups. The control group had two subgroups: four and eight weeks being implanted. The loaded group had two subgroups of immediate loading and delayed (after four weeks healing) loading. Loaded samples were subjected to 200g load for four weeks. After sacrificing the animals micro-implants and surrounding tissues were observed histologically. Bone-implant contact ratios (BIC) were calculated and different groups' results were compared by three-way ANOVA. Results. Mean survival rate was 96.7% in general. Survival rates were 96.7%, 94.4% and 100% for control, immediate and delayed loaded groups, respectively. BIC values were not significantly different in loaded and control groups, immediate and delayed loading groups, and pressure and tension sides. Mandibular micro-implants had significantly higher BIC than maxillary ones in immediate loading, 4-weeks control, and 8-weeks control groups (P = 0.021, P = 0.009, P = 0.003, resp.). Conclusion Immediate or delayed loading of micro-implants in dog did not cause significant difference in Bone-implant contact which could be concluded that healing time had not significant effect on micro-implant stability.

Effect of Healing Time on Bone-Implant Contact of Orthodontic Micro-Implants: A Histologic Study

PubMed Central

Ramazanzadeh, Barat Ali; Fatemi, Kazem; Dehghani, Mahboobe; Mohtasham, Nooshin; Jahanbin, Arezoo; Sadeghian, Hamed

2014-01-01

Objectives. This study aimed to evaluate the effect of immediate and delayed loading of orthodontic micro-implants on bone-implant contact. Materials and Methods. Sixty four micro-implants were implanted in dog's jaw bone. The micro-implants were divided into loaded and unloaded (control) groups. The control group had two subgroups: four and eight weeks being implanted. The loaded group had two subgroups of immediate loading and delayed (after four weeks healing) loading. Loaded samples were subjected to 200g load for four weeks. After sacrificing the animals micro-implants and surrounding tissues were observed histologically. Bone-implant contact ratios (BIC) were calculated and different groups' results were compared by three-way ANOVA. Results. Mean survival rate was 96.7% in general. Survival rates were 96.7%, 94.4% and 100% for control, immediate and delayed loaded groups, respectively. BIC values were not significantly different in loaded and control groups, immediate and delayed loading groups, and pressure and tension sides. Mandibular micro-implants had significantly higher BIC than maxillary ones in immediate loading, 4-weeks control, and 8-weeks control groups (P = 0.021, P = 0.009, P = 0.003, resp.). Conclusion Immediate or delayed loading of micro-implants in dog did not cause significant difference in Bone-implant contact which could be concluded that healing time had not significant effect on micro-implant stability. PMID:25006463

Lack of endogenous parathyroid hormone delays fracture healing by inhibiting vascular endothelial growth factor‑mediated angiogenesis.

PubMed

Ding, Qingfeng; Sun, Peng; Zhou, Hao; Wan, Bowen; Yin, Jian; Huang, Yao; Li, Qingqing; Yin, Guoyong; Fan, Jin

2018-07-01

Intermittent low‑dose injections of parathyroid hormone (PTH) have been reported to exert bone anabolic effects and to promote fracture healing. As an important proangiogenic cytokine, vascular endothelial growth factor (VEGF) is secreted by bone marrow mesenchymal stem cells (BMSCs) and osteoblasts, and serves a crucial regulatory role in the process of vascular development and regeneration. To investigate whether lack of endogenous PTH causes reduced angiogenic capacity and thereby delays the process of fracture healing by downregulating the VEGF signaling pathway, a PTH knockout (PTHKO) mouse fracture model was generated. Fracture healing was observed using X‑ray and micro‑computerized tomography. Bone anabolic and angiogenic markers were analyzed by immunohistochemistry and western blot analysis. The expression levels of VEGF and associated signaling pathways in murine BMSC‑derived osteoblasts were measured by quantitative polymerase chain reaction and western blot analysis. The expression levels of protein kinase A (PKA), phosphorylated‑serine/threonine protein kinase (pAKT), hypoxia‑inducible factor‑1α (HIF1α) and VEGF were significantly decreased in BMSC‑derived osteoblasts from PTHKO mice. In addition, positive platelet endothelial cell adhesion molecule staining was reduced in PTHKO mice, as determined by immunohistochemistry. The expression levels of HIF1α, VEGF, runt‑related transcription factor 2, osteocalcin and alkaline phosphatase were also decreased in PTHKO mice, and fracture healing was delayed. In conclusion, lack of endogenous PTH may reduce VEGF expression in BMSC‑derived osteoblasts by downregulating the activity of the PKA/pAKT/HIF1α/VEGF pathway, thus affecting endochondral bone formation by causing a reduction in angiogenesis and osteogenesis, ultimately leading to delayed fracture healing.

Diabetes mellitus affects the biomechanical function of the callus and the expression of TGF-beta1 and BMP2 in an early stage of fracture healing.

PubMed

Xu, M T; Sun, S; Zhang, L; Xu, F; Du, S L; Zhang, X D; Wang, D W

2016-01-01

Transforming growth factor beta 1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) are important regulators of bone repair and regeneration. In this study, we examined whether TGF-β1 and BMP-2 expressions were delayed during bone healing in type 1 diabetes mellitus. Tibial fractures were created in 95 diabetic and 95 control adult male Wistar rats of 10 weeks of age. At 1, 2, 3, 4, and 5 weeks after fracture induction, five rats were sacrificed from each group. The expressions of TGF-β1 and BMP2 in the fractured tibias were measured by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction, weekly for the first 5 weeks post-fracture. Mechanical parameters (bending rigidity, torsional rigidity, destruction torque) of the healing bones were also assessed at 3, 4, and 5 weeks post-fracture, after the rats were sacrificed. The bending rigidity, torsional rigidity and destruction torque of the two groups increased continuously during the healing process. The diabetes group had lower mean values for bending rigidity, torsional rigidity and destruction torque compared with the control group (P<0.05). TGF-β1 and BMP-2 expression were significantly lower (P<0.05) in the control group than in the diabetes group at postoperative weeks 1, 2, and 3. Peak levels of TGF-β1 and BMP-2 expression were delayed by 1 week in the diabetes group compared with the control group. Our results demonstrate that there was a delayed recovery in the biomechanical function of the fractured bones in diabetic rats. This delay may be associated with a delayed expression of the growth factors TGF-β1 and BMP-2.

Radiographic evaluation for AVN following distal metatarsal Stoffella bunion osteotomy.

PubMed

Klein, Christian; Zembsch, Alexander; Dorn, Ulrich

2009-01-01

Avascular necrosis of the metatarsal head, delayed bone healing and nonunion are complications that may occur after distal first metatarsal osteotomies. Intraoperative damage to the extraosseous blood supply, the location of the osteotomy and postoperative vasospasm have been cited as possible causes of such changes. We evaluated Stoffella's subcapital osteotomies which were performed at our department for the correction of moderate to severe hallux valgus deformities. Standardized radiographs of 300 feet, taken 6weeks, 3 months, and 6 months postoperatively and at the final followup were examined with regard to postoperative AVN or signs of delayed bone healing. Of 228 patients, 202 were women and 26 were men. The patients' mean age was 49 years, and the mean followup was 12 months. In 278 cases the radiographs revealed an unremarkable first metatarsal head. Seventeen cases showed diffuse or localized osteopenia or small cysts in the subchondral bone. These changes fully resolved on subsequent radiographs. The X-rays of two patients revealed progressive narrowing of the joint space, irregular contours on the surface of the joint and an abnormal bone structure. The patients subsequently developed a characteristic picture of avascular necrosis, in one case combined with nonunion. Three patients had delayed bone healing, but ultimately healed successfully. Ischemic changes in bone are known to occur after distal first metatarsal osteotomies. There is a very low incidence of postoperative perfusion problems after Stoffella;s technique, even with lateral soft tissue release.

Delayed Expression of Circulating TGF-β1 and BMP-2 Levels in Human Nonunion Long Bone Fracture Healing.

PubMed

Hara, Yoshiaki; Ghazizadeh, Mohammad; Shimizu, Hajime; Matsumoto, Hisashi; Saito, Nobuyuki; Yagi, Takanori; Mashiko, Kazuki; Mashiko, Kunihiro; Kawai, Makoto; Yokota, Hiroyuki

2017-01-01

The healing process of bone fracture requires a well-controlled multistage and sequential order beginning immediately after the injury. However, complications leading to nonunion exist, creating serious problems and costs for patients. Transforming growth factor-beta 1 (TGF-β1) and bone morphogenic protein 2 (BMP-2) are two major growth factors involved in human bone fracture healing by promoting various stages of bone ossification. In this study, we aimed to determine the role of these factors during the fracture healing of human long bones and assess their impacts on nonunion condition. We performed a comprehensive analysis of plasma TGF-β1 and BMP-2 levels in blood samples from 10 patients with proved nonunion and 10 matched patients with normal union following a predetermined time schedule. The concentrations of TGF-β1 and BMP-2 were measured at each time point using a solid-phase ELISA. TGF-β1 and BMP-2 levels were detectable in all patients. For all patients, a maximal peak for TGF-β1 was found at 3-week. In normal union group, TGF-β1 showed a maximal peak at 2-week while nonunion group had a delayed maximal peak at 3-week. Plasma levels of BMP-2 for all patients and for normal union group reached a maximal peak at 1-week, but nonunion group showed a delayed maximal peak at 2-week. In general, plasma TGF-β1 or BMP-2 level was not significantly different between normal union and nonunion groups. The expression levels of TGF-β1 and BMP-2 appeared to be delayed in nonunion patients which could play an important role in developing an early marker of fracture union condition and facilitate improved patient's management.

CD133: Enhancement of Bone Healing by Local Transplantation of Peripheral Blood Cells in a Biologically Delayed Rat Osteotomy Model

PubMed Central

Preininger, Bernd; Duda, Georg; Gerigk, Hinnerk; Bruckner, Jonas; Ellinghaus, Agnes; Sass, F. Andrea; Perka, Carsten; Schmidt-Bleek, Katharina; Dienelt, Anke

2013-01-01

Sufficient angiogenesis is crucial during tissue regeneration and therefore also pivotal in bone defect healing. Recently, peripheral blood derived progenitor cells have been identified to have in addition to their angiogenic potential also osteogenic characteristics, leading to the hypothesis that bone regeneration could be stimulated by local administration of these cells. The aim of this study was to evaluate the angiogenic potential of locally administered progenitor cells to improve bone defect healing. Cells were separated from the peripheral blood of donor animals using the markers CD34 and CD133. Results of the in vitro experiments confirmed high angiogenic potential in the CD133(+) cell group. CD34(+) and CD133(+) cells were tested in an in vivo rat femoral defect model of delayed healing for their positive effect on the healing outcome. An increased callus formation and higher bone mineral density of callus tissue was found after the CD133(+) cell treatment compared to the group treated with CD34(+) cells and the control group without cells. Histological findings confirmed an increase in vessel formation and mineralization at day 42 in the osteotomy gap after CD133(+) cell transplantation. The higher angiogenic potential of CD133(+) cells from the in vitro experients therefore correlates with the in vivo data. This study demonstrates the suitability of angiogenic precursors to further bone healing and gives an indication that peripheral blood is a promising source for progenitor cells circumventing the problems associated with bone marrow extraction. PMID:23457441

Inhibition of GSK-3β Rescues the Impairments in Bone Formation and Mechanical Properties Associated with Fracture Healing in Osteoblast Selective Connexin 43 Deficient Mice

PubMed Central

Loiselle, Alayna E.; Lloyd, Shane A. J.; Paul, Emmanuel M.; Lewis, Gregory S.; Donahue, Henry J.

2013-01-01

Connexin 43 (Cx43) is the most abundant gap junction protein in bone and is required for osteoblastic differentiation and bone homeostasis. During fracture healing, Cx43 is abundantly expressed in osteoblasts and osteocytes, while Cx43 deficiency impairs bone formation and healing. In the present study we selectively deleted Cx43 in the osteoblastic lineage from immature osteoblasts through osteocytes and tested the hypothesis that Cx43 deficiency results in delayed osteoblastic differentiation and impaired restoration of biomechanical properties due to attenuated β-catenin expression relative to wild type littermates. Here we show that Cx43 deficiency results in alterations in the mineralization and remodeling phases of healing. In Cx43 deficient fractures the mineralization phase is marked by delayed expression of osteogenic genes. Additionally, the decrease in the RankL/ Opg ratio, osteoclast number and osteoclast size suggest decreased osteoclast bone resorption and remodeling. These changes in healing result in functional deficits as shown by a decrease in ultimate torque at failure. Consistent with these impairments in healing, β-catenin expression is attenuated in Cx43 deficient fractures at 14 and 21 days, while Sclerostin (Sost) expression, a negative regulator of bone formation is increased in Cx43cKO fractures at 21 days, as is GSK-3β, a key component of the β-catenin proteasomal degradation complex. Furthermore, we show that alterations in healing in Cx43 deficient fractures can be rescued by inhibiting GSK-3β activity using Lithium Chloride (LiCl). Treatment of Cx43 deficient mice with LiCl restores both normal bone formation and mechanical properties relative to LiCl treated WT fractures. This study suggests that Cx43 is a potential therapeutic target to enhance fracture healing and identifies a previously unknown role for Cx43 in regulating β-catenin expression and thus bone formation during fracture repair. PMID:24260576

A large case-control study reveals a positive association between bisphosphonate use and delayed dental healing and osteonecrosis of the jaw.

PubMed

Borromeo, Gelsomina L; Brand, Caroline; Clement, John G; McCullough, Michael; Crighton, Lisa; Hepworth, Graham; Wark, John D

2014-06-01

This study sought to investigate, using a case-control study design, the association between bisphosphonate therapy and delayed dental healing and osteonecrosis of the jaw. Identification of potential cases of delayed dental healing was by consecutive screening of Specialist Oral and Maxillofacial and Special Needs Dentist clinic records for patients aged older than 50 years, during a 6-month window, in Victoria, Australia. Cases were confirmed by a case adjudication panel blinded to bisphosphonate status. Cases associated with malignancy or local radiotherapy were excluded. Controls were matched for age, sex, and source of dental referral (1:4, n = 160 controls). Variables of interest were dental precipitants, dental clinic type, smoking history, and medical comorbidities. A total of 4212 of 22,358 patients met inclusion criteria, of which 69 were potential cases with 40 (0.95%) confirmed cases. The odds ratio (OR) for developing delayed dental healing when taking an oral bisphosphonate was 13.1 (95% confidence interval [CI] 4.4 to 39.3; p < 0.001). There were no cases associated with intravenous bisphosphonate use. There was some evidence of an interaction with age, sex, and clinic type. When adjusted for smoking, the estimated odds ratio was 11.6 (95% CI 1.9 to 69.4; p = 0.01). There was an association between having another illness and delayed dental healing (OR = 2.3; 95% CI 1.0 to 5.2). A dental precipitant was present in 39 of 40 (97.5%) delayed dental healing cases. An important association between bisphosphonate use and delayed dental healing in the setting of benign bone disease, predominately in individuals with a dental precipitant, has been demonstrated. © 2014 American Society for Bone and Mineral Research.

Is bisphosphonate therapy for benign bone disease associated with impaired dental healing? A case-controlled study

PubMed Central

2011-01-01

Background Bisphosphonates are common first line medications used for the management of benign bone disease. One of the most devastating complications associated with bisphosphonate use is osteonecrosis of the jaws which may be related to duration of exposure and hence cumulative dose, dental interventions, medical co-morbidities or in some circumstances with no identifiable aggravating factor. While jaw osteonecrosis is a devastating outcome which is currently difficult to manage, various forms of delayed dental healing may be a less dramatic and, therefore, poorly-recognised complications of bisphosphonate use for the treatment of osteoporosis. It is hypothesised that long-term (more than 1 year's duration) bisphosphonate use for the treatment of post-menopausal osteoporosis or other benign bone disease is associated with impaired dental healing. Methods/Design A case-control study has been chosen to test the hypothesis as the outcome event rate is likely to be very low. A total of 54 cases will be recruited into the study following review of all dental files from oral and maxillofacial surgeons and special needs dentists in Victoria where potential cases of delayed dental healing will be identified. Potential cases will be presented to an independent case adjudication panel to determine if they are definitive delayed dental healing cases. Two hundred and fifteen controls (1:4 cases:controls), matched for age and visit window period, will be selected from those who have attended local community based referring dental practices. The primary outcome will be the incidence of delayed dental healing that occurs either spontaneously or following dental treatment such as extractions, implant placement, or denture use. Discussion This study is the largest case-controlled study assessing the link between bisphosphonate use and delayed dental healing in Australia. It will provide invaluable data on the potential link between bisphosphonate use and osteonecrosis of the jaws. PMID:21477374

Radiographic and Histological Evaluation of the Healing of Extraction Sockets Filled With Bovine-Derived Xenograft: An Experimental Study in Rats.

PubMed

Zhou, Fengjuan; Zheng, Xiaofei; Xie, Meng; Mo, Anchun; Wu, Hongkun

2017-06-01

To evaluate the microenvironment changes in the sockets substituted with bovine-derived xenografts during the early healing period. After extraction of the right maxillary incisor of Sprague Dawley rats, 48 rats were randomly divided into 2 groups. The extraction sockets of the test group were filled with Bio-Oss, whereas the control group was allowed to heal without intervention. The bone quality of the extraction sockets was observed through micro-CT and immunohistochemistry. Micro-CT scanning showed that the bone mineral density in the test group was significantly higher than that in the control group during the early healing period, whereas immunohistochemistry showed that the bone formation-related factors were significantly different between the test and control groups. The bovine-derived xenografts may interfere with the healing process of the extraction socket in the early healing stage. Bone formation of the extraction socket was delayed after grafting with bone substitute.

Cola beverage consumption delays alveolar bone healing: a histometric study in rats.

PubMed

Teófilo, Juliana Mazzonetto; Leonel, Daniel Vilela; Lamano, Teresa

2010-01-01

Epidemiological studies have suggested that cola beverage consumption may affect bone metabolism and increase bone fracture risk. Experimental evidence linking cola beverage consumption to deleterious effects on bone is lacking. Herein, we investigated whether cola beverage consumption from weaning to early puberty delays the rate of reparative bone formation inside the socket of an extracted tooth in rats. Twenty male Wistar rats received cola beverage (cola group) or tap water (control group) ad libitum from the age of 23 days until tooth extraction at 42 days and euthanasia 2 and 3 weeks later. The neoformed bone volume inside the alveolar socket was estimated in semi-serial longitudinal sections using a quantitative differential point-counting method. Histological examination suggested a decrease in the osteogenic process within the tooth sockets of rats from both cola groups, which had thinner and sparser new bone trabeculae. Histometric data confirmed that alveolar bone healing was significantly delayed in cola-fed rats at three weeks after tooth extraction (ANOVA, p = 0.0006, followed by Tukey's test, p < 0.01). Although the results of studies in rats cannot be extrapolated directly to human clinical dentistry, the present study provides evidence that cola beverage consumption negatively affect maxillary bone formation.

A review of the physiological and histological effects of laser osteotomy.

PubMed

Rajitha Gunaratne, G D; Khan, Riaz; Fick, Daniel; Robertson, Brett; Dahotre, Narendra; Ironside, Charlie

2017-01-01

Osteotomy is the surgical cutting of bone. Some obstacles to laser osteotomy have been melting, carbonisation and subsequent delayed healing. New cooled scanning techniques have resulted in effective bone cuts without the strong thermal side effects, which were observed by inappropriate irradiation techniques with continuous wave and long pulsed lasers. With these new techniques, osteotomy gaps histologically healed with new bone formation without any noticeable or minimum thermal damage. No significant cellular differences in bone healing between laser and mechanical osteotomies were noticed. Some studies even suggest that the healing rate may be enhanced following laser osteotomy compared to conventional mechanical osteotomy. Additional research is necessary to evaluate different laser types with appropriate laser setting variables to increase ablation rates, with control of depth, change in bone type and damage to adjacent soft tissue. Laser osteotomy has the potential to become incorporated into the armamentarium of bone surgery.

Do biodegradable magnesium alloy intramedullary interlocking nails prematurely lose fixation stability in the treatment of tibial fracture? A numerical simulation.

PubMed

Wang, Haosen; Hao, Zhixiu; Wen, Shizhu

2017-01-01

Intramedullary interlocking nailing is an effective technique used to treat long bone fractures. Recently, biodegradable metals have drawn increased attention as an intramedullary interlocking nailing material. In this study, numerical simulations were implemented to determine whether the degradation rate of magnesium alloy makes it a suitable material for manufacturing biodegradable intramedullary interlocking nails. Mechano-regulatory and bone-remodeling models were used to simulate the fracture healing process, and a surface corrosion model was used to simulate intramedullary rod degradation. The results showed that magnesium alloy intramedullary rods exhibited a satisfactory degradation rate; the fracture healed and callus enhancement was observed before complete dissolution of the intramedullary rod. Delayed magnesium degradation (using surface coating techniques) did not confer a significant advantage over the non-delayed degradation process; immediate degradation also achieved satisfactory healing outcomes. However, delayed degradation had no negative effect on callus enhancement, as it did not cause signs of stress shielding. To avoid risks of individual differences such as delayed union, delayed degradation is recommended. Although the magnesium intramedullary rod did not demonstrate rapid degradation, its ability to provide high fixation stiffness to achieve earlier load bearing was inferior to that of the conventional titanium alloy and stainless steel rods. Therefore, light physiological loads should be ensured during the early stages of healing to achieve bony healing; otherwise, with increased loading and degraded intramedullary rods, the fracture may ultimately fail to heal. Copyright © 2016 Elsevier Ltd. All rights reserved.

Composite Bone and Soft Tissue Loss Treated with Distraction Histiogenesis

DTIC Science & Technology

2010-01-01

their frames removed had healed docking sites, and the fourth whose frame remained in place had a healing fracture without evidence of delayed union ...interventions (3–8). The goals of limb salvage surgery in this setting are to restore length and alignment, regenerate bone loss, obtain fracture union ...angulation to manage composite bone and soft tissue loss associated with combat-related type IIIB open tibia fractures . Four patients underwent placement

Genetic factors responsible for long bone fractures non-union.

PubMed

Szczęsny, Grzegorz; Olszewski, Waldemar L; Zagozda, Małgorzata; Rutkowska, Joanna; Czapnik, Zanetta; Swoboda-Kopeć, Ewa; Górecki, Andrzej

2011-02-01

Approximately 10-15% of all fractures of long bones heal with delay, prolonged immobilization and repetitive operative interventions. Despite intense investigations, the pathomechanism of impaired healing of skeletal tissue remains unclear. An important role in the pathomechanism of mal-union of close fractures plays subclinically proceeding infections. The question arises whether colonization and proliferation of bacteria in the fracture gap could be related to the mutation of genes for factors regulating local antimicrobial response, such as pathogen recognizing receptors (PRR), cytokines and chemokines. We carried out studies in patients with delayed long bone fractures estimating the frequency of mutation of genes crucial for pathogen recognition (TLR2, TLR4 and CD14), and elimination (CRP, IL-6, IL-1ra), as well as wound healing (TGF-β). The molecular milieu regulating healing process (IGF-1, COLL1a, TGF-β, BMP-2, and PDGF) was validated by Western blot analysis of the gap tissue. Microbiological investigations showed the presence of viable bacterial strains in 34 out of 108 gaps in patients with non-healing fractures (31.5%) and in 20 out of 122 patients with uneventful healing (16.4%) (P < 0.05). The occurrence of mutated TLR4 1/W but not 2/W gene was significantly higher (P < 0.05) in the non-healing infected than sterile group. In the non-healing infected group 1/W mutated gene frequency was also higher than in healing infected. In the TGF-β codon 10 a significantly higher frequency of mutated homozygote T and heterozygote C/T in the non-healing infected versus non-healing sterile subgroup was observed (P < 0.05). Similar difference was observed in the non-healing infected versus healing infected subgroup (P < 0.05). The CRP (G1059C), IL1ra (genotype 2/2), IL-6 (G176C), CD14 (G-159T), TLR2 (G2259A) and TLR4/2 (Thr399Ile) polymorphisms did not play evident role in the delay of fracture healing. Individuals bearing the mutant TLR 4 gene 1/W (Asp299Gly) and TGF-β gene codon 10 mutant T and T/C allele may predispose to impaired pathogen recognition and elimination, leading to prolonged pathogen existence in the fracture gaps and healing delays.

Interactions between MSCs and Immune Cells: Implications for Bone Healing

PubMed Central

Kovach, Tracy K.; Dighe, Abhijit S.; Lobo, Peter I.; Cui, Quanjun

2015-01-01

It is estimated that, of the 7.9 million fractures sustained in the United States each year, 5% to 20% result in delayed or impaired healing requiring therapeutic intervention. Following fracture injury, there is an initial inflammatory response that plays a crucial role in bone healing; however, prolonged inflammation is inhibitory for fracture repair. The precise spatial and temporal impact of immune cells and their cytokines on fracture healing remains obscure. Some cytokines are reported to be proosteogenic while others inhibit bone healing. Cell-based therapy utilizing mesenchymal stromal cells (MSCs) is an attractive option for augmenting the fracture repair process. Osteoprogenitor MSCs not only differentiate into bone, but they also exert modulatory effects on immune cells via a variety of mechanisms. In this paper, we review the current literature on both in vitro and in vivo studies on the role of the immune system in fracture repair, the use of MSCs in the enhancement of fracture healing, and interactions between MSCs and immune cells. Insight into this paradigm can provide valuable clues in identifying cellular and noncellular targets that can potentially be modulated to enhance both natural bone healing and bone repair augmented by the exogenous addition of MSCs. PMID:26000315

Use of postoperative steroids to reduce pain and inflammation.

PubMed

Fleischli, J W; Adams, W R

1999-01-01

Postoperative injection of a steroid is used by many podiatric surgeons to reduce pain and inflammation after foot surgery. The authors present a review of the literature on postoperative steroid use from many medical specialties as well as a review of wound and bone healing. The literature indicates that using a steroid is a safe and effective means to reduce postoperative pain and edema. Studies have shown steroids to delay healing, inhibit collagen synthesis, and increase the risk of postoperative infection. No author reported a delay in wound or bone healing or increased infection rate in patients in which a steroid was used. Although there is literature to support this practice, many questions remain and further investigation is needed.

VEGF serum concentrations in patients with long bone fractures: a comparison between impaired and normal fracture healing.

PubMed

Sarahrudi, Kambiz; Thomas, Anita; Braunsteiner, Tomas; Wolf, Harald; Vécsei, Vilmos; Aharinejad, Seyedhossein

2009-10-01

Vascular endothelial growth factor (VEGF) plays an important role in the bone repair process as a potent mediator of angiogenesis and it influences directly osteoblast differentiation. Inhibiting VEGF suppresses angiogenesis and callus mineralization in animals. However, no data exist so far on systemic expression of VEGF with regard to delayed or failed fracture healing in humans. One hundred fourteen patients with long bone fractures were included in the study. Serum samples were collected over a period of 6 months following a standardized time schedule. VEGF serum concentrations were measured. Patients were assigned to one of two groups according to their course of fracture healing. The first group contained 103 patients with physiological fracture healing. Eleven patients with delayed or nonunions formed the second group of the study. In addition, 33 healthy volunteers served as controls. An increase of VEGF serum concentration within the first 2 weeks after fracture in both groups with a following decrease within 6 months after trauma was observed. Serum VEGF concentrations in patients with impaired fracture healing were higher compared to the patients with physiological healing during the entire observation period. However, statistically significant differences were not observed at any time point between both groups. VEGF concentrations in both groups were significantly higher than those in controls. The present results show significantly elevated serum concentrations of VEGF in patients after fracture of long bones especially at the initial healing phase, indicating the importance of VEGF in the process of fracture healing in humans. (c) 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

The roles of cellular and molecular components of a hematoma at early stage of bone healing.

PubMed

Shiu, Hoi Ting; Leung, Ping Chung; Ko, Chun Hay

2018-04-01

Bone healing is a complex repair process that commences with the formation of a blood clot at the injured bone, termed hematoma. It has evidenced that a lack of a stable hematoma causes delayed bone healing or non-union. The hematoma at the injured bone constitutes the early healing microenvironment. It appears to dictate healing pathways that ends in a regenerative bone. However, the hematoma is often clinically removed from the damaged site. Conversely, blood-derived products have been used in bone tissue engineering for treating critical sized defects, including fibrin gels and platelet-rich plasma. A second generation of platelet concentrate that is based on leukocyte and fibrin content has also been developed and introduced in market. Conflicting effect of these products in bone repair are reported. We propose that the bone healing response becomes dysregulated if the blood response and subsequent formation and properties of a hematoma are altered. This review focuses on the central structural, cellular, and molecular components of a fracture hematoma, with a major emphasis on their roles in regulating bone healing mechanism, and their interactions with mesenchymal stem cells. New angles towards a better understanding of these factors and relevant mechanisms involved at the beginning of bone healing may help to clarify limited or adverse effects of blood-derived products on bone repair. We emphasize that the recreation of an early hematoma niche with critical compositions might emerge as a viable therapeutic strategy for enhanced skeletal tissue engineering. Copyright © 2017 John Wiley & Sons, Ltd.

MiR-142-5p promotes bone repair by maintaining osteoblast activity.

PubMed

Tu, Manli; Tang, Juanjuan; He, Hongbo; Cheng, Peng; Chen, Chao

2017-05-01

MicroRNAs play important roles in regulating bone regeneration and remodeling. However, the pathophysiological roles of microRNAs in bone repair remain unclear. Here we identify a significant upregulation of miR-142-5p correlated with active osteoblastogenesis during the bone healing process. In vitro, miR-142-5p promoted osteoblast activity and matrix mineralization by targeting the gene encoding WW-domain-containing E3 ubiquitin protein ligase 1. We also found that the expression of miR-142-5p in the callus of aged mice was lower than that in the callus of young mice and directly correlated with the age-related delay in bone healing. Furthermore, treatment with agomir-142-5p in the fracture areas stimulated osteoblast activity which repaired the bone fractures in aged mice. Thus, our study revealed that miR-142-5p plays a crucial role in healing fractures by maintaining osteoblast activity, and provided a new molecular target therapeutic strategy for bone healing.

Multiple roles of tumor necrosis factor-alpha in fracture healing.

PubMed

Karnes, Jonathan M; Daffner, Scott D; Watkins, Colleen M

2015-09-01

This review presents a summary of basic science evidence examining the influence of tumor necrosis factor-alpha (TNF-α) on secondary fracture healing. Multiple studies suggest that TNF-α, in combination with the host reservoir of peri-fracture mesenchymal stem cells, is a main determinant in the success of bone healing. Disease states associated with poor bone healing commonly have inappropriate TNF-α responses, which likely contributes to the higher incidence of delayed and nonunions in these patient populations. Appreciation of TNF-α in fracture healing may lead to new therapies to augment recovery and reduce the incidence of complications. Copyright © 2015 Elsevier Inc. All rights reserved.

High energy focused shock wave therapy accelerates bone healing. A blinded, prospective, randomized canine clinical trial.

PubMed

Kieves, N R; MacKay, C S; Adducci, K; Rao, S; Goh, C; Palmer, R H; Duerr, F M

2015-01-01

To evaluate the influence of shock wave therapy (SWT) on radiographic evidence of bone healing after tibial plateau leveling osteotomy (TPLO). Healthy dogs between two to nine years of age that underwent TPLO were randomly assigned to receive either electro-hydraulic SWT (1,000 shocks) or sham treatment (SHAM). Treatment or SHAM was administered to the osteotomy site immediately postoperatively and two weeks postoperatively. Three blinded radiologists evaluated orthogonal radiographs performed eight weeks postoperatively with both a 5-point and a 10-point bone healing scale. Linear regression analysis was used to compare median healing scores between groups. Forty-two dogs (50 stifles) were included in the statistical analysis. No major complications were observed and all osteotomies healed uneventfully. The median healing scores were significantly higher at eight weeks postoperatively for the SWT group compared to the SHAM group for the 10-point (p <0.0002) and 5-point scoring systems (p <0.0001). Shock wave therapy applied immediately and two weeks postoperatively led to more advanced bone healing at the eight week time point in this study population. The results of this study support the use of electro-hydraulic SWT as a means of accelerating acute bone healing of canine osteotomies. Additional studies are needed to evaluate its use for acceleration of bone healing following fracture, or with delayed union.

Immature myeloid cells are critical for enhancing bone fracture healing through angiogenic cascade

PubMed Central

Levy, Seth; Feduska, Joseph M.; Sawant, Anandi; Gilbert, Shawn; Hensel, Jonathan A.; Ponnazhagan, Selvarangan

2016-01-01

Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling. Osteogenesis and angiogenesis work in concert to control many stages of this process, and when one is impaired it leads to failure of bone healing, termed a nonunion. During fracture repair, there is an infiltration of immune cells at the fracture site that not only mediate the inflammatory responses, but we hypothesize they also exert influence on neovasculature. Thus, further understanding the effects of immune cell participation throughout fracture healing will reveal additional knowledge as to why some fractures heal while others form nonunions, and lead to development of novel therapeutics modulating immune cells, to increase fracture healing and prevent nonunions. Using novel femoral segmental and critical-size defect models in mice, we identified a systemic and significant increase in immature myeloid cell (IMC) infiltration during the initial phase of fracture healing until boney union is complete. Using gemcitabine to specifically ablate the IMC population, we confirmed delayed bone healing. Further, adoptive transfer of IMC increased bone growth in a nonunion model, signifying the role of this unique cell population in fracture healing. We also identified IMC post-fracture have the ability to increase endothelial cell migration, and tube formation, signaling the essential communication between the immune system and angiogenesis as a requirement for proper bone healing. Based on this data we propose that IMC may play a significant role in fracture healing and therapeutic targeting of IMC after fracture would minimize the chances of eventual nonunion pathology. PMID:27664567

Immature myeloid cells are critical for enhancing bone fracture healing through angiogenic cascade.

PubMed

Levy, Seth; Feduska, Joseph M; Sawant, Anandi; Gilbert, Shawn R; Hensel, Jonathan A; Ponnazhagan, Selvarangan

2016-12-01

Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling. Osteogenesis and angiogenesis work in concert to control many stages of this process, and when one is impaired it leads to failure of bone healing, termed a nonunion. During fracture repair, there is an infiltration of immune cells at the fracture site that not only mediate the inflammatory responses, but we hypothesize they also exert influence on neovasculature. Thus, further understanding the effects of immune cell participation throughout fracture healing will reveal additional knowledge as to why some fractures heal while others form nonunions, and lead to development of novel therapeutics modulating immune cells, to increase fracture healing and prevent nonunions. Using novel femoral segmental and critical-size defect models in mice, we identified a systemic and significant increase in immature myeloid cell (IMC) infiltration during the initial phase of fracture healing until boney union is complete. Using gemcitabine to specifically ablate the IMC population, we confirmed delayed bone healing. Further, adoptive transfer of IMC increased bone growth in a nonunion model, signifying the role of this unique cell population in fracture healing. We also identified IMC post-fracture have the ability to increase endothelial cell migration, and tube formation, signaling the essential communication between the immune system and angiogenesis as a requirement for proper bone healing. Based on this data we propose that IMC may play a significant role in fracture healing and therapeutic targeting of IMC after fracture would minimize the chances of eventual nonunion pathology. Copyright © 2016 Elsevier Inc. All rights reserved.

Size Does Matter: An Integrative In Vivo-In Silico Approach for the Treatment of Critical Size Bone Defects

PubMed Central

Carlier, Aurélie; van Gastel, Nick; Geris, Liesbet; Carmeliet, Geert; Van Oosterwyck, Hans

2014-01-01

Although bone has a unique restorative capacity, i.e., it has the potential to heal scarlessly, the conditions for spontaneous bone healing are not always present, leading to a delayed union or a non-union. In this work, we use an integrative in vivo - in silico approach to investigate the occurrence of non-unions, as well as to design possible treatment strategies thereof. The gap size of the domain geometry of a previously published mathematical model was enlarged in order to study the complex interplay of blood vessel formation, oxygen supply, growth factors and cell proliferation on the final healing outcome in large bone defects. The multiscale oxygen model was not only able to capture the essential aspects of in vivo non-unions, it also assisted in understanding the underlying mechanisms of action, i.e., the delayed vascularization of the central callus region resulted in harsh hypoxic conditions, cell death and finally disrupted bone healing. Inspired by the importance of a timely vascularization, as well as by the limited biological potential of the fracture hematoma, the influence of the host environment on the bone healing process in critical size defects was explored further. Moreover, dependent on the host environment, several treatment strategies were designed and tested for effectiveness. A qualitative correspondence between the predicted outcomes of certain treatment strategies and experimental observations was obtained, clearly illustrating the model's potential. In conclusion, the results of this study demonstrate that due to the complex non-linear dynamics of blood vessel formation, oxygen supply, growth factor production and cell proliferation and the interactions thereof with the host environment, an integrative in silico-in vivo approach is a crucial tool to further unravel the occurrence and treatments of challenging critical sized bone defects. PMID:25375821

Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures.

PubMed

Bigham-Sadegh, Amin; Oryan, Ahmad

2015-06-01

Fracture healing is a complex physiological process, which involves a well-orchestrated series of biological events. Repair of large bone defects resulting from trauma, tumours, osteitis, delayed unions, non-unions, osteotomies, arthrodesis and multifragmentary fractures is a current challenge of surgeons and investigators. Different therapeutic modalities have been developed to enhance the healing response and fill the bone defects. Different types of growth factors, stem cells, natural grafts (autografts, allografts or xenografts) and biologic- and synthetic-based tissue-engineered scaffolds are some of the examples. Nevertheless, these organic and synthetic materials and therapeutic agents have some significant limitations, and there are still no well-approved treatment modalities to meet all the expected requirements. Bone tissue engineering is a newer option than the traditional grafts and may overcome many limitations of the bone graft. To select an appropriate treatment strategy in achieving a successful and secure healing, more information concerning injuries of bones, their healing process and knowledge of the factors involved are required. The main goals of this work are to present different treatment modalities of the fractured bones and to explain how fractures normally heal and what factors interfere with fracture healing. This study provides an overview of the processes of fracture healing and discusses the current therapeutic strategies that have been claimed to be effective in accelerating fracture healing. © 2014 The Authors. International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Healing of rabbit calvarial critical-sized defects using autogenous bone grafts and fibrin glue.

PubMed

Lappalainen, Olli-Pekka; Korpi, Riikka; Haapea, Marianne; Korpi, Jarkko; Ylikontiola, Leena P; Kallio-Pulkkinen, Soili; Serlo, Willy S; Lehenkari, Petri; Sándor, George K

2015-04-01

This study aimed to evaluate ossification of cranial bone defects comparing the healing of a single piece of autogenous calvarial bone representing a bone flap as in cranioplasty compared to particulated bone slurry with and without fibrin glue to represent bone collected during cranioplasty. These defect-filling materials were then compared to empty control cranial defects. Ten White New Zealand adult male rabbits had bilateral critical-sized calvarial defects which were left either unfilled as control defects or filled with a single full-thickness piece of autogenous bone, particulated bone, or particulated bone combined with fibrin glue. The defects were left to heal for 6 weeks postoperatively before termination. CT scans of the calvarial specimens were performed. Histomorphometric assessment of hematoxylin-eosin- and Masson trichrome-stained specimens was used to analyze the proportion of new bone and fibrous tissue in the calvarial defects. There was a statistically significant difference in both bone and soft tissue present in all the autogenous bone-grafted defect sites compared to the empty negative control defects. These findings were supported by CT scan findings. While fibrin glue combined with the particulated bone seemed to delay ossification, the healing was more complete compared to empty control non-grafted defects. Autogenous bone grafts in various forms such as solid bone flaps or particulated bone treated with fibrin glue were associated with bone healing which was superior to the empty control defects.

Models of tibial fracture healing in normal and Nf1-deficient mice.

PubMed

Schindeler, Aaron; Morse, Alyson; Harry, Lorraine; Godfrey, Craig; Mikulec, Kathy; McDonald, Michelle; Gasser, Jürg A; Little, David G

2008-08-01

Delayed union and nonunion are common complications associated with tibial fractures, particularly in the distal tibia. Existing mouse tibial fracture models are typically closed and middiaphyseal, and thus poorly recapitulate the prevailing conditions following surgery on a human open distal tibial fracture. This report describes our development of two open tibial fracture models in the mouse, where the bone is broken either in the tibial midshaft (mid-diaphysis) or in the distal tibia. Fractures in the distal tibial model showed delayed repair compared to fractures in the tibial midshaft. These tibial fracture models were applied to both wild-type and Nf1-deficient (Nf1+/-) mice. Bone repair has been reported to be exceptionally problematic in human NF1 patients, and these patients can also spontaneously develop tibial nonunions (known as congenital pseudarthrosis of the tibia), which are recalcitrant to even vigorous intervention. pQCT analysis confirmed no fundamental differences in cortical or cancellous bone in Nf1-deficient mouse tibiae compared to wild-type mice. Although no difference in bone healing was seen in the tibial midshaft fracture model, the healing of distal tibial fractures was found to be impaired in Nf1+/- mice. The histological features associated with nonunited Nf1+/- fractures were variable, but included delayed cartilage removal, disproportionate fibrous invasion, insufficient new bone anabolism, and excessive catabolism. These findings imply that the pathology of tibial pseudarthrosis in human NF1 is complex and likely to be multifactorial.

Early healing in alveolar sockets grafted with titanium granules. An experimental study in a dog model.

PubMed

Arruda, Thiago; Sukekava, Flávia; de Souza, André B; Rasmusson, Lars; Araújo, Maurício G

2013-07-01

The aim of the present study was to evaluate the effect of the placement of titanium granules in fresh extraction sockets on early bone formation. The mesial roots of the third maxillary premolars of five adult beagle dogs were removed. On one side of the maxilla (Test group) the fresh extraction socket was grafted with titanium granules, while the contra-lateral socket was left non-grafted (Control group). After 1 month of healing, the dogs were euthanized and biopsies were obtained. The healing tissues were described, and histometric measurements were performed to obtain the percentage area occupied by connective tissue, new mineralized bone, bone marrow, and biomaterial particles. After 1 month of healing the findings from the histological examination revealed the titanium graft to be well incorporated into the provisional connective tissue or newly formed woven bone. The histometric measurements showed, however, that less mineralized bone was formed in the Test group than in the Control group. The present study suggests that the use of titanium granules in fresh extraction sockets was conducive to new bone formation. The graft of titanium granules seems, however, to delay the early phase of the healing process. Copyright © 2012 Wiley Periodicals, Inc.

Parathyroid hormone and bone healing.

PubMed

Ellegaard, M; Jørgensen, N R; Schwarz, P

2010-07-01

Fracture healing is a complex process, and a significant number of fractures are complicated by impaired healing and non-union. Impaired healing is prevalent in certain risk groups, such as the elderly, osteoporotics, people with malnutrition, and women after menopause. Currently, no pharmacological treatments are available. There is therefore an unmet need for medications that can stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis, and intriguingly a number of animal studies suggest that PTH could be beneficial in the treatment of fractures and could thus be a potentially new treatment option for induction of fracture healing in humans. Furthermore, fractures in animals with experimental conditions of impaired healing such as aging, estrogen withdrawal, and malnutrition can heal in an expedited manner after PTH treatment. Interestingly, fractures occurring at both cancellous and cortical sites can be treated successfully, indicating that both osteoporotic and nonosteoporotic fractures can be the target of PTH-induced healing. Finally, the data suggest that PTH partly prevents the delay in fracture healing caused by aging. Recently, the first randomized, controlled clinical trial investigating the effect of PTH on fracture healing was published, indicating a possible clinical benefit of PTH treatment in inducing fracture healing. The aim of this article is therefore to review the evidence for the potential of PTH in bone healing, including the underlying mechanisms for this, and to provide recommendations for the clinical testing and use of PTH in the treatment of impaired fracture healing in humans.

Modeling Staphylococcus epidermidis-Induced Non-Unions: Subclinical and Clinical Evidence in Rats

PubMed Central

Lovati, Arianna Barbara; Romanò, Carlo Luca; Bottagisio, Marta; Monti, Lorenzo; De Vecchi, Elena; Previdi, Sara; Accetta, Riccardo; Drago, Lorenzo

2016-01-01

S. epidermidis is one of the leading causes of orthopaedic infections associated with biofilm formation on implant devices. Open fractures are at risk of S. epidermidis transcutaneous contamination leading to higher non-union development compared to closed fractures. Although the role of infection in delaying fracture healing is well recognized, no in vivo models investigated the impact of subclinical low-grade infections on bone repair and non-union. We hypothesized that the non-union rate is directly related to the load of this commonly retrieved pathogen and that a low-grade contamination delays the fracture healing without clinically detectable infection. Rat femurs were osteotomized and stabilized with plates. Fractures were infected with a characterized clinical-derived methicillin-resistant S. epidermidis (103, 105, 108 colony forming units) and compared to uninfected controls. After 56 days, bone healing and osteomyelitis were clinically assessed and further evaluated by micro-CT, microbiological and histological analyses. The biofilm formation was visualized by scanning electron microscopy. The control group showed no signs of infection and a complete bone healing. The 103 group displayed variable response to infection with a 67% of altered bone healing and positive bacterial cultures, despite no clinical signs of infection present. The 105 and 108 groups showed severe signs of osteomyelitis and a non-union rate of 83–100%, respectively. The cortical bone reaction related to the periosteal elevation in the control group and the metal scattering detected by micro-CT represented limitations of this study. Our model showed that an intra-operative low-grade S. epidermidis contamination might prevent the bone healing, even in the absence of infectious signs. Our findings also pointed out a dose-dependent effect between the S. epidermidis inoculum and non-union rate. This pilot study identifies a relevant preclinical model to assess the role of subclinical infections in orthopaedic and trauma surgery and to test specifically designed diagnostic, prevention and therapeutic strategies. PMID:26796958

Aging Periosteal Progenitor Cells have Reduced Regenerative Responsiveness to Bone Injury and to the Anabolic Actions of PTH 1-34 Treatment

PubMed Central

Yukata, Kiminori; Xie, Chao; Li, Tian-Fang; Takahata, Masahiko; Hoak, Donna; Kondabolu, Sirish; Zhang, Xinping; Awad, Hani A.; Schwarz, Edward M.; Beck, Christopher A.; Jonason, Jennifer H.; O’Keefe, Regis J.

2014-01-01

A stabilized tibia fracture model was used in young (8-week old) and aged (1-year old) mice to define the relative bone regenerative potential and the relative responsiveness of the periosteal progenitor population with aging and PTH 1-34 (PTH) systemic therapy. Bone regeneration was assessed through gene expressions, radiographic imaging, histology/histomorphometry, and biomechanical testing. Radiographs and microCT showed increased calcified callus tissue and enhanced bone healing in young compared to aged mice. A key mechanism involved reduced proliferation, expansion, and differentiation of periosteal progenitor cell populations in aged mice. The experiments showed that PTH increased calcified callus tissue and torsional strength with a greater response in young mice. Histology and quantitative histomorphometry confirmed that PTH increased callus tissue area due primarily to an increase in bone formation, since minimal changes in cartilage and mesenchyme tissue area occurred. Periosteum examined at 3, 5, and 7 days showed that PTH increased cyclin D1 expression, the total number of cells in the periosteum, and width of the periosteal regenerative tissue. Gene expression showed that aging delayed differentiation of both bone and cartilage tissues during fracture healing. PTH resulted in sustained Col10a1 expression consistent with delayed chondrocyte maturation, but otherwise minimally altered cartilage gene expression. In contrast, PTH 1-34 stimulated expression of Runx2 and Osterix, but resulted in reduced Osteocalcin. β-catenin staining was present in mesenchymal chondroprogenitors and chondrocytes in early fracture healing, but was most intense in osteoblastic cells at later times. PTH increased active β-catenin staining in the osteoblast populations of both young and aged mice, but had a lesser effect in cartilage. Altogether the findings show that reduced fracture healing in aging involves decreased proliferation and differentiation of stem cells lining the bone surface. While PTH 1-34 enhances the proliferation and expansion of the periosteal stem cell population and accelerates bone formation and fracture healing, the effects are proportionately reduced in aged mice compared to young mice. β-catenin is induced by PTH in early and late fracture healing and is a potential target of PTH 1-34 effects. PMID:24530870

Open tibial fractures grade IIIC treated successfully with external fixation, negative-pressure wound therapy and recombinant human bone morphogenetic protein 7.

PubMed

Babiak, Ireneusz

2014-10-01

The aim of the therapy in open tibial fractures grade III was to cover the bone with soft tissue and achieve healed fracture without persistent infection. Open tibial fractures grade IIIC with massive soft tissue damage require combined orthopaedic, vascular and plastic-reconstructive procedures. Negative-pressure wound therapy (NPWT), used in two consecutive cases with open fracture grade IIIC of the tibia diaphysis, healed extensive soft tissue defect with exposure of the bone. NPWT eventually allowed for wound closure by split skin graft within 21-25 days. Ilizarov external fixator combined with application of recombinant human bone morphogenetic protein-7 at the site of delayed union enhanced definitive bone healing within 16-18 months. © 2012 The Authors. International Wound Journal © 2012 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Medicarpin, a Natural Pterocarpan, Heals Cortical Bone Defect by Activation of Notch and Wnt Canonical Signaling Pathways

PubMed Central

Gupta, Chandra Prakash; Kureel, Jyoti; Mansoori, Mohd Nizam; Shukla, Priyanka; John, Aijaz A.; Singh, Kavita; Purohit, Dipak; Awasthi, Pallavi; Singh, Divya; Goel, Atul

2015-01-01

We evaluated the bone regeneration and healing effect of Medicarpin (med) in cortical bone defect model that heals by intramembranous ossification. For the study, female Sprague–Dawley rats were ovariectomized and rendered osteopenic. A drill hole injury was generated in mid femoral bones of all the animals. Med treatment was commenced the day after and continued for 15 days. PTH was taken as a reference standard. Fifteen days post-treatment, animals were sacrificed. Bones were collected for histomorphometry studies at the injury site by micro-computed tomography (μCT) and confocal microscopy. RNA and protein was harvested from newly generated bone. For immunohistochemistry, 5μm sections of decalcified femur bone adjoining the drill hole site were cut. By μCT analysis and calcein labeling of newly generated bone it was found that med promotes bone healing and new bone formation at the injury site and was comparable to PTH in many aspects. Med treatment led to increase in the Runx-2 and osteocalcin signals indicating expansion of osteoprogenitors at the injury site as evaluated by qPCR and immunohistochemical localization. It was observed that med promoted bone regeneration by activating canonical Wnt and notch signaling pathway. This was evident by increased transcript and protein levels of Wnt and notch signaling components in the defect region. Finally, we confirmed that med treatment leads to elevated bone healing in pre-osteoblasts by co localization of beta catenin with osteoblast marker alkaline phosphatase. In conclusion, med treatment promotes new bone regeneration and healing at the injury site by activating Wnt/canonical and notch signaling pathways. This study also forms a strong case for evaluation of med in delayed union and non-union fracture cases. PMID:26657206

Medicarpin, a Natural Pterocarpan, Heals Cortical Bone Defect by Activation of Notch and Wnt Canonical Signaling Pathways.

PubMed

Dixit, Manisha; Raghuvanshi, Ashutosh; Gupta, Chandra Prakash; Kureel, Jyoti; Mansoori, Mohd Nizam; Shukla, Priyanka; John, Aijaz A; Singh, Kavita; Purohit, Dipak; Awasthi, Pallavi; Singh, Divya; Goel, Atul

2015-01-01

We evaluated the bone regeneration and healing effect of Medicarpin (med) in cortical bone defect model that heals by intramembranous ossification. For the study, female Sprague-Dawley rats were ovariectomized and rendered osteopenic. A drill hole injury was generated in mid femoral bones of all the animals. Med treatment was commenced the day after and continued for 15 days. PTH was taken as a reference standard. Fifteen days post-treatment, animals were sacrificed. Bones were collected for histomorphometry studies at the injury site by micro-computed tomography (μCT) and confocal microscopy. RNA and protein was harvested from newly generated bone. For immunohistochemistry, 5μm sections of decalcified femur bone adjoining the drill hole site were cut. By μCT analysis and calcein labeling of newly generated bone it was found that med promotes bone healing and new bone formation at the injury site and was comparable to PTH in many aspects. Med treatment led to increase in the Runx-2 and osteocalcin signals indicating expansion of osteoprogenitors at the injury site as evaluated by qPCR and immunohistochemical localization. It was observed that med promoted bone regeneration by activating canonical Wnt and notch signaling pathway. This was evident by increased transcript and protein levels of Wnt and notch signaling components in the defect region. Finally, we confirmed that med treatment leads to elevated bone healing in pre-osteoblasts by co localization of beta catenin with osteoblast marker alkaline phosphatase. In conclusion, med treatment promotes new bone regeneration and healing at the injury site by activating Wnt/canonical and notch signaling pathways. This study also forms a strong case for evaluation of med in delayed union and non-union fracture cases.

Changes in biochemical markers after lower limb fractures.

PubMed

Stoffel, Karl; Engler, Hanna; Kuster, Markus; Riesen, Walter

2007-01-01

The bone remodeling sequence after bone fracture changes the concentrations of biochemical bone markers, but the relationships of fracture size and of healing time to changes in biomarkers are unclear. The present pilot study was undertaken to determine the changes found in serum bone markers after plate osteosynthesis of closed distal tibial and malleolar fractures during a study period of 24 weeks. We measured tatrate-resistant acid phosphatase (TRACP 5b), collagen type I C-terminal telopeptide (ICTP), bone-specific alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I C-terminal propeptide (PICP), procollagen type III N-terminal propeptide (PIIINP), and human cartilage glycoprotein 39 (YKL-40) in 20 patients with lower limb fractures (10 malleolar, 10 tibia). A physical examination and radiographs were completed to assess evidence of union. All malleolar fractures healed within 6 weeks, whereas 2 tibial fractures did not show complete bone healing after 24 weeks. Changes were comparable but more pronounced in the tibia group, and marker concentrations remained increased at the end of study (bone ALP, 86 vs 74 U/L; OC, 14.9 vs 7.7 microg/L; ICTP: 5.6 vs 3.3 microg/L at day 84 after osteosynthesis, P <0.05 in tibia; 80 vs 70 U/L, 8 vs 5.2 microg/L, and 3.5 vs 3.2 microg/L, respectively, in the malleolar fracture group). In normal bone healing, changes in bone turnover markers were primarily dependent on the fracture size. Delayed tibia fracture healing may involve a disturbance in bone remodeling.

Is Bone Grafting Necessary in the Treatment of Malunited Distal Radius Fractures?

PubMed Central

Disseldorp, Dominique J. G.; Poeze, Martijn; Hannemann, Pascal F. W.; Brink, Peter R. G.

2015-01-01

Background Open wedge osteotomy with bone grafting and plate fixation is the standard procedure for the correction of malunited distal radius fractures. Bone grafts are used to increase structural stability and to enhance new bone formation. However, bone grafts are also associated with donor site morbidity, delayed union at bone–graft interfaces, size mismatch between graft and osteotomy defect, and additional operation time. Purpose The goal of this study was to assess bone healing and secondary fracture displacement in the treatment of malunited distal radius fractures without the use of bone grafting. Methods Between January 1993 and December 2013, 132 corrective osteotomies and plate fixations without bone grafting were performed for malunited distal radius fractures. The minimum follow-up time was 12 months. Primary study outcomes were time to complete bone healing and secondary fracture displacement. Preoperative and postoperative radiographs during follow-up were compared with each other, as well as with radiographs of the uninjured side. Results All 132 osteotomies healed. In two cases (1.5%), healing took more than 4 months, but reinterventions were not necessary. No cases of secondary fracture displacement or hardware failure were observed. Significant improvements in all radiographic parameters were shown after corrective osteotomy and plate fixation. Conclusion This study shows that bone grafts are not required for bone healing and prevention of secondary fracture displacement after corrective osteotomy and plate fixation of malunited distal radius fractures. Level of evidence Therapeutic, level IV, case series with no comparison group PMID:26261748

Platelet-rich plasma for the treatment of bone defects: from pre-clinical rational to evidence in the clinical practice. A systematic review.

PubMed

Roffi, Alice; Di Matteo, Berardo; Krishnakumar, Gopal Shankar; Kon, Elizaveta; Filardo, Giuseppe

2017-02-01

The treatment of large bone defects represents a significant challenge for orthopaedic surgeons. In recent years, biologic agents have also been used to further improve bone healing. Among these, platelet-rich plasma (PRP) is the most exploited strategy. The aim of the present study was to systematically review the available literature to identify: 1) preclinical in-vivo results supporting the rational of PRP use for bone healing; 2) evidence from the clinical practice on the actual clinical benefit of PRP for the treatment of fractures and complications such as delayed unions and non-unions. A systematic review of the literature was performed on the application of PRP in bone healing, using the following inclusion criteria: pre-clinical and clinical reports of any level of evidence, written in English language, published in the last 20 years (1996-2016), on the use of PRP to stimulate long-bone defect treatment, with focus on fracture and delayed/non-unions healing. The search in the Pubmed database identified 64 articles eligible for inclusion: 45 were preclinical in-vivo studies and 19 were clinical studies. Despite the fact that the overall pre-clinical results seem to support the benefit of PRP in 91.1 % of the studies, a more in depth analysis underlined a lower success rate, with a positive outcome of 84.4 % in terms of histological analysis, and even lower values considering radiological and biomechanical results (75.0 % and 72.7 % positive outcome respectively). This was also mirrored in the clinical literature, where the real benefit of PRP use to treat fractures and non-unions is still under debate. Overall, the available literature presents major limitations in terms of low quality and extreme heterogeneity, which hamper the possibility to optimize PRP treatment and translate it into a real clinical benefit despite positive preclinical findings on its biological potential to favour bone healing.

Delayed Union of a Jones Fracture in a Patient With Rothmund-Thomson Syndrome: A Case Report and Review of the Literature.

PubMed

Barisonek, Kirsten L; Protzman, Nicole M; Wobst, Garrett M; Brigido, Stephen A

2016-01-01

Rothmund-Thomson syndrome is a rare autosomal recessive genodermatosis, characterized by poikiloderma, small stature, juvenile cataracts, sparse hair, skeletal abnormalities, and a predisposition to osteogenic sarcomas and skin cancers. Although numerous skeletal abnormalities have been described in patients with Rothmund-Thomson syndrome, to our knowledge, only 1 study has shown evidence of delayed fracture healing in a patient with Rothmund-Thomson syndrome. We present the case of a 13-year-old female diagnosed with Rothmund-Thomson syndrome who demonstrated delayed union of her fifth metatarsal after a Jones fracture. She was treated conservatively for 6 weeks with non-weightbearing cast immobilization and was then transitioned to a controlled ankle motion walker for an additional 4 weeks. Two months later, however, she continued to experience pain, and, on radiographic examination, the fracture remained unchanged. Therefore, with her guardian's consent, the patient elected to undergo open reduction and internal fixation of the fifth metatarsal fracture. At 8 weeks postoperatively, the patient reported a subsidence of symptoms and had returned to normal activity. With our report, we hope to increase practitioner awareness that delayed bone healing could be a possibility in patients with Rothmund-Thomson syndrome and encourage consideration of routine imaging and supplementation with calcium and vitamin D. Additionally, the present findings suggest that patients with Rothmund-Thomson syndrome could benefit from early surgical intervention, given their poor bone healing capacity and high likelihood of nonunion. Although the association between impaired bone healing and Rothmund-Thomson syndrome is rational, additional studies are needed to determine the prevalence of chronic nonunion in this patient population. Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Maxillary post-traumatic outcome correction literature review and our experience. Part I: maxillary bone non-unions-"poor bone positioning".

PubMed

D'Agostino, A; Toffanetti, G; Scala, R; Trevisiol, L; Ferrari, F

2004-04-01

Still today, there is no classification of non-unions in maxillofacial traumatology. There is a broad spectrum of definitions that simultaneously describe the pathological conditions and functional implications determined by the anatomical location of the fractures and the time factor. In this article the authors describe a literature review about bone non-union classification. Weber, in 1973, introduced the term "pseudo-arthrosis" to describe an altered process of bone healing characterised by the presence of fibrous tissue interposed between the fracture segments, that was lined with cartilaginous tissue and joined by a capsule; Spiessl, in 1988, used the term "non-union" to define any alteration of the bone healing process after a time period of more than 6 months from the initial traumatic event; Rosen, in 1990, proposed a new classification of the modes of altered bone healing in fractures, distinguishing 5 categories: delayed consolidation, non-union, non-union vascular, non union avascular, pseudoarthrosis. The authors also talk about "poor bone positioning". This factor describes the incorrect anatomical position of the bone fragments despite perfectly normal healing according to Gruss. In this article they also discuss about the treatment of non-unions and the treatment of occlusal alterations caused by poor post-traumatic bone positioning.

Role of Fas and Treg Cells in Fracture Healing as Characterized in the Fas-Deficient (lpr) Mouse Model of Lupus†

PubMed Central

Al-Sebaei, Maisa O; Daukss, Dana M; Belkina, Anna C; Kakar, Sanjeev; Wigner, Nathan A; Cusher, Daniel; Graves, Dana; Einhorn, Thomas; Morgan, Elise; Gerstenfeld, Louis C

2014-01-01

Previous studies showed that loss of tumor necrosis factor α (TNFα) signaling delayed fracture healing by delaying chondrocyte apoptosis and cartilage resorption. Mechanistic studies showed that TNFα induced Fas expression within chondrocytes; however, the degree to which chondrocyte apoptosis is mediated by TNFα alone or dependent on the induction of Fas is unclear. This question was addressed by assessing fracture healing in Fas-deficient B6.MRL/Faslpr/J mice. Loss of Fas delayed cartilage resorption but also lowered bone fraction in the calluses. The reduced bone fraction was related to elevated rates of coupled bone turnover in the B6.MRL/Faslpr/J calluses, as evidenced by higher osteoclast numbers and increased osteogenesis. Analysis of the apoptotic marker caspase 3 showed fewer positive chondrocytes and osteoclasts in calluses of B6.MRL/Faslpr/J mice. To determine if an active autoimmune state contributed to increased bone turnover, the levels of activated T cells and Treg cells were assessed. B6.MRL/Faslpr/J mice had elevated Treg cells in both spleens and bones of B6.MRL/Faslpr/J but decreased percentage of activated T cells in bone tissues. Fracture led to ∼30% to 60% systemic increase in Treg cells in both wild-type and B6.MRL/Faslpr/J bone tissues during the period of cartilage formation and resorption but either decreased (wild type) or left unchanged (B6.MRL/Faslpr/J) the numbers of activated T cells in bone. These results show that an active autoimmune state is inhibited during the period of cartilage resorption and suggest that iTreg cells play a functional role in this process. These data show that loss of Fas activity specifically in chondrocytes prolonged the life span of chondrocytes and that Fas synergized with TNFα signaling to mediate chondrocyte apoptosis. Conversely, loss of Fas systemically led to increased osteoclast numbers during later periods of fracture healing and increased osteogenesis. These findings suggest that retention of viable chondrocytes locally inhibits osteoclast activity or matrix proteolysis during cartilage resorption. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. PMID:24677136

Diaphyseal long bone nonunions - types, aetiology, economics, and treatment recommendations.

PubMed

Rupp, Markus; Biehl, Christoph; Budak, Matthäus; Thormann, Ulrich; Heiss, Christian; Alt, Volker

2018-02-01

The intention of the current article is to review the epidemiology with related socioeconomic costs, pathophysiology, and treatment options for diaphyseal long bone delayed unions and nonunions. Diaphyseal nonunions in the tibia and in the femur are estimated to occur 4.6-8% after modern intramedullary nailing of closed fractures with an even much higher risk in open fractures. There is a high socioeconomic burden for long bone nonunions mainly driven by indirect costs, such as productivity losses due to long treatment duration. The classic classification of Weber and Cech of the 1970s is based on the underlying biological aspect of the nonunion differentiating between "vital" (hypertrophic) and "avital" (hypo-/atrophic) nonunions, and can still be considered to represent the basis for basic evaluation of nonunions. The "diamond concept" units biomechanical and biological aspects and provides the pre-requisites for successful bone healing in nonunions. For humeral diaphyseal shaft nonunions, excellent results for augmentation plating were reported. In atrophic humeral shaft nonunions, compression plating with stimulation of bone healing by bone grafting or BMPs seem to be the best option. For femoral and tibial diaphyseal shaft fractures, dynamization of the nail is an atraumatic, effective, and cheap surgical possibility to achieve bony consolidation, particularly in delayed nonunions before 24 weeks after initial surgery. In established hypertrophic nonunions in the tibia and femur, biomechanical stability should be addressed by augmentation plating or exchange nailing. Hypotrophic or atrophic nonunions require additional biological stimulation of bone healing for augmentation plating.

Multiple Low Energy Long Bone Fractures in the Setting of Rothmund-Thomson Syndrome.

PubMed

Beckmann, Nicholas

2015-01-01

Rothmund-Thomson syndrome is a rare autosomal recessive genodermatosis characterized by a poikilodermatous rash starting in infancy as well as various skeletal anomalies, juvenile cataracts, and predisposition to certain cancers. Although Rothmund-Thomson syndrome is associated with diminished bone mineral density in addition to multiple skeletal abnormalities, there are few reports of the association with stress fractures or pathologic fractures in low energy trauma or delayed healing of fractures. Presented is a case of a young adult male with Rothmund-Thomson syndrome presenting with multiple episodes of long bone fractures caused by low energy trauma with one of the fractures exhibiting significantly delayed healing. The patient was also found to have an asymptomatic stress fracture of the lower extremity, another finding of Rothmund-Thomson syndrome rarely reported in the literature. A thorough review of the literature and comprehensive presentation of Rothmund-Thomson syndrome is provided in conjunction with our case.

Risk Factors for Injury and Cigarette Smoking and Temporal Trends in Demographic and Lifestyle Characteristics Among U.S. Army Ordinance School Students

DTIC Science & Technology

2008-07-01

took 166 ± 92 days or had a 24% slower healing time to clinical union , compared with nonsmokers at 134 ± 71 days. Possible attributes of the delayed ...1993). Are smokers a risk group for delayed healing of tibial shaft fractures . Annales Chirurgiae et Gynaeacologiae, 82:254-262. 47. Mazess R...experience stress fractures , compared with Caucasians(29), possibly because Blacks having a higher bone density(30,31).Other studies performed

Callus remodelling model

NASA Astrophysics Data System (ADS)

Miodowska, Justyna; Bielski, Jan; Kromka-Szydek, Magdalena

2018-01-01

The objective of this paper is to investigate the healing process of the callus using bone remodelling approach. A new mathematical model of bone remodelling is proposed including both underload and overload resorption, as well as equilibrium and bone growth states. The created model is used to predict the stress-stimulated change in the callus density. The permanent and intermittent loading programs are considered. The analyses indicate that obtaining a sufficiently high values of the callus density (and hence the elasticity) modulus is only possible using time-varying load parameters. The model predictions also show that intermittent loading program causes delayed callus healing. Understanding how mechanical conditions influence callus remodelling process may be relevant in the bone fracture treatment and initial bone loading during rehabilitation.

Anti-DKK1 antibody promotes bone fracture healing through activation of β-catenin signaling

PubMed Central

Jin, Hongting; Wang, Baoli; Li, Jia; Xie, Wanqing; Mao, Qiang; Li, Shan; Dong, Fuqiang; Sun, Yan; Ke, Hua-Zhu; Babij, Philip; Tong, Peijian; Chen, Di

2015-01-01

In this study we investigated if Wnt/β-catenin signaling in mesenchymal progenitor cells plays a role in bone fracture repair and if DKK1-Ab promotes fracture healing through activation of β-catenin signaling. Unilateral open transverse tibial fractures were created in CD1 mice and in β-cateninPrx1ER conditional knockout (KO) and Cre-negative control mice (C57BL/6 background). Bone fracture callus tissues were collected and analyzed by radiography, micro-CT (μCT), histology, biomechanical testing and gene expression analysis. The results demonstrated that treatment with DKK1-Ab promoted bone callus formation and increased mechanical strength during the fracture healing processinCD1 mice. DKK1-Ab enhanced fracture repair by activation of endochondral ossification. The normal rate of bone repair was delayed when the β-catenin gene was conditionally deleted in mesenchymal progenitor cells during the early stages of fracture healing. DKK1-Ab appeared to act through β-catenin signaling to enhance bone repair since the beneficial effect of DKK1-Ab was abrogated in β-cateninPrx1ER conditional KO mice. Further understanding of the signaling mechanism of DKK1-Ab in bone formation and bone regeneration may facilitate the clinical translation of this anabolic agent into therapeutic intervention. PMID:25263522

The dawn of computer-assisted robotic osteotomy with ytterbium-doped fiber laser.

PubMed

Sotsuka, Yohei; Nishimoto, Soh; Tsumano, Tomoko; Kawai, Kenichiro; Ishise, Hisako; Kakibuchi, Masao; Shimokita, Ryo; Yamauchi, Taisuke; Okihara, Shin-ichiro

2014-05-01

Currently, laser radiation is used routinely in medical applications. For infrared lasers, bone ablation and the healing process have been reported, but no laser systems are established and applied in clinical bone surgery. Furthermore, industrial laser applications utilize computer and robot assistance; medical laser radiations are still mostly conducted manually nowadays. The purpose of this study was to compare the histological appearance of bone ablation and healing response in rabbit radial bone osteotomy created by surgical saw and ytterbium-doped fiber laser controlled by a computer with use of nitrogen surface cooling spray. An Ytterbium (Yb)-doped fiber laser at a wavelength of 1,070 nm was guided by a computer-aided robotic system, with a spot size of 100 μm at a distance of approximately 80 mm from the surface. The output power of the laser was 60 W at the scanning speed of 20 mm/s scan using continuous wave system with nitrogen spray level 0.5 MPa (energy density, 3.8 × 10(4) W/cm(2)). Rabbits radial bone osteotomy was performed by an Yb-doped fiber laser and a surgical saw. Additionally, histological analyses of the osteotomy site were performed on day 0 and day 21. Yb-doped fiber laser osteotomy revealed a remarkable cutting efficiency. There were little signs of tissue damage to the muscle. Lased specimens have shown no delayed healing compared with the saw osteotomies. Computer-assisted robotic osteotomy with Yb-doped fiber laser was able to perform. In rabbit model, laser-induced osteotomy defects, compared to those by surgical saw, exhibited no delayed healing response.

Rap system of stress stimulation can promote bone union after lower tibial bone fracture: a clinical research.

PubMed

Yao, Jian-fei; Shen, Jia-zuo; Li, Da-kun; Lin, Da-sheng; Li, Lin; Li, Qiang; Qi, Peng; Lian, Ke-jian; Ding, Zhen-qi

2012-01-01

Lower tibial bone fracture may easily cause bone delayed union or nonunion because of lacking of dynamic mechanical load. Research Group would design a new instrument as Rap System of Stress Stimulation (RSSS) to provide dynamic mechanical load which would promote lower tibial bone union postoperatively. This clinical research was conducted from January 2008 to December 2010, 92 patients(male 61/female 31, age 16-70 years, mean 36.3 years) who suffered lower tibial bone closed fracture were given intramedullary nail fixation and randomly averagely separated into experimental group and control group(according to the successively order when patients went for the admission procedure). Then researchers analysed the clinical healing time, full weight bearing time, VAS (Visual Analogue Scales) score and callus growth score of Lane-Sandhu in 3,6,12 months postoperatively. The delayed union and nonunion rates were compared at 6 and 12 months separately. All the 92 patients had been followed up (mean 14 months). Clinical bone healing time in experimental group was 88.78±8.80 days but control group was 107.91±9.03 days. Full weight bearing time in experimental group was 94.07±9.81 days but control group was 113.24±13.37 days respectively (P<0.05). The delayed union rate in 6 months was 4.3% in experimental group but 10.9% in control group(P<0.05). The nonunion rate in 12 months was 6.5% in experimental group but 19.6% in control group(P<0.05). In 3, 6, 12 months postoperatively, VAS score and Lane-Sandhu score in experimental group had more significantly difference than them in control group. RSSS can intermittently provide dynamic mechanical load and stimulate callus formation, promote lower tibial bone union, reduce bone delayed union or nonunion rate. It is an adjuvant therapy for promoting bone union after lower tibial bone fracture.

Vertebral Compression Fractures

MedlinePlus

... and monitored to avoid putting pressure on the ribs that can cause new fractures. Surgical Procedures • When there is severe incapacitating pain • When healing is delayed or when bone fragments ...

Rotary self-locking intramedullary nail for long tubular bone fractures.

PubMed

Huang, Zhong-lian; Yang, Hai-long; Xu, Jian-kun; Xia, Xue; Wang, Xin-jia; Song, Jian-xin; Hu, Jun

2013-10-01

Intramedullary nails had been widely used in the treatment of long-bone fractures because of less interference of fractures and center bearing biomechanical advantage. However, it had been also found many shortcomings such as broken nails, delayed healing and was modified in order to achieve better efficacy and reduce complications. The aim of the present study is to compare the efficacy of rotary self-locking intramedullary nails (RSIN) with that of interlocking intramedullary nails (IIN) in the treatment of long-bone fractures. A retrospective study investigated 129 cases with long-bone fractures (36 with femoral fracture, 81 with tibial fracture, and 12 with humeral fracture). The fractures were fixed using either an RSIN or IIN. All patients underwent followup for 12-30 months. All patients in both groups achieved a clinical fracture healing standard and the postoperative affected limb muscle strength and joint function were well restored. The RSIN group required a shorter operative time and the fracture healed faster. There was no significant difference in the hospital stay, intraoperative blood loss or postoperative complications between the two groups. RSIN is used to treat long-bone fractures. Its healing efficacy is equivalent to the IIN. Moreover, the RSIN method is simpler and causes less tissue damage than the IIN, therefore having the advantage of accelerated healing.

Biological Perspectives of Delayed Fracture Healing

PubMed Central

Hankenson, KD; Zmmerman, G; Marcucio, R

2015-01-01

Fracture healing is a complex biological process that requires interaction among a series of different cell types. Maintaining the appropriate temporal progression and spatial pattern is essential to achieve robust healing. We can temporally assess the biological phases via gene expression, protein analysis, histologically, or non-invasively using biomarkers as well as imaging techniques. However, determining what leads to normal verses abnormal healing is more challenging. Since the ultimate outcome of the process of fracture healing is to restore the original functions of bone, assessment of fracture healing should include not only monitoring the restoration of structure and mechanical function, but also an evaluation of the restoration of normal bone biology. Currently very few non-invasive measures of the biology of healing exist; however, recent studies that have correlated non-invasive measures with fracture healing outcome in humans have shown that serum TGFbeta1 levels appear to be an indicator of healing vs non-healing. In the future, developing additional serum measures to assess biological healing will improve the reliability and permit us to assess stages of fracture healing. Additionally, new functional imaging technologies could prove useful for better understanding both normal fracture healing and predicting dysfunctional healing in human patients. PMID:24857030

Mathematical evaluation of the influence of multiple factors on implant stability quotient values in clinical practice: a retrospective study

PubMed Central

Huang, Hairong; Wismeijer, Daniel; Shao, Xianhong; Wu, Gang

2016-01-01

Objectives The objective of this study is to mathematically evaluate the influence of multiple factors on implant stability quotient values in clinical practice. Patients and methods Resonance frequency analysis was performed at T1 (measured immediately at the time of implant placement) and at T2 (measured before dental restoration) in 177 patients (329 implants). Using a multivariate linear regression model, we analyzed the influence of the following eleven candidate factors: sex, age, maxillary/mandibular location, bone type, immediate/delayed implantation, bone grafting (presence or absence), insertion torque, I-/II-stage healing pattern, implant diameter, implant length, and T1–T2 time interval. Results The following factors were identified to significantly influence the implant stability quotient (ISQ) values at T1: insertion torque, bone grafting, I-/II-stage healing pattern, immediate/delayed implantation, maxillary/mandibular location, implant diameter, and sex. In contrast, the ISQ values at T2 were significantly influenced only by three factors: implant diameter, T1–T2 time interval, and insertion torque. Conclusion Among the eleven candidate factors, seven key factors were found to influence the T1-ISQ values, while only three key factors influenced the T2-ISQ values. Both T1 and T2-ISQ values were found to be influenced by implant diameter and insertion torque. T1 was influenced specifically by the sex of the patient, the location (maxillary or mandibular), the implantation mode (immediate/delayed implantation), the healing stage, and the absence or presence of bone graft materials. PMID:27785040

Site Specific Effects of Zoledronic Acid during Tibial and Mandibular Fracture Repair

PubMed Central

Yu, Yan Yiu; Lieu, Shirley; Hu, Diane; Miclau, Theodore; Colnot, Céline

2012-01-01

Numerous factors can affect skeletal regeneration, including the extent of bone injury, mechanical loading, inflammation and exogenous molecules. Bisphosphonates are anticatabolic agents that have been widely used to treat a variety of metabolic bone diseases. Zoledronate (ZA), a nitrogen-containing bisphosphonate (N-BP), is the most potent bisphosphonate among the clinically approved bisphosphonates. Cases of bisphosphonate-induced osteonecrosis of the jaw have been reported in patients receiving long term N-BP treatment. Yet, osteonecrosis does not occur in long bones. The aim of this study was to compare the effects of zoledronate on long bone and cranial bone regeneration using a previously established model of non-stabilized tibial fractures and a new model of mandibular fracture repair. Contrary to tibial fractures, which heal mainly through endochondral ossification, mandibular fractures healed via endochondral and intramembranous ossification with a lesser degree of endochondral ossification compared to tibial fractures. In the tibia, ZA reduced callus and cartilage formation during the early stages of repair. In parallel, we found a delay in cartilage hypertrophy and a decrease in angiogenesis during the soft callus phase of repair. During later stages of repair, ZA delayed callus, cartilage and bone remodeling. In the mandible, ZA delayed callus, cartilage and bone remodeling in correlation with a decrease in osteoclast number during the soft and hard callus phases of repair. These results reveal a more profound impact of ZA on cartilage and bone remodeling in the mandible compared to the tibia. This may predispose mandible bone to adverse effects of ZA in disease conditions. These results also imply that therapeutic effects of ZA may need to be optimized using time and dose-specific treatments in cranial versus long bones. PMID:22359627

Open reduction of nasal bone fractures through an intercartilaginous incision.

PubMed

Kim, Ji Heui; Lee, Jun Ho; Hong, Seok Min; Park, Chan Hum

2013-01-01

Open reduction through an intercartilaginous incision was useful for treating delayed-diagnosed nasal bone fractures because it resulted in a successful outcome with minimal complications. Nasal bone fractures are generally managed with closed reduction, which is usually inadequate and results in airway obstruction with a delayed diagnosis of nasal bone fracture when bone healing and fibrotic adhesions around the bone fragment have progressed. This study investigated the surgical outcome of open reduction through an intercartilaginous incision for delayed-diagnosis nasal bone fractures. The study enrolled 18 patients who underwent open reduction through an intercartilaginous incision to correct delayed-diagnosis nasal bone fractures. Three independent otorhinolaryngologists evaluated the outcomes 4-35 months (average 12.7 months) postoperatively as excellent, fair or poor. The time from injury to surgery was 11-39 days (20-39 days in adults and 11-30 days in children). The 18 cases included 16 primary repairs and two revisions. A Kirschner wire was inserted in six (33.3%) patients who had unstable reduced nasal bones. Postoperatively, l5 (83%) patients had excellent results, two (11%) had fair, and one (6%) had a poor outcome. No patient experienced any complication.

The effect of mesenchymal stem cells delivered via hydrogel-based tissue engineered periosteum on bone allograft healing

PubMed Central

Hoffman, Michael D.; Xie, Chao; Zhang, Xinping; Benoit, Danielle S.W.

2013-01-01

Allografts remain the clinical “gold standard” for treatment of critical sized bone defects despite minimal engraftment and ~60% long-term failure rates. Therefore, the development of strategies to improve allograft healing and integration are necessary. The periosteum and its associated stem cell population, which are lacking in allografts, coordinate autograft healing. Herein we utilized hydrolytically degradable hydrogels to transplant and localize mesenchymal stem cells (MSCs) to allograft surfaces, creating a periosteum mimetic, termed a ‘tissue engineered periosteum’. Our results demonstrated that this tissue engineering approach resulted in increased graft vascularization (~2.4-fold), endochondral bone formation (~2.8-fold), and biomechanical strength (1.8-fold), as compared to untreated allografts, over 16 weeks of healing. Despite this enhancement in healing, the process of endochondral ossification was delayed compared to autografts, requiring further modifications for this approach to be clinically acceptable. However, this bottom-up biomaterials approach, the engineered periosteum, can be augmented with alternative cell types, matrix cues, growth factors, and/or other small molecule drugs to expedite the process of ossification. PMID:23958029

Nanomedicine for safe healing of bone trauma: Opportunities and challenges

PubMed Central

Behzadi, Shahed; Luther, Gaurav A.; Harris, Mitchel B.; Farokhzad, Omid C.; Mahmoudi, Morteza

2017-01-01

Historically, high-energy extremity injuries resulting in significant soft-tissue trauma and bone loss were often deemed unsalvageable and treated with primary amputation. With improved soft-tissue coverage and nerve repair techniques, these injuries now present new challenges in limb-salvage surgery. High-energy extremity trauma is pre-disposed to delayed or unpredictable bony healing and high rates of infection, depending on the integrity of the soft-tissue envelope. Furthermore, orthopedic trauma surgeons are often faced with the challenge of stabilizing and repairing large bony defects while promoting an optimal environment to prevent infection and aid bony healing. During the last decade, nanomedicine has demonstrated substantial potential in addressing the two major issues intrinsic to orthopedic traumas (i.e., high infection risk and low bony reconstruction) through combatting bacterial infection and accelerating/increasing the effectiveness of the bone-healing process. This review presents an overview and discusses recent challenges and opportunities to address major orthopedic trauma through nanomedical approaches. PMID:28918266

Biomechanical assessment and clinical analysis of different intramedullary nailing systems for oblique fractures.

PubMed

Alierta, J A; Pérez, M A; Seral, B; García-Aznar, J M

2016-09-01

The aim of this study is to evaluate the fracture union or non-union for a specific patient that presented oblique fractures in tibia and fibula, using a mechanistic-based bone healing model. Normally, this kind of fractures can be treated through an intramedullary nail using two possible configurations that depends on the mechanical stabilisation: static and dynamic. Both cases are simulated under different fracture geometries in order to understand the effect of the mechanical stabilisation on the fracture healing outcome. The results of both simulations are in good agreement with previous clinical experience. From the results, it is demonstrated that the dynamization of the fracture improves healing in comparison with a static or rigid fixation of the fracture. This work shows the versatility and potential of a mechanistic-based bone healing model to predict the final outcome (union, non-union, delayed union) of realistic 3D fractures where even more than one bone is involved.

Role of Cbl-PI3K Interaction during Skeletal Remodeling in a Murine Model of Bone Repair.

PubMed

Scanlon, Vanessa; Soung, Do Yu; Adapala, Naga Suresh; Morgan, Elise; Hansen, Marc F; Drissi, Hicham; Sanjay, Archana

2015-01-01

Mice in which Cbl is unable to bind PI3K (YF mice) display increased bone volume due to enhanced bone formation and repressed bone resorption during normal bone homeostasis. We investigated the effects of disrupted Cbl-PI3K interaction on fracture healing to determine whether this interaction has an effect on bone repair. Mid-diaphyseal femoral fractures induced in wild type (WT) and YF mice were temporally evaluated via micro-computed tomography scans, biomechanical testing, histological and histomorphometric analyses. Imaging analyses revealed no change in soft callus formation, increased bony callus formation, and delayed callus remodeling in YF mice compared to WT mice. Histomorphometric analyses showed significantly increased osteoblast surface per bone surface and osteoclast numbers in the calluses of YF fractured mice, as well as increased incorporation of dynamic bone labels. Furthermore, using laser capture micro-dissection of the fracture callus we found that cells lacking Cbl-PI3K interaction have higher expression of Osterix, TRAP, and Cathepsin K. We also found increased expression of genes involved in propagating PI3K signaling in cells isolated from the YF fracture callus, suggesting that the lack of Cbl-PI3K interaction perhaps results in enhanced PI3K signaling, leading to increased bone formation, but delayed remodeling in the healing femora.

In vivo effect of shock-waves on the healing of fractured bone.

PubMed

Augat, P; Claes, L; Suger, G

1995-10-01

In a controlled animal experiment we attempted to clarify the question of whether there is a stimulating effect of extracorporeal shock-waves on the repair process of fractured long bones. As a fracture model we used an osteotomy in the diaphysis of the ovine tibia and an external fixation device. Shock-wave treatment at two levels of intensity and with four different numbers of applied shocks was performed with an electromagnetic acoustic source. Healing of the osteotomized bone was evaluated by biomechanical and radiological investigations on the whole bone as well as on bone sections from areas of the fracture gap and the periosteal fracture callus. We found a non-significant tendency to deterioration of the fracture healing with increasing shock-wave intensities. The study of treatment parameters led neither to significantly different biomechanical outcomes nor to altered radiological results in comparison to the untreated control group. RELEVANCE:--While we cannot comment upon the effectiveness of extracorporeal shock-waves in the delayed treatment of fractures or pseudarthrosis, our results suggest that shock-waves have no beneficial effect in acute fracture repair.

Whole body vibration during fracture healing intensifies the effects of estradiol and raloxifene in estrogen-deficient rats.

PubMed

Stuermer, Ewa K; Komrakova, Marina; Sehmisch, Stephan; Tezval, Mohammad; Dullin, Christian; Schaefer, Nadine; Hallecker, Jan; Stuermer, Klaus M

2014-07-01

Current osteoporosis therapies aim to delay bone destruction and have additional anabolic effects. While they have demonstrated some positive effects on bone healing, more progress is needed in this area. This study used the well-known osteoporotic agents estrogen (E) and raloxifene (R) in conjunction with biomechanical whole body vibration (WBV) at a frequency of 70 Hz twice daily for six weeks to stimulate bone healing. Eighty-four 3-month old female Sprague-Dawley rats (12 per group) were bilaterally ovariectomized to develop osteopenia within eight weeks. Osteotomy of the metaphyseal tibiae was performed and fracture healing was then studied using mechanical tests, histomorphometry, computed tomography (μCT), and gene analysis. We found that E and R improved the structure of osteopenic bones as did WBV alone, although significant levels for WBV were seldom reached. Combination treatments significantly enhanced stiffness (R+WBV; p<0.05), endosteal bone (R+WBV; p<0.01), and trabecular density (E+WBV; p<0.05, R+WBV; p<0.05). In addition, the expression of osteoclast-specific Trap was significantly reduced after treatment with E, R, or their combination with WBV (p<0.01). The effects were additive and not inhibitory, leading us to conclude that the combined applications of WBV with E or R may improve the healing of osteopenic bones. The therapies studied are all currently approved for human use, suggesting ready applicability to clinical practice. To better understand the effects of WBV on osteopenic bones, the ideal vibration regime will require further study. Copyright © 2014 Elsevier Inc. All rights reserved.

Combined application of latissimus dorsi myocutaneous flap and iliac bone flap in the treatment of chronic osteomyelitis of the lower extremity.

PubMed

Ju, Jihui; Li, Lei; Zhou, Rong; Hou, Ruixing

2018-05-18

To evaluate the clinical efficacy and safety of latissimus dorsi myocutaneous flap (stage I) combined with iliac bone flap (stage II) in the treatment of chronic osteomyelitis of the lower extremity. Clinical data of 18 patients undergoing latissimus dorsi myocutaneous flap in combination with iliac bone flap grafting were retrospectively analyzed. Among them, 2 patients developed chronic osteomyelitis of the lower segment of the femur, 4 were diagnosed with chronic osteomyelitis of the tibial plateau, and 12 with chronic osteomyelitis of the lower segment of the tibia. All the latissimus dorsi myocutaneous flaps survived in 18 patients. After the corresponding surgery, primary wound healing was achieved in 11 patients, and delayed wound healing was obtained in 7 cases. All wounds were completely healed with postoperative 2 months. Following the iliac bone flap grafting, primary would healing was accomplished in all cases. All dorsal window chambers survived. The bone defects were properly restored within 4-12 postoperative months. Functional training was performed after removal of the internal and external fixators. Postoperative follow-up was endured from 6 months to 10 years. All patients were satisfied with the bone healing and flap texture without the incidence of osteomyelitis and sinus tract. No contraction was observed in the grafting area of 2 patients receiving latissimus dorsi myocutaneous flap grafting. Residual linear scars were noted in the dorsal and iliac donor sites. Combined usage of stage I latissimus dorsi myocutaneous flap and stage II iliac bone flap grafting is an efficacious and safe surgical technique in clinical practice.

Optimisation of composite bone plates for ulnar transverse fractures.

PubMed

Chakladar, N D; Harper, L T; Parsons, A J

2016-04-01

Metallic bone plates are commonly used for arm bone fractures where conservative treatment (casts) cannot provide adequate support and compression at the fracture site. These plates, made of stainless steel or titanium alloys, tend to shield stress transfer at the fracture site and delay the bone healing rate. This study investigates the feasibility of adopting advanced composite materials to overcome stress shielding effects by optimising the geometry and mechanical properties of the plate to match more closely to the bone. An ulnar transverse fracture is characterised and finite element techniques are employed to investigate the feasibility of a composite-plated fractured bone construct over a stainless steel equivalent. Numerical models of intact and fractured bones are analysed and the mechanical behaviour is found to agree with experimental data. The mechanical properties are tailored to produce an optimised composite plate, offering a 25% reduction in length and a 70% reduction in mass. The optimised design may help to reduce stress shielding and increase bone healing rates. Copyright © 2016 Elsevier Ltd. All rights reserved.

Factors Associated With Development of Nonunion or Delayed Healing After an Open Long Bone Fracture: A Prospective Cohort Study of 736 Subjects.

PubMed

Westgeest, Joseph; Weber, Donald; Dulai, Sukhdeep K; Bergman, Joseph W; Buckley, Richard; Beaupre, Lauren A

2016-03-01

To determine factors associated with developing nonunion or delayed healing after open fracture. Prospective cohort between 2001 and 2009. Three level 1 Canadian trauma centers. Seven hundred thirty-six (791 fractures) subjects were enrolled. Six hundred eighty-nine (94%) subjects (739 fractures) provided adequate outcome data. Subjects were followed until fracture(s) healed; phone interviews and chart reviews were conducted 1 year after fracture. Patient, fracture, and injury information, and time to surgery and antibiotics were recorded during hospitalization. Nonunion defined as unplanned surgical intervention after definitive wound closure or incomplete radiographic healing at 1 year and delayed healing defined as 2 consecutive clinical assessments showing no radiographic progression or incomplete radiographic healing between 6 months and 1 year. There were 413 (52%) tibia/fibular, 285 (36%) upper extremity, and 93 (13%) femoral fractures. Nonunion developed in 124 (17%) and delayed healing in 63 (8%) fractures. The median time to surgery was not different for fractures that developed nonunion compared with those who did not (P = 0.36). Deep infection [Odd ratio (OR) 12.75; 95% confidence interval (CI) 6.07-26.8], grade 3A fractures (OR 2.49; 95% CI, 1.30-4.78), and smoking (OR 1.73; 95% CI, 1.09-2.76) were significantly associated with developing a nonunion. Delayed healing was also significantly associated with deep infection (OR 4.34; 95% CI, 1.22-15.48) and grade 3B/C fractures (OR 3.69; 95% CI, 1.44-9.44). Multivariate regression found no association between nonunion and time to surgery (P = 0.15) or antibiotics (P = 0.70). Deep infection and higher Gustilo grade fractures were associated with nonunion and delayed healing. Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

Complex ankle arthrodesis: Review of the literature

PubMed Central

Rabinovich, Remy V; Haleem, Amgad M; Rozbruch, S Robert

2015-01-01

Complex ankle arthrodesis is defined as an ankle fusion that is at high risk of delayed and nonunion secondary to patient comorbidities and/or local ankle/hindfoot factors. Risk factors that contribute to defining this group of patients can be divided into systemic factors and local factors pertaining to co-existing ankle or hindfoot pathology. Orthopaedic surgeons should be aware of these risk factors and their association with patients’ outcomes after complex ankle fusions. Both external and internal fixations have demonstrated positive outcomes with regards to achieving stable fixation and minimizing infection. Recent innovations in the application of biophysical agents and devices have shown promising results as adjuncts for healing. Both osteoconductive and osteoinductive agents have been effectively utilized as biological adjuncts for bone healing with low complication rates. Devices such as pulsed electromagnetic field bone stimulators, internal direct current stimulators and low-intensity pulsed ultrasound bone stimulators have been associated with faster bone healing and improved outcomes scores when compared with controls. The aim of this review article is to present a comprehensive approach to the management of complex ankle fusions, including the use of biophysical adjuncts for healing and a proposed algorithm for their treatment. PMID:26396936

Gene therapy for bone healing.

PubMed

Evans, Christopher H

2010-06-23

Clinical problems in bone healing include large segmental defects, spinal fusions, and the nonunion and delayed union of fractures. Gene-transfer technologies have the potential to aid healing by permitting the local delivery and sustained expression of osteogenic gene products within osseous lesions. Key questions for such an approach include the choice of transgene, vector and gene-transfer strategy. Most experimental data have been obtained using cDNAs encoding osteogenic growth factors such as bone morphogenetic protein-2 (BMP-2), BMP-4 and BMP-7, in conjunction with both nonviral and viral vectors using in vivo and ex vivo delivery strategies. Proof of principle has been convincingly demonstrated in small-animal models. Relatively few studies have used large animals, but the results so far are encouraging. Once a reliable method has been developed, it will be necessary to perform detailed pharmacological and toxicological studies, as well as satisfy other demands of the regulatory bodies, before human clinical trials can be initiated. Such studies are very expensive and often protracted. Thus, progress in developing a clinically useful gene therapy for bone healing is determined not only by scientific considerations, but also by financial constraints and the ambient regulatory environment.

Effect of the Interposition of Calcium Phosphate Materials on Tendon-Bone Healing During Repair of Chronic Rotator Cuff Tear.

PubMed

Zhao, Song; Peng, Lingjie; Xie, Guoming; Li, Dingfeng; Zhao, Jinzhong; Ning, Congqin

2014-08-01

The current nature of tendon-bone healing after rotator cuff (RC) repair is still the formation of granulation tissue at the tendon-bone interface rather than the formation of fibrocartilage, which is the crucial structure in native tendon insertion and can be observed after knee ligament reconstruction. The interposition of calcium phosphate materials has been found to be able to enhance tendon-bone healing in knee ligament reconstruction. However, whether the interposition of these kinds of materials can enhance tendon-bone healing or even change the current nature of tendon-bone healing after RC repair still needs to be explored. The interposition of calcium phosphate materials during RC repair would enhance tendon-bone healing or change its current nature of granulation tissue formation into a more favorable process. Controlled laboratory study. A total of 144 male Sprague-Dawley rats underwent unilateral detachment of the supraspinatus tendon, followed by delayed repair after 3 weeks. The animals were allocated into 1 of 3 groups: (1) repair alone, (2) repair with Ca5(PO4)2SiO4 (CPS) bioceramic interposition, or (3) repair with hydroxyapatite (HA) bioceramic interposition at the tendon-bone interface. Animals were sacrificed at 2, 4, or 8 weeks postoperatively, and microcomputed tomography (micro-CT) was used to quantify the new bone formation at the repair site. New fibrocartilage formation and collagen organization at the tendon-bone interface was evaluated by histomorphometric analysis. Biomechanical testing of the supraspinatus tendon-bone complex was performed. Statistical analysis was performed using 1-way analysis of variance. Significance was set at P < .05. The micro-CT analysis demonstrated remarkable osteogenic activity and osteoconductivity to promote new bone formation and ingrowth of CPS and HA bioceramic, with CPS bioceramic showing better results than HA. Histological observations indicated that CPS bioceramic had excellent biocompatibility and biodegradability. At early time points after the RC repair, CPS bioceramic significantly increased the area of fibrocartilage at the tendon-bone interface compared with the control and HA groups. Moreover, CPS and HA bioceramics had significantly improved collagen organization. Biomechanical tests indicated that the CPS and HA groups have greater ultimate load to failure and stiffness than the control group at 4 and 8 weeks, and the CPS specimens exhibited the maximum ultimate load to failure, stiffness, and stress of the healing enthesis. Both CPS and HA bioceramics aid in cell attachment and proliferation and accelerate new bone formation, and CPS bioceramic has a more prominent effect on tendon-to-bone healing. Local application of CPS and HA bioceramic at the tendon-bone interface shows promise in improving healing after rotator cuff tear repair. © 2014 The Author(s).

The effect of mesenchymal stem cells delivered via hydrogel-based tissue engineered periosteum on bone allograft healing.

PubMed

Hoffman, Michael D; Xie, Chao; Zhang, Xinping; Benoit, Danielle S W

2013-11-01

Allografts remain the clinical "gold standard" for treatment of critical sized bone defects despite minimal engraftment and ∼60% long-term failure rates. Therefore, the development of strategies to improve allograft healing and integration are necessary. The periosteum and its associated stem cell population, which are lacking in allografts, coordinate autograft healing. Herein we utilized hydrolytically degradable hydrogels to transplant and localize mesenchymal stem cells (MSCs) to allograft surfaces, creating a periosteum mimetic, termed a 'tissue engineered periosteum'. Our results demonstrated that this tissue engineering approach resulted in increased graft vascularization (∼2.4-fold), endochondral bone formation (∼2.8-fold), and biomechanical strength (1.8-fold), as compared to untreated allografts, over 16 weeks of healing. Despite this enhancement in healing, the process of endochondral ossification was delayed compared to autografts, requiring further modifications for this approach to be clinically acceptable. However, this bottom-up biomaterials approach, the engineered periosteum, can be augmented with alternative cell types, matrix cues, growth factors, and/or other small molecule drugs to expedite the process of ossification. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dental implants typically help retain peri-implant vertical bone height: evidence-based analysis.

PubMed

Greenstein, Gary; Cavallaro, John

2013-01-01

The dental literature is assessed regarding the ability of dental implants to maintain vertical bone height after various implant placement scenarios: immediate, delayed, insertion into partially and fully edentate healed ridges, and under overdentures. Studies are also reviewed to determine if bone loss after implant insertion is continuous. Numerous investigations that support the concept that implants preserve bone height are identified. In addition, the data indicate that a minuscule amount of annual bone loss usually persists after implant placement, but it is often clinically imperceptible.

Alveolar ridge preservation with deproteinized bovine bone graft and collagen membrane and delayed implants.

PubMed

Pang, Chaoyuan; Ding, Yuxiang; Zhou, Hongzhi; Qin, Ruifeng; Hou, Rui; Zhang, Guoliang; Hu, Kaijin

2014-09-01

To evaluate clinically and radiographically an alveolar ridge, preservation technique with deproteinized bovine bone graft and absorbable collagen membrane and then restoration with delayed implants were done. The study included 30 patients. The trial group's sockets were filled with deproteinized bovine bone graft (Bio-Oss) and covered with absorbable collagen membrane (Bio-Gide). The control group's sockets healed without any treatment. Panoramic radiograph and computed tomography were taken immediately after graft and 3 and 6 months later to evaluate the height, width, and volume change of the alveolar ridge bone. Dental implants were inserted in all sockets at 6 months, and osseointegration condition was evaluated in the following 12 months. All sockets healed uneventfully. In the trial group, the mean (SD) height reduction of the alveolar ridge bone was 1.05 (0.24) mm at 3 months and 1.54 (0.25) mm at 6 months. The width reduction was 1.11 (0.13) mm at 3 months and 1.84 (0.35) mm at 6 months. Bone volume reduction was 193.79 (21.47) mm at 3 months and 262.06 (33.08) mm at 6 months. At the same trend, in the control group, the bone height reduction was 2.12 (0.15) mm at 3 months and 3.26 (0.29) mm at 6 months. The width reduction was 2.72 (0.19) mm at 3 months and 3.56 (0.28) mm at 6 months. Bone volume reduction was 252.19 (37.21) mm at 3 months and 342.32 (36.41) mm at 6 months. There was a significant difference in alveolar ridge bone height, width, and volume reduction in the 2 groups. The osseointegration condition had no significant difference between the 2 groups. This study suggested that the deproteinized bovine bone graft and absorbable collagen membrane were beneficial to preserve the alveolar ridge bone and had no influence on the osseointegration of delayed implant.

Beta-Catenin Signaling Plays a Disparate Role in Different Phases of Fracture Repair: Implications for Therapy to Improve Bone Healing

PubMed Central

Chen, Yan; Whetstone, Heather C; Lin, Alvin C; Nadesan, Puviindran; Wei, Qingxia; Poon, Raymond; Alman, Benjamin A

2007-01-01

Background Delayed fracture healing causes substantial disability and usually requires additional surgical treatments. Pharmacologic management to improve fracture repair would substantially improve patient outcome. The signaling pathways regulating bone healing are beginning to be unraveled, and they provide clues into pharmacologic management. The β-catenin signaling pathway, which activates T cell factor (TCF)-dependent transcription, has emerged as a key regulator in embryonic skeletogenesis, positively regulating osteoblasts. However, its role in bone repair is unknown. The goal of this study was to explore the role of β-catenin signaling in bone repair. Methods and Findings Western blot analysis showed significant up-regulation of β-catenin during the bone healing process. Using a β-Gal activity assay to observe activation during healing of tibia fractures in a transgenic mouse model expressing a TCF reporter, we found that β-catenin-mediated, TCF-dependent transcription was activated in both bone and cartilage formation during fracture repair. Using reverse transcription-PCR, we observed that several WNT ligands were expressed during fracture repair. Treatment with DKK1 (an antagonist of WNT/β-catenin pathway) inhibited β-catenin signaling and the healing process, suggesting that WNT ligands regulate β-catenin. Healing was significantly repressed in mice conditionally expressing either null or stabilized β-catenin alleles induced by an adenovirus expressing Cre recombinase. Fracture repair was also inhibited in mice expressing osteoblast-specific β-catenin null alleles. In stark contrast, there was dramatically enhanced bone healing in mice expressing an activated form of β-catenin, whose expression was restricted to osteoblasts. Treating mice with lithium activated β-catenin in the healing fracture, but healing was enhanced only when treatment was started subsequent to the fracture. Conclusions These results demonstrate that β-catenin functions differently at different stages of fracture repair. In early stages, precise regulation of β-catenin is required for pluripotent mesenchymal cells to differentiate to either osteoblasts or chondrocytes. Once these undifferentiated cells have become committed to the osteoblast lineage, β-catenin positively regulates osteoblasts. This is a different function for β-catenin than has previously been reported during development. Activation of β-catenin by lithium treatment has potential to improve fracture healing, but only when utilized in later phases of repair, after mesenchymal cells have become committed to the osteoblast lineage. PMID:17676991

Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing.

PubMed

Chen, Yan; Whetstone, Heather C; Lin, Alvin C; Nadesan, Puviindran; Wei, Qingxia; Poon, Raymond; Alman, Benjamin A

2007-07-31

Delayed fracture healing causes substantial disability and usually requires additional surgical treatments. Pharmacologic management to improve fracture repair would substantially improve patient outcome. The signaling pathways regulating bone healing are beginning to be unraveled, and they provide clues into pharmacologic management. The beta-catenin signaling pathway, which activates T cell factor (TCF)-dependent transcription, has emerged as a key regulator in embryonic skeletogenesis, positively regulating osteoblasts. However, its role in bone repair is unknown. The goal of this study was to explore the role of beta-catenin signaling in bone repair. Western blot analysis showed significant up-regulation of beta-catenin during the bone healing process. Using a beta-Gal activity assay to observe activation during healing of tibia fractures in a transgenic mouse model expressing a TCF reporter, we found that beta-catenin-mediated, TCF-dependent transcription was activated in both bone and cartilage formation during fracture repair. Using reverse transcription-PCR, we observed that several WNT ligands were expressed during fracture repair. Treatment with DKK1 (an antagonist of WNT/beta-catenin pathway) inhibited beta-catenin signaling and the healing process, suggesting that WNT ligands regulate beta-catenin. Healing was significantly repressed in mice conditionally expressing either null or stabilized beta-catenin alleles induced by an adenovirus expressing Cre recombinase. Fracture repair was also inhibited in mice expressing osteoblast-specific beta-catenin null alleles. In stark contrast, there was dramatically enhanced bone healing in mice expressing an activated form of beta-catenin, whose expression was restricted to osteoblasts. Treating mice with lithium activated beta-catenin in the healing fracture, but healing was enhanced only when treatment was started subsequent to the fracture. These results demonstrate that beta-catenin functions differently at different stages of fracture repair. In early stages, precise regulation of beta-catenin is required for pluripotent mesenchymal cells to differentiate to either osteoblasts or chondrocytes. Once these undifferentiated cells have become committed to the osteoblast lineage, beta-catenin positively regulates osteoblasts. This is a different function for beta-catenin than has previously been reported during development. Activation of beta-catenin by lithium treatment has potential to improve fracture healing, but only when utilized in later phases of repair, after mesenchymal cells have become committed to the osteoblast lineage.

Acellular fetal bovine dermal matrix in the treatment of nonhealing wounds in patients with complex comorbidities.

PubMed

Lullove, Eric

2012-01-01

In contrast to the narrow indications for living skin equivalents, extracellular matrix biomaterials are clinically used in a wide range of wound-healing applications. Given the breadth of possible uses, the goal of this study was to retrospectively compile and analyze the clinical application and effectiveness of an extracellular matrix biomaterial derived from fetal bovine dermis (PriMatrix; TEI Biosciences, Boston, Massachusetts) in patients treated by a single physician and monitored postsurgically in an outpatient wound care center. A retrospective medical record review was conducted of consecutive patients treated from January 2007 through January 2009 with meshed PriMatrix after sharp/surgical debridement and coverage with standard moist wound therapy dressings. Twenty-nine patients and 34 wounds were compiled. All of the wounds were unresponsive to conservative treatment owing to complications, including infection, exposed bone or tendon, and other comorbidities known to delay healing. Wounds included 11 diabetic ulcers, 8 venous stasis ulcers, 10 nonhealing traumatic wounds, and 5 other chronic wounds. Thirty of 34 wounds healed, with four patients lost to follow-up. Mean time to healing for diabetic foot ulcers was 105 days with an average of 2.6 PriMatrix applications. Mean time to healing for venous, traumatic, and other chronic wounds was 74 to 82 days with an average of 1.2 to 1.4 PriMatrix applications. In patients with comorbidities known to delay healing, the implantation of PriMatrix promoted the healing and, ultimately, full reepithelialization of otherwise unresponsive wounds of varied etiology, including those with complications of infection or exposed bone or tendon.

Biomechanics of bone-fracture fixation by stiffness-graded plates in comparison with stainless-steel plates

PubMed Central

Ganesh, VK; Ramakrishna, K; Ghista, Dhanjoo N

2005-01-01

Background In the internal fixation of fractured bone by means of bone-plates fastened to the bone on its tensile surface, an on-going concern has been the excessive stress-shielding of the bone by the excessively-stiff stainless-steel plate. The compressive stress-shielding at the fracture-interface immediately after fracture-fixation delays callus formation and bone healing. Likewise, the tensile stress-shielding of the layer of the bone underneath the plate can cause osteoporosis and decrease in tensile strength of this layer. Method In order to address this problem, we propose to use stiffness-graded plates. Accordingly, we have computed (by finite-element analysis) the stress distribution in the fractured bone fixed by composite plates, whose stiffness is graded both longitudinally and transversely. Results It can be seen that the stiffness-graded composite-plates cause less stress-shielding (as an example: at 50% of the healing stage, stress at the fracture interface is compressive in nature i.e. 0.002 GPa for stainless steel plate whereas stiffness graded plates provides tensile stress of 0.002 GPa. This means that stiffness graded plate is allowing the 50% healed bone to participate in loadings). Stiffness-graded plates are more flexible, and hence permit more bending of the fractured bone. This results in higher compressive stresses induced at the fractured faces accelerate bone-healing. On the other hand, away from the fracture interface the reduced stiffness and elastic modulus of the plate causes the neutral axis of the composite structure to be lowered into the bone resulting in the higher tensile stress in the bone-layer underneath the plate, wherein is conducive to the bone preserving its tensile strength. Conclusion Stiffness graded plates (with in-built variable stiffness) are deemed to offer less stress-shielding to the bone, providing higher compressive stress at the fractured interface (to induce accelerated healing) as well as higher tensile stress in the intact portion of the bone (to prevent bone remodeling and osteoporosis). PMID:16045807

PEMF as treatment for delayed healing of foot and ankle arthrodesis.

PubMed

Saltzman, Charles; Lightfoot, Andrew; Amendola, Annunziato

2004-11-01

Arthrodesis is the most common surgical treatment for foot and ankle arthritis. In adults, these procedures are associated with a 5% to 10% rate of nonunion. Pulsed electromagnetic field (PEMF) stimulation was approved by the Federal Drug Administration (FDA) for treatment of delayed unions after long-bone fractures and joint arthrodesis. The purpose of this study was to examine the results of PEMF treatment for delayed healing after foot and ankle arthrodesis. Three hundred and thirty-four foot and ankle arthrodeses were done. Nineteen resulted in delayed unions that were treated with a protocol of immobilization, limited weightbearing, and PEMF stimulation for a median of 7 (range 5 to 27) months. All patients were followed clinically and radiographically. The use of PEMF, immobilization, and limited weightbearing to treat delayed union after foot and ankle arthrodesis was successful in 5 of 19 (26%) patients. Of the other 14 patients with nonunions, nine had revision surgery with autogenous grafting, continued immobilization, and PEMF stimulation. Seven of these eventually healed at a median of 5.5 (range 2 to 26) months and two did not heal. One patient had a below-knee amputation, and four refused further treatment. The protocol of PEMF, immobilization, and limited weightbearing had a relatively low success rate in this group of patients. We no longer use this protocol alone to treat delayed union after foot and ankle arthrodesis.

Periodontal and endodontic pathology delays extraction socket healing in a canine model

PubMed Central

2017-01-01

Purpose The aim of the present exploratory study was to evaluate extraction socket healing at sites with a history of periodontal and endodontic pathology. Methods The mandibular 4th premolar teeth in 5 adult beagle dogs served as experimental units. Periodontal and endodontic lesions were induced in 1 premolar site in each animal using wire ligatures and pulpal exposure over 3 months (diseased sites). The contralateral premolar sites served as healthy controls. The mandibular 4th premolar teeth were then extracted with minimal trauma, followed by careful wound debridement. The animals were sacrificed at days 1, 7, 30, 60, and 90 post-extraction for analysis, and the healing patterns at the healthy and diseased extraction sites were compared using radiography, scanning electron microscopy, histology, and histometry. Results During the first 7 days of healing, a significant presence of inflammatory granulation tissue was noted at the diseased sites (day 1), along with a slightly accelerated rate of fibrin clot resolution on day 7. On day 30, the diseased extraction sites showed a greater percentage of persistent fibrous connective tissue, and an absence of bone marrow formation. In contrast, healthy sites showed initial signs of bone marrow formation on day 30, and subsequently a significantly greater proportion of mature bone marrow formation on both days 60 and 90. Radiographs exhibited sclerotic changes adjoining apical endodontic lesions, with scanning electron microscopy showing collapsed Volkmann canals protruding from these regions in the diseased sites. Furthermore, periodontal ligament fibers exhibited a parallel orientation to the alveolar walls of the diseased sites, in contrast to a perpendicular arrangement in the healthy sites. Conclusions Within the limitations of this study, it appears that a history of periodontal and endodontic pathology may critically affect bone formation and maturation, leading to delayed and compromised extraction socket healing. PMID:28680710

Socket preservation.

PubMed

Fee, L

2017-04-21

Socket preservation maintains bone volume post-extraction in anticipation of an implant placement or fixed partial denture pontic site. This procedure helps compensate for the resorption of the facial bone wall. Socket preservation should be considered when implant placement needs to be delayed for patient or site-related reasons. The ideal healing time before implant placement is six months. Socket preservation can reduce the need for later bone augmentation. By reducing bone resorption and accelerating bone formation it increases implant success and survival. Biomaterials for socket grafting including autograft, allograft, xenograft and alloplast. A bone substitute with a low substitution rate is recommended.

Anti-osteoporosis therapy and fracture healing.

PubMed

Larsson, Sune; Fazzalari, Nicola L

2014-02-01

A number of medications are approved for treatment of osteoporosis. As mode of action usually is anti-catabolic/anti-resorptive or anabolic, it is of interest to know whether these drugs affect not only normal bone remodeling, but also fracture healing. The purpose of this paper is to give a short overview of the potential effect of various anti-osteoporotic medication on fracture healing. A narrative literature review was performed to describe the current knowledge. Anti-catabolic/anti-resorptive drugs: for bisphosphonates, the most common class of drugs in this group, experimental studies have shown a larger and stronger callus and delayed remodeling but no evidence of delayed healing. A human monoclonal antibody to RANKL is another anti-catabolic drug, with the only report to date showing enhanced healing in an animal model. Strontium ranelate is a drug where both anti-catabolic and a weak anabolic effect have been proposed, with experimental data ranging from no effect to significant increase in both callus volume and strength. Anabolic drugs: PTH has demonstrated accelerated healing of various experimental fractures and of distal radius and pelvic fractures in humans. While the exact mechanism is not fully understood, PTH results in increased recruitment and differentiation of chondrocytes and enhancement of endochondral ossification. A monoclonal antibody to block sclerostin is another potential anabolic pathway, where animal data have shown increase in bone mass and strength. The potential effect on fracture healing is yet to be studied. There are still large gaps in the understanding of the potential effect of anti-osteoporotic drugs on fracture healing, although based on present knowledge a recent or present fracture should not be considered as a contraindication to such treatment.

Radiation-induced impairment of osseous healing: Quantitative studies usine a standard drilling defect in rat femur

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arnold, M.; Kummermehr, J.; Trott, K.R.

1995-07-01

The femora of adult Wistar rats were locally irradiated with single doses of X rays and 1 day later were wounded by a standardized drilling defect that extended through the diaphyseal cortex into the marrow cavity. Healing of the lesion was followed over 30 weeks to assess the time course of osseous closure. In unirradiated bones healing was complete by week 7. Irradiation with doses up to 15 Gy imparted a dose-dependent delay in the formation of primary callus and its subsequent replacement by more mature bone, while after higher doses healing doses healing remained permanently comprised or even suppressed.more » Using histomorphometry, osseous closure was also measured quantitatively for healing periods of 7, 10, 16 and 30 weeks and the data were expressed as the percentage of responders with {ge}40% fractional closure. the resulting dose-response curves were steep, displaying a large threshold dose and ED{sub 50} values between 16.8 to 17.5 Gy (7 to 16 weeks) and 19.4 Gy (30 weeks), respectively. 35 refs., 4 figs., 2 tabs.« less

[Calcium and vitamin D in bone metabolism: Clinical importance for fracture treatment].

PubMed

Amling, M

2015-12-01

A balanced calcium homeostasis is of critical importance not only for bone remodeling, the physiological process of bone resorption and bone formation that constantly renews bone throughout life but also for normal fracture healing. Given that disturbances of calcium homeostasis are present in 50 % of the German population and that this might result in delayed fracture healing after correct surgical treatment, this paper focusses on calcium and vitamin D in the daily practice in orthopedics and trauma surgery. To ensure the required enteral calcium uptake the following three conditions are required: (1) sufficient calcium intake via the nutrition, (2) a 25-hydroxyvitamin D serum level > 30 µg/l and (3) the presence of sufficient gastric acidification. Given the endemic vitamin D deficiency in Germany as well as the constantly increasing number of people using proton pump inhibitors on a regular basis, it is necessary to closely connect trauma orthopedic surgery and osteological treatment. The first issue to be dealt with is to control and if needed normalize calcium homeostasis in order to allow a normal undisturbed fracture healing process after both conservative as well as operative treatment of fractures.

Complications of ankle fracture in patients with diabetes.

PubMed

Chaudhary, Saad B; Liporace, Frank A; Gandhi, Ankur; Donley, Brian G; Pinzur, Michael S; Lin, Sheldon S

2008-03-01

Ankle fractures in patients with diabetes mellitus have long been recognized as a challenge to practicing clinicians. Complications of impaired wound healing, infection, malunion, delayed union, nonunion, and Charcot arthropathy are prevalent in this patient population. Controversy exists as to whether diabetic ankle fractures are best treated noninvasively or by open reduction and internal fixation. Patients with diabetes are at significant risk for soft-tissue complications. In addition, diabetic ankle fractures heal, but significant delays in bone healing exist. Also, Charcot ankle arthropathy occurs more commonly in patients who were initially undiagnosed and had a delay in immobilization and in patients treated nonsurgically for displaced ankle fractures. Several techniques have been described to minimize complications associated with diabetic ankle fractures (eg, rigid external fixation, use of Kirschner wires or Steinmann pins to increase rigidity). Regardless of the specifics of treatment, adherence to the basic principles of preoperative planning, meticulous soft-tissue management, and attention to stable, rigid fixation with prolonged, protected immobilization are paramount in minimizing problems and yielding good functional outcomes.

History of internal fixation with plates (part 2): new developments after World War II; compressing plates and locked plates.

PubMed

Hernigou, Philippe; Pariat, Jacques

2017-07-01

The first techniques of operative fracture with plates were developed in the 19th century. In fact, at the beginning these methods consisted of an open reduction of the fracture usually followed by a very unstable fixation. As a consequence, the fracture had to be opened with a real risk of (sometimes lethal) infection, and due to unstable fixation, protection with a cast was often necessary. During the period between World Wars I and II, plates for fracture fixation developed with great variety. It became increasingly recognised that, because a fracture of a long bone normally heals with minimal resorption at the bone ends, this may result in slight shortening and collapse, so a very rigid plate might prevent such collapse. However, as a consequence, delayed healing was observed unless the patient was lucky enough to have the plate break. One way of dealing with this was to use a slotted plate in which the screws could move axially, but the really important advance was recognition of the role of compression. After the first description of compression by Danis with a "coapteur", Bagby and Müller with the AO improved the technique of compression. The classic dynamic compression plates from the 1970s were the key to a very rigid fixation, leading to primary bone healing. Nevertheless, the use of strong plates resulted in delayed union and the osteoporosis, cancellous bone, comminution, and/or pathological bone resulted in some failures due to insufficient stability. Finally, new devices represented by locking plates increased the stability, contributing to the principles of a more biological osteosynthesis while giving enough stability to allow immediate full weight bearing in some patients.

Effects of long-term administration of carprofen on healing of a tibial osteotomy in dogs.

PubMed

Ochi, Hiroki; Hara, Yasushi; Asou, Yoshinori; Harada, Yasuji; Nezu, Yoshinori; Yogo, Takuya; Shinomiya, Kenichi; Tagawa, Masahiro

2011-05-01

To evaluate effects of long-term administration of carprofen on healing of a tibial osteotomy in dogs. 12 healthy female Beagles. A mid-diaphyseal transverse osteotomy (stabilized with an intramedullary pin) of the right tibia was performed in each dog. The carprofen group (n = 6 dogs) received carprofen (2.2 mg/kg, PO, q 12 h) for 120 days; the control group (6) received no treatment. Bone healing and change in callus area were assessed radiographically over time. Dogs were euthanized 120 days after surgery, and tibiae were evaluated biomechanically and histologically. The osteotomy line was not evident in the control group on radiographs obtained 120 days after surgery. In contrast, the osteotomy line was still evident in the carprofen group. Callus area was significantly less in the carprofen group, compared with the area in the control group, at 20, 30, and 60 days after surgery. At 120 days after surgery, stiffness, elastic modulus, and flexural rigidity in the carprofen group were significantly lower than corresponding values in the control group. Furthermore, histologic evaluation revealed that the cartilage area within the callus in the carprofen group was significantly greater than that in the control group. Long-term administration of carprofen appeared to inhibit bone healing in dogs that underwent tibial osteotomy. We recommend caution for carprofen administration when treating fractures that have delays in healing associated with a reduction in osteogenesis as well as fractures associated with diseases that predispose animals to delays of osseous repair.

The effect of strontium ranelate on the healing of a fractured ulna with bone gap in rabbit.

PubMed

Ibrahim, Mohd Rafiq Mohd; Singh, Simmrat; Merican, Azhar Mahmood; Raghavendran, Hanumantha Rao Balaji; Murali, Malliga Raman; Naveen, Sangeetha Vasudevaraj; Kamarul, Tunku

2016-06-16

Fracture healing in bone gap is one of the major challenges encountered in Orthopedic Surgery. At present, the treatment includes bone graft, employing either internal or external fixation which has a significant impact on the patient, family and even society. New drugs are emerging in the markets such as anabolic bone-forming agents including teriparatide and strontium ranelate to stimulate bone growth. Based on the mechanism of their actions, we embarked on a study on the healing of a fractured ulna with bone gap in a rabbit model. We segregated ten rabbits into two groups: five rabbits in the test group and five rabbits in the control group. We created a 5 mm bone gap in the ulna bone, removing the periosteum as well. Rabbits in the test group received 450 mg/kg of strontium ranelate via oral administration, daily, for six weeks. The x-rays, CT scans and blood tests were performed every two weeks. At the end of six weeks, the rabbits were sacrificed, and the radius and ulna bones harvested for histopathological examination. Based on the x-rays and CT scans, fracture healing or bone formation was observed to be faster in the control group. From the x-ray findings, 80 % of the fracture united and by CT scan, 60 % of the fracture united in the control group at the end of the six-week study. None of the fractures united in the test group. However, the histopathology report showed that a callus of different stages was being formed in both groups, consisting of 80 % of bone. The serum levels of osteocalcin and alkaline phosphatase initially remained similar up to three weeks and changed slightly at the end of six weeks. We conclude that the strontium effect begins slowly, and while it may not interfere with bone cell proliferation it may interfere in the mineralization and delay the acute stage of fracture healing. We recommend that a larger sample size and a longer duration of the study period be implemented to confirm our finding.

Hyaluronic Acid Improves Bone Formation in Extraction Sockets With Chronic Pathology: A Pilot Study in Dogs.

PubMed

Kim, Jung-Ju; Song, Hyun Young; Ben Amara, Heithem; Kyung-Rim, Kang; Koo, Ki-Tae

2016-07-01

Previous studies on ridge preservation focusing on fresh extraction sockets using graft materials for ridge preservation procedures have reported a delay in the tissue modeling and remodeling phases. The objective of this study is to evaluate the effect of hyaluronic acid (HA) on healing of infected sockets. Six beagle dogs were used in this study. Both mandibular third premolars were hemisected, and the distal roots were extracted. Subsequently, periodontal and endodontic lesions were induced at the remaining mesial root. After communication of the periodontal lesion, an endodontic periapical lesion was observed at 4 months, and the mesial roots of both the right and left sides were extracted. HA was applied into the socket of the test group, and no treatment was administered to the other group (control group). Three months after extraction of the mesial roots, the dogs were sacrificed, and histologic evaluations were performed. The sockets were filled by mineralized bone (47.80% ± 6.60%) and bone marrow (50.47% ± 6.38%) in the control group, whereas corresponding values were 63.29% ± 9.78% and 34.73% ± 8.97% for the test group, respectively. There was a statistically significant difference between the groups. Reversal lines and a copious lineup of osteoblasts were observed in the middle and apical parts of the sockets in the test group. An infected socket shows delayed healing of the socket wound, and HA, because of its osteoinductive, bacteriostatic, and anti-inflammatory properties, may improve bone formation and accelerate wound healing in infected sockets.

The effect of methotrexate on the bone healing of mandibular condylar process fracture: an experimental study in rats.

PubMed

Cavalcanti, Samantha Cristine Santos X B; Corrêa, Luciana; Mello, Suzana Beatriz Veríssimo; Luz, João Gualberto C

2014-10-01

Methotrexate (MTX) is an anti-metabolite used in rheumatology and oncology. High doses are indicated for oncological treatment, whereas low doses are indicated for chronic inflammatory diseases. This study evaluated the effect of two MTX treatment schedules on the bone healing of the temporomandibular joint fracture in rats. Seventy-five adult male Wistar rats were used to generate an experimental unilateral medially rotated condylar fracture model that allows an evaluation of bone healing and the articular structures. The animals were subdivided into three groups that each received one of the following treatments intraperitoneally: saline (1 mL/week), low-dose MTX (3 mg/kg/week) and high-dose MTX (30 mg/kg). The histological study comprised fracture site and temporomandibular joint evaluations and bone neoformation was evaluated by histomorphometric analysis. A biochemical parameter of bone formation was also assessed. When compared with saline, high-dose MTX delayed bone fracture repairs. In this latter group, after 90 days, the histological analysis revealed atrophy of the fibrocartilage and the presence of fibrous tissue in the joint space. The histomorphometric analysis revealed diminished bone neoformation. The alkaline phosphatase levels also decreased after MTX treatment. It was concluded that high-dose MTX impaired mandibular condyle repair and induced degenerative articular changes. Copyright © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Early Loading of Fluoridated Implants Placed in Fresh Extraction Sockets and Healed Bone: A 3- to 5-Year Clinical and Radiographic Follow-Up Study of 39 Consecutive Patients.

PubMed

Oxby, Gert; Oxby, Fredrik; Oxby, Johan; Saltvik, Tomas; Nilsson, Peter

2015-10-01

Immediate placement of implants in extraction sockets for early loading is an attractive treatment modality due to reduced treatment time. However, the outcome of fluoridated implants in this situation with regard to bone levels and health of soft tissues is not well documented. To evaluate the outcome of early loading of OsseoSpeed(™) dental implants placed into fresh extraction sockets and healed bone in consecutive patients treated in a private clinic. A total of 182 OsseoSpeed(™) implants (Astra Tech Implant System, DENTSPLY Implants, Mölndal, Sweden), 72 in immediate extraction sockets and 110 in healed sites, were placed in 39 consecutive patients. The implants were loaded with permanent restorations within 60 days (average 31 days). Clinical and radiographic follow-up examinations were performed annually for at least 3 years (mean 55 months). An aesthetic index was used to evaluate the soft tissues adjacent to the prosthetic restorations. No implant was lost during the observation period, giving a survival rate of 100%. Bone level changes during the observation period were minimal, with a mean marginal bone loss of 0.3 ± 0.9 mm around the delayed implants and a mean marginal bone gain of 0.3 ± 1.4 mm around the immediate implants (p = .0036). The frequency distribution of bone level revealed that 85% of implants placed in fresh extraction sockets and 84% of implants in healed bone did not show any loss of bone level during follow-up (p = NS). Soft tissue complications were observed at two immediate implant sites in one patient. The remaining 180 implants received the highest aesthetic score. Moreover, no signs of peri-implant purulent infection or aggressive bone loss were found during the follow-up period. Early loading of fluoridated implants with permanent constructions appears to be a viable therapy for implants placed immediately in extraction sites and in healed bone. © 2014 Wiley Periodicals, Inc.

Coupled external fixator and skin flap transposition for treatment of exposed and nonunion bone.

PubMed

Zhao, Yong-gang; Ding, Jing; Wang, Neng

2011-02-01

To discuss the effect of coupled external fixator and skin flap transposition on exposed and nonunion bones. The data of 12 cases of infected nonunion and exposed bone following open fracture treated in our hospital during the period of March 1998 to June 2008 were analysed. There were 10 male patients, 2 female patients, whose age were between 19-52 years and averaged 28 years. There were 10 tibial fractures and 2 femoral fractures. The course of diseases lasted for 12-39 months with the mean period of 19 months. All the cases were treated by the coupled external fixator and skin flap transposition. Primary healing were achieved in 10 cases and delayed healing in 2 cases in whom the tibia was exposed due to soft tissue defect and hence local flap transposition was performed. All the 12 cases had bony union within 6-12 months after operation with the average time of 8 months. They were followed up for 1-3 years and all fractures healed up with good function and no infection recurrence. The coupled external fixator and skin flap transposition therapy have shown optimal effects on treating infected, exposed and nonunion bones.

The effects of a CO2 laser on the healing of a bone defect.

PubMed

Corsair, A

1997-03-01

This case report illustrates a potentially valuable application of the CO2 laser in periodontal surgery. An intrabony defect was treated with a bone allograft. During the 28-day postsurgical period, epithelialization of the wound was delayed by lasing the soft tissue over the bony defect at weekly intervals for 4 weeks. This procedure resulted in complete regeneration of the bone defect in this case. Controlled studies need to be carried out to determine if the use of the laser to retard epithelial downgrowth has a clinically significant effect on bone regeneration.

Texture analysis of computed tomographic images in osteoporotic patients with sinus lift bone graft reconstruction.

PubMed

Marchand-Libouban, Hélène; Guillaume, Bernard; Bellaiche, Norbert; Chappard, Daniel

2013-05-01

Bone implants are now widely used to replace missing teeth. Bone grafting (sinus lift) is a very useful way to increase the bone volume of the maxilla in patients with bone atrophy. There is a 6- to 9-month delay for the receiver grafted site to heal before the implants can be placed. Computed tomography is a useful method to measure the amount of remaining bone before implantation and to evaluate the quality of the receiver bone at the end of the healing period. Texture analysis is a non-invasive method useful to characterize bone microarchitecture on X-ray images. Ten patients in which a sinus lift surgery was necessary before implantation were analyzed in the present study. All had a bone reconstruction with a combination of a biomaterial (beta tricalcium phosphate) and autograft bone harvested at the chin. Computed tomographic images were obtained before grafting (t0), at mid-interval (t1, 4.2 ± 0.7 months) and before implant placement (t2, 9.2 ± 0.6 months). Texture analysis was done with the run-length method. A significant increase of texture parameters at t1 reflected a gain of homogeneity due to the graft and the beginning of bone remodeling. At t2, some parameters remained high and corresponded to the persistence of bone trabeculae while the resorption of biomaterials was identified by other parameters which tended to return to pregraft values. Texture analysis identified changes during the healing of the receiver site. The method is known to correlate with microarchitectural changes in bone and could be a useful approach to characterized osseointegrated grafts.

The connection between cellular mechanoregulation and tissue patterns during bone healing.

PubMed

Repp, Felix; Vetter, Andreas; Duda, Georg N; Weinkamer, Richard

2015-09-01

The formation of different tissues in the callus during secondary bone healing is at least partly influenced by mechanical stimuli. We use computer simulations to test the consequences of different hypotheses of the mechanoregulation at the cellular level on the patterns of tissues formed during healing. The computational study is based on an experiment on sheep, where after a tibial osteotomy, histological sections were harvested at different time points. In the simulations, we used a recently proposed basic phenomenological model, which allows ossification to occur either via endochondral or intramembranous ossification, but tries otherwise to employ a minimal number of simulation parameters. The model was extended to consider also the possibility of bone resorption and consequently allowing a description of the full healing progression till the restoration of the cortex. Specifically, we investigated how three changes in the mechanoregulation influence the resulting tissue patterns: (1) a time delay between stimulation of the cell and the formation of the tissue, (2) a variable mechanosensitivity of the cells, and (3) an independence of long time intervals of the soft tissue maturation from the mechanical stimulus. For all three scenarios, our simulations do not show qualitative differences in the time development of the tissue patterns. Largest differences were observed in the intermediate phases of healing in the amount and location of the cartilage. Interestingly, the course of healing was virtually unaltered in case of scenario (3) where tissue maturation proceeded independent of mechanical stimulation.

Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing: A Systematic Review of Research Quality.

PubMed

Marquez-Lara, Alejandro; Hutchinson, Ian D; Nuñez, Fiesky; Smith, Thomas L; Miller, Anna N

2016-03-15

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often avoided by orthopaedic surgeons because of their possible influence on bone-healing. This belief stems from multiple studies, in particular animal studies, that show delayed bone-healing or nonunions associated with NSAID exposure. The purpose of this review was to critically analyze the quality of published literature that evaluates the impact of NSAIDs on clinical bone-healing. A MEDLINE and Embase search was conducted to identify all articles relating to bone and fracture-healing and the utilization of NSAIDs. All human studies, including review articles, were identified for further analysis. Non-English-language manuscripts and in vitro and animal studies were excluded. A total of twelve clinical articles and twenty-four literature reviews were selected for analysis. The quality of the clinical studies was assessed with a modified Coleman Methodology Score with emphasis on the NSAID utilization. Review articles were analyzed with regard to variability in the cited literature and final conclusions. The mean modified Coleman Methodology Score (and standard deviation) was significantly lower (p = 0.032) in clinical studies that demonstrated a negative effect of NSAIDs on bone-healing (40.0 ± 14.3 points) compared with those that concluded that NSAIDs were safe (58.8 ± 10.3 points). Review articles also demonstrated substantial variability in the number of cited clinical studies and overall conclusions. There were only two meta-analyses and twenty-two narrative reviews. The mean number (and standard deviation) of clinical studies cited was significantly greater (p = 0.008) for reviews that concluded that NSAIDs were safe (8.0 ± 4.8) compared with those that recommended avoiding them (2.1 ± 2.1). Unanimously, all reviews admitted to the need for prospective randomized controlled trials to help clarify the effects of NSAIDs on bone-healing. This systematic literature review highlights the great variability in the interpretation of the literature addressing the impact of NSAIDs on bone-healing. Unfortunately, there is no consensus regarding the safety of NSAIDs following orthopaedic procedures, and future studies should aim for appropriate methodological designs to help to clarify existing discrepancies to improve the quality of care for orthopaedic patients. This systematic review highlights the limitations in the current understanding of the effects of NSAIDs on bone healing. Thus, withholding these medications does not have any proven scientific benefit to patients and may even cause harm by increasing narcotic requirements in cases in which they could be beneficial for pain management. This review should encourage further basic-science and clinical studies to clarify the risks and benefits of anti-inflammatory medications in the postoperative period, with the aim of improving patient outcomes.

Influence of low-level laser therapy on the healing process of autogenous bone block grafts in the jaws of systemically nicotine-modified rats: A histomorphometric study.

PubMed

de Almeida, Juliano Milanezi; de Moraes, Ricardo Oliveira; Gusman, David Jonathan Rodrigues; Faleiros, Paula Lazilha; Nagata, Maria José Hitomi; Garcia, Valdir Gouveia; Theodoro, Letícia Helena; Bosco, Alvaro Francisco

2017-03-01

To analyze the influence of low-level laser therapy (LLLT) on the bone healing process of autogenous bone block grafts installed in nicotine systemically modified rats. Seventy-two rats (Wistar) were randomly assigned into 4 groups (n=18). SS-BG: saline application+bone graft. SS-BG/LLLT: saline application+bone graft+LLLT. NIC-BG: nicotine application+bone graft. NIC-BG/LLLT: nicotine application+bone graft+LLLT. After 30days of application of solutions, all animals received autogenous bone block graft in the jaw, with the donation from the parietal bone's calvarial area. Treatment with LLLT was in bed-graft interface, after accommodation of the graft. The animals in each group were sacrificed at 7, 14, and 28days after graft surgery. The histologic analyses of NIC-BG group depicted a delay of osteogenic activity in the recipient bed-graft interface and the irradiation of tissue with LLLT provided better bone healing. The histometric analysis revealed that SS-BG/LLLT and NIC-BG/LLLT groups showed increased bone formation compared to BG-SS and NIC-BG groups, after 14days (SS-BG 24.94%±13.06% versus SS-BG/LLLT 27.53%±19.07% and NIC-BG 14.27%±2.22% versus NIC-BG/LLLT 24.37%±11.93%) and 28days (SS-BG 50.31%±2.69% versus SS-BG/LLLT 58 19%±12.32% and NIC-BG 36.89%±8.40% versus NIC-BG/LLLT 45.81%±6.03%). Nicotine harms bone formation in the bed-graft interface and LLLT action can mitigate this. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes.

PubMed

Hu, Diane P; Ferro, Federico; Yang, Frank; Taylor, Aaron J; Chang, Wenhan; Miclau, Theodore; Marcucio, Ralph S; Bahney, Chelsea S

2017-01-15

Fractures heal predominantly through the process of endochondral ossification. The classic model of endochondral ossification holds that chondrocytes mature to hypertrophy, undergo apoptosis and new bone forms by invading osteoprogenitors. However, recent data demonstrate that chondrocytes transdifferentiate to osteoblasts in the growth plate and during regeneration, yet the mechanism(s) regulating this process remain unknown. Here, we show a spatially-dependent phenotypic overlap between hypertrophic chondrocytes and osteoblasts at the chondro-osseous border in the fracture callus, in a region we define as the transition zone (TZ). Hypertrophic chondrocytes in the TZ activate expression of the pluripotency factors [Sox2, Oct4 (Pou5f1), Nanog], and conditional knock-out of Sox2 during fracture healing results in reduction of the fracture callus and a delay in conversion of cartilage to bone. The signal(s) triggering expression of the pluripotency genes are unknown, but we demonstrate that endothelial cell conditioned medium upregulates these genes in ex vivo fracture cultures, supporting histological evidence that transdifferentiation occurs adjacent to the vasculature. Elucidating the cellular and molecular mechanisms underlying fracture repair is important for understanding why some fractures fail to heal and for developing novel therapeutic interventions. © 2017. Published by The Company of Biologists Ltd.

Type 2 Diabetes and Metformin Influence on Fracture Healing in an Experimental Rat Model.

PubMed

La Fontaine, Javier; Chen, Chris; Hunt, Nathan; Jude, Edward; Lavery, Lawrence

2016-01-01

Persons with diabetes have a greater incidence of fractures compared with persons without diabetes. However, very little published information is available concerning the deleterious effect of late-stage diabetes on osseous structure and bone healing. The purpose of the present study was to evaluate the role of diabetes on fracture healing in a rat femur repair model. Thirty-six lean and diabetic Zucker rats were subdivided into 3 groups: (1) 12 lean rats as the control group; (2) 12 diabetic rats without blood glucose control (DM group); and (3) 12 diabetic rats treated with 300 mg/kg metformin to reduce the blood glucose levels (DM + Met group). Radiographs were taken every week to determine the incidence of bone repair and delayed union. All the rats were killed at 6 weeks after surgery. In both the sham-operated and the fractured and repaired femurs, significant decreases in the fracture-load/weight and marginal decreases in the fracture-load between the lean and DM groups were found. Metformin treatment significantly reduced the blood glucose and body weight 12 days postoperatively. Furthermore, a decrease in the fracture-load and fracture-load/weight in the repaired femurs was found in the DM + Met group. Diabetes impairs bone fracture healing. Metformin treatment reduces the blood glucose and body weight but had an adverse effect on fracture repair in diabetic rats. Further investigations are needed to reveal the mechanisms responsible for the effects of type 2 diabetes mellitus on bone and bone quality and the effect of medications such as metformin might have in diabetic bone in the presence of neuropathy and vascular disease. Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Alveolar bone healing process in spontaneously hypertensive rats (SHR). A radiographic densitometry study

PubMed Central

MANRIQUE, Natalia; PEREIRA, Cassiano Costa Silva; GARCIA, Lourdes Maria Gonzáles; MICARONI, Samuel; de CARVALHO, Antonio Augusto Ferreira; PERRI, Sílvia Helena Venturoli; OKAMOTO, Roberta; SUMIDA, Doris Hissako; ANTONIALI, Cristina

2012-01-01

Hypertension is one of the most important public health problems worldwide. If undiagnosed or untreated, this pathology represents a systemic risk factor and offers unfavorable conditions for dental treatments, especially those requiring bone healing. Objectives The purpose of this study was to demonstrate, by analysis of bone mineral density (BMD), that the alveolar bone healing process is altered in spontaneously hypertensive rats (SHRs). Material and Methods Wistar rats and SHRs were submitted to extraction of the upper right incisor and were euthanized 7, 14, 21, 28 and 42 days after surgery. Right maxillae were collected, radiographed and analyzed using Digora software. BMD was expressed as minimum (min), middle (med) and maximum (max) in the medium (MT) and apical (AT) thirds of the dental alveolus. Results The results were compared across days and groups. Wistar showed difference in med and max BMD in the MT between 7 and 28 and also between 14 and 28 days. The AT exhibited significant difference in med and min BMD between 7 and 28 days, as well as difference in min BMD between 28 and 42 days. SHRs showed lower med BMD in the MT at 28 days when compared to 21 and 42 days. Differences were observed across groups in med and min BMD at day 28 in the MT and AT; and in max BMD at 14, 21 and 42 days in the MT. Conclusions These results suggest that the alveolar bone healing process is delayed in SHRs comparing with Wistar rats. PMID:22666841

Treatment of type II and type III open tibia fractures in children.

PubMed

Bartlett, C S; Weiner, L S; Yang, E C

1997-07-01

To determine whether severe open tibial fractures in children behave like similar fractures in adults. A combined retrospective and prospective review evaluated treatment protocol for type II and type III open tibial fractures in children over a ten-year period from 1984 to 1993. Twenty-three fractures were studied in children aged 3.5 to 14.5 (18 boys and 5 girls). There were six type II, eight type IIIA, and nine type IIIB fractures. Type I fractures were not included. Seven fractures were comminuted with significant butterfly fragments or segmental patterns. Treatment consisted of adequate debridement of soft tissues, closure of dead space, and stabilization with external fixation. Bone debridement only included contaminated devitalized bone or devitalized bone without soft tissue coverage. Bone that could be covered despite periosteal stripping was preserved. Clinical and roentgenographic examinations were used to determine time to union. All fractures in this series healed between eight and twenty-six weeks. Wound coverage included two flaps, three skin grafts, and two delayed primary closures. No bone grafts were required. There were no deep infections, growth arrests, or malunions. Follow-up has ranged from six months to four years. Open tibia fractures in children differ from similar fractures in adults in the following ways: soft tissues have excellent healing capacity, devitalized bone that is not contaminated or exposed can be saved and will become incorporated, and external fixation can be maintained until the fracture has healed. Periosteum in young children can form bone even in the face of bone loss.

Local delivery of HMGB1 in gelatin sponge scaffolds combined with mesenchymal stem cell sheets to accelerate fracture healing.

PubMed

Xue, Deting; Zhang, Wei; Chen, Erman; Gao, Xiang; Liu, Ling; Ye, Chenyi; Tan, Yanbin; Pan, Zhijun; Li, Hang

2017-06-27

Fracture nonunion and delayed union continue to pose challenges for orthopedic surgeons. In the present study, we combined HMGB1 gelatin sponges with MSC sheets to promote bone healing after surgical treatment of rat tibial fractures. The HMGB1 gelatin sponge scaffolds supported the expansion of mesenchymal stem cells (MSCs) and promoted the osteogenic differentiation of MSCs and MSC sheets. Lentiviral vectors were then used to overexpress HMGB1 in MSCs. The results indicated that HMGB1 promotes the osteogenic differentiation of MSCs through the STAT3 pathway. Both siRNA and a STAT3 inhibitor downregulated STAT3, further confirming that HMGB1 induces the osteogenic differentiation of MSCs partly via the STAT3 signal pathway. In a rat tibial osteotomy model, we demonstrated the ability of HMGB1 gelatin sponge scaffolds to increase bone formation. The addition of MSC sheets further enhanced fracture healing. These findings support the use of HMGB1-loaded gelatin sponge scaffolds combined with MSC sheets to enhance fracture healing after surgical intervention.

Local delivery of HMGB1 in gelatin sponge scaffolds combined with mesenchymal stem cell sheets to accelerate fracture healing

PubMed Central

Xue, Deting; Zhang, Wei; Chen, Erman; Gao, Xiang; Liu, Ling; Ye, Chenyi; Tan, Yanbin; Pan, Zhijun; Li, Hang

2017-01-01

Fracture nonunion and delayed union continue to pose challenges for orthopedic surgeons. In the present study, we combined HMGB1 gelatin sponges with MSC sheets to promote bone healing after surgical treatment of rat tibial fractures. The HMGB1 gelatin sponge scaffolds supported the expansion of mesenchymal stem cells (MSCs) and promoted the osteogenic differentiation of MSCs and MSC sheets. Lentiviral vectors were then used to overexpress HMGB1 in MSCs. The results indicated that HMGB1 promotes the osteogenic differentiation of MSCs through the STAT3 pathway. Both siRNA and a STAT3 inhibitor downregulated STAT3, further confirming that HMGB1 induces the osteogenic differentiation of MSCs partly via the STAT3 signal pathway. In a rat tibial osteotomy model, we demonstrated the ability of HMGB1 gelatin sponge scaffolds to increase bone formation. The addition of MSC sheets further enhanced fracture healing. These findings support the use of HMGB1-loaded gelatin sponge scaffolds combined with MSC sheets to enhance fracture healing after surgical intervention. PMID:28431400

Delayed early passive motion is harmless to shoulder rotator cuff healing in a rabbit model.

PubMed

Zhang, Shurong; Li, Hong; Tao, Hongyue; Li, Hongyun; Cho, Samson; Hua, Yinghui; Chen, Jiwu; Chen, Shiyi; Li, Yunxia

2013-08-01

Postoperative passive motion is the most widely accepted rehabilitation protocol after rotator cuff repair; however, a rotator cuff retear remains a frequent surgical complication. Clinical outcomes indicate that early passive motion is harmless to rotator cuff healing, but no laboratory evidence supports this proposition. (1) Immediate postoperative immobilization improves rotator cuff healing in rabbits. (2) Early passive motion after short-term immobilization does not harm rotator cuff healing in rabbits. Controlled laboratory study. An injury to the supraspinatus tendon was created and repaired in 90 New Zealand White rabbits, after which they were randomly separated into 3 groups: (1) nonimmobilization (NI; n = 30), (2) continuous immobilization (IM; n = 30), and (3) immobilization with early passive motion (IP; n = 30). At 3, 6, and 12 weeks postoperatively, 5 rabbits from each group were sacrificed for histological evaluation, biomechanical testing, and magnetic resonance imaging. The histological study demonstrated better postoperative healing in the IM and IP groups, with clusters of chondrocytes accumulated at the tendon-bone junction. Magnetic resonance imaging illustrated that the tendon-bone junction was intact in the IM and IP groups. The magnetic resonance quantification analysis showed that the signal-to-noise quotient (SNQ) of the NI group was not significantly higher than that of the immobilization groups at 3 weeks (P = .232) or 6 weeks (P = .117), but it was significantly different at 12 weeks (NI vs IM, P = .006; NI vs IP, P = .009). At 12 weeks, the failure load was significantly higher in the IM and IP groups than in the NI group (NI vs IM, P = .002; NI vs IP, P = .002), but no difference was found between the IM and IP groups (P = .599). Immediate postoperative immobilization led to better tendon-bone healing than immediate postoperative mobilization, and under immobilization, early passive motion was harmless to tendon-bone healing in this study. The results have an implication in supporting the rehabilitation protocol of early passive motion after rotator cuff repair.

Reduced COX-2 expression in aged mice is associated with impaired fracture healing.

PubMed

Naik, Amish A; Xie, Chao; Zuscik, Michael J; Kingsley, Paul; Schwarz, Edward M; Awad, Hani; Guldberg, Robert; Drissi, Hicham; Puzas, J Edward; Boyce, Brendan; Zhang, Xinping; O'Keefe, Regis J

2009-02-01

The cellular and molecular events responsible for reduced fracture healing with aging are unknown. Cyclooxygenase 2 (COX-2), the inducible regulator of prostaglandin E(2) (PGE(2)) synthesis, is critical for normal bone repair. A femoral fracture repair model was used in mice at either 7-9 or 52-56 wk of age, and healing was evaluated by imaging, histology, and gene expression studies. Aging was associated with a decreased rate of chondrogenesis, decreased bone formation, reduced callus vascularization, delayed remodeling, and altered expression of genes involved in repair and remodeling. COX-2 expression in young mice peaked at 5 days, coinciding with the transition of mesenchymal progenitors to cartilage and the onset of expression of early cartilage markers. In situ hybridization and immunohistochemistry showed that COX-2 is expressed primarily in early cartilage precursors that co-express col-2. COX-2 expression was reduced by 75% and 65% in fractures from aged mice compared with young mice on days 5 and 7, respectively. Local administration of an EP4 agonist to the fracture repair site in aged mice enhanced the rate of chondrogenesis and bone formation to levels observed in young mice, suggesting that the expression of COX-2 during the early inflammatory phase of repair regulates critical subsequent events including chondrogenesis, bone formation, and remodeling. The findings suggest that COX-2/EP4 agonists may compensate for deficient molecular signals that result in the reduced fracture healing associated with aging.

Effects of Untreated Periodontitis on Osseointegration of Dental Implants in a Beagle Dog Model.

PubMed

Lee, Daehyun; Sohn, Byungjin; Kim, Kyoung Hwa; Kim, Sungtae; Koo, Ki-Tae; Kim, Tae-Il; Seol, Yang-Jo; Lee, Yong-Moo; Rhyu, In-Chul; Ku, Young

2016-10-01

There have been previous studies on the relationship between periodontitis and peri-implantitis, but limited information is available on how periodontitis affects osseointegration and wound healing of newly placed dental implants adjacent to natural teeth. The objective of the present experiment is to evaluate healing around dental implants adjacent to teeth with untreated experimental periodontitis. The study included six male beagle dogs. Scaling and plaque control procedures were performed on three dogs (control group). In the other three dogs (experimental group), retraction cords and ligature wires were placed subgingivally around all premolars and the first molars. Induced experimental periodontitis was confirmed after 3 months. Each control or experimental group was divided into two subgroups depending on the timing of implant placement (immediate/delayed). Twelve dental implants (two implants for each dog) were placed immediately, and the other 12 dental implants (two implants for each dog) were placed 2 months after extraction. The animals were sacrificed 2 months after implant placement. Histologic and histometric analyses were performed. Four implants (three from the immediate placement group and one from the delayed placement group) failed in the experimental group. There were significant differences in the percentage of bone-to-implant contact and marginal bone volume density between the control and experimental groups. Both parameters were significantly lower in the experimental group than in the control group (P <0.05). There was a tendency toward more marginal bone loss in the experimental group than the control group. Immediate placement of implants is associated with a higher failure rate compared with delayed placement. Untreated experimental periodontitis was correlated with compromised osseointegration in the implants with delayed placement.

Recurrent Proximal Femur Fractures in a Teenager With Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating?

PubMed

Vasanwala, Rashida F; Sanghrajka, Anish; Bishop, Nicholas J; Högler, Wolfgang

2016-07-01

Long-term bisphosphonate (BP) therapy in adults with osteoporosis is associated with atypical femoral fractures, caused by increased material bone density and prolonged suppression of bone remodeling which may reduce fracture toughness. In children with osteogenesis imperfecta (OI), long-term intravenous BP therapy improves bone structure and mass without further increasing the already hypermineralized bone matrix, and is generally regarded as safe. Here we report a teenage girl with OI type IV, who was started on cyclical intravenous pamidronate therapy at age 6 years because of recurrent fractures. Transiliac bone biopsy revealed classical structural features of OI but unusually low bone resorption surfaces. She made substantial improvements in functional ability, bone mass, and fracture rate. However, after 5 years of pamidronate therapy she started to develop recurrent, bilateral, nontraumatic, and proximal femur fractures, which satisfied the case definition for atypical femur fractures. Some fractures were preceded by periosteal reactions and prodromal pain. Pamidronate was discontinued after 7 years of therapy, following which she sustained two further nontraumatic femur fractures, and continued to show delayed tibial osteotomy healing. Despite rodding surgery, and very much in contrast to her affected, untreated, and normally mobile mother, she remains wheelchair-dependent. The case of this girl raises questions about the long-term safety of BP therapy in some children, in particular about the risk of oversuppressed bone remodeling with the potential for microcrack accumulation, delayed healing, and increased stiffness. The principal concern is whether there is point at which benefit from BP therapy could turn into harm, where fracture risk increases again. This case should stimulate debate whether current adult atypical femoral fracture guidance should apply to children, and whether low-frequency, low-dose cyclical, intermittent, or oral treatment maintenance regimens should be considered on a case-by-case basis. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

Opioids delay healing of spinal fusion: a rabbit posterolateral lumbar fusion model.

PubMed

Jain, Nikhil; Himed, Khaled; Toth, Jeffrey M; Briley, Karen C; Phillips, Frank M; Khan, Safdar N

2018-04-19

Opioid use is prevalent for management of pre- and post-operative pain in patients undergoing spinal fusion. There is evidence that opioids downregulate osteoblasts in-vitro, and one previous study found that morphine delays the maturation and remodeling of callus in a rat femur fracture model. However, the effect of opioids on healing of spinal fusion has not been investigated before. Isolating the effect of opioid exposure in humans would be limited by the numerous confounding factors that affect fusion healing. Therefore, we have used a well-established rabbit model to study the process of spinal fusion healing that closely mimics humans. To study the effect of systemic opioids on the process of healing of spinal fusion in a rabbit posterolateral spinal fusion model. Pre-clinical animal study. 24 adult New Zealand white rabbits were studied in two groups after approval from the Institutional Animal Care and Use Committee (IACUC). The opioid group (n=12) received four-weeks pre-operative and six-weeks post-operative transdermal fentanyl. Serum fentanyl levels were measured just before surgery and four-weeks post-operatively to ensure adequate levels. The control group (n=12) received only peri-operative pain control as necessary. All animals received a bilateral L5-L6 posterolateral spinal fusion using iliac crest autograft. Animals were euthanized at the six-week post-operative time point, and assessment of fusion was done by manual palpation, plain radiographs, micro-computed tomography (microCT), and histology. 12 animals in control group and 11 animals in the opioid group were available for analysis at the end of six weeks. The fusion scores on manual palpation, radiographs, and microCT were not statistically different. Three-dimensional microCT morphometry found that the fusion mass in the opioid group had a lower bone volume (p=0.09), lower trabecular number (p=0.02) and higher trabecular separation (p=0.02) as compared to control. Histological analysis found areas of incorporation of autograft, and unincorporated graft fragments in both groups. In the control group, there was remodeling of de-novo woven bone to lamellar organization with incorporation of osteocytes, formation of mature marrow, and relative paucity of hypertrophied osteoblasts lining new bone. Sections from the opioid group showed formation of de-novo woven bone, and hypertrophied osteoblasts seen lining the new bone. There were no sections showing lamellar organization and development of mature marrow elements in the opioid group. Less dense trabeculae on microCT correlated with histological findings of relatively immature fusion mass in the opioid group. Systemic opioids led to an inferior quality fusion mass with delay in maturation and remodeling at six-weeks in this rabbit spinal fusion model. These preliminary results lay foundation for further research to investigate underlying cellular mechanisms, temporal fusion process, and dose-duration relationship of opioids responsible for our findings. Copyright © 2018 Elsevier Inc. All rights reserved.

[Comparative study on graft of autogeneic iliac bone and tissue engineered bone].

PubMed

Shen, Bing; Xie, Fu-lin; Xie, Qing-fang

2002-11-01

To compare the clinical results of repairing bone defect of limbs with tissue engineering technique and with autogeneic iliac bone graft. From July 1999 to September 2001, 52 cases of bone fracture were randomly divided into two groups (group A and B). Open reduction and internal fixation were performed in all cases as routine operation technique. Autogeneic iliac bone was implanted in group A, while tissue engineered bone was implanted in group B. Routine postoperative treatment in orthopedic surgery was taken. The operation time, bleeding volume, wound healing and drainage volume were compared. The bone union was observed by the X-ray 1, 2, 3, and 5 months after operation. The sex, age and disease type had no obvious difference between groups A and B. all the wounds healed with first intention. The swelling degree of wound and drainage volume had no obvious difference. The operation time in group A was longer than that in group B (25 minutes on average) and bleeding volume in group A was larger than that in group B (150 ml on average). Bone union completed within 3 to 7 months in both groups. But there were 2 cases of delayed union in group A and 1 case in group B. Repair of bone defect with tissue engineered bone has as good clinical results as that with autogeneic iliac bone graft. In aspect of operation time and bleeding volume, tissue engineered bone graft is superior to autogeneic iliac bone.

Correlation between RUST assessments of fracture healing to structural and biomechanical properties.

PubMed

Cooke, Margaret E; Hussein, Amira I; Lybrand, Kyle E; Wulff, Alexander; Simmons, Erin; Choi, Jeffrey H; Litrenta, Jody; Ricci, William M; Nascone, Jason W; O'Toole, Robert V; Morgan, Elise F; Gerstenfeld, Louis C; Tornetta, Paul

2018-03-01

Radiographic Union Score for Tibia (RUST) and modified RUST (mRUST) are radiographic tools for quantitatively evaluating fracture healing using a cortical scoring system. This tool has high intra-class correlation coefficients (ICCs); however, little evidence has evaluated the scores against the physical properties of bone healing. Closed, stabilized fractures were made in the femora of C3H/HeJ male mice (8-12 week-old) of two dietary groups: A control and a phosphate restricted diet group. Micro-computed tomography (µCT) and torsion testing were carried out at post-operative days (POD) 14, 21, 35, and 42 (n = 10-16) per group time-point. Anteroposterior and lateral radiographic views were constructed from the µCT scans and scored by five raters. The raters also indicated if the fracture were healed. ICCs were 0.71 (mRUST) and 0.63 (RUST). Both RUST scores were positively correlated with callus bone mineral density (BMD) (r = 0.85 and 0.80, p < 0.001) and bone volume fraction (BV/TV) (r = 0.86 and 0.80, p < 0.001). Both RUST scores positively correlated with callus strength (r = 0.35 and 0.26, p < 0.012) and rigidity (r = 0.50 and 0.39, p < 0.001). Radiographically healed calluses had a mRUST ≥13 and a RUST ≥10 and had excellent relationship to structural and biomechanical metrics. Effect of delayed healing due to phosphate dietary restrictions was found at later time points with all mechanical properties (p < 0.011), however no differences found in the RUST scores (p > 0.318). Clinical relevance of this study is both RUST scores showed high correlation to physical properties of healing and generally distinguished healed vs. non-healed fractures. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:945-953, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Novel Therapy for Bone Regeneration in Large Segmental Defects

DTIC Science & Technology

2016-10-01

reamed and nonreamed intrame- dullary nailing on fracture healing. Clin Orthop Relat Res. 1998;355(Suppl):S230–8. 37. Pape HC, Giannoudis PV. Fat embolism ...extension period (Year 4). 15. SUBJECT TERMS Bone healing, bone morphogenetic protein (BMP), thrombopoietin (TPO), therapy, fracture healing, bone...Bone healing, bone morphogenetic protein (BMP), thrombopoietin (TPO), therapy, fracture healing, bone regeneration, minipig, pig 3. OVERALL PROJECT

Biomechanical assessment of composite versus metallic intramedullary nailing system in femoral shaft fractures: A finite element study.

PubMed

Samiezadeh, Saeid; Tavakkoli Avval, Pouria; Fawaz, Zouheir; Bougherara, Habiba

2014-08-01

Intramedullary nails are the primary choice for treating long bone fractures. However, complications following nail surgery including non-union, delayed union, and fracture of the bone or the implant still exist. Reducing nail stiffness while still maintaining sufficient stability seems to be the ideal solution to overcome the abovementioned complications. In this study, a new hybrid concept for nails made of carbon fibers/flax/epoxy was developed in order to reduce stress shielding. The mechanical performance of this new implant in terms of fracture stability and load sharing was assessed using a comprehensive non-linear FE model. This model considers several mechanical factors in nine fracture configurations at immediately post-operative, and in the healed bone stages. Post-operative results showed that the hybrid composite nail increases the average normal force at the fracture site by 319.23N (P<0.05), and the mean stress in the vicinity of fracture by 2.11MPa (P<0.05) at 45% gait cycle, while only 0.33mm and 0.39mm (P<0.05) increases in the fracture opening and the fragments' shear movement were observed. The healed bone results revealed that implantation of the titanium nail caused 20.2% reduction in bone stiffness, while the composite nail lowered the stiffness by 11.8% as compared to an intact femur. Our results suggest that the composite nail can provide a preferred mechanical environment for healing, particularly in transverse shaft fractures. This may help bioengineers better understand the biomechanics of fracture healing, and aid in the design of effective implants. Copyright © 2014. Published by Elsevier Ltd.

* Calvarial Bone Regeneration Is Enhanced by Sequential Delivery of FGF-2 and BMP-2 from Layer-by-Layer Coatings with a Biomimetic Calcium Phosphate Barrier Layer.

PubMed

Gronowicz, Gloria; Jacobs, Emily; Peng, Tao; Zhu, Li; Hurley, Marja; Kuhn, Liisa T

2017-12-01

A drug delivery coating for synthetic bone grafts has been developed to provide sequential delivery of multiple osteoinductive factors to better mimic aspects of the natural regenerative process. The coating is composed of a biomimetic calcium phosphate (bCaP) layer that is applied to a synthetic bone graft and then covered with a poly-l-Lysine/poly-l-Glutamic acid polyelectrolyte multilayer (PEM) film. Bone morphogenetic protein-2 (BMP-2) was applied before the coating process directly on the synthetic bone graft and then, bCaP-PEM was deposited followed by adsorption of fibroblast growth factor-2 (FGF-2) into the PEM layer. Cells access the FGF-2 immediately, while the bCaP-PEM temporally delays the cell access to BMP-2. In vitro studies with cells derived from mouse calvarial bones demonstrated that Sca-1 and CD-166 positive osteoblast progenitor cells proliferated in response to media dosing with FGF-2. Coated scaffolds with BMP-2 and FGF-2 were implanted in mouse calvarial bone defects and harvested at 1 and 3 weeks. After 1 week in vivo, proliferation of cells, including Sca-1+ progenitors, was observed with low dose FGF-2 and BMP-2 compared to BMP-2 alone, indicating that in vivo delivery of FGF-2 activated a similar population of cells as shown by in vitro testing. At 3 weeks, FGF-2 and BMP-2 delivery increased bone formation more than BMP-2 alone, particularly in the center of the defect, confirming that the proliferation of the Sca-1 positive osteoprogenitors by FGF-2 was associated with increased bone healing. Areas of bone mineralization were positive for double fluorochrome labeling of calcium and alkaline phosphatase staining of osteoblasts, along with increased TRAP+ osteoclasts, demonstrating active bone formation distinct from the bone-like collagen/hydroxyapatite scaffold. In conclusion, the addition of a bCaP layer to PEM delayed access to BMP-2 and allowed the FGF-2 stimulated progenitors to populate the scaffold before differentiating in response to BMP-2, leading to improved bone defect healing.

In vivo systemic chlorogenic acid therapy under diabetic conditions: Wound healing effects and cytotoxicity/genotoxicity profile.

PubMed

Bagdas, Deniz; Etoz, Betul Cam; Gul, Zulfiye; Ziyanok, Sedef; Inan, Sevda; Turacozen, Ozge; Gul, Nihal Yasar; Topal, Ayse; Cinkilic, Nilufer; Tas, Sibel; Ozyigit, Musa Ozgur; Gurun, Mine Sibel

2015-07-01

Oxidative stress occurs following the impairment of pro-oxidant/antioxidant balance in chronic wounds and leads to harmful delays in healing progress. A fine balance between oxidative stress and endogenous antioxidant defense system may be beneficial for wound healing under redox control. This study tested the hypothesis that oxidative stress in wound area can be controlled with systemic antioxidant therapy and therefore wound healing can be accelerated. We used chlorogenic acid (CGA), a dietary antioxidant, in experimental diabetic wounds that are characterized by delayed healing. Additionally, we aimed to understand possible side effects of CGA on pivotal organs and bone marrow during therapy. Wounds were created on backs of streptozotocin-induced diabetic rats. CGA (50 mg/kg/day) was injected intraperitoneally. Animals were sacrificed on different days. Biochemical and histopathological examinations were performed. Side effects of chronic antioxidant treatment were tested. CGA accelerated wound healing, enhanced hydroxyproline content, decreased malondialdehyde/nitric oxide levels, elevated reduced-glutathione, and did not affect superoxide dismutase/catalase levels in wound bed. While CGA induced side effects such as cyto/genotoxicity, 15 days of treatment attenuated blood glucose levels. CGA decreased lipid peroxidation levels of main organs. This study provides a better understanding for antioxidant intake on diabetic wound repair and possible pro-oxidative effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Histologic and histomorphometric evaluation of peri-implant bone of immediate or delayed occlusal-loaded non-splinted implants in the posterior mandible--an experimental study in monkeys.

PubMed

Stokholm, Rie; Isidor, Flemming; Nyengaard, Jens R

2014-11-01

The primary aim of this study was to compare the bone reaction around immediate-loaded non-splinted single implants vs. delayed loaded non-splinted single implants placed in healed ridges in the posterior mandible. Six adult Macaca Fascicularis monkeys were used in this study. The first and second premolars and the first molar were extracted in both sides of the mandible. After 3 months of healing, four implants (Replace Select Tapered; Nobel Biocare, Gothenburg, Sweden) with a moderately rough surface (TiUnite, Nobel Biocare) were placed in the edentulous areas of each monkey, two in each side. The implants had a length of 10 mm and a diameter of 3.5 mm. Four groups of varying time and occlusal loading aspects were created: (i) control group: implant placed non-loaded for 3 months; (ii) immediate loaded: implant placed and loaded immediately for 3 months; (iii) immediate loaded: implant placed and loaded immediately for 6 months; and (iv) delayed loaded: implant placed submerged for 3 months and then loaded for 3 months. At the loaded implants, after a second stage surgery, a composite crown was made directly on an abutment mounted on the implant reinsuring simultaneous occlusal contact on the implant crown and the neighboring teeth. After euthanization of the animals, histologic specimens were quantified in the light microscope. All implants were clinically, radiographically, and histologically osseointegrated at the time of euthanization and with only mild signs of inflammation in the peri-implant mucosa. The histologic marginal bone level was located on average 1.14-1.74 mm apical to the margin of the implants in the various groups. The average bone-to-implant contact (BIC) varied between 55% and 65% and the average bone density (i.e., the proportion of mineralized bone tissue from the implant surface and to a distance of 1 mm lateral to the implant) varied between 30.6% and 34.2%. No statistical significant differences between groups were observed in the above-stated histomorphometric parameters. Similar histologic and histomorphometric findings were observed in immediately and delayed loaded non-splinted implants placed in the posterior mandible of macaque monkeys. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Development of controlled drug delivery systems for bone fracture-targeted therapeutic delivery: A review.

PubMed

Wang, Yuchen; Newman, Maureen R; Benoit, Danielle S W

2018-06-01

Impaired fracture healing is a major clinical problem that can lead to patient disability, prolonged hospitalization, and significant financial burden. Although the majority of fractures heal using standard clinical practices, approximately 10% suffer from delayed unions or non-unions. A wide range of factors contribute to the risk for nonunions including internal factors, such as patient age, gender, and comorbidities, and external factors, such as the location and extent of injury. Current clinical approaches to treat nonunions include bone grafts and low-intensity pulsed ultrasound (LIPUS), which realizes clinical success only to select patients due to limitations including donor morbidities (grafts) and necessity of fracture reduction (LIPUS), respectively. To date, therapeutic approaches for bone regeneration rely heavily on protein-based growth factors such as INFUSE, an FDA-approved scaffold for delivery of bone morphogenetic protein 2 (BMP-2). Small molecule modulators and RNAi therapeutics are under development to circumvent challenges associated with traditional growth factors. While preclinical studies has shown promise, drug delivery has become a major hurdle stalling clinical translation. Therefore, this review overviews current therapies employed to stimulate fracture healing pre-clinically and clinically, including a focus on drug delivery systems for growth factors, parathyroid hormone (PTH), small molecules, and RNAi therapeutics, as well as recent advances and future promise of fracture-targeted drug delivery. Copyright © 2018 Elsevier B.V. All rights reserved.

Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice

PubMed Central

McGee-Lawrence, Meghan E.; Carpio, Lomeli R.; Bradley, Elizabeth W.; Dudakovic, Amel; Lian, Jane B.; van Wijnen, Andre J.; Kakar, Sanjeev; Hsu, Wei; Westendorf, Jennifer J.

2014-01-01

Runx2 and Axin2 regulate skeletal development. We recently determined that Axin2 and Runx2 molecularly interact in differentiating osteoblasts to regulate intramembranous bone formation, but the relationship between these factors in endochondral bone formation was unresolved. To address this, we examined the effects of Axin2 deficiency on the cleidocranial dysplasia (CCD) phenotype of Runx2+/− mice, focusing on skeletal defects attributed to improper endochondral bone formation. Axin2 deficiency unexpectedly exacerbated calvarial components of the CCD phenotype in the Runx2+/− mice; the endocranial layer of the frontal suture, which develops by endochondral bone formation, failed to mineralize in the Axin2−/−:Runx2+/− mice, resulting in a cartilaginous, fibrotic and larger fontanel than observed in Runx2+/− mice. Transcripts associated with cartilage development (e.g., Acan, miR140) were expressed at higher levels, whereas blood vessel morphogenesis transcripts (e.g., Slit2) were suppressed in Axin2−/−:Runx2+/− calvaria. Cartilage maturation was impaired, as primary chondrocytes from double mutant mice demonstrated delayed differentiation and produced less calcified matrix in vitro. The genetic dominance of Runx2 was also reflected during endochondral fracture repair, as both Runx2+/− and double mutant Axin2−/−:Runx2+/− mice had enlarged fracture calluses at early stages of healing. However, by the end stages of fracture healing, double mutant animals diverged from the Runx2+/− mice, showing smaller calluses and increased torsional strength indicative of more rapid end stage bone formation as seen in the Axin2−/− mice. Taken together, our data demonstrate a dominant role for Runx2 in chondrocyte maturation, but implicate Axin2 as an important modulator of the terminal stages of endochondral bone formation. PMID:24973690

Limb reconstruction with vascularized fibular grafts after bone tumor resection.

PubMed

Brown, K L

1991-01-01

Limb-salvage operations are being used with increasing frequency for patients with malignant bone tumors. For children, when a biologic reconstruction is desired, the choice is often between conventional and vascularized fibular grafts. An experimental study was performed in dogs to compare the two types of fibular grafts for bridging segmental defects in the radius and ulna. Twenty-six adult dogs were divided into two groups and studied at intervals of two, three, four, six, and 12 months after transplantation. The conventional grafts healed by creeping substitution i.e., they were first partially resorbed before new bone was laid down. In contrast, the vascularized fibulae maintained their normal structure and hypertrophied by subperiosteal new bone formation. The conventional fibulae eventually hypertrophied but much later than the vascularized grafts. The vascularized grafts were stronger at four and six months. Between six and 12 months, both grafts remodeled to resemble the size and shape of the forearm bones they were replacing. These experimental results have influenced the treatment of patients. Vascularized fibular grafts are ideal for diaphyseal defects greater than 10 cm long, especially in very young children, a poorly vascularized bed, or when bone healing is delayed by chemotherapeutic agents. To maximize hypertrophy, an external fixator is used to immobilize the graft rather than a plate, which acts as a stress shield.

Can Time of Implant Placement influence Bone Remodeling?

PubMed

Rafael, Caroline F; Passoni, Bernardo; Araúio, Carlos; de Araúio, Maria A; Benfatti, César; Volpato, Claudia

2016-04-01

Since the alveolar process is tissue "dental dependent," after the extraction of the dental element, this process suffers some degree of atrophy during the healing process, which can be reduced with the installation of immediate implants, aiming to maintain the original bone architecture. The aim of this study was to investigate the influence of the time of implant placement on bone formation around them. Seven dogs were selected and randomly divided into two groups: Group 1, where implants were placed immediately after extraction of two lower premolars without flap elevation, and group 2, where implants were delayed by 4 months after extractions. Each group received 14 implants, and 4 months after the second surgery, the samples were processed and analyzed histomorphometrically. A mean average analysis and the Kruskal-Wallis test (p < 0.05) were performed. The buccal bone-implant contact (BIC) mean average was found larger in immediate implants (42.61%) compared with delayed implants (37.69%). Group 1 had statistically higher outcomes in bone formation and BIC on the buccal bone wall. It was concluded that performing immediate implants with the palatal approach technique and leaving a buccal GAP enables a higher or at least equal rate to BIC and bone area around them, when compared with delayed implants. Actually, the patients and dentists want to do a shorter treatment with satisfactory results, but it is necessary to understand whether different times of implant placement can influence the results and longevity of the treatment.

Bone healing in children.

PubMed

Lindaman, L M

2001-01-01

Just as pediatric fractures and bones are basically similar to adult fractures and bones, pediatric bone healing is basically similar to adult bone healing. They both go through the three same phases of inflammation, reparation, and remodeling. It is those differences between pediatric and adult bone, however, that affect the differences in the healing of pediatric bone. Because pediatric bone can fail in compression, less initial stability and less callus formation is required to achieve a clinically stable or healed fracture. The greater subperiosteal hematoma and the stronger periosteum all contribute to a more rapid formation of callous strong enough to render the fracture healed more rapidly than the adult. Genes and hormones that are necessary for the initial formation of the skeleton are the same as, or at least similar in most instances, to those necessary for the healing of fractures. This osteogenic environment of the pediatric bone means that these fracture healing processes are already ongoing in the child at the time of the fracture. In the adult, these factors must be reawakened, leading to the slower healing time in the adult. Once the fracture is healed, the still-growing pediatric bone can correct any "sins" of fracture alignment or angulation leaving the bone with no signs of having ever been broken. The final result is bone that is, in the child's words, "as good as new."

Do estrogen and alendronate improve metaphyseal fracture healing when applied as osteoporosis prophylaxis?

PubMed

Kolios, Leila; Hoerster, Ann Kristin; Sehmisch, Stephan; Malcherek, Marie Christin; Rack, Thomas; Tezval, Mohammed; Seidlova-Wuttke, Dana; Wuttke, Wolfgang; Stuermer, Klaus Michael; Stuermer, Ewa Klara

2010-01-01

Osteoporosis is accompanied by predominantly metaphyseal fractures with a delayed and qualitatively reduced healing process. This study addressed the question of whether fracture healing in the context of osteoporosis prophylaxis is improved with estrogen (E) or alendronate (ALN). Thirty-six ovariectomized and 12 sham-operated 12-week-old rats received soy-free (osteoporotic C, sham), E-, or ALN- supplemented diets. After 10 weeks, a metaphyseal tibia osteotomy and standardized T-plate fixation were performed. After a 5-week healing process, the fracture callus was evaluated qualitatively by biomechanical bending test and quantitatively in microradiographic sections. The time course of callus formation was examined using fluorochrome-labeled histological sections. Administration of E improved the biomechanical properties of callus (stiffness [N/mm]: sham: 110.2 + or - 76.07, C: 41.28 + or - 33.70, E: 85.72 + or - 47.24, ALN: 72.07 + or - 34.68). The resistance to microfracturing seen in E-treated animals was significantly enhanced and even superior to sham (yield load [N] sham: 27.44 + or - 9.72, C: 21.04 + or - 12.47, E: 42.85 + or - 13.74(Delta), ALN: 25.28 + or - 6.4(.)) (* P < 0.05 vs. sham group, (Delta) P < 0.05 vs. C group, (*) P < 0.05 vs. E group). Trabecular bone in particular was improved, indicating the presence of physiological endosteal bridging (Tr.Dn [%] sham: 10.53 + or - 18.9, C: 1.01 + or - 0.14, E: 24.13 + or - 34.09(Delta), ALN: 3.99 + or - 8.3(.)). ALN did not help bone healing, as shown by mechanical tests. Compared to the C group, statistically, ALN did not show worse properties. The induction of callus formation under ALN treatment was slightly delayed (Tt.Cl [mm(2)] sham: 3.68 + or - 0.66, C: 3.44 + or - 0.42, E: 3.69 + or - 0.58, ALN: 3.06 + or - 0.56). Osteoporotic metaphyseal fracture healing was qualitatively and quantitatively improved by E prophylaxis. The process of fracture healing occurred nearly physiologically (shamlike). Notably, ALN hardly improved metaphyseal callus properties when assessed as osteoporosis prophylaxis, but to a lesser extent than E.

A Pronounced Inflammatory Activity Characterizes the Early Fracture Healing Phase in Immunologically Restricted Patients

PubMed Central

Hoff, Paula; Gaber, Timo; Strehl, Cindy; Jakstadt, Manuela; Hoff, Holger; Schmidt-Bleek, Katharina; Lang, Annemarie; Röhner, Eric; Huscher, Dörte; Matziolis, Georg; Burmester, Gerd-Rüdiger; Schmidmaier, Gerhard; Perka, Carsten; Duda, Georg N.; Buttgereit, Frank

2017-01-01

Immunologically restricted patients such as those with autoimmune diseases or malignancies often suffer from delayed or insufficient fracture healing. In human fracture hematomas and the surrounding bone marrow obtained from immunologically restricted patients, we analyzed the initial inflammatory phase on cellular and humoral level via flow cytometry and multiplex suspension array. Compared with controls, we demonstrated higher numbers of immune cells like monocytes/macrophages, natural killer T (NKT) cells, and activated T helper cells within the fracture hematomas and/or the surrounding bone marrow. Also, several pro-inflammatory cytokines such as Interleukin (IL)-6 and Tumor necrosis factor α (TNFα), chemokines (e.g., Eotaxin and RANTES), pro-angiogenic factors (e.g., IL-8 and Macrophage migration inhibitory factor: MIF), and regulatory cytokines (e.g., IL-10) were found at higher levels within the fracture hematomas and/or the surrounding bone marrow of immunologically restricted patients when compared to controls. We conclude here that the inflammatory activity on cellular and humoral levels at fracture sites of immunologically restricted patients considerably exceeds that of control patients. The initial inflammatory phase profoundly differs between these patient groups and is probably one of the reasons for prolonged or insufficient fracture healing often occurring within immunologically restricted patients. PMID:28282868

Three-phase bone scan in osteomyelitis and other musculoskeletal disorders.

PubMed

Sutter, C W; Shelton, D K

1996-10-01

The three-phase bone scan is very sensitive and is the study of choice in the evaluation of patients with suspected osteomyelitis and normal radiographs. If the underlying bone pathology, such as a healing fracture or degenerative disease, is detected on radiographs of the bone, the indium-111-labeled autologous leukocyte scan is the most cost-effective second study. When fracture of the long bones is clinically suspected but radiographs are normal and a delay in definitive diagnosis is acceptable, it is practical and economical to take follow-up films in 10 to 14 days. In cases requiring prompt diagnosis or when follow-up radiographic films are not diagnostic, the three-phase bone scan is the most cost-effective study. The three-phase bone scan is also used in the evaluation of occupational and sports injuries, including shin splints, stress and occult fractures, enthesiopathies and reflex sympathetic dystrophy.

Two-stage distraction lengthening of the forearm.

PubMed

Taghinia, Amir H; Al-Sheikh, Ayman A; Panossian, Andre E; Upton, Joseph

2013-01-01

Single-stage lengthening of the forearm using callus distraction is well described; however, forearm lengthening using a 2-stage technique of distraction followed by bone grafting has received less attention. A 2-staged technique can be a better alternative in cases where the surgeon desires extensive lengthening. A retrospective review was undertaken of eleven 2-stage forearm lengthening procedures performed by 1 surgeon over a 15-year period. Indications were radial longitudinal deficiency (8 patients), neonatal ischemic contractures (2 patients), and septic growth arrest (1 patient). Average follow-up was 2.8 years. Distraction was performed on patients an average of 82 mm over an average duration of 24 weeks. Average time to union from the time of distractor removal and grafting was 87 days. Average healing index was 32.1 d/cm. Distraction problems were common and related to the length of time that the distractor was in place; they included pain, pin-related infections, and multiple mechanical device difficulties. Three patients had nonunion, and another had delayed union; however, additional procedures resulted in ultimate bony union in all patients. Demineralized bone matrix and autologous corticocancellous bone grafts yielded predictable healing and good functional results in short-distance distractions. For longer distractions, free vascularized fibula transfer produced the best outcomes. Intercalary cortical allografts did not heal well. Patients with neonatal Volkmann contractures had the most difficulty with distraction and healing, ultimately obtaining little to no lengthening and poor functional outcomes.

Novel Therapy for Bone Regeneration in Large Segmental Defects

DTIC Science & Technology

2017-12-01

healing. Clin Orthop Relat Res. 1998;355(Suppl):S230–8. 37. Pape HC, Giannoudis PV. Fat embolism and IM nailing. Injury. 2006;37(Suppl 4):S1–2. 38. Wenda...mechanisms to elicit bone healing. 15. SUBJECT TERMS Bone healing, bone morphogenetic protein (BMP), thrombopoietin (TPO), therapy, fracture healing...thrombopoietin (TPO), therapy, fracture healing, bone regeneration, minipig, pig 3. OVERALL PROJECT SUMMARY: Project start date 30/09/2013 Project end

Immediate implant placement into fresh extraction sockets versus delayed implants into healed sockets: A systematic review and meta-analysis.

PubMed

Mello, C C; Lemos, C A A; Verri, F R; Dos Santos, D M; Goiato, M C; Pellizzer, E P

2017-09-01

The aim of this systematic review and meta-analysis was to compare the survival rate of the implants and the peri-implant tissue changes associated with implants inserted in fresh extraction sockets and those inserted in healed sockets. This review has been registered at PROSPERO under the number CRD42016043309. A systematic search was conducted by two reviewers independently in the databases PubMed/MEDLINE, Embase, and the Cochrane Library using different search terms; articles published until November 2016 were searched for. The searches identified 30 eligible studies. A total of 3,049 implants were installed in a total of 1,435 patients with a mean age of 46.68 years and a minimum of 6 months of follow-up. The survival rate of delayed implants (98.38%) was significantly greater than immediate implants (95.21%) (p=.001). For the marginal bone loss (p=.32), implant stability quotients values (p=.44), and pocket probing depth (p=.94) there was no significant difference between the analysed groups. The immediate implants placed in fresh sockets should be performed with caution because of the significantly lower survival rates than delayed implants inserted in healed sockets. Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Sclerostin Antibody Treatment Enhances Rotator Cuff Tendon-to-Bone Healing in an Animal Model.

PubMed

Shah, Shivam A; Kormpakis, Ioannis; Havlioglu, Necat; Ominsky, Michael S; Galatz, Leesa M; Thomopoulos, Stavros

2017-05-17

Rotator cuff tears are a common source of pain and disability, and poor healing after repair leads to high retear rates. Bone loss in the humeral head before and after repair has been associated with poor healing. The purpose of the current study was to mitigate bone loss near the repaired cuff and improve healing outcomes. Sclerostin antibody (Scl-Ab) treatment, previously shown to increase bone formation and strength in the setting of osteoporosis, was used in the current study to address bone loss and enhance rotator cuff healing in an animal model. Scl-Ab was administered subcutaneously at the time of rotator cuff repair and every 2 weeks until the animals were sacrificed. The effect of Scl-Ab treatment was evaluated after 2, 4, and 8 weeks of healing, using bone morphometric analysis, biomechanical evaluation, histological analysis, and gene expression outcomes. Injury and repair led to a reduction in bone mineral density after 2 and 4 weeks of healing in the control and Scl-Ab treatment groups. After 8 weeks of healing, animals receiving Scl-Ab treatment had 30% greater bone mineral density than the controls. A decrease in biomechanical properties was observed in both groups after 4 weeks of healing compared with healthy tendon-to-bone attachments. After 8 weeks of healing, Scl-Ab-treated animals had improved strength (38%) and stiffness (43%) compared with control animals. Histological assessment showed that Scl-Ab promoted better integration of tendon and bone by 8 weeks of healing. Scl-Ab had significant effects on gene expression in bone, indicative of enhanced bone formation, and no effect on the expression of genes in tendon. This study provides evidence that Scl-Ab treatment improves tendon-to-bone healing at the rotator cuff by increasing attachment-site bone mineral density, leading to improved biomechanical properties. Scl-Ab treatment may improve outcomes after rotator cuff repair.

Numerical Simulation of Callus Healing for Optimization of Fracture Fixation Stiffness

PubMed Central

Steiner, Malte; Claes, Lutz; Ignatius, Anita; Simon, Ulrich; Wehner, Tim

2014-01-01

The stiffness of fracture fixation devices together with musculoskeletal loading defines the mechanical environment within a long bone fracture, and can be quantified by the interfragmentary movement. In vivo results suggested that this can have acceleratory or inhibitory influences, depending on direction and magnitude of motion, indicating that some complications in fracture treatment could be avoided by optimizing the fixation stiffness. However, general statements are difficult to make due to the limited number of experimental findings. The aim of this study was therefore to numerically investigate healing outcomes under various combinations of shear and axial fixation stiffness, and to detect the optimal configuration. A calibrated and established numerical model was used to predict fracture healing for numerous combinations of axial and shear fixation stiffness under physiological, superimposed, axial compressive and translational shear loading in sheep. Characteristic maps of healing outcome versus fixation stiffness (axial and shear) were created. The results suggest that delayed healing of 3 mm transversal fracture gaps will occur for highly flexible or very rigid axial fixation, which was corroborated by in vivo findings. The optimal fixation stiffness for ovine long bone fractures was predicted to be 1000–2500 N/mm in the axial and >300 N/mm in the shear direction. In summary, an optimized, moderate axial stiffness together with certain shear stiffness enhances fracture healing processes. The negative influence of one improper stiffness can be compensated by adjustment of the stiffness in the other direction. PMID:24991809

Platelet-rich preparations to improve healing. Part I: workable options for every size practice.

PubMed

Davis, Vicki L; Abukabda, Alaeddin B; Radio, Nicholas M; Witt-Enderby, Paula A; Clafshenkel, William P; Cairone, J Vito; Rutkowski, James L

2014-08-01

Numerous studies have demonstrated that platelet-rich preparations applied to surgical sites, injuries, or wounds are a safe and effective way to promote soft tissue healing and bone growth. Various protocols have been developed for preparing platelet-rich preparations, with subtle but important differences between them. Unfortunately, only a minority of clinicians use platelet-rich preparations, such as platelet-rich plasma and platelet-rich fibrin, in their practice, possibly due to confusion about the different methods and their advantages and disadvantages. Therefore, the different types of preparations are described to help guide the selection of the best method for any size practice. Classic methods generally require large volumes of blood and can be expensive, complicated, and time-intensive. Simpler protocols have been developed recently, which require relatively inexpensive equipment and small blood volumes and, thus, may be more applicable for small clinical practices. Platelet-rich preparations accelerate healing at earlier time points to reduce discomfort and the potential for adverse outcomes, including infection, poor wound closure, and delays in forming strong bone for subsequent procedures (such as implants). However, platelet-rich preparations may also improve long-term outcomes in patients expected to have impaired healing, such as with lifestyle choices (eg, smoking), medications (eg, steroids), diseases (eg, diabetes, osteoporosis, atherosclerosis), and aging, by supplementing the deficient wound environment to restore proper healing. Therefore, both large and small clinical practices would benefit from utilizing platelet-rich preparations to enhance healing in their patients.

Numerical simulation of callus healing for optimization of fracture fixation stiffness.

PubMed

Steiner, Malte; Claes, Lutz; Ignatius, Anita; Simon, Ulrich; Wehner, Tim

2014-01-01

The stiffness of fracture fixation devices together with musculoskeletal loading defines the mechanical environment within a long bone fracture, and can be quantified by the interfragmentary movement. In vivo results suggested that this can have acceleratory or inhibitory influences, depending on direction and magnitude of motion, indicating that some complications in fracture treatment could be avoided by optimizing the fixation stiffness. However, general statements are difficult to make due to the limited number of experimental findings. The aim of this study was therefore to numerically investigate healing outcomes under various combinations of shear and axial fixation stiffness, and to detect the optimal configuration. A calibrated and established numerical model was used to predict fracture healing for numerous combinations of axial and shear fixation stiffness under physiological, superimposed, axial compressive and translational shear loading in sheep. Characteristic maps of healing outcome versus fixation stiffness (axial and shear) were created. The results suggest that delayed healing of 3 mm transversal fracture gaps will occur for highly flexible or very rigid axial fixation, which was corroborated by in vivo findings. The optimal fixation stiffness for ovine long bone fractures was predicted to be 1000-2500 N/mm in the axial and >300 N/mm in the shear direction. In summary, an optimized, moderate axial stiffness together with certain shear stiffness enhances fracture healing processes. The negative influence of one improper stiffness can be compensated by adjustment of the stiffness in the other direction.

Bone fracture healing in mechanobiological modeling: A review of principles and methods.

PubMed

Ghiasi, Mohammad S; Chen, Jason; Vaziri, Ashkan; Rodriguez, Edward K; Nazarian, Ara

2017-06-01

Bone fracture is a very common body injury. The healing process is physiologically complex, involving both biological and mechanical aspects. Following a fracture, cell migration, cell/tissue differentiation, tissue synthesis, and cytokine and growth factor release occur, regulated by the mechanical environment. Over the past decade, bone healing simulation and modeling has been employed to understand its details and mechanisms, to investigate specific clinical questions, and to design healing strategies. The goal of this effort is to review the history and the most recent work in bone healing simulations with an emphasis on both biological and mechanical properties. Therefore, we provide a brief review of the biology of bone fracture repair, followed by an outline of the key growth factors and mechanical factors influencing it. We then compare different methodologies of bone healing simulation, including conceptual modeling (qualitative modeling of bone healing to understand the general mechanisms), biological modeling (considering only the biological factors and processes), and mechanobiological modeling (considering both biological aspects and mechanical environment). Finally we evaluate different components and clinical applications of bone healing simulation such as mechanical stimuli, phases of bone healing, and angiogenesis.

Biomimetics of Bone Implants: The Regenerative Road.

PubMed

Brett, Elizabeth; Flacco, John; Blackshear, Charles; Longaker, Michael T; Wan, Derrick C

2017-01-01

The current strategies for healing bone defects are numerous and varied. At the core of each bone healing therapy is a biomimetic mechanism, which works to enhance bone growth. These range from porous scaffolds, bone mineral usage, collagen, and glycosaminoglycan substitutes to transplanted cell populations. Bone defects face a range of difficulty in their healing, given the composite of dense outer compact bone and blood-rich inner trabecular bone. As such, the tissue possesses a number of inherent characteristics, which may be clinically harnessed as promoters of bone healing. These include mechanical characteristics, mineral composition, native collagen content, and cellular fraction of bone. This review charts multiple biomimetic strategies to help heal bony defects in large and small osseous injury sites, with a special focus on cell transplantation.

Wound Administration of M2-Polarized Macrophages Does Not Improve Murine Cutaneous Healing Responses

PubMed Central

Jetten, Nadine; Roumans, Nadia; Gijbels, Marion J.; Romano, Andrea; Post, Mark J.; de Winther, Menno P. J.; van der Hulst, Rene R. W. J.; Xanthoulea, Sofia

2014-01-01

Macrophages play a crucial role in all stages of cutaneous wound healing responses and dysregulation of macrophage function can result in derailed wound repair. The phenotype of macrophages is influenced by the wound microenvironment and evolves during healing from a more pro-inflammatory (M1) profile in early stages, to a less inflammatory pro-healing (M2) phenotype in later stages of repair. The aim of the current study was to investigate the potential of exogenous administration of M2 macrophages to promote wound healing in an experimental mouse model of cutaneous injury. Bone marrow derived macrophages were stimulated in-vitro with IL-4 or IL-10 to obtain two different subsets of M2-polarized cells, M2a or M2c respectively. Polarized macrophages were injected into full-thickness excisional skin wounds of either C57BL/6 or diabetic db/db mice. Control groups were injected with non-polarized (M0) macrophages or saline. Our data indicate that despite M2 macrophages exhibit an anti-inflammatory phenotype in-vitro, they do not improve wound closure in wild type mice while they delay healing in diabetic mice. Examination of wounds on day 15 post-injury indicated delayed re-epithelialization and persistence of neutrophils in M2 macrophage treated diabetic wounds. Therefore, topical application of ex-vivo generated M2 macrophages is not beneficial and contraindicated for cell therapy of skin wounds. PMID:25068282

Psychological Stress Delays Periodontitis Healing in Rats: The Involvement of Basic Fibroblast Growth Factor

PubMed Central

Zhao, Ya-Juan; Li, Qiang; Cheng, Bai-Xiang; Zhang, Min; Chen, Yong-Jin

2012-01-01

Objective. To evaluate the effects of psychological stress on periodontitis healing in rats and the contribution of basic fibroblast growth factor (bFGF) expression to the healing process. Methods. Ninety-six rats were randomly distributed into control group, periodontitis group, and periodontitis plus stress group. Then, the rats were sacrificed at baseline and week(s) 1, 2, and 4. The periodontitis healing condition was assessed, and the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and bFGF were tested by immunohistochemistry. Results. The stressed rats showed reduced body weight gain, behavioral changes, and increased serum corticosterone and ACTH levels (P < 0.05). The surface of inflammatory infiltrate, alveolar bone loss, attachment loss, and expression of IL-1β and TNF-α in the stress group were higher than those in the periodontitis group at weeks 2 and 4 (P < 0.05). Rats with experimental periodontitis showed decreased bFGF expression (P < 0.05), and the recovery of bFGF expression in the stress group was slower than that in the periodontitis group (P < 0.05). Negative correlations between inflammatory cytokines and bFGF were detected. Conclusion. Psychological stress could delay periodontitis healing in rats, which may be partly mediated by downregulation of the expression of bFGF in the periodontal ligament. PMID:23326020

Fracture healing in osteoporotic bone.

PubMed

Cheung, Wing Hoi; Miclau, Theodore; Chow, Simon Kwoon-Ho; Yang, Frank F; Alt, Volker

2016-06-01

As the world population rises, osteoporotic fracture is an emerging global threat to the well-being of elderly patients. The process of fracture healing by intramembranous ossification or/and endochondral ossification involve many well-orchestrated events including the signaling, recruitment and differentiation of mesenchymal stem cells (MSCs) during the early phase; formation of a hard callus and extracellular matrix, angiogenesis and revascularization during the mid-phase; and finally callus remodeling at the late phase of fracture healing. Through clinical and animal research, many of these factors are shown to be impaired in osteoporotic bone. Animal studies related to post-menopausal estrogen deficient osteoporosis (type I) have shown healing to be prolonged with decreased levels of MSCs and decreased levels of angiogenesis. Moreover, the expression of estrogen receptor (ER) was shown to be delayed in ovariectomy-induced osteoporotic fracture. This might be related to the observed difference in mechanical sensitivity between normal and osteoporotic bones, which requires further experiments to elucidate. In mice fracture models related to senile osteoporosis (type II), it was observed that chondrocyte and osteoblast differentiation were impaired; and that transplantation of juvenile bone marrow would result in enhanced callus formation. Other factors related to angiogenesis and vasculogenesis have also been noted to be impaired in aged models, affecting the degradation of cartilaginous matrixes and vascular invasion; the result is changes in matrix composition and growth factors concentrations that ultimately impairs healing during age-related osteoporosis. Most osteoporotic related fractures occur at metaphyseal sites clinically, and reports have indicated that differences exist between diaphyseal and metaphyseal fractures. An animal model that satisfies three main criteria (metaphyseal region, plate fixation, osteoporosis) is suggested for future research for more comprehensive understanding of the impairment in osteoporotic fractures. Therefore, a metaphyseal fracture or osteotomy that achieves complete discontinuity fixed with metal implants is suggested on ovariectomized aged rodent models. © 2016 Elsevier Ltd. All rights reserved.

Bone stimulation for fracture healing: What's all the fuss?

PubMed Central

Victoria, Galkowski; Petrisor, Brad; Drew, Brian; Dick, David

2009-01-01

Approximately 10% of the 7.9 million annual fracture patients in the United States experience nonunion and/or delayed unions, which have a substantial economic and quality of life impact. A variety of devices are being marketed under the name of “bone growth stimulators.” This article provides an overview of electrical and electromagnetic stimulation, ultrasound, and extracorporeal shock waves. More research is needed for knowledge of appropriate device configurations, advancement in the field, and encouragement in the initiation of new trials, particularly large multicenter trials and randomized control trials that have standardized device and protocol methods. PMID:19838359

Novel Therapy for Bone Regeneration in Large Segmental Defects

DTIC Science & Technology

2017-12-01

on fracture healing. Clin Orthop Relat Res. 1998;355(Suppl):S230–8. 37. Pape HC, Giannoudis PV. Fat embolism and IM nailing. Injury. 2006;37(Suppl 4...BMP), thrombopoietin (TPO), therapy, fracture healing, bone regeneration, minipig, pig 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT...2, TPO, or saline control. 2. KEYWORDS: Bone healing, bone morphogenetic protein (BMP), thrombopoietin (TPO), therapy, fracture healing, bone

Pathophysiology and new strategies for the treatment of Legg-Calvé-Perthes disease.

PubMed

Kim, Harry K W

2012-04-04

Legg-Calvé-Perthes disease is a juvenile form of idiopathic osteonecrosis of the femoral head that can lead to permanent femoral head deformity and premature osteoarthritis. According to two recent multicenter, prospective cohort studies, current nonoperative and operative treatments have modest success rates of producing a good outcome with a spherical femoral head in older children with Legg-Calvé-Perthes disease. Experimental studies have revealed that the immature femoral head is mechanically weakened following ischemic necrosis. Increased bone resorption and delayed new bone formation, in combination with continued mechanical loading of the hip, contribute to the pathogenesis of the femoral head deformity. Biological treatment strategies to improve the healing process by decreasing bone resorption and stimulating bone formation appear promising in nonhuman preclinical studies.

A unified theory of bone healing and nonunion: BHN theory.

PubMed

Elliott, D S; Newman, K J H; Forward, D P; Hahn, D M; Ollivere, B; Kojima, K; Handley, R; Rossiter, N D; Wixted, J J; Smith, R M; Moran, C G

2016-07-01

This article presents a unified clinical theory that links established facts about the physiology of bone and homeostasis, with those involved in the healing of fractures and the development of nonunion. The key to this theory is the concept that the tissue that forms in and around a fracture should be considered a specific functional entity. This 'bone-healing unit' produces a physiological response to its biological and mechanical environment, which leads to the normal healing of bone. This tissue responds to mechanical forces and functions according to Wolff's law, Perren's strain theory and Frost's concept of the "mechanostat". In response to the local mechanical environment, the bone-healing unit normally changes with time, producing different tissues that can tolerate various levels of strain. The normal result is the formation of bone that bridges the fracture - healing by callus. Nonunion occurs when the bone-healing unit fails either due to mechanical or biological problems or a combination of both. In clinical practice, the majority of nonunions are due to mechanical problems with instability, resulting in too much strain at the fracture site. In most nonunions, there is an intact bone-healing unit. We suggest that this maintains its biological potential to heal, but fails to function due to the mechanical conditions. The theory predicts the healing pattern of multifragmentary fractures and the observed morphological characteristics of different nonunions. It suggests that the majority of nonunions will heal if the correct mechanical environment is produced by surgery, without the need for biological adjuncts such as autologous bone graft. Cite this article: Bone Joint J 2016;98-B:884-91. ©2016 The British Editorial Society of Bone & Joint Surgery.

Effect of Zoledronate on Oral Wound Healing in Rats

PubMed Central

Yamashita, Junro; Koi, Kiyono; Yang, Dong-Ye; McCauley, Laurie K.

2010-01-01

Purpose Osteonecrosis of the jaw (ONJ) is a growing concern in patients who receive bisphosphonates which target osteoclasts. Since osteoclasts play multifunctional roles in the bone marrow, their suppression likely affects bone homeostasis and alters wound healing of the jaw. The objective was to delineate the impact of osteoclast suppression in the bone marrow and wound healing of the jaw. Experimental Design Zoledronate was administered to senile rats for 14 weeks. A portion of the gingiva was removed to denude the palatal bone. Gene expression in the bone marrow was assessed and histologic sections analyzed to determine the wound healing status. Results Angiogenesis-related genes, CD31 and VEGF-A, were not altered by zoledronate. VEGF-C, which plays a role in lymphangiogenesis, was suppressed. There was a decrease in gene expression of Tcirg1 and MMP-13. Bone denudation caused extensive osteocyte death indicative of bone necrosis. In zoledronate-treated rats, the necrotic bone was retained in the wound while, in controls, osteoclastic resorption of the necrotic bone was prominent. Even though large necrotic bone areas existed in zoledronate-treated rats, overlaying soft tissue healed clinically. Immunohistochemical staining showed rich vascularity in the overlaying soft tissue. Conclusions Zoledronate therapy impacts bone marrow by suppressing genes associated with lymphoangiogenesis and tissue remodeling, such as VEGF-C and MMP-13. Zoledronate was associated with impaired osseous wound healing but had no effect on angiogenic markers in the bone marrow or soft tissue wound healing. Zoledronate selectively blunts healing in bone but does not effect soft tissue healing in the oral cavity. PMID:21149614

Can Spatiotemporal Fluoride (18F-) Uptake be Used to Assess Bone Formation in the Tibia? A Longitudinal Study Using PET/CT.

PubMed

Lundblad, Henrik; Karlsson-Thur, Charlotte; Maguire, Gerald Q; Jonsson, Cathrine; Noz, Marilyn E; Zeleznik, Michael P; Weidenhielm, Lars

2017-05-01

When a bone is broken for any reason, it is important for the orthopaedic surgeon to know how bone healing is progressing. There has been resurgence in the use of the fluoride ( 18 F - ) ion to evaluate various bone conditions. This has been made possible by availability of positron emission tomography (PET)/CT hybrid scanners together with cyclotrons. Absorbed on the bone surface from blood flow, 18 F - attaches to the osteoblasts in cancellous bone and acts as a pharmacokinetic agent, which reflects the local physiologic activity of bone. This is important because it shows bone formation indicating that the bone is healing or no bone formation indicating no healing. As 18 F - is extracted from blood in proportion to blood flow and bone formation, it thus enables determination of bone healing progress. The primary objective of this study was to determine whether videos showing the spatiotemporal uptake of 18 F - via PET bone scans could show problematic bone healing in patients with complex tibia conditions. A secondary objective was to determine if semiquantification of radionuclide uptake was consistent with bone healing. This study investigated measurements of tibia bone formation in patients with complex fractures, osteomyelitis, and osteotomies treated with a Taylor Spatial Frame TM (TSF) by comparing clinical healing progress with spatiotemporal fluoride ( 18 F - ) uptake and the semiquantitative standardized uptake value (SUV). This procedure included static and dynamic image acquisition. For intrapatient volumes acquired at different times, the CT and PET data were spatially registered to bring the ends of the bones that were supposed to heal into alignment. To qualitatively observe how and where bone formation was occurring, time-sequenced volumes were reconstructed and viewed as a video. To semiquantify the uptake, the mean and maximum SUVs (SUVmean, SUVmax) were calculated for the ends of the bones that were supposed to heal and for normal bone, using a spherical volume of interest drawn on the registered volumes. To make the semiquantitative data comparable for all patients with multiple examinations, the SUVmean and SUVmax difference per day (SUVmeanDPD and SUVmaxDPD) between the first PET/CT scan and each subsequent one was calculated. Indicators of poor healing progress were (1) uneven distribution of the radionuclide uptake between ends of the bones that were supposed to heal as seen in the video or, (2) low absolute magnitude of the SUV difference data. Twenty-four patients treated between October 2013 and April 2015 with a TSF gave informed consent to be examined with 18 F - PET/CT bone scans. Twenty-two patients successfully completed treatment, one of whom had only one PET/CT scan. Observation of 18 F - uptake was able to identify three patients whose healing progress was poor, indicated by uneven distribution of radionuclide uptake across the ends of the bones that were supposed to heal. An absolute magnitude of the SUVmaxDPD of 0.18 or greater indicated good bone formation progress. This was verified in 10 patients by the days between the operation to attach and to remove the TSF being less than 250 days, whereas other SUVmaxDPD values were ambiguous, with 11 patients achieving successful completion. Observation of the spatiotemporal uptake of 18 F - appears to be a promising method to enable the clinician to assess the progress of bone formation in different parts of the bone. Bone uptake which is uneven across the ends of bone that were supposed to heal or very low bone uptake might indicate impaired bone healing where early intervention may then be needed. However, semiquantification of 18 F - uptake (SUVmaxDPD), SUVmeanDPD) was ambiguous in showing consistency with the bone-healing progress. Level III, diagnostic study.

Characterizing the composition of bone formed during fracture healing using scanning electron microscopy techniques.

PubMed

Perdikouri, Christina; Tägil, Magnus; Isaksson, Hanna

2015-01-01

About 5-10% of all bone fractures suffer from delayed healing, which may lead to non-union. Bone morphogenetic proteins (BMPs) can be used to induce differentiation of osteoblasts and enhance the formation of the bony callus, and bisphosphonates help to retain the newly formed callus. The aim of this study was to investigate if scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) can identify differences in the mineral composition of the newly formed bone compared to cortical bone from a non-fractured control. Moreover, we investigate whether the use of BMPs and bisphosphonates-alone or combined-may have an effect on bone mineralization and composition. Twelve male Sprague-Dawley rats at 9 weeks of age were randomly divided into four groups and treated with (A) saline, (B) BMP-7, (C) bisphosphonates (Zoledronate), and (D) BMP-7 + Zoledronate. The rats were sacrificed after 6 weeks. All samples were imaged using SEM and chemically analyzed with EDS to quantify the amount of C, N, Ca, P, O, Na, and Mg. The Ca/P ratio was the primary outcome. In the fractured samples, two areas of interest were chosen for chemical analysis with EDS: the callus and the cortical bone. In the non-fractured samples, only the cortex was analyzed. Our results showed that the element composition varied to a small extent between the callus and the cortical bone in the fractured bones. However, the Ca/P ratio did not differ significantly, suggesting that the mineralization at all sites is similar 6 weeks post-fracture in this rat model.

Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response

PubMed Central

Chan, James K; Glass, Graeme E; Ersek, Adel; Freidin, Andrew; Williams, Garry A; Gowers, Kate; Espirito Santo, Ana I; Jeffery, Rosemary; Otto, William R; Poulsom, Richard; Feldmann, Marc; Rankin, Sara M; Horwood, Nicole J; Nanchahal, Jagdeep

2015-01-01

The mechanism by which trauma initiates healing remains unclear. Precise understanding of these events may define interventions for accelerating healing that could be translated to the clinical arena. We previously reported that addition of low-dose recombinant human TNF (rhTNF) at the fracture site augmented fracture repair in a murine tibial fracture model. Here, we show that local rhTNF treatment is only effective when administered within 24 h of injury, when neutrophils are the major inflammatory cell infiltrate. Systemic administration of anti-TNF impaired fracture healing. Addition of rhTNF enhanced neutrophil recruitment and promoted recruitment of monocytes through CCL2 production. Conversely, depletion of neutrophils or inhibition of the chemokine receptor CCR2 resulted in significantly impaired fracture healing. Fragility, or osteoporotic, fractures represent a major medical problem as they are associated with permanent disability and premature death. Using a murine model of fragility fractures, we found that local rhTNF treatment improved fracture healing during the early phase of repair. If translated clinically, this promotion of fracture healing would reduce the morbidity and mortality associated with delayed patient mobilization. PMID:25770819

Optimal Treatment of Malignant Long Bone Fracture: Influence of Method of Repair and External Beam Irradiation on the Pathway and Efficacy of Fracture Healing

DTIC Science & Technology

2014-10-01

Long Bone Fracture: Influence of Method of Repair and External Beam Irradiation on the Pathway and Efficacy of Fracture Healing 5a. CONTRACT NUMBER...in the fifth quarter of the award. 15. SUBJECT TERMS Fracture healing , bone healing , endochondral ossification, intramembranous ossification...of radiation on the two pathways of bone healing and propose an optimal method of surgical fracture repair for managing malignant osteoporotic

Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial.

PubMed

Grbic, John T; Landesberg, Regina; Lin, Shou-Qing; Mesenbrink, Peter; Reid, Ian R; Leung, Ping-Chung; Casas, Noemi; Recknor, Christopher P; Hua, Ye; Delmas, Pierre D; Eriksen, Erik F

2008-01-01

The authors determined incidence of osteonecrosis of the jaw (ONJ) in a large, prospective three-year clinical trial of zoledronic acid in women with postmenopausal osteoporosis (PMO). A total of 7,714 women with PMO received intravenous zoledronic acid 5 mg or a placebo. No spontaneous reports of ONJ were received. An independent, blinded adjudication committee searched the trial's adverse event database by using 60 terms. On an ongoing basis, the committee reviewed the identified events, and it defined ONJ as exposed bone in the maxillofacial area with delayed healing for more than six weeks despite appropriate care. One participant who received a placebo and one participant who received zoledronic acid experienced delayed healing associated with infection. Both conditions resolved after antibiotic therapy, débridement or both. The occurrence of ONJ is rare in a PMO population, and delayed healing of lesions can occur with and without bisphosphonate use over three years. The low incidence of ONJ must be assessed in the context of the clinical benefit of zoledronic acid therapy in reducing hip, vertebral and nonvertebral fractures in this at-risk population. There is no evidence to suggest that healthy patients with osteoporosis who are receiving bisphosphonates require any special treatment beyond routine dental care or to support altering standard treatment practices.

A small interfering RNA targeting Lnk accelerates bone fracture healing with early neovascularization.

PubMed

Kawakami, Yohei; Ii, Masaaki; Matsumoto, Tomoyuki; Kawamoto, Atsuhiko; Kuroda, Ryosuke; Akimaru, Hiroshi; Mifune, Yutaka; Shoji, Taro; Fukui, Tomoaki; Asahi, Michio; Kurosaka, Masahiro; Asahara, Takayuki

2013-09-01

Lnk, an intracellular adapter protein, is expressed in hematopoietic cell lineages, which has recently been proved as an essential inhibitory signaling molecule for stem cell self-renewal in the stem cell factor-c-Kit signaling pathway with enhanced hematopoietic and osteogenic reconstitution in Lnk-deficient mice. Moreover, the therapeutic potential of hematopoietic stem/endothelial progenitor cells (EPCs) for fracture healing has been demonstrated with mechanistic insight into vasculogenesis/angiogenesis and osteogenesis enhancement in the fracture sites. We report here, Lnk siRNA-transfected endothelial commitment of c-kit+/Sca-1+/lineage- subpopulations of bone marrow cells have high EPC colony-forming capacity exhibiting endothelial markers, VE-Cad, VEGF and Ang-1. Lnk siRNA-transfected osteoblasts also show highly osteoblastic capacity. In vivo, locally transfected Lnk siRNA could successfully downregulate the expression of Lnk at the fracture site up to 1 week, and radiological and histological examination showed extremely accelerated fracture healing in Lnk siRNA-transfected mice. Moreover, Lnk siRNA-transfected mice exhibited sufficient therapeutic outcomes with intrinstic enhancement of angiogenesis and osteogenesis, specifically, the mice demonstrated better blood flow recovery in the sites of fracture. In our series of experiments, we clarified that a negatively regulated Lnk system contributed to a favorable circumstance for fracture healing by enhancing vasculogenesis/angiogenesis and osteogenesis. These findings suggest that downregulation of Lnk system may have the clinical potential for faster fracture healing, which contributes to the reduction of delayed unions or non-unions.

An interface finite element model can be used to predict healing outcome of bone fractures.

PubMed

Alierta, J A; Pérez, M A; García-Aznar, J M

2014-01-01

After fractures, bone can experience different potential outcomes: successful bone consolidation, non-union and bone failure. Although, there are a lot of factors that influence fracture healing, experimental studies have shown that the interfragmentary movement (IFM) is one of the main regulators for the course of bone healing. In this sense, computational models may help to improve the development of mechanical-based treatments for bone fracture healing. Hence, based on this fact, we propose a combined repair-failure mechanistic computational model to describe bone fracture healing. Despite being a simple model, it is able to correctly estimate the time course evolution of the IFM compared to in vivo measurements under different mechanical conditions. Therefore, this mathematical approach is especially suitable for modeling the healing response of bone to fractures treated with different mechanical fixators, simulating realistic clinical conditions. This model will be a useful tool to identify factors and define targets for patient specific therapeutics interventions. © 2013 Published by Elsevier Ltd.

A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering

PubMed Central

Winkler, T.; Sass, F. A.; Schmidt-Bleek, K.

2018-01-01

Despite its intrinsic ability to regenerate form and function after injury, bone tissue can be challenged by a multitude of pathological conditions. While innovative approaches have helped to unravel the cascades of bone healing, this knowledge has so far not improved the clinical outcomes of bone defect treatment. Recent findings have allowed us to gain in-depth knowledge about the physiological conditions and biological principles of bone regeneration. Now it is time to transfer the lessons learned from bone healing to the challenging scenarios in defects and employ innovative technologies to enable biomaterial-based strategies for bone defect healing. This review aims to provide an overview on endogenous cascades of bone material formation and how these are transferred to new perspectives in biomaterial-driven approaches in bone regeneration. Cite this article: T. Winkler, F. A. Sass, G. N. Duda, K. Schmidt-Bleek. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. Bone Joint Res 2018;7:232–243. DOI: 10.1302/2046-3758.73.BJR-2017-0270.R1.

In silico Mechano-Chemical Model of Bone Healing for the Regeneration of Critical Defects: The Effect of BMP-2

PubMed Central

2015-01-01

The healing of bone defects is a challenge for both tissue engineering and modern orthopaedics. This problem has been addressed through the study of scaffold constructs combined with mechanoregulatory theories, disregarding the influence of chemical factors and their respective delivery devices. Of the chemical factors involved in the bone healing process, bone morphogenetic protein-2 (BMP-2) has been identified as one of the most powerful osteoinductive proteins. The aim of this work is to develop and validate a mechano-chemical regulatory model to study the effect of BMP-2 on the healing of large bone defects in silico. We first collected a range of quantitative experimental data from the literature concerning the effects of BMP-2 on cellular activity, specifically proliferation, migration, differentiation, maturation and extracellular matrix production. These data were then used to define a model governed by mechano-chemical stimuli to simulate the healing of large bone defects under the following conditions: natural healing, an empty hydrogel implanted in the defect and a hydrogel soaked with BMP-2 implanted in the defect. For the latter condition, successful defect healing was predicted, in agreement with previous in vivo experiments. Further in vivo comparisons showed the potential of the model, which accurately predicted bone tissue formation during healing, bone tissue distribution across the defect and the quantity of bone inside the defect. The proposed mechano-chemical model also estimated the effect of BMP-2 on cells and the evolution of healing in large bone defects. This novel in silico tool provides valuable insight for bone tissue regeneration strategies. PMID:26043112

Comparative Evaluation of Enalapril and Losartan in Pharmacological Correction of Experimental Osteoporosis and Fractures of Its Background

PubMed Central

Rajkumar, D. S. R.; Faitelson, A. V.; Gudyrev, O. S.; Dubrovin, G. M.; Pokrovski, M. V.; Ivanov, A. V.

2013-01-01

In the experiment on the white Wistar female rats (222 animals), the osteoprotective effect of enalapril and losartan was studied on experimental models of osteoporosis and osteoporotic fractures. It was revealed that in rats after ovariectomy, the endothelial dysfunction of microcirculation vessels of osteal tissue develops, resulting in occurrence of osteoporosis and delay of consolidation of experimental fractures. Enalapril and losartan prevented the reduction of microcirculation in bone, which was reflected in slowing the thinning of bone trabeculae and in preventing the occurrence of these microfractures, as well as increasing quality of experimental fractures healing. PMID:23401845

Translational Research to Improve the Treatment of Severe Extremity Injuries

DTIC Science & Technology

2014-01-24

implantation of antibiotic-impregnated PMMA beads) was delayed by 2, 6 or 24 h and subsequent bacterial load in the wounds quantified 2 weeks later. Bacterial...supplemented by local antibiotics in the form of non-biodegradable antibiotic-impregnated poly- methymethacrylate ( PMMA ) beads, which will require removal at a...which K wires are passed to fix the implant to the femur. This produces a standardised and reproducible bone defect which will not heal spontaneously

Combined injury syndrome in space-related radiation environments

NASA Astrophysics Data System (ADS)

Dons, R. F.; Fohlmeister, U.

The risk of combined injury (CI) to space travelers is a function of exposure to anomalously large surges of a broad spectrum of particulate and photon radiations, conventional trauma (T), and effects of weightlessness including decreased intravascular fluid volume, and myocardial deconditioning. CI may occur even at relatively low doses of radiation which can synergistically enhance morbidity and mortality from T. Without effective countermeasures, prolonged residence in space is expected to predispose most individuals to bone fractures as a result of calcium loss in the microgravity environment. Immune dysfunction may occur from residence in space independent of radiation exposure. Thus, wound healing would be compromised if infection were to occur. Survival of the space traveler with CI would be significantly compromised if there were delays in wound closure or in the application of simple supportive medical or surgical therapies. Particulate radiation has the potential for causing greater gastrointestinal injury than photon radiation, but bone healing should not be compromised at the expected doses of either type of radiation in space.

Mechanical rigidity of the Ortho-SUV frame compared to the Ilizarov frame in the correction of femoral deformity.

PubMed

Skomoroshko, Petr V; Vilensky, Victor A; Hammouda, Ahmed I; Fletcher, Matt D A; Solomin, Leonid N

2015-04-01

The Ortho-SUV frame (OSF) is a novel hexapod circular external fixator which draws upon the innovation of the Ilizarov method and the advantages of hexapod construction in the three-dimensional control of bone segments. Stability of fixation is critical to the success or failure of an external circular fixator for fracture or osteotomy healing. In vitro biomechanical modelling study was performed comparing the stability of the OSF under load in both original form and after dynamisation to the Ilizarov fixator in all zones of the femur utilising optimal frame configuration. A superior performance of the OSF in terms of resistance to deforming forces in both original and dynamised forms over that of the original Ilizarov fixator was found. The OSF shows higher rigidity than the Ilizarov in the control of forces acting upon the femur. This suggests better stabilisation of femoral fractures and osteotomies and thus improved healing with a reduced incidence of instability-related bone segment deformity, non-union and delayed union.

Substance P accelerates wound healing in type 2 diabetic mice through endothelial progenitor cell mobilization and Yes-associated protein activation

PubMed Central

Um, Jihyun; Yu, Jinyeong; Park, Ki-Sook

2017-01-01

Wound healing is delayed in diabetes due to a number of factors, including impaired angiogenesis and poor dermal healing. The present study demonstrated that subcutaneous administration of substance P (SP) accelerates wound healing in db/db type 2 diabetic mice (db/db mice). SP injection (10 nM/kg, subcutaneously) enhanced angiogenesis, induced the mobilization of endothelial progenitor cells (EPCs) and increased the number of EPC-colony forming units (EPC-CFUs) in the bone marrow of db/db mice. Immunohistochemistry was performed to check the effects of SP on the cellular proliferation and the subcellular localization of Yes-associated protein (YAP) in the wound dermis. SP also upregulated cellular proliferation in the injured dermis of db/db mice. Compared with the control group, an increased number of cells in the wound dermis of SP-treated mice exhibited nuclear localization of YAP, which induces cellular proliferation. The results of the current study indicate that subcutaneous administration of SP may be a promising therapeutic strategy to treat diabetic wounds exhibiting impaired angiogenesis and dysfunctional dermal wound healing. PMID:28339006

The Biology of Bone and Ligament Healing.

PubMed

Cottrell, Jessica A; Turner, Jessica Cardenas; Arinzeh, Treena Livingston; O'Connor, J Patrick

2016-12-01

This review describes the normal healing process for bone, ligaments, and tendons, including primary and secondary healing as well as bone-to-bone fusion. It depicts the important mediators and cell types involved in the inflammatory, reparative, and remodeling stages of each healing process. It also describes the main challenges for clinicians when trying to repair bone, ligaments, and tendons with a specific emphasis on Charcot neuropathy, fifth metatarsal fractures, arthrodesis, and tendon sheath and adhesions. Current treatment options and research areas are also reviewed. Copyright © 2016 Elsevier Inc. All rights reserved.

Healing of extraction sockets filled with BoneCeramic® prior to implant placement: preliminary histological findings.

PubMed

De Coster, Peter; Browaeys, Hilde; De Bruyn, Hugo

2011-03-01

Various grafting materials have been designed to minimize edentulous ridge volume loss following tooth extraction by encouraging new bone formation in healing sockets. BoneCeramic® is a composite of hydroxyapatite and bèta-tricalcium phosphate with pores of 100-500 microns. The aim of this study was to evaluate bone regeneration in healing sockets substituted with BoneCeramic® prior to implant procedures. Fifteen extraction sockets were substituted with BoneCeramic® and 14 sockets were left to heal naturally in 10 patients (mean age 59.6 years). Biopsies were collected only from the implant recipient sites during surgery after healing periods ranging from 6-74 weeks (mean 22). In total, 24 biopsies were available; 10 from substituted and 14 from naturally healed sites. In one site, the implant was not placed intentionally and, in four substituted sites, implant placement had to be postponed due to inappropriate healing, hence from five sites biopsies were not available. Histological sections were examined by transmitted light microscope. At the time of implant surgery, bone at substituted sites was softer than in controls, compromising initial implant stability. New bone formation at substituted sites was consistently poorer than in controls, presenting predominantly loose connective tissue and less woven bone. The use of BoneCeramic® as a grafting material in fresh extraction sockets appears to interfere with normal healing processes of the alveolar bone. On the basis of the present preliminary findings, its indication as a material for bone augmentation, when implant placement is considered within 6-38 weeks after extraction, should be revised. © 2009, Copyright the Authors. Journal Compilation © 2011, Wiley Periodicals, Inc.

The use of weightbearing radiographs to assess the stability of supination-external rotation fractures of the ankle.

PubMed

Weber, Martin; Burmeister, Helge; Flueckiger, Gerhard; Krause, Fabian G

2010-05-01

Isolated lateral malleolar fractures usually result from a supination-external rotation (SER) injury and may include a deltoid ligament rupture. The necessity of operative treatment is based on the recognition of a relevant medial soft-tissue disruption. Currently used tests to assess ankle stability include manual stress radiographs and gravity stress radiographs, but seem to overestimate the need for fracture fixation. We investigated the use of weightbearing radiographs to distinguish stable and unstable isolated lateral malleolar fractures induced by the SER mechanism in 57 patients. Patients with stable fractures (SER type II according to the Lauge-Hansen classification) were treated non-operatively with varying external support. Forty-seven patients were evaluated by questionnaire and AOFAS ankle-hindfoot score. Follow-up was 18-120 months (mean 62). Fifty-one of fifty-seven (90%) patients were found to have stable fractures (SER type II) and were treated nonoperatively. The AOFAS score was 96.1 points on average (range 85-100) at latest follow-up. Four patients reported minor complaints. A "moderate" correlation of risk factors (i.e. smoking) to delayed bone healing was found while the correlation of varying external support (i.e. bandage, cast) to the AOFAS score and delayed bone healing was "poor". The use of weightbearing radiographs is an easy, pain-free, safe and reliable method to exclude the need for operative treatment, with excellent clinical outcome in the majority of the patients seen at latest follow-up. The delay of 3-10 days until the decision about surgical treatment is well accepted by the patients.

Formation of blood clot on biomaterial implants influences bone healing.

PubMed

Shiu, Hoi Ting; Goss, Ben; Lutton, Cameron; Crawford, Ross; Xiao, Yin

2014-12-01

The first step in bone healing is forming a blood clot at injured bones. During bone implantation, biomaterials unavoidably come into direct contact with blood, leading to a blood clot formation on its surface prior to bone regeneration. Despite both situations being similar in forming a blood clot at the defect site, most research in bone tissue engineering virtually ignores the important role of a blood clot in supporting healing. Dental implantology has long demonstrated that the fibrin structure and cellular content of a peri-implant clot can greatly affect osteoconduction and de novo bone formation on implant surfaces. This article reviews the formation of a blood clot during bone healing in relation to the use of platelet-rich plasma (PRP) gels. It is implicated that PRP gels are dramatically altered from a normal clot in healing, resulting in conflicting effect on bone regeneration. These results indicate that the effect of clots on bone regeneration depends on how the clots are formed. Factors that influence blood clot structure and properties in relation to bone healing are also highlighted. Such knowledge is essential for developing strategies to optimally control blood clot formation, which ultimately alter the healing microenvironment of bone. Of particular interest are modification of surface chemistry of biomaterials, which displays functional groups at varied composition for the purpose of tailoring blood coagulation activation, resultant clot fibrin architecture, rigidity, susceptibility to lysis, and growth factor release. This opens new scope of in situ blood clot modification as a promising approach in accelerating and controlling bone regeneration.

Plate Fixation With Autogenous Calcaneal Dowel Grafting Proximal Fourth and Fifth Metatarsal Fractures: Technique and Case Series.

PubMed

Seidenstricker, Chad L; Blahous, Edward G; Bouché, Richard T; Saxena, Amol

Metaphyseal and proximal diaphyseal fractures of the lateral column metatarsals can have problems with healing. In particular, those involving the fifth metatarsal have been associated with a high nonunion rate with nonoperative treatment. Although intramedullary screw fixation results in a high union rate, delayed healing and complications can occur. We describe an innovative technique to treat both acute and chronic injuries involving the metatarsal base from the metaphysis to the proximal diaphyseal bone of the fourth and fifth metatarsals. The surgical technique involves evacuation of sclerotic bone at the fracture site, packing the fracture site with compact cancellous bone, and plate fixation. In our preliminary results, 4 patients displayed 100% radiographic union at a mean of 4.75 (range 4 to 6) weeks with no incidence of refracture, at a mean follow-up point of 3.5 (range 1 to 5) years. The early results with our small series suggest that this technique is a useful treatment choice for metaphyseal and proximal diaphyseal fractures of the fourth and fifth metatarsals. Copyright © 2017 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Specific Biomimetic Hydroxyapatite Nanotopographies Enhance Osteoblastic Differentiation and Bone Graft Osteointegration

PubMed Central

Loiselle, Alayna E.; Wei, Lai; Faryad, Muhammad; Paul, Emmanuel M.; Lewis, Gregory S.; Gao, Jun; Lakhtakia, Akhlesh

2013-01-01

Impaired healing of cortical bone grafts represents a significant clinical problem. Cadaveric bone grafts undergo extensive chemical processing to decrease the risk of disease transmission; however, these processing techniques alter the bone surface and decrease the osteogenic potential of cells at the healing site. Extensive work has been done to optimize the surface of bone grafts, and hydroxyapatite (HAP) and nanotopography both increase osteoblastic differentiation. HAP is the main mineral component of bone and can enhance osteoblastic differentiation and bone implant healing in vivo, while nanotopography can enhance osteoblastic differentiation, adhesion, and proliferation. This is the first study to test the combined effects of HAP and nanotopographies on bone graft healing. With the goal of identifying the optimized surface features to improve bone graft healing, we tested the hypothesis that HAP-based nanotopographic resurfacing of bone grafts improves integration of cortical bone grafts by enhancing osteoblastic differentiation. Here we show that osteoblastic cells cultured on processed bones coated with specific-scale (50–60 nm) HAP nanotopographies display increased osteoblastic differentiation compared to cells on uncoated bone, bones coated with poly-l-lactic acid nanotopographies, or other HAP nanotopographies. Further, bone grafts coated with 50–60-nm HAP exhibited increased formation of new bone and improved healing, with mechanical properties equivalent to live autografts. These data indicate the potential for specific HAP nanotopographies to not only increase osteoblastic differentiation but also improve bone graft incorporation, which could significantly increase patient quality of life after traumatic bone injuries or resection of an osteosarcoma. PMID:23510012

Hard tissue regeneration using bone substitutes: an update on innovations in materials

PubMed Central

Sarkar, Swapan Kumar

2015-01-01

Bone is a unique organ composed of mineralized hard tissue, unlike any other body part. The unique manner in which bone can constantly undergo self-remodeling has created interesting clinical approaches to the healing of damaged bone. Healing of large bone defects is achieved using implant materials that gradually integrate with the body after healing is completed. Such strategies require a multidisciplinary approach by material scientists, biological scientists, and clinicians. Development of materials for bone healing and exploration of the interactions thereof with the body are active research areas. In this review, we explore ongoing developments in the creation of materials for regenerating hard tissues. PMID:25995658

Hard tissue regeneration using bone substitutes: an update on innovations in materials.

PubMed

Sarkar, Swapan Kumar; Lee, Byong Taek

2015-05-01

Bone is a unique organ composed of mineralized hard tissue, unlike any other body part. The unique manner in which bone can constantly undergo self-remodeling has created interesting clinical approaches to the healing of damaged bone. Healing of large bone defects is achieved using implant materials that gradually integrate with the body after healing is completed. Such strategies require a multidisciplinary approach by material scientists, biological scientists, and clinicians. Development of materials for bone healing and exploration of the interactions thereof with the body are active research areas. In this review, we explore ongoing developments in the creation of materials for regenerating hard tissues.

High dose teriparatide (rPTH1-34) therapy increases callus volume and enhances radiographic healing at 8-weeks in a massive canine femoral allograft model.

PubMed

Nishitani, Kohei; Mietus, Zachary; Beck, Christopher A; Ito, Hiromu; Matsuda, Shuichi; Awad, Hani A; Ehrhart, Nicole; Schwarz, Edward M

2017-01-01

Small animal studies have demonstrated significant high-dose recombinant parathyroid hormone1-34 (rPTH1-34) effects on intercalary allograft healing. Towards a human adjuvant therapy to decrease non-unions, we evaluated rPTH1-34 safety and efficacy in a clinically relevant canine femoral allograft model. Adult female mongrel hounds (n = 20) received a 5cm mid-diaphyseal osteotomy reconstructed with a plated allograft, and were randomized to: 1) Placebo (n = 5; daily saline), 2) Continuous rPTH1-34 (n = 7; 5 μg/kg/day s.c. from day 1-55 post-op), or 3) Delayed rPTH1-34 (n = 8; 5 μg/kg/day s.c. from day 14-28 post-op). Safety was assessed by physical behavior and blood calcium monitoring. Cone beam CT (CB-CT) was performed on days 14, 28 and 56 post-op to assess 2D cortical healing, 3D bone volume, and Union Ratio. Biomechanical testing and dynamic histomorphometry were also performed. The high drug dose was poorly tolerated, as most dogs receiving rPTH1-34 had to be given intravenous saline, and one dog died from hypercalcemia. Continuous rPTH1-34 significantly increased 2D healing and callus volumes at 4-weeks versus Placebo, and sustained the significant increase in cortical union at 8-week (p<0.05). These rPTH1-34 effects were confirmed by histomorphometry, revealing significant increases in mineral apposition rates (MAR) on host bone and graft-host junctions (p<0.05). Delayed rPTH1-34 significantly increased callus volume and MAR at 8 weeks (p<0.05). Although no biomechanical differences were observed, as expected for early healing, the results demonstrated that 2D RUST scoring significantly correlated with torsional biomechanics (p<0.01). In conclusion, 8-weeks of intermittent high-dose rPTH1-34 treatment significantly increases callus formation and accelerates bony union of intercalary massive allografts in a clinically relevant canine model, but with serious side-effects from hypercalcemia.

High dose teriparatide (rPTH1-34) therapy increases callus volume and enhances radiographic healing at 8-weeks in a massive canine femoral allograft model

PubMed Central

Mietus, Zachary; Beck, Christopher A.; Ito, Hiromu; Matsuda, Shuichi; Awad, Hani A.; Ehrhart, Nicole; Schwarz, Edward M.

2017-01-01

Small animal studies have demonstrated significant high-dose recombinant parathyroid hormone1-34 (rPTH1-34) effects on intercalary allograft healing. Towards a human adjuvant therapy to decrease non-unions, we evaluated rPTH1-34 safety and efficacy in a clinically relevant canine femoral allograft model. Adult female mongrel hounds (n = 20) received a 5cm mid-diaphyseal osteotomy reconstructed with a plated allograft, and were randomized to: 1) Placebo (n = 5; daily saline), 2) Continuous rPTH1-34 (n = 7; 5 μg/kg/day s.c. from day 1–55 post-op), or 3) Delayed rPTH1-34 (n = 8; 5 μg/kg/day s.c. from day 14–28 post-op). Safety was assessed by physical behavior and blood calcium monitoring. Cone beam CT (CB-CT) was performed on days 14, 28 and 56 post-op to assess 2D cortical healing, 3D bone volume, and Union Ratio. Biomechanical testing and dynamic histomorphometry were also performed. The high drug dose was poorly tolerated, as most dogs receiving rPTH1-34 had to be given intravenous saline, and one dog died from hypercalcemia. Continuous rPTH1-34 significantly increased 2D healing and callus volumes at 4-weeks versus Placebo, and sustained the significant increase in cortical union at 8-week (p<0.05). These rPTH1-34 effects were confirmed by histomorphometry, revealing significant increases in mineral apposition rates (MAR) on host bone and graft-host junctions (p<0.05). Delayed rPTH1-34 significantly increased callus volume and MAR at 8 weeks (p<0.05). Although no biomechanical differences were observed, as expected for early healing, the results demonstrated that 2D RUST scoring significantly correlated with torsional biomechanics (p<0.01). In conclusion, 8-weeks of intermittent high-dose rPTH1-34 treatment significantly increases callus formation and accelerates bony union of intercalary massive allografts in a clinically relevant canine model, but with serious side-effects from hypercalcemia. PMID:29020057

Biomaterial delivery of morphogens to mimic the natural healing cascade in bone

PubMed Central

Mehta, Manav; Schmidt-Bleek, Katharina; Duda, Georg N; Mooney, David J

2012-01-01

Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing. PMID:22626978

Monitoring the mechanical properties of healing bone.

PubMed

Claes, L E; Cunningham, J L

2009-08-01

Fracture healing is normally assessed through an interpretation of radiographs, clinical evaluation, including pain on weight bearing, and a manual assessment of the mobility of the fracture. These assessments are subjective and their accuracy in determining when a fracture has healed has been questioned. Viewed in mechanical terms, fracture healing represents a steady increase in strength and stiffness of a broken bone and it is only when these values are sufficiently high to support unrestricted weight bearing that a fracture can be said to be healed. Information on the rate of increase of the mechanical properties of a healing bone is therefore valuable in determining both the rate at which a fracture will heal and in helping to define an objective and measurable endpoint of healing. A number of techniques have been developed to quantify bone healing in mechanical terms and these are described and discussed in detail. Clinical studies, in which measurements of fracture stiffness have been used to identify a quantifiable end point of healing, compare different treatment methods, predictably determine whether a fracture will heal, and identify factors which most influence healing, are reviewed and discussed.

Novel Therapy for Bone Regeneration in Large Segmental Defects

DTIC Science & Technology

2016-10-01

Giannoudis PV. Fat embolism and IM nailing. Injury. 2006;37(Suppl 4):S1–2. 38. Wenda K, Ritter G, Degreif J, Rudigier J. Pathogenesis of pul- monary... fracture healing, bone regeneration, minipig, pig 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF...saline control. 2. KEYWORDS: Bone healing, bone morphogenetic protein (BMP), thrombopoietin (TPO), therapy, fracture healing, bone regeneration, minipig

Possible benefits of strontium ranelate in complicated long bone fractures.

PubMed

Alegre, Duarte Nuno; Ribeiro, Costa; Sousa, Carlos; Correia, João; Silva, Luís; de Almeida, Luís

2012-02-01

Osteoporosis drugs are prescribed to prevent fragility fractures, which is the principal aim of the management of osteoporosis. However, if fracture does occur, then it is also important to promote a fast and uneventful healing process. Despite this, little is known about the effect of osteoporosis drugs on bone healing in humans. Strontium ranelate is an osteoporosis agent that increases bone formation and reduces bone resorption and may therefore be beneficial in fracture healing. We report four cases of fracture non-union for up to 20 months. Treatment with strontium ranelate (2 g/day) for between 6 weeks and 6 months appeared to contribute to bone consolidation in the four cases. Animal studies support beneficial effects of strontium ranelate on bone healing via improvement of bone material properties and microarchitecture in the vicinity of the fracture. The clinical cases described herein provide new information on these effects, in the absence of randomized controlled studies on the clinical efficacy of pharmacological treatments in osteoporosis in fracture repair. Further studies are necessary. Fracture healing is an important topic in orthopedic research and is also a concern for patients with postmenopausal osteoporosis. Evidence from case reports and animal studies suggests that strontium ranelate improves bone microarchitecture and accelerates fracture healing. A positive effect of osteoporosis treatments on bone healing is an interesting possibility and merits further clinical research.

Osthole Promotes Bone Fracture Healing through Activation of BMP Signaling in Chondrocytes.

PubMed

Wang, Pinger; Ying, Jun; Luo, Cheng; Jin, Xing; Zhang, Shanxing; Xu, Taotao; Zhang, Lei; Mi, Meng; Chen, Di; Tong, Peijian; Jin, Hongting

2017-01-01

Osthole is a bioactive coumarin derivative and has been reported to be able to enhance bone formation and improve fracture healing. However, the molecular mechanism of Osthole in bone fracture healing has not been fully defined. In this study we determined if Osthole enhances bone fracture healing through activation of BMP2 signaling in mice. We performed unilateral open transverse tibial fracture procedure in 10-week-old C57BL/6 mice which were treated with or without Osthole. Our previous studies demonstrated that chondrocyte BMP signaling is required for bone fracture healing, in this study we also performed tibial fracture procedure in Cre-negative and Col2-Cre;Bmp2 flox/flox conditional knockout (KO) mice ( Bmp2 Col2Cre ) to determine if Osthole enhances fracture healing in a BMP2-dependent manner. Fracture callus tissues were collected and analyzed by X-ray, micro-CT (μCT), histology, histomorphometry, immunohistochemistry (IHC), biomechanical testing and quantitative gene expression analysis. In addition, mouse chondrogenic ATDC5 cells were cultured with or without Osthole and the expression levels of chondrogenic marker genes were examined. The results demonstrated that Osthole promotes bone fracture healing in wild-type (WT) or Cre - control mice. In contrast, Osthole failed to promote bone fracture healing in Bmp2 Col2Cre conditional KO mice. In the mice receiving Osthole treatment, expression of cartilage marker genes was significantly increased. We conclude that Osthole could promote bone strength and enhance fracture healing by activation of BMP2 signaling. Osthole may be used as an alternative approach in the orthopaedic clinic for the treatment of fracture healing.

Osthole Promotes Bone Fracture Healing through Activation of BMP Signaling in Chondrocytes

PubMed Central

Wang, Pinger; Ying, Jun; Luo, Cheng; Jin, Xing; Zhang, Shanxing; Xu, Taotao; Zhang, Lei; Mi, Meng; Chen, Di; Tong, Peijian; Jin, Hongting

2017-01-01

Osthole is a bioactive coumarin derivative and has been reported to be able to enhance bone formation and improve fracture healing. However, the molecular mechanism of Osthole in bone fracture healing has not been fully defined. In this study we determined if Osthole enhances bone fracture healing through activation of BMP2 signaling in mice. We performed unilateral open transverse tibial fracture procedure in 10-week-old C57BL/6 mice which were treated with or without Osthole. Our previous studies demonstrated that chondrocyte BMP signaling is required for bone fracture healing, in this study we also performed tibial fracture procedure in Cre-negative and Col2-Cre;Bmp2flox/flox conditional knockout (KO) mice (Bmp2Col2Cre) to determine if Osthole enhances fracture healing in a BMP2-dependent manner. Fracture callus tissues were collected and analyzed by X-ray, micro-CT (μCT), histology, histomorphometry, immunohistochemistry (IHC), biomechanical testing and quantitative gene expression analysis. In addition, mouse chondrogenic ATDC5 cells were cultured with or without Osthole and the expression levels of chondrogenic marker genes were examined. The results demonstrated that Osthole promotes bone fracture healing in wild-type (WT) or Cre- control mice. In contrast, Osthole failed to promote bone fracture healing in Bmp2Col2Creconditional KO mice. In the mice receiving Osthole treatment, expression of cartilage marker genes was significantly increased. We conclude that Osthole could promote bone strength and enhance fracture healing by activation of BMP2 signaling. Osthole may be used as an alternative approach in the orthopaedic clinic for the treatment of fracture healing. PMID:28924381

Hypochlorhydria-induced calcium malabsorption does not affect fracture healing but increases post-traumatic bone loss in the intact skeleton.

PubMed

Haffner-Luntzer, Melanie; Heilmann, Aline; Heidler, Verena; Liedert, Astrid; Schinke, Thorsten; Amling, Michael; Yorgan, Timur Alexander; Vom Scheidt, Annika; Ignatius, Anita

2016-11-01

Efficient calcium absorption is essential for skeletal health. Patients with impaired gastric acidification display low bone mass and increased fracture risk because calcium absorption is dependent on gastric pH. We investigated fracture healing and post-traumatic bone turnover in mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells. Cckbr-/- mice display hypochlorhydria, calcium malabsorption, and osteopenia. Cckbr-/- and wildtype (WT) mice received a femur osteotomy and were fed either a standard or calcium-enriched diet. Healed and intact bones were assessed by biomechanical testing, histomorphometry, micro-computed tomography, and quantitative backscattering. Parathyroid hormone (PTH) serum levels were determined by enzyme-linked immunosorbent assay. Fracture healing was unaffected in Cckbr-/- mice. However, Cckbr-/- mice displayed increased calcium mobilization from the intact skeleton during bone healing, confirmed by significantly elevated PTH levels and osteoclast numbers compared to WT mice. Calcium supplementation significantly reduced secondary hyperparathyroidism and bone resorption in the intact skeleton in both genotypes, but more efficiently in WT mice. Furthermore, calcium administration improved bone healing in WT mice, indicated by significantly increased mechanical properties and bone mineral density of the fracture callus, whereas it had no significant effect in Cckbr-/- mice. Therefore, under conditions of hypochlorhydria-induced calcium malabsorption, calcium, which is essential for callus mineralization, appears to be increasingly mobilized from the intact skeleton in favor of fracture healing. Calcium supplementation during fracture healing prevented systemic calcium mobilization, thereby maintaining bone mass and improving fracture healing in healthy individuals whereas the effect was limited by gastric hypochlorhydria. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1914-1921, 2016. © 2016 The Authors. Journal of Orthopaedic Research Published by by Wiley Periodicals, Inc.

Secretion of SDF-1α by bone marrow-derived stromal cells enhances skin wound healing of C57BL/6 mice exposed to ionizing radiation

PubMed Central

Landry, Yannick; Lê, Oanh; Mace, Kimberly A; Restivo, Terry E; Beauséjour, Christian M

2010-01-01

Abstract Patients treated for cancer therapy using ionizing radiation (IR) have delayed tissue repair and regeneration. The mechanisms mediating these defects remain largely unknown at present, thus limiting the development of therapeutic approaches. Using a wound healing model, we here investigate the mechanisms by which IR exposure limits skin regeneration. Our data show that induction of the stromal cell-derived growth factor 1α (SDF-1α) is severely impaired in the wounded skin of irradiated, compared to non-irradiated, mice. Hence, we evaluated the potential of bone marrow-derived multipotent stromal cells (MSCs), which secrete high levels of SDF-1α, to improve skin regeneration in irradiated mice. Injection of MSCs into the wound margin led to remarkable enhancement of skin healing in mice exposed to IR. Injection of irradiated MSCs into the wound periphery of non-irradiated mice delayed wound closure, also suggesting an important role for the stromal microenvironment in skin repair. The beneficial actions of MSCs were mainly paracrine, as the cells did not differentiate into keratinocytes. Specific knockdown of SDF-1α expression led to drastically reduced efficiency of MSCs in improving wound closure, indicating that SDF-1α secretion by MSCs is largely responsible for their beneficial action. We also found that one mechanism by which SDF-1α enhances wound closure likely involves increased skin vascularization. Our findings collectively indicate that SDF-1α is an important deregulated cytokine in irradiated wounded skin, and that the decline in tissue regeneration potential following IR can be reversed, given adequate microenvironmental support PMID:19725920

Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton

PubMed Central

Yue, Rui; Shen, Bo; Morrison, Sean J

2016-01-01

Bone marrow stromal cells maintain the adult skeleton by forming osteoblasts throughout life that regenerate bone and repair fractures. We discovered that subsets of these stromal cells, osteoblasts, osteocytes, and hypertrophic chondrocytes secrete a C-type lectin domain protein, Clec11a, which promotes osteogenesis. Clec11a-deficient mice appeared developmentally normal and had normal hematopoiesis but reduced limb and vertebral bone. Clec11a-deficient mice exhibited accelerated bone loss during aging, reduced bone strength, and delayed fracture healing. Bone marrow stromal cells from Clec11a-deficient mice showed impaired osteogenic differentiation, but normal adipogenic and chondrogenic differentiation. Recombinant Clec11a promoted osteogenesis by stromal cells in culture and increased bone mass in osteoporotic mice in vivo. Recombinant human Clec11a promoted osteogenesis by human bone marrow stromal cells in culture and in vivo. Clec11a thus maintains the adult skeleton by promoting the differentiation of mesenchymal progenitors into mature osteoblasts. In light of this, we propose to call this factor Osteolectin. DOI: http://dx.doi.org/10.7554/eLife.18782.001 PMID:27976999

Bone morphogenetic protein (BMP)1-3 enhances bone repair.

PubMed

Grgurevic, Lovorka; Macek, Boris; Mercep, Mladen; Jelic, Mislav; Smoljanovic, Tomislav; Erjavec, Igor; Dumic-Cule, Ivo; Prgomet, Stefan; Durdevic, Dragan; Vnuk, Drazen; Lipar, Marija; Stejskal, Marko; Kufner, Vera; Brkljacic, Jelena; Maticic, Drazen; Vukicevic, Slobodan

2011-04-29

Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP-1) regulate morphogenesis by processing precursors to mature functional extracellular matrix (ECM) proteins and several growth factors including TGFβ, BMP2, BMP4 and GFD8. We have recently discovered that BMP1-3 isoform of the Bmp-1 gene circulates in the human plasma and is significantly increased in patients with acute bone fracture. We hypothesized that circulating BMP1-3 might have an important role in bone repair and serve as a novel bone biomarker. When administered systemically to rats with a long bone fracture and locally to rabbits with a critical size defect of the ulna, recombinant human BMP1-3 enhanced bone healing. In contrast, neutralization of the endogenous BMP1-3 by a specific polyclonal antibody delayed the bone union. Invitro BMP1-3 increased the expression of collagen type I and osteocalcin in MC3T3-E(1) osteoblast like cells, and enhanced the formation of mineralized bone nodules from bone marrow mesenchymal stem cells. We suggest that BMP1-3 is a novel systemic regulator of bone repair. Copyright © 2011 Elsevier Inc. All rights reserved.

Experimental models for cancellous bone healing in the rat

PubMed Central

Bernhardsson, Magnus; Sandberg, Olof; Aspenberg, Per

2015-01-01

Background and purpose — Cancellous bone appears to heal by mechanisms different from shaft fracture healing. There is a paucity of animal models for fractures in cancellous bone, especially with mechanical evaluation. One proposed model consists of a screw in the proximal tibia of rodents, evaluated by pull-out testing. We evaluated this model in rats by comparing it to the healing of empty drill holes, in order to explain its relevance for fracture healing in cancellous bone. To determine the sensitivity to external influences, we also compared the response to drugs that influence bone healing. Methods — Mechanical fixation of the screws was measured by pull-out test and related to the density of the new bone formed around similar, but radiolucent, PMMA screws. The pull-out force was also related to the bone density in drill holes at various time points, as measured by microCT. Results — The initial bone formation was similar in drill holes and around the screw, and appeared to be reflected by the pull-out force. Both models responded similarly to alendronate or teriparatide (PTH). Later, the models became different as the bone that initially filled the drill hole was resorbed to restore the bone marrow cavity, whereas on the implant surface a thin layer of bone remained, making it change gradually from a trauma-related model to an implant fixation model. Interpretation — The similar initial bone formation in the different models suggests that pull-out testing in the screw model is relevant for assessment of metaphyseal bone healing. The subsequent remodeling would not be of clinical relevance in either model. PMID:26200395

Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response.

PubMed

Chan, James K; Glass, Graeme E; Ersek, Adel; Freidin, Andrew; Williams, Garry A; Gowers, Kate; Espirito Santo, Ana I; Jeffery, Rosemary; Otto, William R; Poulsom, Richard; Feldmann, Marc; Rankin, Sara M; Horwood, Nicole J; Nanchahal, Jagdeep

2015-05-01

The mechanism by which trauma initiates healing remains unclear. Precise understanding of these events may define interventions for accelerating healing that could be translated to the clinical arena. We previously reported that addition of low-dose recombinant human TNF (rhTNF) at the fracture site augmented fracture repair in a murine tibial fracture model. Here, we show that local rhTNF treatment is only effective when administered within 24 h of injury, when neutrophils are the major inflammatory cell infiltrate. Systemic administration of anti-TNF impaired fracture healing. Addition of rhTNF enhanced neutrophil recruitment and promoted recruitment of monocytes through CCL2 production. Conversely, depletion of neutrophils or inhibition of the chemokine receptor CCR2 resulted in significantly impaired fracture healing. Fragility, or osteoporotic, fractures represent a major medical problem as they are associated with permanent disability and premature death. Using a murine model of fragility fractures, we found that local rhTNF treatment improved fracture healing during the early phase of repair. If translated clinically, this promotion of fracture healing would reduce the morbidity and mortality associated with delayed patient mobilization. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

Bone morphogenetic protein 2 and decorin expression in old fracture fragments and surrounding tissues.

PubMed

Han, X G; Wang, D K; Gao, F; Liu, R H; Bi, Z G

2015-09-21

Bone morphogenetic protein 2 (BMP-2) can promote fracture healing. Although the complex role BMP-2 in bone formation is increasingly understood, the role of endogenous BMP-2 in nonunion remains unclear. Decorin (DCN) can promote the formation of bone matrix and calcium deposition to control bone morphogenesis. In this study, tissue composition and expression of BMP-2 and DCN were detected in different parts of old fracture zones to explore inherent anti-fibrotic ability and osteogenesis. Twenty-three patients were selected, including eight cases of delayed union and 15 cases of nonunion. Average duration of delayed union or nonunion was 15 months. Fracture fragments and surrounding tissues, including bone grafts, marrow cavity contents, and sticking scars, were categorically sampled during surgery. Through observation and histological testing, component comparisons were made between fracture fragments and surrounding tissue. The expression levels of DCN and BMP-2 in different tissues were detected by immunohistochemical staining and real-time polymerase chain reaction. The expression of DCN and BMP- 2 in different parts of the nonunion area showed that, compared with bone graft and marrow cavity contents, sticking scars had the highest expression of BMP-2. Compared with the marrow cavity contents and sticking scars, bone grafts had the highest expression of DCN. The low antifibrotic and osteogenic activity of the nonunion area was associated with non-co-expression of BMP-2 and DCN. Therefore, the co-injection of osteogenic factor BMP and DCN into the nonunion area can improve the induction of bone formation and enhance the conversion of the old scar, thereby achieving better nonunion treatment.

Effects of coffee intake and intraperitoneal caffeine on bone repair process--a histologic and histometric study.

PubMed

Macedo, Rander Moreira; Brentegani, Luiz Guilherme; Lacerda, Suzie Aparecida de

2015-01-01

Studies have suggested that caffeine acts on bone promoting an increase of calcium excretion, inhibition of osteoblast proliferation and delay in tissue repair process, raising the risk of fractures, osteoporosis, periodontal disease and affecting the success of bone reconstructive procedures. The aim of this study was to analyze histomorphometrically the process of alveolar bone healing after tooth extraction in rats subjected to daily intake of boiled coffee or intraperitoneal administration of caffeine. Forty-five male rats were divided according to the treatment in Control group (C); Coffee group (CO) - treated with coffee since birth; and Caffeine (CAF) - intraperitoneal injection of aqueous solution of caffeine 1.5% (0.2 mL/100g body weight) for 30 days. When weighing between 250-300 g they were anesthetized, subjected to extraction of the maxillary right incisor, and euthanized 7, 21 and 42 days after surgery for histological assessments of bone volume and the quality of formed bone in the dental socket. The qualitative results demonstrated larger amounts of blood clot and immature bone in animals under treatment of pure caffeine compared to coffee and control. Histometric analysis revealed that coffee treatment led to a 40% drop in bone formation, and caffeine a 60% drop in comparison to control animals (ANOVA p≤0.01). It was concluded that both the daily ingestion of coffee and the intraperitoneal administration of caffeine in rats delayed the alveolar bone reparative process after tooth extraction, and this effect was more aggressive when pure caffeine was used.

Application of a novel bone osteotomy plate leads to reduction in heat-induced bone tissue necrosis in sheep.

PubMed

Bekić, Marijo; Davila, Slavko; Hrskanović, Mato; Bekić, Marijana; Seiwerth, Sven; Erdeljić, Viktorija; Capak, Darko; Butković, Vladimir

2008-12-01

Previous studies have shown substantial effect thermal damage can have on new bone formation following osteotomy. In this study we evaluated the extent of thermal damage which occurs in four different methods of osteotomy and the effects it can have on bone healing. We further wanted to test whether a special osteotomy plate we constructed can lead to diminished heat generation during osteotomy and enhanced bone healing. The four methods evaluated included osteotomy performed by chisel, a newly constructed osteotomy plate, Gigly and oscillating saw. Twelve adult sheep underwent osteotomy performed on both tibiae. Bone fragments were stabilized using a fixation plate. Callus size was assessed using standard radiographs. Densitometry and histological evaluation were performed at 8 weeks following osteotomy. Temperature measurements were performed both in vivo during the operation, and ex vivo on explanted tibiae. The defects healed without complications and showed typical course of secondary fracture healing with callus ingrowth into the osteotomy gap. Radiographic examination of bone healing showed a tendency towards more callus formation in bones osteotomized using Gigly and oscillating saw, but this difference lacked significance. Use of Gigly and oscillating saw elicited much higher temperatures at the bone cortex surface, which subsequently lead to slightly impaired bone healing according to histological analysis. BMD was equal among all bones. In conclusion, the time required for complete healing of the defect differed depended greatly on the instruments used. The newly constructed osteotomy plate showed best results based on histological findings of capillary and osteoblast density.

Vitamin E and the Healing of Bone Fracture: The Current State of Evidence

PubMed Central

Borhanuddin, Boekhtiar; Mohd Fozi, Nur Farhana; Naina Mohamed, Isa

2012-01-01

Background. The effect of vitamin E on health-related conditions has been extensively researched, with varied results. However, to date, there was no published review of the effect of vitamin E on bone fracture healing. Purpose. This paper systematically audited past studies of the effect of vitamin E on bone fracture healing. Methods. Related articles were identified from Medline, CINAHL, and Scopus databases. Screenings were performed based on the criteria that the study must be an original study that investigated the independent effect of vitamin E on bone fracture healing. Data were extracted using standardised forms, followed by evaluation of quality of reporting using ARRIVE Guidelines, plus recalculation procedure for the effect size and statistical power of the results. Results. Six animal studies fulfilled the selection criteria. The study methods were heterogeneous with mediocre reporting quality and focused on the antioxidant-related mechanism of vitamin E. The metasynthesis showed α-tocopherol may have a significant effect on bone formation during the normal bone remodeling phase of secondary bone healing. Conclusion. In general, the effect of vitamin E on bone fracture healing remained inconclusive due to the small number of heterogeneous and mediocre studies included in this paper. PMID:23304211

Preparation and Evaluations of Mangiferin-Loaded PLGA Scaffolds for Alveolar Bone Repair Treatment Under the Diabetic Condition.

PubMed

Li, Hao; Liao, Hongbing; Bao, Chongyun; Xiao, Yu; Wang, Qi

2017-02-01

The aim of the present study was to prepare and evaluate a sustained-release mangiferin scaffold for improving alveolar bone defect repair in diabetes. Mangiferin-loaded poly(D,L-lactide-co-glycolide) (PLGA) scaffolds were prepared using a freeze-drying technique with ice particles as the porogen material. The produced scaffolds were examined using a scanning electron microscope (SEM). Drug content and drug release were detected using a spectrophotometer. Degradation behaviors were monitored as a measure of weight loss and examined using SEM. Then, the scaffolds were incubated with rat bone marrow stromal cells under the diabetic condition in vitro, and cell viability was assessed using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Afterward, the scaffolds were implanted into alveolar bone defects of diabetic rats, and bone repair was examined using hematoxylin and eosin staining. The fabricated scaffolds showed porous structures, with average pore size range from 111.35 to 169.45 μm. A higher PLGA concentration led to decreased average pore size. A lower PLGA concentration or a higher mangiferin concentration resulted in increased drug content. The prepared scaffolds released mangiferin in a sustained manner with relatively low initial burst during 10 weeks. Their degradation ratios gradually increased as degradation proceeded. The mangiferin-loaded scaffolds attenuated cell viability decrease under the diabetic condition in vitro. Moreover, they increased histological scorings of bone regeneration and improved delayed alveolar bone defect healing in diabetic rats. These results suggest that the produced mangiferin-loaded scaffolds may provide a potential approach in the treatment of impaired alveolar bone healing in diabetes.

Holding fast.

PubMed

Gourville, John T

2005-06-01

CEO Peter Walsh faces a classic innovator's dilemma. His company, Crescordia, produces high-quality metal plates, pins, and screws that orthopedic surgeons use to repair broken bones. In fact, because the company has for decades refused to compromise on quality, there are orthopedic surgeons who use nothing but Crescordia hardware. And now these customers have begun to clamor for the next generation technology: resorbable hardware. Resorbables offer clear advantages over the traditional hardware. Like dissolving sutures, resorbable plates and screws are made of biodegradable polymers. They hold up long enough to support a healing bone, then gradually and harmlessly disintegrate in the patient's body. Surgeons are especially looking forward to using resorbables on children, so kids won't have to undergo a second operation to remove the old hardware after their bones heal, a common procedure in pediatrics. The new products, however, are not yet reliable; they fail about 8% of the time, sometimes disintegrating before the bone completely heals and sometimes not ever fully disintegrating. That's why Crescordia, mindful of its hard-earned reputation, has delayed launching a line using the new technology. But time is running out. A few competitors have begun to sell resorbables despite their imperfections, and these companies are picking up market share. Should Crescordia join the fray and risk tarnishing its brand? Or should the company sit tight until it can offer a perfect product? Commenting on this fictional case study are Robert A. Lutz, vice chairman of product development at General Motors; Clayton M. Christensen, the Robert and Jane Cizik Professor of Business Administration at Harvard Business School; Jason Wittes, a senior equity analyst covering medical supplies and devices at Leerink Swann; and Nick Galakatos, a general partner of MPM Capital.

Histologic Evaluation of Critical Size Defect Healing With Natural and Synthetic Bone Grafts in the Pigeon ( Columba livia ) Ulna.

PubMed

Tunio, Ahmed; Jalila, Abu; Goh, Yong Meng; Shameha-Intan; Shanthi, Ganabadi

2015-06-01

Fracture and bone segment loss are major clinical problems in birds. Achieving bone formation and clinical union in a fracture case is important for the survival of the bird. To evaluate the efficacy of bone grafts for defect healing in birds, 2 different bone grafts were investigated in the healing of a bone defect in 24 healthy pigeons ( Columba livia ). In each bird, a 1-cm critical size defect (CSD) was created in the left ulna, and the fracture was stabilized with external skeletal fixation (ESF). A graft of hydroxyapatite (HA) alone (n = 12 birds) or demineralized bone matrix (DBM) combined with HA (n = 12 birds) was implanted in the CSD. The CSD healing was evaluated at 3 endpoints: 3, 6, and 12 weeks after surgery. Four birds were euthanatized at each endpoint from each treatment group, and bone graft healing in the ulna CSD was evaluated by histologic examination. The CSD and graft implants were evaluated for quality of union, cortex development, and bone graft incorporation. Results showed no graft rejection in any bird, and all birds had connective tissue formation in the defect because of the bone graft application. These results suggest that bone defect healing can be achieved by a combination of osteoinductive and osteoconductive bone graft materials for clinical union and new bone regeneration in birds. The combination of DBM and HA resulted in a better quality bone graft (P < .05) than did HA alone, but there was no significant differences in cortex development or bone graft incorporation at 3, 6, or 12 weeks. From the results of this study, we conclude that HA bone grafts, alone or in combination with DBM, with external skeletal fixation is suitable and safe for bone defect and fracture treatment in pigeons.

Bringing new life to damaged bone: the importance of angiogenesis in bone repair and regeneration.

PubMed

Stegen, Steve; van Gastel, Nick; Carmeliet, Geert

2015-01-01

Bone has the unique capacity to heal without the formation of a fibrous scar, likely because several of the cellular and molecular processes governing bone healing recapitulate the events during skeletal development. A critical component in bone healing is the timely appearance of blood vessels in the fracture callus. Angiogenesis, the formation of new blood vessels from pre-existing ones, is stimulated after fracture by the local production of numerous angiogenic growth factors. The fracture vasculature not only supplies oxygen and nutrients, but also stem cells able to differentiate into osteoblasts and in a later phase also the ions necessary for mineralization. This review provides a concise report of the regulation of angiogenesis by bone cells, its importance during bone healing and its possible therapeutic applications in bone tissue engineering. This article is part of a Special Issue entitled "Stem Cells and Bone". Copyright © 2014 Elsevier Inc. All rights reserved.

Bmp2 conditional knockout in osteoblasts and endothelial cells does not impair bone formation after injury or mechanical loading in adult mice

PubMed Central

McKenzie, Jennifer A.; Buettmann, Evan G.; Gardner, Michael J.; Silva, Matthew J.

2015-01-01

Post-natal osteogenesis after mechanical trauma or stimulus occurs through either endochondral healing, intramembranous healing or lamellar bone formation. Bone morphogenetic protein 2 (BMP2) is up-regulated in each of these osteogenic processes and is expressed by a variety of cells including osteoblasts and vascular cells. It is known that genetic knockout of Bmp2 in all cells or in osteo-chondroprogenitor cells completely abrogates endochondral healing after full fracture. However, the importance of BMP2 from differentiated osteoblasts and endothelial cells is not known. Moreover, the importance of BMP2 in non-endochondral bone formation such as intramembranous healing or lamellar bone formation is not known. Using inducible and tissue-specific Cre-lox mediated targeting of Bmp2 in adult (10–24 week old) mice, we assessed the role of BMP2 expression globally, by osteoblasts, and by vascular endothelial cells in endochondral healing, intramembranous healing and lamellar bone formation. These three osteogenic processes were modeled using full femur fracture, ulnar stress fracture, and ulnar non-damaging cyclic loading, respectively. Our results confirmed the requirement of BMP2 for endochondral fracture healing, as mice in which Bmp2 was knocked out in all cells prior to fracture failed to form a callus. Targeted deletion of Bmp2 in osteoblasts (osterix-expressing) or vascular endothelial cells (vascular endothelial cadherin-expressing) did not impact fracture healing in any way. Regarding non-endochondral bone formation, we found that BMP2 is largely dispensable for intramembranous bone formation after stress fracture and also not required for lamellar bone formation induced by mechanical loading. Taken together our results indicate that osteoblasts and endothelial cells are not a critical source of BMP2 in endochondral fracture healing, and that non-endochondral bone formation in the adult mouse is not as critically dependent on BMP2. PMID:26344756

Emulating Native Periosteum Cell Population and Subsequent Paracrine Factor Production To Promote Tissue Engineered Periosteum-Mediated Allograft Healing

PubMed Central

Hoffman, Michael D.

2015-01-01

Emulating autograft healing within the context of decellularized bone allografts has immediate clinical applications in the treatment of critical-sized bone defects. The periosteum, a thin, osteogenic tissue that surrounds bone, houses a heterogeneous population of stem cells and osteoprogenitors. There is evidence that periosteum-cell derived paracrine factors, specifically vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2), orchestrate autograft healing through host cell recruitment and subsequent tissue elaboration. In previous work, we demonstrated that the use of poly(ethylene glycol) (PEG) hydrogels as a tissue engineered (T.E.) periosteum to localize mesenchymal stem cells (MSCs) to the surface of decellularized bone enhances allograft healing and integration. Herein, we utilize a mixed population of 50:50 MSCs and osteoprogenitor cells to better mimic native periosteum cell population and paracrine factor production to further promote allograft healing. This mixed cell population was localized to the surface of decellularized allografts within degradable hydrogels and shown to expedite allograft healing. Specifically, bone callus formation and biomechanical graft-host integration are increased as compared to unmodified allografts. These results demonstrate the dual importance of periosteum-mediated paracrine factors orchestrating host cell recruitment as well as new bone formation while developing clinically translatable strategies for allograft healing and integration. PMID:25818449

Are bone turnover markers capable of predicting callus consolidation during bone healing?

PubMed

Klein, P; Bail, H J; Schell, H; Michel, R; Amthauer, H; Bragulla, H; Duda, G N

2004-07-01

The aim of this study was to determine the ability of the following bone turnover markers to monitor the course of callus consolidation during bone healing: Carboxy-terminal propeptide of procollagen type I (PICP), skeletal alkaline phosphatase (sALP), and amino-terminal propeptide of type III procollagen (PIlINP). Since interfragmentary movements have been proven to possess the ability to document the progression of bone healing in experimental studies, correlations between bone turnover markers and interfragmentary movements in vivo were investigated. Therefore, two different types of osteosyntheses representing different mechanical situations at the fracture site were compared in an ovine osteotomy model. Blood samples were taken preoperatively and postoperatively in weekly intervals over a nine-week healing period. At the same intervals, interfragmentary movements were measured in all sheep. After nine weeks, animals were sacrificed and the tibiae were evaluated both mechanically and histologically. Wide interindividual ranges were observed for all bone turnover markers. The systemic PICP level did not increase with callus consolidation. The bone-healing model seemed to influence the systemic level of PIIINP and sALP but no general correlation between bone turnover markers and interfragmentary movements could be detected. No differences between the different types of osteosyntheses and thus the different mechanical situations were observed. All analyzed markers failed as general predictors for the course of callus consolidation during bone healing.

Ketorolac administration does not delay early fracture healing in a juvenile rat model: a pilot study.

PubMed

Cappello, Teresa; Nuelle, Julia A V; Katsantonis, Nicolas; Nauer, Rachel K; Lauing, Kristen L; Jagodzinski, Jason E; Callaci, John J

2013-06-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective at controlling pain in children, especially in the treatment of fractures. Adult animal and adult clinical studies demonstrate conflicting evidence for the inhibitory relationship between NSAIDs and fracture healing. Published pediatric orthopaedic clinical studies do not demonstrate an inhibitory effect of ketorolac on bone healing. Little is known about the effects of any NSAID on bone formation in juvenile animals. This study investigates the effects of the NSAID ketorolac on fracture healing in a juvenile rat model. Unilateral surgically induced and stabilized tibial shaft fractures were created in 45 juvenile (3 to 4 wk old) male Sprague-Dawley rats. Either ketorolac (5 mg/kg; n=24) or saline (0.9% normal saline; n=21) was then administered to the rats 6 d/wk by intraperitoneal injections. Animals were then randomly assigned into time groups and euthanized at 7 days (n=8 ketorolac, n=7 saline), 14 days (n=8 ketorolac, n=7 saline), or 21 days (n=8 ketorolac, n=7 saline) postfracture. Biomechanical analysis was performed using a custom-designed 4-point bending loading apparatus. Statistics for tibial stiffness and strength data were performed using software package Systat 11. Specimens were also evaluated histologically using hematoxylin and eosin staining. Strength and stiffness of all fractured tibiae increased over time from day 7 to day 21 regardless of treatment type. No statistical difference was found between the fractured tibiae strength or stiffness in the ketorolac or control-treated specimens at the same time point. In addition, the quality of the fracture callus was similar in both groups at each of the time points. In this study of a juvenile rat model with a stabilized tibia fracture, fracture callus strength, stiffness, and histologic characteristics were not affected by the administration of ketorolac during the first 21 days of fracture healing. The absence of inhibitory effects of ketorolac on early juvenile rat fracture healing supports the clinical practice of utilizing NSAIDs for analgesia in children with long bone fractures.

Ketorolac Administration Does Not Delay Early Fracture Healing in a Juvenile Rat Model

PubMed Central

Cappello, Teresa; Nuelle, Julia A.V.; Katsantonis, Nicolas; Nauer, Rachel K.; Lauing, Kristen L.; Jagodzinski, Jason E.; Callaci, John J.

2014-01-01

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective at controlling pain in children, especially in the treatment of fractures. Adult animal and adult clinical studies demonstrate conflicting evidence for the inhibitory relationship between NSAIDs and fracture healing. Published pediatric orthopaedic clinical studies do not demonstrate an inhibitory effect of ketorolac on bone healing. Little is known about the effects of any NSAID on bone formation in juvenile animals. This study investigates the effects of the NSAID ketorolac on fracture healing in a juvenile rat model. Methods Unilateral surgically induced and stabilized tibial shaft fractures were created in 45 juvenile (3 to 4wk old) male Sprague-Dawley rats. Either ketorolac (5 mg/kg; n=24) or saline (0.9% normal saline; n=21) was then administered to the rats 6 d/wk by intraperitoneal injections. Animals were then randomly assigned into time groups and euthanized at 7 days (n=8 ketorolac, n=7 saline), 14 days (n=8 ketorolac, n=7 saline), or 21 days (n=8 ketorolac, n=7 saline) postfracture. Biomechanical analysis was performed using a custom-designed 4-point bending loading apparatus. Statistics for tibial stiffness and strength data were performed using software package Systat 11. Specimens were also evaluated histologically using hematoxylin and eosin staining. Results Strength and stiffness of all fractured tibiae increased over time from day 7 to day 21 regardless of treatment type. No statistical difference was found between the fractured tibiae strength or stiffness in the ketorolac or control-treated specimens at the same time point. In addition, the quality of the fracture callus was similar in both groups at each of the time points. Conclusions In this study of a juvenile rat model with a stabilized tibia fracture, fracture callus strength, stiffness, and histologic characteristics were not affected by the administration of ketorolac during the first 21 days of fracture healing. Clinical Relevance The absence of inhibitory effects of ketorolac on early juvenile rat fracture healing supports the clinical practice of utilizing NSAIDs for analgesia in children with long bone fractures. PMID:23653032

Biomaterial delivery of morphogens to mimic the natural healing cascade in bone.

PubMed

Mehta, Manav; Schmidt-Bleek, Katharina; Duda, Georg N; Mooney, David J

2012-09-01

Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing. Copyright © 2012 Elsevier B.V. All rights reserved.

IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4+ T cells

PubMed Central

Xu, Jiajia; Wang, Yiyun; Li, Jing; Zhang, Xudong; Geng, Yiyun; Huang, Yan; Dai, Kerong; Zhang, Xiaoling

2016-01-01

Severe or prolonged inflammatory response caused by infection or biomaterials leads to delayed healing or bone repair failure. This study investigated the important roles of the proinflammatory cytokines of the interleukin-12 (IL-12) family, namely, IL-12 and IL-23, in the inflammation-mediated inhibition of bone formation in vivo. IL-12p40−/− mice lacking IL-12 and IL-23 exhibited enhanced bone formation. IL-12 and IL-23 indirectly inhibited bone marrow mesenchymal stem cell (BMMSC) differentiation by stimulating CD4+ T cells to increase interferon γ (IFN-γ) and IL-17 levels. Mechanistically, IL-17 synergistically enhanced IFN-γ-induced BMMSC apoptosis. Moreover, INF-γ and IL-17 exerted proapoptotic effects by upregulating the expression levels of Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as by activating the caspase cascade in BMMSCs. IL-12p40 depletion in mice could promote ectopic bone formation. Thus, IL-12p40 is an attractive therapeutic target to overcome the inflammation-mediated inhibition of bone formation in vivo. PMID:27472064

Simulation of peri-implant bone healing due to immediate loading in dental implant treatments.

PubMed

Chou, Hsuan-Yu; Müftü, Sinan

2013-03-15

The goal of this work was to investigate the role of immediate loading on the peri-implant bone healing in dental implant treatments. A mechano-regulatory tissue differentiation model that takes into account the stimuli through the solid and the fluid components of the healing tissue, and the diffusion of pluripotent stem cells into the healing callus was used. A two-dimensional axisymmetric model consisting of a dental implant, the healing callus tissue and the host bone tissue was constructed for the finite element analysis. Poroelastic material properties were assigned to the healing callus and the bone tissue. The effects of micro-motion, healing callus size, and implant thread design on the length of the bone-to-implant contact (BIC) and the bone volume (BV) formed in the healing callus were investigated. In general, the analysis predicted formation of a continuous layer of soft tissue along the faces of the implant which are parallel to the loading direction. This was predicted to be correlated with the high levels of distortional strain transferred through the solid component of the stimulus. It was also predicted that the external threads on the implant, redistribute the interfacial load, thus help reduce the high distortional stimulus and also help the cells to differentiate to bone tissue. In addition, the region underneath the implant apex was predicted to experience high fluid stimulus that results in the development of soft tissue. The relationship between the variables considered in this study and the outcome measures, BV and BIC, was found to be highly nonlinear. A three-way analysis of variance (ANOVA) of the results was conducted and it showed that micro-motion presents the largest hindrance to bone formation during healing. Copyright © 2013 Elsevier Ltd. All rights reserved.

Delayed union and nonunions: epidemiology, clinical issues, and financial aspects.

PubMed

Hak, David J; Fitzpatrick, Daniel; Bishop, Julius A; Marsh, J Lawrence; Tilp, Susanne; Schnettler, Reinhard; Simpson, Hamish; Alt, Volker

2014-06-01

Fracture healing is a critically important clinical event for fracture patients and for clinicians who take care of them. The clinical evaluation of fracture healing is based on both radiographic findings and clinical findings. Risk factors for delayed union and nonunion include patient dependent factors such as advanced age, medical comorbidities, smoking, non-steroidal anti-inflammatory use, various genetic disorders, metabolic disease and nutritional deficiency. Patient independent factors include fracture pattern, location, and displacement, severity of soft tissue injury, degree of bone loss, quality of surgical treatment and presence of infection. Established nonunions can be characterised in terms of biologic capacity, deformity, presence or absence of infection, and host status. Hypertrophic, oligotrophic and atrophic radiographic appearances allow the clinician to make inferences about the degree of fracture stability and the biologic viability of the fracture fragments while developing a treatment plan. Non-unions are difficult to treat and have a high financial impact. Indirect costs, such as productivity losses, are the key driver for the overall costs in fracture and non-union patients. Therefore, all strategies that help to reduce healing time with faster resumption of work and activities not only improve medical outcome for the patient, they also help reduce the financial burden in fracture and non-union patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

Accelerated Bone Repair After Plasma Laser Corticotomies

PubMed Central

Leucht, Philipp; Lam, Kentson; Kim, Jae-Beom; Mackanos, Mark A.; Simanovskii, Dmitrii M.; Longaker, Michael T.; Contag, Christopher H.; Schwettman, H Alan; Helms, Jill A.

2007-01-01

Objective: To reveal, on a cellular and molecular level, how skeletal regeneration of a corticotomy is enhanced when using laser-plasma mediated ablation compared with conventional mechanical tissue removal. Summary Background Data: Osteotomies are well-known for their most detrimental side effect: thermal damage. This thermal and mechanical trauma to adjacent bone tissue can result in the untoward consequences of cell death and eventually in a delay in healing. Methods: Murine tibial corticotomies were performed using a conventional saw and a Ti:Sapphire plasma-generated laser that removes tissue with minimal thermal damage. Our analyses began 24 hours after injury and proceeded to postsurgical day 6. We investigated aspects of wound repair ranging from vascularization, inflammation, cell proliferation, differentiation, and bone remodeling. Results: Histology of mouse corticotomy sites uncovered a significant difference in the onset of bone healing; whereas laser corticotomies showed abundant bone matrix deposition at postsurgical day 6, saw corticotomies only exhibited undifferentiated tissue. Our analyses uncovered that cutting bone with a saw caused denaturation of the collagen matrix due to thermal effects. This denatured collagen represented an unfavorable scaffold for subsequent osteoblast attachment, which in turn impeded deposition of a new bony matrix. The matrix degradation induced a prolonged inflammatory reaction at the cut edge to create a surface favorable for osteochondroprogenitor cell attachment. Laser corticotomies were absent of collagen denaturation, therefore osteochondroprogenitor cell attachment was enabled shortly after surgery. Conclusion: In summary, these data demonstrate that corticotomies performed with Ti:Sapphire lasers are associated with a reduced initial inflammatory response at the injury site leading to accelerated osteochondroprogenitor cell migration, attachment, differentiation, and eventually matrix deposition. PMID:17592303

Marginal bone loss around non-submerged implants is associated with salivary microbiome during bone healing.

PubMed

Duan, Xiao-Bo; Wu, Ting-Xi; Guo, Yu-Chen; Zhou, Xue-Dong; Lei, Yi-Ling; Xu, Xin; Mo, An-Chun; Wang, Yong-Yue; Yuan, Quan

2017-06-01

Marginal bone loss during bone healing exists around non-submerged dental implants. The aim of this study was to identify the relationship between different degrees of marginal bone loss during bone healing and the salivary microbiome. One hundred patients were recruited, and marginal bone loss around their implants was measured using cone beam computed tomography during a 3-month healing period. The patients were divided into three groups according to the severity of marginal bone loss. Saliva samples were collected from all subjected and were analysed using 16S MiSeq sequencing. Although the overall structure of the microbial community was not dramatically altered, the relative abundance of several taxonomic groups noticeably changed. The abundance of species in the phyla Spirochaeta and Synergistetes increased significantly as the bone loss became more severe. Species within the genus Treponema also exhibited increased abundance, whereas Veillonella, Haemophilus and Leptotrichia exhibited reduced abundances, in groups with more bone loss. Porphyromonasgingivalis, Treponemadenticola and Streptococcus intermedius were significantly more abundant in the moderate group and/or severe group. The severity of marginal bone loss around the non-submerged implant was associated with dissimilar taxonomic compositions. An increased severity of marginal bone loss was related to increased proportions of periodontal pathogenic species. These data suggest a potential role of microbes in the progression of marginal bone loss during bone healing.

Tendon Healing in Bone Tunnel after Human Anterior Cruciate Ligament Reconstruction: A Systematic Review of Histological Results.

PubMed

Lu, Hongbin; Chen, Can; Xie, Shanshan; Tang, Yifu; Qu, Jin

2018-05-21

Most studies concerning to tendon healing and incorporation into bone are mainly based on animal studies due to the invasive nature of the biopsy procedure. The evidence considering tendon graft healing to bone in humans is limited in several case series or case reports, and therefore, it is difficult to understand the healing process. A computerized search using relevant search terms was performed in the PubMed, EMBASE, Scopus, and Cochrane Library databases, as well as a manual search of reference lists. Searches were limited to studies that investigated tendon graft healing to bone by histologic examination after anterior cruciate ligament (ACL) reconstruction with hamstring. Ten studies were determined to be eligible for this systematic review. Thirty-seven cases were extracted from the included studies. Most studies showed that a fibrovascular interface would form at the tendon-bone interface at the early stage and a fibrous indirect interface with Sharpey-like fibers would be expected at the later stage. Cartilage-like tissue at tendon graft-bone interface was reported in three studies. Tendon graft failed to integrate with the surrounding bone in 10 of the 37 cases. Unexpectedly, suspensory type of fixation was used for the above failure cases. An indirect type of insertion with Sharpey-like fibers at tendon-bone interface could be expected after ACL reconstruction with hamstring. Regional cartilage-like tissue may form at tendon-bone interface occasionally. The underlying tendon-to-bone healing process is far from understood in the human hamstring ACL reconstruction. Further human studies are highly needed to understand tendon graft healing in bone tunnel after hamstring ACL reconstruction. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing.

PubMed

Wang, Tao; Wang, Yongmei; Menendez, Alicia; Fong, Chak; Babey, Muriel; Tahimic, Candice G T; Cheng, Zhiqiang; Li, Alfred; Chang, Wenhan; Bikle, Daniel D

2015-09-01

Insulin-like growth factors (IGFs) are important local regulators during fracture healing. Although IGF1 deficiency is known to increase the risk of delayed union or non-union fractures in the elderly population, the underlying mechanisms that contribute to this defect remains unclear. In this study, IGF1 signaling during fracture healing was investigated in an osteoblast-specific IGF1 receptor (IGF1R) conditional knockout (KO) mouse model. A closed tibial fracture was induced in IGF1R(flox/flox) /2.3-kb α1(1)-collagen-Cre (KO) and IGF1R(flox/flox) (control) mice aged 12 weeks. Fracture callus samples and nonfractured tibial diaphysis were collected and analyzed by μCT, histology, immunohistochemistry, histomorphometry, and gene expression analysis at 10, 15, 21, and 28 days after fracture. A smaller size callus, lower bone volume accompanied by a defect in mineralization, bone microarchitectural abnormalities, and a higher cartilage volume were observed in the callus of these KO mice. The levels of osteoblast differentiation markers (osteocalcin, alkaline phosphatase, collagen 1α1) were significantly reduced, but the early osteoblast transcription factor runx2, as well as chondrocyte differentiation markers (collagen 2α1 and collagen 10α1) were significantly increased in the KO callus. Moreover, increased numbers of osteoclasts and impaired angiogenesis were observed during the first 15 days of fracture repair, but decreased numbers of osteoclasts were found in the later stages of fracture repair in the KO mice. Although baseline nonfractured tibias of KO mice had decreased trabecular and cortical bone compared to control mice, subsequent studies with mice expressing the 2.3-kb α1(1)-collagen-Cre ERT2 construct and given tamoxifen at the time of fracture and so starting with comparable bone levels showed similar impairment in fracture repair at least initially. Our data indicate that not only is the IGF1R in osteoblasts involved in osteoblast differentiation during fracture repair, but it plays an important role in coordinating chondrocyte, osteoclast, and endothelial responses that all contribute to the endochondral bone formation required for normal fracture repair. © 2015 American Society for Bone and Mineral Research.

The variation in breast density and its relationship to delayed wound healing: a prospective study of 40 reduction mammoplasties.

PubMed

Baldwin, C J; Kelly, E J; Batchelor, A G

2010-04-01

The proportions of glandular and adipose tissue within the breast vary. This study records the variation in density of breast tissue excised at 40 consecutive bilateral breast reductions. Age, body mass index (BMI), breast size and wound healing problems were related to breast density. The removed breast tissue was weighed and volume determined by water displacement. Delayed wound healing was defined as any breast unhealed after 2 weeks. The density of excised tissue varied between 0.8 and 1.2g/cm(3). There was no correlation between age or BMI and breast density. Delayed wound healing occurred in 32% of patients. There was no correlation between delayed wound healing and breast density. However, there was a direct relationship between increasing BMI and delayed wound healing. In this study, breast density varied by up to 50%. The density of breast tissue cannot be predicted by age, BMI or breast size. There is no relationship between delayed wound healing and breast density. Copyright 2009. Published by Elsevier Ltd.

Phosphorus Necrosis of the Jaw: A Present-day Study

PubMed Central

Hughes, J. P. W.; Baron, R.; Buckland, D. H.; Cooke, M. A.; Craig, J. D.; Duffield, D. P.; Grosart, A. W.; Parkes, P. W. J.; Porter, A.

1962-01-01

A historical note on the aetiology of phossy jaw shows that present-day knowledge is little greater than it was a century ago. The varied clinical course of the disease is described together with a report of 10 classical cases not previously reported. Six cases, not amounting to true necrosis but in which healing after dental extraction was delayed, and described, and mention is made of the noticeable differences in the oral state and appearances of tartar of healthy workmen exposed to phosphorus compared with healthy workmen not exposed. But no systematic differences of any kind were found in the incidence of general infections, fractures of bones, haematological findings, and biochemical studies of blood and urine in two groups of healthy men most exposed and least exposed to phosphorous in the same factory. An intensive study in hospital of a case of classical necrosis showed no departure from normal, except delayed healing following bone biopsy from the iliac crest, and a reversed polymorphonuclear/lymphocyte ratio. In the discussion the time of onset of necrosis after first exposure to phosphorus, clinical and radiological diagnosis, the organisms present, personal susceptibility, the appearance of the sequestra, and regeneration of bone are considered. An up-to-date note on prevention of the disease is given, although this has met with only partial success. Some persons are highly susceptible and, whilst complete protection is impossible in the light of our present knowledge, early diagnosis and modern treatment have robbed the disease of its terrible manifestations of Victorian times and turned it into a minor, although often uncomfortable complaint, with little or no resulting disability. Images PMID:14449812

Platelet-Rich Plasma in the Animal Long-Bone Model: An Analysis of Basic Science Evidence.

PubMed

Gianakos, Arianna; Zambrana, Lester; Savage-Elliott, Ian; Lane, Joseph M; Kennedy, John G

2015-12-01

Platelet-rich plasma (PRP) has been suggested as an adjunct to aid in long-bone healing. The purpose of this study was to systematically review the basic science in vivo evidence for the use of PRP in the treatment of bone pathology. The PubMed/MEDLINE and EMBASE databases were screened using the following search criteria: "(Platelet-rich plasma OR PRP OR autologous conditioned plasma OR ACP) AND (bone OR osteocytes OR osteogenesis OR nonunion OR delayed union)." Studies were included if they fulfilled the following criteria: (1) studied the effect of PRP or a similar concentrated platelet product, defined as a blood product with platelet concentration elevated to higher than baseline; (2) established a control with which to compare PRP; (3) were published in a peer-reviewed journal; and (4) looked specifically at animal long-bone models. All review articles and clinical studies, including randomized controlled trials and case series, were excluded from the review. Studies examining the effects of PRP on bones of animals with confounding pathology were excluded. In studies that contained additional treatment variables, only the portion of the experiment that compared PRP directly with the control were evaluated. Data were then extracted with a standardized table. The search yielded 29 articles for inclusion. Seventy-two percent of the studies reported platelet concentrations. Eighty-nine percent of studies reported significant improvement in earlier bone healing on histologic/histomorphometric assessment. One hundred percent showed significant increase in bone formation on radiographs in the PRP group. Eighty percent of studies reported a significant increase in bone area on microcomputed tomography. One hundred percent of studies showed a higher torsional stiffness for the PRP-treated defects. In the in vivo studies evaluated, PRP confers several beneficial effects on animal long-bone models. Proof of concept for PRP as a biologic adjunct in long-bone models has been determined. Copyright 2015, SLACK Incorporated.

Adjustable stiffness, external fixator for the rat femur osteotomy and segmental bone defect models.

PubMed

Glatt, Vaida; Matthys, Romano

2014-10-09

The mechanical environment around the healing of broken bone is very important as it determines the way the fracture will heal. Over the past decade there has been great clinical interest in improving bone healing by altering the mechanical environment through the fixation stability around the lesion. One constraint of preclinical animal research in this area is the lack of experimental control over the local mechanical environment within a large segmental defect as well as osteotomies as they heal. In this paper we report on the design and use of an external fixator to study the healing of large segmental bone defects or osteotomies. This device not only allows for controlled axial stiffness on the bone lesion as it heals, but it also enables the change of stiffness during the healing process in vivo. The conducted experiments have shown that the fixators were able to maintain a 5 mm femoral defect gap in rats in vivo during unrestricted cage activity for at least 8 weeks. Likewise, we observed no distortion or infections, including pin infections during the entire healing period. These results demonstrate that our newly developed external fixator was able to achieve reproducible and standardized stabilization, and the alteration of the mechanical environment of in vivo rat large bone defects and various size osteotomies. This confirms that the external fixation device is well suited for preclinical research investigations using a rat model in the field of bone regeneration and repair.

Balancing the Rates of New Bone Formation and Polymer Degradation Enhances Healing of Weight-Bearing Allograft/Polyurethane Composites in Rabbit Femoral Defects

PubMed Central

Dumas, Jerald E.; Prieto, Edna M.; Zienkiewicz, Katarzyna J.; Guda, Teja; Wenke, Joseph C.; Bible, Jesse; Holt, Ginger E.

2014-01-01

There is a compelling clinical need for bone grafts with initial bone-like mechanical properties that actively remodel for repair of weight-bearing bone defects, such as fractures of the tibial plateau and vertebrae. However, there is a paucity of studies investigating remodeling of weight-bearing bone grafts in preclinical models, and consequently there is limited understanding of the mechanisms by which these grafts remodel in vivo. In this study, we investigated the effects of the rates of new bone formation, matrix resorption, and polymer degradation on healing of settable weight-bearing polyurethane/allograft composites in a rabbit femoral condyle defect model. The grafts induced progressive healing in vivo, as evidenced by an increase in new bone formation, as well as a decrease in residual allograft and polymer from 6 to 12 weeks. However, the mismatch between the rates of autocatalytic polymer degradation and zero-order (independent of time) new bone formation resulted in incomplete healing in the interior of the composite. Augmentation of the grafts with recombinant human bone morphogenetic protein-2 not only increased the rate of new bone formation, but also altered the degradation mechanism of the polymer to approximate a zero-order process. The consequent matching of the rates of new bone formation and polymer degradation resulted in more extensive healing at later time points in all regions of the graft. These observations underscore the importance of balancing the rates of new bone formation and degradation to promote healing of settable weight-bearing bone grafts that maintain bone-like strength, while actively remodeling. PMID:23941405

Meta-analysis of Timing for Microsurgical Free-Flap Reconstruction for Lower Limb Injury: Evaluation of the Godina Principles.

PubMed

Haykal, Siba; Roy, Mélissa; Patel, Ashit

2018-05-01

 In 1986, Marko Godina published his seminal work regarding the timing of free-flap reconstruction for traumatic extremity defects. Early reconstruction, compared with delayed and late reconstruction resulted in significant decreases in free-flap failure rate, post-operative infections, hospitalization time, bone healing time, and number of additional anesthesias. The objective of this manuscript was to evaluate whether these principles continue to apply.  A meta-analysis was performed analyzing articles from Medline, Embase, and Pubmed. Four hundred and ninety-two articles were screened, and 134 articles were assessed for eligibility. Following full-text review, 43 articles were included in this study.  The exact timing for free-flap reconstruction, free-flap failure rate, infection rate, and follow-up was defined in all 43 articles. Early free-flap reconstruction was found to have significantly lower rates of free-flap failure and infection in comparison to delayed reconstruction ( p  = 0.008; p  = 0.0004). Compared with late reconstruction, early reconstruction was found to have significantly lower infection rates only ( p  = 0.01) with no difference in free-flap failures rates. Early reconstruction was found to lead to fewer additional procedures ( p  = 0.03). No statistical significance was found for bone healing time or hospitalization time.  Early free-flap reconstruction performed within the first 72 hours resulted in a decreased rate of free-flap failures, infection, and additional procedures with no difference in other parameters. The largest majority of free flaps continue to be performed in a delayed time frame. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Delayed healing of lower limb fractures with bisphosphonate therapy.

PubMed

Yue, B; Ng, A; Tang, H; Joseph, S; Richardson, M

2015-07-01

Bisphosphonate therapy (BT) is used commonly in the management of osteoporosis. A systematic review was conducted investigating delayed union of lower limb, long bone fractures in patients on BT. We specifically assessed whether BT increases the risk of delayed union or non-union in lower limb, long bone fractures. A literature search was conducted in the PubMed and Embase™ on 4 November 2014. Articles that investigated lower limb fractures, history of BT and fracture union were included in the review. A total of 9,809 papers were retrieved and 14 were deemed suitable for this review. The mean time to union in patients on BT was 8.5 months. A longer time to union was reported in a study investigating BT users versus controls (6.5 vs 4.8 months respectively). The mean rate of delayed or non-union for BT associated atypical fractures was 20% per fracture. Specifically in one study, delayed union was more common in the cohort with more than three years of BT (67%) than in the group with less than three years of BT (26%). Surgical fixation was associated with improved outcomes compared with non-operative management. BT has been described to be associated with multiple adverse outcomes related to atypical fractures. Current evidence recommends operative management for this patient group. Further investigation is required to evaluate the exact effects of BT on lower limb fractures, in particular typical femoral fractures.

Analysis of relevant proteins from bone graft harvested using the reamer irrigator and aspirator system (RIA) versus iliac crest (IC) bone graft and RIA waste water.

PubMed

Crist, Brett D; Stoker, Aaron M; Stannard, James P; Cook, James L

2016-08-01

Femoral reaming using a Reamer Irrigator Aspirator (RIA) can produce greater than three liters of waste water per procedure, which contains cells and proteins that could promote bone healing. This purpose of this study was to determine the protein profile of RIA waste water and compare protein synthesis by cells harvested via RIA versus iliac crest (IC) bone graft. Bone graft was collected from 30 patients-15 using RIA from the femur and 15 harvested from the iliac crest. Waste water collected during the RIA procedure was analyzed in 12 patients. Cells from each graft were cultured in monolayer using growth media for 14days and inductive media for the next 14days. Media samples were collected on days 14, 21, and 28. Proteins for analysis were chosen based on their potential in bone healing, pro-inflammatory, and anti-inflammatory processes. Proteins present in RIA waste water indicate the potential for clinical use of this filtrate as an adjunct for enhancing bone production, healing, and remodeling. Similarly, cells cultured from RIA bone graft harvests compared favorably to those from iliac crest bone grafts with respect to their potential to aid in bone healing. RIA waste water has potential to serve as an autogenic and allogenic enhancer for bone healing. Continued development of processing protocols for viable commercial use of the waste water and pre-clinical studies designed to evaluate RIA waste water products for bone healing are ongoing. Copyright © 2016 Elsevier Ltd. All rights reserved.

Direct transplantation of native pericytes from adipose tissue: A new perspective to stimulate healing in critical size bone defects.

PubMed

König, Matthias A; Canepa, Daisy D; Cadosch, Dieter; Casanova, Elisa; Heinzelmann, Michael; Rittirsch, Daniel; Plecko, Michael; Hemmi, Sonja; Simmen, Hans-Peter; Cinelli, Paolo; Wanner, Guido A

2016-01-01

Fractures with a critical size bone defect (e.g., open fracture with segmental bone loss) are associated with high rates of delayed union and non-union. The prevention and treatment of these complications remain a serious issue in trauma and orthopaedic surgery. Autologous cancellous bone grafting is a well-established and widely used technique. However, it has drawbacks related to availability, increased morbidity and insufficient efficacy. Mesenchymal stromal cells can potentially be used to improve fracture healing. In particular, human fat tissue has been identified as a good source of multilineage adipose-derived stem cells, which can be differentiated into osteoblasts. The main issue is that mesenchymal stromal cells are a heterogeneous population of progenitors and lineage-committed cells harboring a broad range of regenerative properties. This heterogeneity is also mirrored in the differentiation potential of these cells. In the present study, we sought to test the possibility to enrich defined subpopulations of stem/progenitor cells for direct therapeutic application without requiring an in vitro expansion. We enriched a CD146+NG2+CD45- population of pericytes from freshly isolated stromal vascular fraction from mouse fat tissue and tested their osteogenic differentiation capacity in vitro and in vivo in a mouse model for critical size bone injury. Our results confirm the ability of enriched CD146+NG2+CD45- cells to efficiently generate osteoblasts in vitro, to colonize cancellous bone scaffolds and to successfully contribute to regeneration of large bone defects in vivo. This study represents proof of principle for the direct use of enriched populations of cells with stem/progenitor identity for therapeutic applications. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Osteoporotic Animal Models of Bone Healing: Advantages and Pitfalls.

PubMed

Calciolari, Elena; Donos, Nikolaos; Mardas, Nikos

2017-10-01

The aim of this review was to summarize the advantages and pitfalls of the available osteoporotic animal models of bone healing. A thorough literature search was performed in MEDLINE via OVID and EMBASE to identify animal studies investigating the effect of experimental osteoporosis on bone healing and bone regeneration. The osteotomy model in the proximal tibia is the most popular osseous defect model to study the bone healing process in osteoporotic-like conditions, although other well-characterized models, such as the post-extraction model, might be taken into consideration by future studies. The regenerative potential of osteoporotic bone and its response to biomaterials/regenerative techniques has not been clarified yet, and the critical size defect model might be an appropriate tool to serve this purpose. Since an ideal animal model for simulating osteoporosis does not exist, the type of bone remodeling, the animal lifespan, the age of peak bone mass, and the economic and ethical implications should be considered in our selection process. Furthermore, the influence of animal species, sex, age, and strain on the outcome measurement should be taken into account. In order to make future studies meaningful, standardized international guidelines for osteoporotic animal models of bone healing need to be set up.

Calcium-phosphate matrix with or without TGF-β3 improves tendon-bone healing after rotator cuff repair.

PubMed

Kovacevic, David; Fox, Alice J; Bedi, Asheesh; Ying, Liang; Deng, Xiang-Hua; Warren, Russell F; Rodeo, Scott A

2011-04-01

Rotator cuff tendon heals by formation of an interposed zone of fibrovascular scar tissue. Recent studies demonstrate that transforming growth factor-beta 3 (TGF-β(3)) is associated with tissue regeneration and "scarless" healing, in contrast to scar-mediated healing that occurs with TGF-β(1). Delivery of TGF-β(3) in an injectable calcium-phosphate matrix to the healing tendon-bone interface after rotator cuff repair will result in increased attachment strength secondary to improved bone formation and collagen organization and reduced scar formation of the healing enthesis. Controlled laboratory study. Ninety-six male Sprague-Dawley rats underwent unilateral detachment of the supraspinatus tendon followed by acute repair using transosseous suture fixation. Animals were allocated into 1 of 3 groups: (1) repair alone (controls, n = 32), (2) repair augmented by application of an osteoconductive calcium-phosphate (Ca-P) matrix only (n = 32), or (3) repair augmented with Ca-P matrix + TGF-β(3) (2.75 µg) at the tendon-bone interface (n = 32). Animals were euthanized at either 2 weeks or 4 weeks postoperatively. Biomechanical testing of the supraspinatus tendon-bone complex was performed at 2 and 4 weeks (n = 8 per group). Microcomputed tomography was utilized to quantitate bone microstructure at the repair site. The healing tendon-bone interface was evaluated with histomorphometry and immunohistochemical localization of collagen types I (COLI) and III (COLIII). Statistical analysis was performed using 2-way analysis of variance with significance set at P < .05. There was significantly greater load to failure of the Ca-P matrix + TGF-β(3) group compared with matrix alone or untreated controls at 4 weeks postoperatively (P = .04). At 2 weeks, microcomputed tomography revealed a larger volume of newly formed bone present at the healing enthesis in both experimental groups compared with the control group. By 4 weeks, this newly formed, woven bone had matured into calcified, lamellar bone. Histomorphometric analysis demonstrated significantly greater fibrocartilage and increased collagen organization at the healing tendon-bone insertion site in both experimental groups compared with the control group at 2 weeks (P = .04). Over time, TGF-β(3) delivery led to greater COLI expression compared with COLIII at the healing enthesis, indicating a more favorable COLI to COLIII ratio with administration of TGF-β(3). Augmentation with an osteoconductive Ca-P matrix at the tendon-bone repair site is associated with new bone formation, increased fibrocartilage, and improved collagen organization at the healing tendon-bone interface in the early postoperative period after rotator cuff repair. The addition of TGF-β(3) significantly improved strength of the repair at 4 weeks postoperatively and resulted in a more favorable COLI/COLIII ratio. The delivery of TGF-β(3) with an injectable Ca-P matrix at the supraspinatus tendon footprint has promise to improve healing after soft tissue repair.

Comparison of ossification of demineralized bone, hydroxyapatite, Gelfoam, and bone wax in cranial defect repair.

PubMed

Papay, F A; Morales, L; Ahmed, O F; Neth, D; Reger, S; Zins, J

1996-09-01

Demineralized bone allografts in the repair of calvarial defects are compared with other common bone fillers. This study uses a video-digitizing radiographic analysis of calvarial defect ossification to determine calcification of bone defects and its relation to postoperative clinical examination and regional controls. The postoperative clinical results at 3 months demonstrated that bony healing was greatest in bur holes filled with demineralized bone and hydroxyapatite. Radiographic analysis demonstrated calcification of demineralized bone-filled defects compared to bone wax- and Gelfoam-filled regions. Hydroxyapatite granules are radiographically dense, thus not allowing accurate measurement of true bone healing. The results suggest that demineralized bone and hydroxyapatite provide better structural support via bone healing to defined calvarial defects than do Gelfoam and bone wax.

Injection of demineralized bone matrix with bone marrow concentrate improves healing in unicameral bone cyst.

PubMed

Di Bella, Claudia; Dozza, Barbara; Frisoni, Tommaso; Cevolani, Luca; Donati, Davide

2010-11-01

Unicameral bone cysts are benign lesions that usually spontaneously regress with skeletal maturity; however, the high risk of pathologic fractures often justifies treatment that could reinforce a weakened bone cortex. Various treatments have been proposed but there is no consensus regarding the best procedure. We compared the healing rates and failures of two methods of cure based on multiple injections of corticosteroid or a single injection of demineralized bone matrix (DBM) in association with bone marrow concentrate (BMC). We retrospectively reviewed 184 patients who had one of the two treatments for unicameral bone cysts with cortical erosion. Clinical records were reviewed for treatment failures and radiographs for healing in all patients. The minimum followup was 12 months for the Steroids Group (mean, 48 months; range, 12-120 months) and 12 months for the DBM + BMC Group (mean, 20 months; range, 12-28 months). After one treatment we observed a lower healing rate of cysts treated with multiple injections of steroids compared with the healing after the first injection of DBM + BMC (21% versus 58%, respectively). At last followup, 38% healed with steroids and 71% with DBM + BMC. The rate of failure after one steroid injection was higher than after a single injection of BDM + BMC (63% versus 24%, respectively). We observed no difference in fracture rates after treatment between the two groups. A single injection of DBM added with autologous bone marrow concentrate appears to provide a higher healing rate with a lower number of failures compared with a single injection of steroids.

Nutritional Aspects of Bone Health and Fracture Healing

PubMed Central

Karpouzos, Athanasios; Diamantis, Evangelos; Farmaki, Paraskevi

2017-01-01

Introduction Fractures are quite common, especially among the elderly. However, they can increase in prevalence in younger ages too if the bone health is not good. This may happen as a result of bad nutrition. Methods A customized, retrospective review of available literature was performed using the following keywords: bone health, nutrition, and fractures. Results Insufficient intake of certain vitamins, particularly A and D, and other nutrients, such as calcium, may affect bone health or even the time and degree of bone healing in case of fracture. The importance of different nutrients, both dietary and found in food supplements, is discussed concerning bone health and fracture healing. Conclusion A healthy diet with adequate amounts of both macro- and micronutrients is essential, for both decreasing fracture risk and enhancing the healing process after fracture. PMID:29464131

Achilles detachment in rat and stable gastric pentadecapeptide BPC 157: Promoted tendon-to-bone healing and opposed corticosteroid aggravation.

PubMed

Krivic, Andrija; Anic, Tomislav; Seiwerth, Sven; Huljev, Dubravko; Sikiric, Predrag

2006-05-01

Stable gastric pentadecapeptide BPC 157 (BPC 157, as an antiulcer agent in clinical trials for inflammatory bowel disease; PLD-116, PL 14736, Pliva, no toxicity reported) alone (without carrier) ameliorates healing of tendon and bone, respectively, as well as other tissues. Thereby, we focus on Achilles tendon-to-bone healing: tendon to bone could not be healed spontaneously, but it was recovered by this peptide. After the rat's Achilles tendon was sharply transected from calcaneal bone, agents [BPC 157 (10 microg, 10 ng, 10 pg), 6alpha-methylprednisolone (1 mg), 0.9% NaCl (5 mL)] were given alone or in combination [/kg body weight (b.w.) intraperitoneally, once time daily, first 30-min after surgery, last 24 h before analysis]. Tested at days 1, 4, 7, 10, 14, and 21 after Achilles detachment, BPC 157 improves healing functionally [Achilles functional index (AFI) values substantially increased], biomechanically (load to failure, stiffness, and Young elasticity modulus significantly increased), macro/microscopically, immunohistochemistry (better organization of collagen fibers, and advanced vascular appearance, more collagen type I). 6alpha-Methylprednisolone consistently aggravates the healing, while BPC 157 substantially reduces 6alpha-methylprednisolone healing aggravation. Thus, direct tendon-to-bone healing using stabile nontoxic peptide BPC 157 without a carrier might successfully exchange the present reconstructive surgical methods. Copyright 2006 Orthopaedic Research Society.

A Concert between Biology and Biomechanics: The Influence of the Mechanical Environment on Bone Healing

PubMed Central

Glatt, Vaida; Evans, Christopher H.; Tetsworth, Kevin

2017-01-01

In order to achieve consistent and predictable fracture healing, a broad spectrum of growth factors are required to interact with one another in a highly organized response. Critically important, the mechanical environment around the fracture site will significantly influence the way bone heals, or if it heals at all. The role of the various biological factors, the timing, and spatial relationship of their introduction, and how the mechanical environment orchestrates this activity, are all crucial aspects to consider. This review will synthesize decades of work and the acquired knowledge that has been used to develop new treatments and technologies for the regeneration and healing of bone. Moreover, it will discuss the current state of the art in experimental and clinical studies concerning the application of these mechano-biological principles to enhance bone healing, by controlling the mechanical environment under which bone regeneration takes place. This includes everything from the basic principles of fracture healing, to the influence of mechanical forces on bone regeneration, and how this knowledge has influenced current clinical practice. Finally, it will examine the efforts now being made for the integration of this research together with the findings of complementary studies in biology, tissue engineering, and regenerative medicine. By bringing together these diverse disciplines in a cohesive manner, the potential exists to enhance fracture healing and ultimately improve clinical outcomes. PMID:28174539

Mechanical and structural properties of bone in non-critical and critical healing in rat.

PubMed

Hoerth, Rebecca M; Seidt, Britta M; Shah, Miheer; Schwarz, Carolin; Willie, Bettina M; Duda, Georg N; Fratzl, Peter; Wagermaier, Wolfgang

2014-09-01

A fracture in bone results in a dramatic change of mechanical loading conditions at the site of injury. Usually, bone injuries heal normally but with increasing fracture gaps, healing is retarded, eventually leading to non-unions. The clinical situation of these two processes with different outcomes is well described. However, the exact relation between the mechanical environment and characteristics of the tissues at all levels of structural hierarchy remains unclear. Here we studied the differences in material formation of non-critical (1mm) and critical (5mm gap) healing. We employed a rat osteotomy model to explore bone material structure depending upon the different mechanical conditions. In both cases, primary bone formation was followed by secondary bone deposition with mineral particle sizes changing from on average short and thick to long and thin particles. Bony bridging occurred at first in the endosteal callus and the nanostructure and microstructure developed towards cortical ordered material organization. In contrast, in critical healing, instead of bridging, a marrow cavity closure was formed endosteal, exhibiting tissue structure oriented along the curvature and a periosteal callus with less mature material structure. The two healing processes separated between 4 and 6 weeks post-osteotomy. The outcome of healing was determined by the varied geometrical conditions in critical and non-critical healing, inducing completely different mechanical situations. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Bone regeneration by polyhedral microcrystals from silkworm virus

PubMed Central

Matsumoto, Goichi; Ueda, Takayo; Shimoyama, Junko; Ijiri, Hiroshi; Omi, Yasushi; Yube, Hisato; Sugita, Yoshihiko; Kubo, Katsutoshi; Maeda, Hatsuhiko; Kinoshita, Yukihiko; Arias, Duverney Gaviria; Shimabukuro, Junji; Kotani, Eiji; Kawamata, Shin; Mori, Hajime

2012-01-01

Bombyx mori cypovirus is a major pathogen which causes significant losses in silkworm cocoon harvests because the virus particles are embedded in micrometer-sized protein crystals called polyhedra and can remain infectious in harsh environmental conditions for years. But the remarkable stability of polyhedra can be applied on slow-release carriers of cytokines for tissue engineering. Here we show the complete healing in critical-sized bone defects by bone morphogenetic protein-2 (BMP-2) encapsulated polyhedra. Although absorbable collagen sponge (ACS) safely and effectively delivers recombinant human BMP-2 (rhBMP-2) into healing tissue, the current therapeutic regimens release rhBMP-2 at an initially high rate after which the rate declines rapidly. ACS impregnated with BMP-2 polyhedra had enough osteogenic activity to promote complete healing in critical-sized bone defects, but ACS with a high dose of rhBMP-2 showed incomplete bone healing, indicating that polyhedral microcrystals containing BMP-2 promise to advance the state of the art of bone healing. PMID:23226833

Bone morphogenetic proteins: a powerful osteoinductive compound with non-negligible side effects and limitations.

PubMed

Oryan, Ahmad; Alidadi, Soodeh; Moshiri, Ali; Bigham-Sadegh, Amin

2014-01-01

Healing and regeneration of large bone defects leading to non-unions is a great concern in orthopedic surgery. Since auto- and allografts have limitations, bone tissue engineering and regenerative medicine (TERM) has attempted to solve this issue. In TERM, healing promotive factors are necessary to regulate the several important events during healing. An ideal treatment strategy should provide osteoconduction, osteoinduction, osteogenesis, and osteointegration of the graft or biomaterials within the healing bone. Since many materials have osteoconductive properties, only a few biomaterials have osteoinductive properties which are important for osteogenesis and osteointegration. Bone morphogenetic proteins (BMPs) are potent inductors of the osteogenic and angiogenic activities during bone repair. The BMPs can regulate the production and activity of some growth factors which are necessary for the osteogenesis. Since the introduction of BMP, it has added a valuable tool to the surgeon's possibilities and is most commonly used in bone defects. Despite significant evidences suggesting their potential benefit on bone healing, there are some evidences showing their side effects such as ectopic bone formation, osteolysis and problems related to cost effectiveness. Bone tissue engineering may create a local environment, using the delivery systems, which enables BMPs to carry out their activities and to lower cost and complication rate associated with BMPs. This review represented the most important concepts and evidences regarding the role of BMPs on bone healing and regeneration from basic to clinical application. The major advantages and disadvantages of such biologic compounds together with the BMPs substitutes are also discussed. © 2014 International Union of Biochemistry and Molecular Biology.

Early mechanical stimulation only permits timely bone healing in sheep.

PubMed

Tufekci, Pelin; Tavakoli, Aramesh; Dlaska, Constantin; Neumann, Mirjam; Shanker, Mihir; Saifzadeh, Siamak; Steck, Roland; Schuetz, Michael; Epari, Devakar

2018-06-01

Bone fracture healing is sensitive to the fixation stability. However, it is unclear which phases of healing are mechano-sensitive and if mechanical stimulation is required throughout repair. In this study, a novel bone defect model, which isolates an experimental fracture from functional loading, was applied in sheep to investigate if stimulation limited to the early proliferative phase is sufficient for bone healing. An active fixator controlled motion in the fracture. Animals of the control group were unstimulated. In the physiological-like group, 1 mm axial compressive movements were applied between day 5 and 21, thereafter the movements were decreased in weekly increments and stopped after 6 weeks. In the early stimulatory group, the movements were stopped after 3 weeks. The experimental fractures were evaluated with mechanical and micro-computed tomography methods after 9 weeks healing. The callus strength of the stimulated fractures (physiological-like and early stimulatory) was greater than the unstimulated control group. The control group was characterized by minimal external callus formation and a lack of bone bridging at 9 weeks. In contrast, the stimulated groups exhibited advanced healing with solid bone formation across the defect. This was confirmed quantitatively by a lower bone volume in the control group compared to the stimulated groups.The novel experimental model permits the application of a well-defined load history to an experimental bone fracture. The poor healing observed in the control group is consistent with under-stimulation. This study has shown early mechanical stimulation only is sufficient for a timely healing outcome. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1790-1796, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Nano-engineered titanium for enhanced bone therapy

NASA Astrophysics Data System (ADS)

Gulati, Karan; Atkins, Gerald J.; Findlay, David M.; Losic, Dusan

2013-09-01

Current treatment of a number of orthopaedic conditions, for example fractures, bone infection, joint replacement and bone cancers, could be improved if mechanical support could be combined with drug delivery. A very challenging example is that of infection following joint replacement, which is very difficult to treat, can require multiple surgeries and compromises both the implant and the patient's wellbeing. An implant capable of providing appropriate biomechanics and releasing drugs/proteins locally might ensure improved healing of the traumatized bone. We propose fabrication of nanoengineered titanium bone implants using bioinert titanium wires in order to achieve this goal. Titanium in the form of flat foils and wires were modified by fabrication of titania nanotubes (TNTs), which are hollow self-ordered cylindrical tubes capable of accommodating substantial drug amounts and releasing them locally. To further control the release of drug to over a period of months, a thin layer of biodegradable polymer PLGA poly(lactic-coglycolic acid) was coated onto the drug loaded TNTs. This delayed release of drug and additionally the polymer enhanced bone cell adhesion and proliferation.

Vitamin D and the immunomodulation of rotator cuff injury

PubMed Central

Dougherty, Kaitlin A; Dilisio, Matthew F; Agrawal, Devendra K

2016-01-01

Tendon-to-bone healing after rotator cuff repair surgery has a failure rate of 20%–94%. There has been a recent interest to determine the factors that act as determinants between successful and unsuccessful rotator cuff repair. Vitamin D level in patients is one of the factors that have been linked to bone and muscle proliferation and healing, and it may have an effect on tendon-to-bone healing. The purpose of this article is to critically review relevant published research that relates to the effect of vitamin D on rotator cuff tears and subsequent healing. A review of the literature was conducted to identify all studies that investigate the relationship between vitamin D and tendon healing, in addition to its mechanism of action. The data were then analyzed in order to summarize what is currently known about vitamin D, rotator cuff pathology, and tendon-to-bone healing. The activated metabolite of vitamin D, 1α,25-dihydroxyvitamin D3, affects osteoblast proliferation and differentiation. Likewise, vitamin D plays a significant role in the tendon-to-bone healing process by increasing the bone mineral density and strengthening the skeletal muscles. The 1α,25-dihydroxyvitamin D3 binds to vitamin D receptors on myocytes to stimulate growth and proliferation. The form of vitamin D produced by the liver, calcifediol, is a key initiator of the myocyte healing process by moving phosphate into myocytes, which improves function and metabolism. Investigation into the effect of vitamin D on tendons has been sparse, but limited studies have been promising. Matrix metalloproteinases play an active role in remodeling the extracellular matrix (ECM) of tendons, particularly deleterious remodeling of the collagen fibers. Also, the levels of transforming growth factor-β3 positively influence the success of the surgery for rotator cuff repair. In the tendon-to-bone healing process, vitamin D has been shown to successfully influence bone and muscle healing, but more research is needed to delve into the mechanisms of vitamin D as a factor in skeletal tendon health and healing. PMID:27366101

Inter-species investigation of the mechano-regulation of bone healing: comparison of secondary bone healing in sheep and rat.

PubMed

Checa, Sara; Prendergast, Patrick J; Duda, Georg N

2011-04-29

Inter-species differences in regeneration exist in various levels. One aspect is the dynamics of bone regeneration and healing, e.g. small animals show a faster healing response when compared to large animals. Mechanical as well as biological factors are known to play a key role in the process. However, it remains so far unknown whether different animals follow at all comparable mechano-biological rules during tissue regeneration, and in particular during bone healing. In this study, we investigated whether differences observed in vivo in the dynamics of bone healing between rat and sheep are only due to differences in the animal size or whether these animals have a different mechano-biological response during the healing process. Histological sections from in vivo experiments were compared to in silico predictions of a mechano-biological computer model for the simulation of bone healing. Investigations showed that the healing processes in both animal models occur under significantly different levels of mechanical stimuli within the callus region, which could explain histological observations of early intramembranous ossification at the endosteal side. A species-specific adaptation of a mechano-biological model allowed a qualitative match of model predictions with histological observations. Specifically, when keeping cell activity processes at the same rate, the amount of tissue straining defining favorable mechanical conditions for the formation of bone had to be increased in the large animal model, with respect to the small animal, to achieve a qualitative agreement of model predictions with histological data. These findings illustrate that geometrical (size) differences alone cannot explain the distinctions seen in the histological appearance of secondary bone healing in sheep and rat. It can be stated that significant differences in the mechano-biological regulation of the healing process exist between these species. Future investigations should aim towards understanding whether these differences are due to differences in cell behavior, material properties of the newly formed tissues within the callus and/or differences in response to the mechanical environment. Copyright © 2011 Elsevier Ltd. All rights reserved.

Wound healing delays in α-Klotho-deficient mice that have skin appearance similar to that in aged humans - Study of delayed wound healing mechanism.

PubMed

Yamauchi, Makoto; Hirohashi, Yoshihiko; Torigoe, Toshihiko; Matsumoto, Yoshitaka; Yamashita, Ken; Kayama, Musashi; Sato, Noriyuki; Yotsuyanagi, Takatoshi

2016-05-13

Skin atrophy and delayed wound healing are observed in aged humans; however, the molecular mechanism are still elusive. The aim of this study was to analyze the molecular mechanisms of delayed wound healing by aging using α-Klotho-deficient (kl/kl) mice, which have phenotypes similar to those of aged humans. The kl/kl mice showed delayed wound healing and impaired granulation formation compared with those in wild-type (WT) mice. The skin graft experiments revealed that delayed wound healing depends on humoral factors, but not on kl/kl skin tissue. The mRNA expression levels of cytokines related to acute inflammation including IL-1β, IL-6 and TNF-α were higher in wound lesions of kl/kl mice compared with the levels in WT mice by RT-PCR analysis. LPS-induced TNF-α production model using spleen cells revealed that TNF-α production was significantly increased in the presence of FGF23. Thus, higher levels of FGF23 in kl/kl mouse may have a role to increase TNF-α production in would lesion independently of α-Klotho protein, and impair granulation formation and delay wound healing. Copyright © 2016 Elsevier Inc. All rights reserved.

Risk factors of delayed ulcer healing after gastric endoscopic submucosal dissection.

PubMed

Lim, Joo Hyun; Kim, Sang Gyun; Choi, Jeongmin; Im, Jong Pil; Kim, Joo Sung; Jung, Hyun Chae

2015-12-01

Although post-endoscopic submucosal dissection (ESD) iatrogenic ulcer is known to heal faster than peptic ulcer, some iatrogenic ulcers show delayed healing. The aim of this study was to clarify risk factors of delayed ulcer healing after gastric ESD. We retrospectively reviewed medical records of all patients who had ESD for gastric neoplasms (866 adenomas and 814 early gastric cancers) between January 2005 and February 2011. Of 1680 subjects, 95 had delayed ulcer healing in 3-month follow-up. Multivariate analysis showed that diabetes (OR 1.743; 95% CI 1.017-2.989, p = 0.043), coagulation abnormality (OR 3.195; 95% CI 1.535-6.650, p = 0.002), specimen size greater than 4 cm (OR 2.999; 95% CI 1.603-5.611, p = 0.001), and electrocoagulation (OR 7.149; 95% CI 1.738-29.411, p = 0.006) were revealed to be independent risk factors of delayed ulcer healing. Meanwhile, persistent Helicobacter pylori infection was not related to the delayed ulcer healing. Large iatrogenic ulcer by ESD with massive hemostasis, especially in patients with diabetes mellitus or coagulation abnormalities, tends to take more than 3 months to heal. For such cases, initial dosage increment of PPI or addition of other anti-ulcer agents after ESD may be beneficial.

Correlation of bone defect dimensions with healing outcome one year after apical surgery.

PubMed

von Arx, Thomas; Hänni, Stefan; Jensen, Simon Storgård

2007-09-01

This clinical study prospectively evaluated the healing outcome 1 year after apical surgery in relation to bony crypt dimensions measured intraoperatively. The study cohort included 183 teeth in an equal number of patients. For statistical analysis, results were dichotomized (healed versus non-healed cases). The overall success rate was 83% (healed cases). Healing outcome was not significantly related to the level and height of the facial bone plate. In contrast, a significant difference was found for the mean size of the bony crypt when healed cases (395 mm(3)) were compared with non-healed cases (554 mm(3)). In addition, healed cases had a significantly shorter mean distance (4.30 mm) from the facial bone surface to the root canal (horizontal access) compared with non-healed cases (5.13 mm). With logistic regression, however, the only parameter found to be significantly related to healing outcome was the length of the access window to the bony crypt.

Comparison of two kinds of bovine bone in maxillary sinus augmentation: a histomorphometric study.

PubMed

Moon, Jee-Won; Sohn, Dong-Seok; Heo, Jeung-Uk; Kim, Jin Sun

2015-02-01

The purpose of this study was to compare the histomorphometric from sinus augmentation with calcium-phosphate nanocrystal-coated bovine bone (Biocera) and anorganic bovine bone matrix (Bio-Oss). Bilateral maxillary sinus augmentations were performed on 5 patients with delayed placement of implants. The lateral bony window was created using a piezoelectric saw, and the sinus membrane was elevated to make a new compartment. Bio-Oss was grafted in one sinus as the control group and Biocera was grafted in the opposite sinus as the test group. The bony window was repositioned over the bone graft. In all cases, samples were taken for biopsy at the time of implant placement, 6 to 8 months after the grafting procedure. Independent t tests were used to examine between-group differences. None of the 5 patients had complications during healing period. Histomorphometrically, the Bio-Oss group showed 28.46% (±5.28%) of newly formed bone. Biocera group showed 29.94% (±8.72%) of newly formed bone. Newly formed bone along inner surface of repositioned bony window area showed more mature and dense bone structure than new bone formed along bone graft. This study revealed that both bovine bone grafts were considered as suitable bone graft materials for maxillary sinus augmentation.

Bone Healing in Extraction Sockets Covered With Collagen Membrane Alone or Associated With Porcine-Derived Bone Graft: a Comparative Histological and Histomorphometric Analysis.

PubMed

Guarnieri, Renzo; Testarelli, Luca; Stefanelli, Luigi; De Angelis, Francesca; Mencio, Francesca; Pompa, Giorgio; Di Carlo, Stefano

2017-01-01

The present paper reports data of a randomized study aimed to analyse and compare the histologic and histomorphometric aspects of bone healing in extraction sites covered with collagen membrane alone or associated with porcine-derived bone graft. Thirty patients, with single extraction sockets without severe bone wall defects in the premolar/molar region, were included. Ten extraction sockets were grafted with porcine-derived bone and covered with collagen membrane (group 1), 10 sites were covered with collagen membrane alone (group 2), and 10 sites healed spontaneously (group 3). After 4 months of healing, 26 (8 in group 1, 9 in group 2, and 9 in group 3) bone core specimens were harvested for histologic evaluation, then dental implants were placed. Sites in the group 1 and in the group 2 showed similar histologic and histomorphometric results without significantly differences in the percentage of vital bone (57.43% [SD 4.8] vs. 60.01% [SD 3.2]), and non-mineralized connective tissue 22.99% (SD 5.3) vs. 18.53% (SD 6.2). In group 1 a 16.57% (SD 3.8) of residual material was found. Results showed that the use of collagen membrane alone or associated to porcine-derived bone improves the healing bone process compared to that of extraction sites spontaneously healed. Moreover, histomorphometric data related to bone quality, indicated that extraction sites without severe walls defects and with a vestibular bone thickness > 1.5 mm, treated with a low resorbtion rate collagen membrane alone, do not need more than 4 months for dental implant insertion.

Distinct frequency dependent effects of whole-body vibration on non-fractured bone and fracture healing in mice.

PubMed

Wehrle, Esther; Wehner, Tim; Heilmann, Aline; Bindl, Ronny; Claes, Lutz; Jakob, Franz; Amling, Michael; Ignatius, Anita

2014-08-01

Low-magnitude high-frequency vibration (LMHFV) provokes anabolic effects in non-fractured bone; however, in fracture healing, inconsistent results were reported and optimum vibration conditions remain unidentified. Here, we investigated frequency dependent effects of LMHFV on fracture healing. Twelve-week-old, female C57BL/6 mice received a femur osteotomy stabilized using an external fixator. The mice received whole-body vibrations (20 min/day) with 0.3g peak-to-peak acceleration and a frequency of either 35 or 45 Hz. After 10 and 21 days, the osteotomized femurs and intact bones (contra-lateral femurs, lumbar spine) were evaluated using bending-testing, µ-computed tomography, and histomorphometry. In non-fractured trabecular bone, vibration with 35 Hz significantly increased the relative amount of bone (+28%) and the trabecular number (+29%), whereas cortical bone was not influenced. LMHFV with 45 Hz failed to provoke anabolic effects in trabecular or cortical bone. Fracture healing was not significantly influenced by whole-body vibration with 35 Hz, whereas 45 Hz significantly reduced bone formation (-64%) and flexural rigidity (-34%) of the callus. Although the exact mechanisms remain open, our results suggest that small vibration setting changes could considerably influence LMHFV effects on bone formation in remodeling and repair, and even disrupt fracture healing, implicating caution when treating patients with impaired fracture healing. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

A Passive and Wireless Sensor for Bone Plate Strain Monitoring.

PubMed

Tan, Yisong; Hu, Jiale; Ren, Limin; Zhu, Jianhua; Yang, Jiaqi; Liu, Di

2017-11-16

This paper reports on a sensor for monitoring bone plate strain in real time. The detected bone plate strain could be used for judging the healing state of fractures in patients. The sensor consists of a magnetoelastic material, which can be wirelessly connected and passively embedded. In order to verify the effectiveness of the sensor, a tibia-bone plate-screw (TBS) model was established using the finite element analysis method. A variation of the bone plate strain was obtained via this model. A goat hindquarter tibia was selected as the bone fracture model in the experiment. The tibia was fixed on a high precision load platform and an external force was applied. Bone plate strain variation during the bone fracture healing process was acquired with sensing coils. Simulation results indicated that bone plate strain decreases as the bone gradually heals, which is consistent with the finite element analysis results. This validated the soundness of the sensor reported here. This sensor has wireless connections, no in vivo battery requirement, and long-term embedding. These results can be used not only for clinical practices of bone fracture healing, but also for bone fracture treatment and rehabilitation equipment design.

Changes in bone microstructure and toughness during the healing process of long bones

NASA Astrophysics Data System (ADS)

Ishimoto, T.; Nakano, T.; Umakoshi, Y.; Tabata, Y.

2009-05-01

It is of great importance to understand how bone defects regain the microstructure and mechanical function of bone and how the microstructure affects the mechanical function during the bone healing process. In the present study on long bone defects, we investigated the relationship between the recovery process of fracture toughness and biological apatite (BAp)/collagen (Col) alignment as an index of the bone microstructure to clarify the bone toughening mechanisms. A 5-mm defect introduced in the rabbit ulna was allowed to heal naturally and a three-point bending test was conducted on the regenerated site to assess bone toughness. The bone toughness was quite low at the early stage of bone regeneration but increased during the postoperative period. The change in toughness agreed well with the characteristics of the fracture surface morphology, which reflected the history of the crack propagation. SEM and microbeam X-ray diffraction analyses indicated that the toughness was dominated by the degree and orientation of the preferred BAp/Col alignment, i.e. bundles aligned perpendicular to the crack propagation clearly contributed to the bone toughening owing to extra energy consumption for resistance to crack propagation. In conclusion, regenerated bone improves fracture toughness by reconstructing the preferred BAp/Col alignment along the bone longitudinal axis during the healing process of long bones.

Dual delivery of rhPDGF-BB and bone marrow mesenchymal stromal cells expressing the BMP2 gene enhance bone formation in a critical-sized defect model.

PubMed

Park, Shin-Young; Kim, Kyoung-Hwa; Shin, Seung-Yun; Koo, Ki-Tae; Lee, Yong-Moo; Seol, Yang-Jo

2013-11-01

Bone tissue healing is a dynamic, orchestrated process that relies on multiple growth factors and cell types. Platelet-derived growth factor-BB (PDGF-BB) is released from platelets at wound sites and induces cellular migration and proliferation necessary for bone regeneration in the early healing process. Bone morphogenetic protein-2 (BMP-2), the most potent osteogenic differentiation inducer, directs new bone formation at the sites of bone defects. This study evaluated a combinatorial treatment protocol of PDGF-BB and BMP-2 on bone healing in a critical-sized defect model. To mimic the bone tissue healing process, a dual delivery approach was designed to deliver the rhPDGF-BB protein transiently during the early healing phase, whereas BMP-2 was supplied by rat bone marrow stromal cells (BMSCs) transfected with an adenoviral vector containing the BMP2 gene (AdBMP2) for prolonged release throughout the healing process. In in vitro experiments, the dual delivery of rhPDGF-BB and BMP2 significantly enhanced cell proliferation. However, the osteogenic differentiation of BMSCs was significantly suppressed even though the amount of BMP-2 secreted by the AdBMP2-transfected BMSCs was not significantly affected by the rhPDGF-BB treatment. In addition, dual delivery inhibited the mRNA expression of BMP receptor type II and Noggin in BMSCs. In in vivo experiments, critical-sized calvarial defects in rats showed enhanced bone regeneration by dual delivery of autologous AdBMP2-transfected BMSCs and rhPDGF-BB in both the amount of new bone formed and the bone mineral density. These enhancements in bone regeneration were greater than those observed in the group treated with AdBMP2-transfected BMSCs alone. In conclusion, the dual delivery of rhPDGF-BB and AdBMP2-transfected BMSCs improved the quality of the regenerated bone, possibly due to the modulation of PDGF-BB on BMP-2-induced osteogenesis.

The influence of collagen membrane and autogenous bone chips on bone augmentation in the anterior maxilla: a preclinical study.

PubMed

Janner, Simone F M; Bosshardt, Dieter D; Cochran, David L; Chappuis, Vivianne; Huynh-Ba, Guy; Jones, Archie A; Buser, Daniel

2017-11-01

To evaluate the effect of a resorbable collagen membrane and autogenous bone chips combined with deproteinized bovine bone mineral (DBBM) on the healing of buccal dehiscence-type defects. The second incisors and the first premolars were extracted in the maxilla of eight mongrels. Reduced diameter, bone-level implants were placed 5 weeks later. Standardized buccal dehiscence-type defects were created and grafted at implant surgery. According to an allocation algorithm, the graft composition of each of the four maxillary sites was DBBM + membrane (group D + M), autogenous bone chips + DBBM + membrane (group A + D + M), DBBM alone (group D) or autogenous bone chips + DBBM (group A + D). Four animals were sacrificed after 3 weeks of healing and four animals after 12 weeks. Histological and histomorphometric analyses were performed on oro-facial sections. The pattern of bone formation and resorption within the grafted area showed high variability among the same group and healing time. The histomorphometric analysis of the 3-week specimens showed a positive effect of autogenous bone chips on both implant osseointegration and bone formation into the grafted region (P < 0.05). The presence of the collagen membrane correlated with greater bone formation around the DBBM particles and greater bone formation in the grafted region after 12 weeks of healing (P < 0.05). The oro-facial width of the augmented region at the level of the implant shoulder was significantly reduced in cases where damage of the protection splints occurred in the first week of healing (P < 0.05). The addition of autogenous bone chips and the presence of the collagen membrane increased bone formation around DBBM particles. Wound protection from mechanical noxa during early healing may be critical for bone formation within the grafted area. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle.

PubMed

Liu, F; Ferreira, E; Porter, R M; Glatt, V; Schinhan, M; Shen, Z; Randolph, M A; Kirker-Head, C A; Wehling, C; Vrahas, M S; Evans, C H; Wells, J W

2015-09-21

Large segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinical trials requires, inter alia, demonstration of efficacy in a large animal, such as the sheep. Scale-up is fraught with numerous biological, anatomical, mechanical and structural variables, which cannot be addressed systematically because of cost and other practical issues. For this reason, we developed a translational model enabling us to isolate the biological question of whether sheep muscle, transduced with adenovirus expressing BMP-2, could heal critical size defects in vivo. Initial experiments in athymic rats noted strong healing in only about one-third of animals because of unexpected immune responses to sheep antigens. For this reason, subsequent experiments were performed with Fischer rats under transient immunosuppression. Such experiments confirmed remarkably rapid and reliable healing of the defects in all rats, with bridging by 2 weeks and remodelling as early as 3-4 weeks, despite BMP-2 production only in nanogram quantities and persisting for only 1-3 weeks. By 8 weeks the healed defects contained well-organised new bone with advanced neo-cortication and abundant marrow. Bone mineral content and mechanical strength were close to normal values. These data demonstrate the utility of this model when adapting this technology for bone healing in sheep, as a prelude to human clinical trials.

Immediate placement of endosseous implants into the extraction sockets.

PubMed

Ebenezer, Vijay; Balakrishnan, K; Asir, R Vigil Dev; Sragunar, Banu

2015-04-01

Implant by definition "means any object or material, such as an alloplastic substance or other tissue, which is partial or completely inserted into the body for therapeutic, diagnostic, prosthetic, or experimental purpose." The placement of a dental implant in an extraction socket at the time of extraction or explantation is known as immediate implant placement whereas delayed placement of implant signifies the implant placement in edentulous areas where healing has completed with new bone formation after the loss of tooth/teeth. Recent idea goes by "why late when it can be done immediately." There are several advantages of immediate placement of implants, and lots of studies have been done. In this article, the advantages and disadvantages of immediate versus delayed placement of implants have been reviewed.

Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing

PubMed Central

Wang, Tao; Wang, Yongmei; Menendez, Alicia; Fong, Chak; Babey, Muriel; Tahimic, Candice GT; Cheng, Zhiqiang; Li, Alfred; Chang, Wenhan; Bikle, Daniel D.

2017-01-01

Insulin-like growth factors (IGFs) are important local regulators during fracture healing. Although IGF1 deficiency is known to increase the risk of delayed union or non-union fractures in the elderly population, the underlying mechanisms that contribute to this defect remains unclear. In this study, IGF1 signaling during fracture healing was investigated in an osteoblast-specific IGF1 receptor (IGF1R) conditional knockout (KO) mouse model. A closed tibial fracture was induced in IGF1Rflox/flox/2.3-kb α1(1)-collagen-Cre (KO) and IGF1Rflox/flox (control) mice aged 12 weeks. Fracture callus samples and nonfractured tibial diaphysis were collected and analyzed by μCT, histology, immunohistochemistry, histomorphometry, and gene expression analysis at 10, 15, 21, and 28 days after fracture. A smaller size callus, lower bone volume accompanied by a defect in mineralization, bone microarchitectural abnormalities, and a higher cartilage volume were observed in the callus of these KO mice. The levels of osteoblast differentiation markers (osteocalcin, alkaline phosphatase, collagen 1α1) were significantly reduced, but the early osteoblast transcription factor runx2, as well as chondrocyte differentiation markers (collagen 2α1 and collagen 10α1) were significantly increased in the KO callus. Moreover, increased numbers of osteoclasts and impaired angiogenesis were observed during the first 15 days of fracture repair, but decreased numbers of osteoclasts were found in the later stages of fracture repair in the KO mice. Although baseline nonfractured tibias of KO mice had decreased trabecular and cortical bone compared to control mice, subsequent studies with mice expressing the 2.3-kb α1(1)-collagen-Cre ERT2 construct and given tamoxifen at the time of fracture and so starting with comparable bone levels showed similar impairment in fracture repair at least initially. Our data indicate that not only is the IGF1R in osteoblasts involved in osteoblast differentiation during fracture repair, but it plays an important role in coordinating chondrocyte, osteoclast, and endothelial responses that all contribute to the endochondral bone formation required for normal fracture repair. PMID:25801198

Advances in bone surgery: the Er:YAG laser in oral surgery and implant dentistry

PubMed Central

Stübinger, Stefan

2010-01-01

The erbium-doped yttrium aluminium garnet (Er:YAG) laser has emerged as a possible alternative to conventional methods of bone ablation because of its wavelength of 2.94 μm, which coincides with the absorption peak of water. Over the last decades in several experimental and clinical studies, the widespread initial assumption that light amplification for stimulated emission of radiation (laser) osteotomy inevitably provokes profound tissue damage and delayed wound healing has been refuted. In addition, the supposed disadvantage of prolonged osteotomy times could be overcome by modern short-pulsed Er:YAG laser systems. Currently, the limiting factors for a routine application of lasers for bone ablation are mainly technical drawbacks such as missing depth control and a difficult and safe guidance of the laser beam. This article gives a short overview of the development process and current possibilities of noncontact Er:YAG laser osteotomy in oral and implant surgery. PMID:23662082

Bisphosphonates inhibit bone remodeling in the jaw bones of rats and delay healing following tooth extractions.

PubMed

Jabbour, Zaher; El-Hakim, Michel; Henderson, Janet E; de Albuquerque, Rubens F

2014-05-01

This study aimed to evaluate the impact of concurrent administration of clinically relevant doses of zoledronic acid (ZA) and dexamethasone (DX) on bone healing after tooth extraction (EXO). Forty-four Sprague-Dawley rats (6-8 month old) were randomized into five groups: ZA + DX = weekly injection of ZA with DX for 7 weeks; WD = ZA with DX for 3 weeks then DX alone for 4 weeks; C = control saline for 7 weeks; ZA = ZA alone for 7 weeks and DX = DX alone for 7 weeks. ZA was administered at 0.13 mg/kg/week and DX at 3.8 mg/kg/week and body weights recorded at the time of injection. All rats underwent extraction (EXO) of the mandibular and maxillary first molars at 3 weeks and were euthanized at 7 weeks. The extracted and non-extracted sides of both jaws were harvested for micro-CT analyses. All rats, particularly those injected with ZA, exhibited weight gain till EXO followed by decline then recovery. ZA + DX group demonstrated highest fractional bone to tissue volume (BV/TV) in the non-extracted side. ZA + DX rats exhibited also highest volume and surface of sequestra. Only sequestra volume was statistically higher in the WD group compared to C group. Combined treatment with ZA and DX over a prolonged period inhibits bone remodeling and increased sequestra formation to a greater extent than either drug alone. Trauma caused by these sequestra cutting through the mucosa could play a key role in the development of BRONJ by potentially facilitating infection. ZA withdrawal may promote bone-remodeling reactivation following EXO. Copyright © 2014 Elsevier Ltd. All rights reserved.

Clinical Results and Complications of Lower Limb Lengthening for Fibular Hemimelia: A Report of Eight Cases.

PubMed

Mishima, Kenichi; Kitoh, Hiroshi; Iwata, Koji; Matsushita, Masaki; Nishida, Yoshihiro; Hattori, Tadashi; Ishiguro, Naoki

2016-05-01

Fibular hemimelia is a rare but the most common congenital long bone deficiency, encompassing a broad range of anomalies from isolated fibular hypoplasia up to substantial femoral and tibial shortening with ankle deformity and foot deficiency. Most cases of fibular hemimelia manifest clinically significant leg length discrepancy (LLD) with time that requires adequate correction by bone lengthening for stable walking. Bone lengthening procedures, especially those for pathological bones, are sometimes associated with severe complications, such as delayed consolidation, fractures, and deformities of the lengthened bones, leading to prolonged healing time and residual LLD at skeletal maturity. The purpose of this study was to review our clinical results of lower limb lengthening for fibular hemimelia.This study included 8 Japanese patients who diagnosed with fibular hemimelia from physical and radiological findings characteristic of fibular hemimelia and underwent single or staged femoral and/or tibial lengthening during growth or after skeletal maturity. LLD, state of the lengthened callus, and bone alignment were evaluated with full-length radiographs of the lower limb. Previous interventions, associated congenital anomalies, regenerate fractures were recorded with reference to medical charts and confirmed on appropriate radiographs. Successful lengthening was defined as the healing index <50 days/cm without regenerate fractures.A significant difference was observed in age at surgery between successful and unsuccessful lengthening. The incidence of regenerate fractures was significantly correlated with callus maturity before frame removal. LLD was corrected within 11 mm, whereas mechanical axis deviated laterally.Particular attention should be paid to the status of callus maturation and the mechanical axis deviation during the treatment period in fibular hemimelia.

Determining the Role of Sost and Sostdc1 During Fracture Healing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yee, Cristal Sook Ngei

The bone is a dynamic organ, often changing throughout the course of the human lifespan with its continuous remodeling, laying down new bone and resorbing old bone. With age, the bone becomes increasingly porous and mechanically unstable, leading to the development of osteoporosis in some individuals. Elderly patients with osteoporosis are at an increased risk of fracturing their bones which contributes to a higher mortality rate. Recent studies have revealed that type 1 diabetic mellitus (T1DM) patients also have an osteoporotic bone phenotype and impaired fracture healing, independent of age. Currently, there is a lack of available treatments that canmore » improve impaired healing and directly enhance bone formation. Therefore, there is a great need for developing new therapies that can not only aid type 1 diabetic patients with osteoporosis to improve bone phenotype, but that could also aid patients with difficult or impaired fracture healing. In this thesis, I will be discussing the role of Wnt signaling and Sclerostin, a Wnt antagonist that negatively regulates bone formation, in the content of fracture repair.« less

The Impact of Type 2 Diabetes on Bone Fracture Healing

PubMed Central

Marin, Carlos; Luyten, Frank P.; Van der Schueren, Bart; Kerckhofs, Greet; Vandamme, Katleen

2018-01-01

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease known by the presence of elevated blood glucose levels. Nowadays, it is perceived as a worldwide epidemic, with a very high socioeconomic impact on public health. Many are the complications caused by this chronic disorder, including a negative impact on the cardiovascular system, kidneys, eyes, muscle, blood vessels, and nervous system. Recently, there has been increasing evidence suggesting that T2DM also adversely affects the skeletal system, causing detrimental bone effects such as bone quality deterioration, loss of bone strength, increased fracture risk, and impaired bone healing. Nevertheless, the precise mechanisms by which T2DM causes detrimental effects on bone tissue are still elusive and remain poorly studied. The aim of this review was to synthesize current knowledge on the different factors influencing the impairment of bone fracture healing under T2DM conditions. Here, we discuss new approaches used in recent studies to unveil the mechanisms and fill the existing gaps in the scientific understanding of the relationship between T2DM, bone tissue, and bone fracture healing. PMID:29416527

Extracorporeal shockwaves as regenerative therapy in orthopedic traumatology: a narrative review from basic research to clinical practice.

PubMed

D Agostino, M C; Frairia, R; Romeo, P; Amelio, E; Berta, L; Bosco, V; Gigliotti, S; Guerra, C; Messina, S; Messuri, L; Moretti, B; Notarnicola, A; Maccagnano, G; Russo, S; Saggini, R; Vulpiani, M C; Buselli, P

2016-01-01

Extracorporeal Shock Wave Therapy (ESWT), after its first medical application in the urological field for lithotripsy, nowadays represents a valid therapeutical tool also for many musculoskeletal diseases, as well as for regenerative medicine applications. This is possible thanks to its mechanisms of action, which in the non-urological field are not related to mechanical disruption (as for renal stones), but rather to the capacity, by mechanotransduction, to induce neoangiogenesis, osteogenesis and to improve local tissue trophism, regeneration and remodeling, through stem cell stimulation. On the basis of these biological assumptions, it becomes clear that ESWT can represent a valid therapeutic tool also for all those pathological conditions that derive from musculoskeletal trauma, and are characterized by tissue loss and/or delayed healing and regeneration (mainly bone and skin, but not only). As a safe, repeatable and non–invasive therapy, in many cases it can represent a first–line therapeutic option, as an alternative to surgery (for example, in bone and skin healing disorders), or in combination with some other treatment options. It is hoped that with its use in daily practice also the muscle–skeletal field will grow, not only for standard indications, but also in post–traumatic sequelae, in order to improve recovery and shorten healing time, with undoubted advantages for the patients and lower health service expenses.

Cellular therapy in bone-tendon interface regeneration

PubMed Central

Rothrauff, Benjamin B; Tuan, Rocky S

2014-01-01

The intrasynovial bone-tendon interface is a gradual transition from soft tissue to bone, with two intervening zones of uncalcified and calcified fibrocartilage. Following injury, the native anatomy is not restored, resulting in inferior mechanical properties and an increased risk of re-injury. Recent in vivo studies provide evidence of improved healing when surgical repair of the bone-tendon interface is augmented with cells capable of undergoing chondrogenesis. In particular, cellular therapy in bone-tendon healing can promote fibrocartilage formation and associated improvements in mechanical properties. Despite these promising results in animal models, cellular therapy in human patients remains largely unexplored. This review highlights the development and structure-function relationship of normal bone-tendon insertions. The natural healing response to injury is discussed, with subsequent review of recent research on cellular approaches for improved healing. Finally, opportunities for translating in vivo findings into clinical practice are identified. PMID:24326955

Healing of osteotomy sites applying either piezosurgery or two conventional saw blades: a pilot study in rabbits.

PubMed

Ma, Li; Stübinger, Stefan; Liu, Xi Ling; Schneider, Urs A; Lang, Niklaus P

2013-08-01

The purpose of this study was to compare bone healing of experimental osteotomies applying either piezosurgery or two different oscillating saw blades in a rabbit model. The 16 rabbits were randomly assigned into four groups to comply with observation periods of one, two, three and five weeks. In all animals, four osteotomy lines were performed on the left and right nasal bone using a conventional saw blade, a novel saw blade and piezosurgery. All three osteotomy techniques revealed an advanced gap healing starting after one week. The most pronounced new bone formation took place between two and three weeks, whereby piezoelectric surgery revealed a tendency to faster bone formation and remodelling. Yet, there were no significant differences between the three modalities. The use of a novel as well as the piezoelectric bone-cutting instrument revealed advanced bone healing with a favourable surgical performance compared to a traditional saw.

Benzo[a]pyrene impedes self-renewal and differentiation of mesenchymal stem cells and influences fracture healing.

PubMed

Zhou, Yiqing; Jiang, Rong; An, Liqin; Wang, Hong; Cheng, Sicheng; Qiong, Shi; Weng, Yaguang

2017-06-01

Mesenchymal stem cells (MSCs) are implicated in the bone-forming process during fracture repair. Benzo[a]pyrene (BaP)-a cigarette smoke component and powerful motivator of the aryl hydrocarbon receptor (Ahr)-unfavorably influences bone condition and osteoblast differentiation. The first thing we noticed decreases self-renewal and differentiation of human bone marrow mesenchymal stem (hBM-MSCs) from smokers and activates Ahr signaling in MSCs by up-regulating the Ahr target gene cytochrome P450 (CYP) 1B1 expression. In vitro studies, we employed C3H10T1/2 and bone marrow mesenchymal stem cells (BM-MSCs) with BaP and discovered that BaP impaired innate properties of MSCs. Further investigation into MSCs showed that exposure to BaP activated Ahr signaling and inhibited TGF-β1/SMAD4 and TGF-β1/ERK/AKT signaling pathways. Corresponding with the outcomes, tibial fracture calluses produced by BaP-administered rats appeared to delay healing. This effect of BaP was abrogated by resveratrol, a natural Ahr antagonist, in vitro and in vivo. These data demonstrated that Ahr may play a key role in BaP-impaired innate properties by inhibiting SMAD-dependent signaling pathways TGF-β1/SMAD4 and SMAD-independent TGF-β1/ERK/AKT signaling pathways. Furthermore, resveratrol inhibited MSCs from adverse effects caused by BaP. Copyright © 2017. Published by Elsevier B.V.

Partial gravity unloading inhibits bone healing responses in a large animal model.

PubMed

Gadomski, Benjamin C; McGilvray, Kirk C; Easley, Jeremiah T; Palmer, Ross H; Santoni, Brandon G; Puttlitz, Christian M

2014-09-22

The reduction in mechanical loading associated with space travel results in dramatic decreases in the bone mineral density (BMD) and mechanical strength of skeletal tissue resulting in increased fracture risk during spaceflight missions. Previous rodent studies have highlighted distinct bone healing differences in animals in gravitational environments versus those during spaceflight. While these data have demonstrated that microgravity has deleterious effects on fracture healing, the direct translation of these results to human skeletal repair remains problematic due to substantial differences between rodent and human bone. Thus, the objective of this study was to investigate the effects of partial gravitational unloading on long-bone fracture healing in a previously-developed large animal Haversian bone model. In vivo measurements demonstrated significantly higher orthopedic plate strains (i.e. load burden) in the Partial Unloading (PU) Group as compared to the Full Loading (FL) Group following the 28-day healing period due to inhibited healing in the reduced loading environment. DEXA BMD in the metatarsus of the PU Group decreased 17.6% (p<0.01) at the time of the ostectomy surgery. Four-point bending stiffness of the PU Group was 4.4 times lower than that of the FL Group (p<0.01), while µCT and histomorphometry demonstrated reduced periosteal callus area (p<0.05), mineralizing surface (p<0.05), mineral apposition rate (p<0.001), bone formation rate (p<0.001), and periosteal/endosteal osteoblast numbers (p<0.001/p<0.01, respectively) as well as increased periosteal osteoclast number (p<0.05). These data provide strong evidence that the mechanical environment dramatically affects the fracture healing cascade, and likely has a negative impact on Haversian system healing during spaceflight. Copyright © 2014 Elsevier Ltd. All rights reserved.

Platelet-rich plasma for bone healing and regeneration.

PubMed

Oryan, Ahmad; Alidadi, Soodeh; Moshiri, Ali

2016-01-01

Successful healing of large bone defects (LBDs) is a complicated phenomenon because the body's natural ability often fails to effectively repair the LBDs. New modalities should be utilized to increase the quality and accelerate bone healing. Platelet concentrates in different forms can be considered an attractive option for such purpose. Platelets as a natural source of growth factors, cytokines, and other micro and macromolecules are hypothesized to improve bone healing. This review has covered important concepts regarding platelet-rich plasma (PRP) including mechanisms of action, preparation protocols and their differences, and factors affecting the PRP efficacy during bone healing. In addition, the most recent studies in different levels which evaluated the role of PRP on bone repair has been reviewed and discussed to clarify the controversies and conflicts, and to illustrate a future prospective and directions for orthopedic surgeons to overcome current limitations and difficulties. As the efficacy of PRP is dependent on various factors, the outcome of PRP therapy is variable and unpredictable in orthopedic patients. Therefore, it is still too soon to suggest PRP as the first line treatment option in complicated bone injuries such as LBDs and nonunions. However, combination of PRP with natural and synthetic biomaterials can enhance the effectiveness of PRP.

Use of the Er:YAG laser for improved plating in maxillofacial surgery: comparison of bone healing in laser and drill osteotomies.

PubMed

Lewandrowski, K U; Lorente, C; Schomacker, K T; Flotte, T J; Wilkes, J W; Deutsch, T F

1996-01-01

Surgical reconstruction of bony defects in the maxillofacial region involves fixation of bony fragments with mini and micro plates. Bone stabilization during hole drilling is often challenging due to the need to apply pressure when using a conventional mechanical Hall drill. In addition, fragmentation of the fragile bones may occur and complicate the reconstruction. The pulsed Er:YAG laser offers an attractive alternative drilling modality because it does not require physical contact with the bone in order to drill holes, cuts bone with minimal thermal damage, and allows precise control of bone cutting. The objective of this study was to investigate the pulsed Er:YAG laser as an alternative to the mechanical bur by comparing bone healing using both modalities. Bone healing in an inferior border defect of the rat mandible was examined using either an Er:YAG laser or a mechanical bur for drilling. The healing of osteotomies in facial bones and of screw holes for plate stabilization of free bone fragments was studied. All defects healed by 4 weeks postoperatively. Histologic evaluation demonstrated no difference in the amount of newly formed woven bone at the osteotomy site or screw holes made by either the laser or the drill. The extent of thermal damage at the osteotomy sites was comparable in laser and mechanically cut bone fragments. On the basis of this study we suggest that the Er: YAG laser can be used clinically in thin, fragile bones in the maxillofacial region.

Fracture healing using degradable magnesium fixation plates and screws.

PubMed

Chaya, Amy; Yoshizawa, Sayuri; Verdelis, Kostas; Noorani, Sabrina; Costello, Bernard J; Sfeir, Charles

2015-02-01

Internal bone fixation devices made with permanent metals are associated with numerous long-term complications and may require removal. We hypothesized that fixation devices made with degradable magnesium alloys could provide an ideal combination of strength and degradation, facilitating fracture fixation and healing while eliminating the need for implant removal surgery. Fixation plates and screws were machined from 99.9% pure magnesium and compared with titanium devices in a rabbit ulnar fracture model. Magnesium device degradation and the effect on fracture healing and bone formation were assessed after 4 weeks. Fracture healing with magnesium device fixation was compared with that of titanium devices using qualitative histologic analysis and quantitative histomorphometry. Micro-computed tomography showed device degradation after 4 weeks in vivo. In addition, 2-dimensional micro-computed tomography slices and histologic staining showed that magnesium degradation did not inhibit fracture healing or bone formation. Histomorphology showed no difference in bone-bridging fractures fixed with magnesium and titanium devices. Interestingly, abundant new bone was formed around magnesium devices, suggesting a connection between magnesium degradation and bone formation. Our results show potential for magnesium fixation devices in a loaded fracture environment. Furthermore, these results suggest that magnesium fixation devices may enhance fracture healing by encouraging localized new bone formation. Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Targeted delivery of lovastatin and tocotrienol to fracture site promotes fracture healing in osteoporosis model: micro-computed tomography and biomechanical evaluation.

PubMed

Ibrahim, Nurul 'Izzah; Khamis, Mohd Fadhli; Mod Yunoh, Mohd Faridz; Abdullah, Shahrum; Mohamed, Norazlina; Shuid, Ahmad Nazrun

2014-01-01

Osteoporosis is becoming a major health problem that is associated with increased fracture risk. Previous studies have shown that osteoporosis could delay fracture healing. Although there are potential agents available to promote fracture healing of osteoporotic bone such as statins and tocotrienol, studies on direct delivery of these agents to the fracture site are limited. This study was designed to investigate the effects of two potential agents, lovastatin and tocotrienol using targeted drug delivery system on fracture healing of postmenopausal osteoporosis rats. The fracture healing was evaluated using micro CT and biomechanical parameters. Forty-eight Sprague-Dawley female rats were divided into 6 groups. The first group was sham-operated (SO), while the others were ovariectomized (OVx). After two months, the right tibiae of all rats were fractured at metaphysis region using pulsed ultrasound and were fixed with plates and screws. The SO and OVxC groups were given two single injections of lovastatin and tocotrienol carriers. The estrogen group (OVx+EST) was given daily oral gavages of Premarin (64.5 µg/kg). The Lovastatin treatment group (OVx+Lov) was given a single injection of 750 µg/kg lovastatin particles. The tocotrienol group (OVx+TT) was given a single injection of 60 mg/kg tocotrienol particles. The combination treatment group (OVx+Lov+TT) was given two single injections of 750 µg/kg lovastatin particles and 60 mg/kg tocotrienol particles. After 4 weeks of treatment, the fractured tibiae were dissected out for micro-CT and biomechanical assessments. The combined treatment group (OVx+Lov+TT) showed significantly higher callus volume and callus strength than the OVxC group (p<0.05). Both the OVx+Lov and OVx+TT groups showed significantly higher callus strength than the OVxC group (p<0.05), but not for callus volume. In conclusion, combined lovastatin and tocotrienol may promote better fracture healing of osteoporotic bone.

Assessment of carbon fibre composite fracture fixation plate using finite element analysis.

PubMed

Saidpour, Seyed H

2006-07-01

In the internal fixation of fractured bone by means of bone-plates fastened to the bone on its tensile surface, an on-going concern has been the excessive stress shielding of the bone by the excessively-stiff stainless-steel plate. The compressive stress shielding at the fracture-interface immediately after fracture-fixation delays callus formation and bone healing. Likewise, the tensile stress shielding in the layer of bone underneath the plate can cause osteoporosis and decrease in tensile strength of this layer. In this study a novel forearm internal fracture fixation plate made from short carbon fibre reinforced plastic (CFRP) was used in an attempt to address the problem. Accordingly, it has been possible to analyse the stress distribution in the composite plates using finite-element modelling. A three-dimensional, quarter-symmetric finite element model was generated for the plate system. The stress state in the underlying bone was examined for several loading conditions. Based on the analytical results the composite plate system is likely to reduce stress-shielding effects at the fracture site when subjected to bending and torsional loads. The design of the plate was further optimised by reducing the width around the innermost holes.

Effect on Clinical Outcome and Growth Factor Synthesis With Adjunctive Use of Pulsed Electromagnetic Fields for Fifth Metatarsal Nonunion Fracture: A Double-Blind Randomized Study.

PubMed

Streit, Adam; Watson, B Collier; Granata, Jaymes D; Philbin, Terrence M; Lin, Hsuan-Ni; O'Connor, J Patrick; Lin, Sheldon

2016-09-01

Electromagnetic bone growth stimulators have been found to biologically enhance the bone healing environment, with upregulation of numerous growth factors. The purpose of the study was to quantify the effect, in vivo, of pulsed electromagnetic fields (PEMFs) on growth factor expression and healing time in fifth metatarsal nonunions. This was a prospective, randomized, double-blind trial of patients, cared for by 2 fellowship-trained orthopedic foot and ankle surgeons. Inclusion criteria consisted of patients between 18 and 75 years old who had been diagnosed with a fifth metatarsal delayed or nonunion, with no progressive signs of healing for a minimum of 3 months. Eight patients met inclusion criteria and were randomized to receive either an active stimulation or placebo PEMF device. Each patient then underwent an open biopsy of the fracture site and was fitted with the appropriate PEMF device. The biopsy was analyzed for messenger-ribonucleic acid (mRNA) levels using quantitative competitive reverse transcription polymerase chain reaction (QT-RT-PCR). Three weeks later, the patient underwent repeat biopsy and open reduction and internal fixation of the nonunion site. The patients were followed at 2- to 4-week intervals with serial radiographs and were graded by the number of cortices of healing. All fractures healed, with an average time to complete radiographic union of 14.7 weeks and 8.9 weeks for the inactive and active PEMF groups, respectively. A significant increase in placental growth factor (PIGF) level was found after active PEMF treatment (P = .043). Other factors trended higher following active PEMF including brain-derived neurotrophic factor (BDNF), bone morphogenetic protein (BMP) -7, and BMP-5. The adjunctive use of PEMF for fifth metatarsal fracture nonunions produced a significant increase in local placental growth factor. PEMF also produced trends toward higher levels of multiple other factors and faster average time to radiographic union compared to unstimulated controls. Level I, prospective randomized trial. © The Author(s) 2016.

In vivo study of microarc oxidation coated biodegradable magnesium plate to heal bone fracture defect of 3mm width.

PubMed

Wu, Y F; Wang, Y M; Jing, Y B; Zhuang, J P; Yan, J L; Shao, Z K; Jin, M S; Wu, C J; Zhou, Y

2017-10-01

Microarc oxidation (MAO) coated magnesium (Mg) with improved corrosion resistance appeal increasing interests as a revolutionary biodegradable metal for fractured bone fixing implants application. However, the in vivo corrosion degradation of the implants and bone healing response are not well understood, which is highly required in clinic. In the present work, 10μm and 20μm thick biocompatible MAO coatings mainly composed of MgO, Mg 2 SiO 4 , CaSiO 3 and Mg 3 (PO 4 ) 2 phases were fabricated on AZ31 magnesium alloy. The electrochemical tests indicated an improved corrosion resistance of magnesium by the MAO coatings. The 10μm and 20μm coated and uncoated magnesium plates were separately implanted into the radius bone fracture site of adult New Zealand white rabbits using a 3mm width bone fracture defect model to investigate the magnesium implants degradation and uninhibited bone healing. Taking advantage of the good biocompatibility of the MAO coatings, no adverse effects were detected through the blood test and histological examination. The implantation groups of coated and uncoated magnesium plates were both observed the promoting effect of bone fracture healing compared with the simple fracture group without implant. The releasing Mg 2+ by the degradation of implants into the fracture site improved the bone fracture healing, which is attributed to the magnesium promoting CGRP-mediated osteogenic differentiation. Mg degradation and bone fracture healing promoting must be tailored by microarc oxidation coating with different thickness for potential clinic application. Copyright © 2017. Published by Elsevier B.V.

Differences of bone healing in metaphyseal defect fractures between osteoporotic and physiological bone in rats.

PubMed

Thormann, Ulrich; El Khawassna, Thaqif; Ray, Seemun; Duerselen, Lutz; Kampschulte, Marian; Lips, Katrin; von Dewitz, Helena; Heinemann, Sascha; Heiss, Christian; Szalay, Gabor; Langheinrich, Alexander C; Ignatius, Anita; Schnettler, Reinhard; Alt, Volker

2014-03-01

Discrepancies in bone healing between osteoporotic and non-osteoporotic bone remain uncertain. The focus of the current work is to evaluate potential healing discrepancies in a metaphyseal defect model in rat femora. Female Sprague-Dawley rats were either ovariectomized (OVX, n=14) and combined with a calcium-, phosphorus- and vitamin D3-, soy- and phytoestrogen-free diet or received SHAM operation with standard diet rat (SHAM, n=14). Three months post-ovariectomy, DEXA measurement showed a reduction of bone mineral density reflecting an osteoporotic bone status in OVX rats. Rats then underwent a 3 mm wedge-shaped osteotomy at the distal metaphyseal area of the left femur stabilized with a T-shaped mini-plate and allowed to heal for 6 weeks. Biomechanical competence by means of a non-destructive three-point bending test showed significant lower flexural rigidity in the OVX rats at 3 mm lever span compared to SHAM animals (p=0.048) but no differences at 10 mm lever span. Microcomputer tomography (μCT) showed bridging cortices and consolidation of the defect in both groups, however, no measurable differences were found in either total ossified tissue or vascular volume fraction. Furthermore, histology showed healing discrepancies that were characterized by cartilaginous remnant and more unmineralized tissue presence in the OVX rats compared to more mature consolidation appearance in the SHAM group. In summary, bone defect healing in metaphyseal bone slightly differs between osteoporotic and non-osteoporotic bone in the current 3 mm defect model in both 3mm lever span biomechanical testing and histology. Copyright © 2013 Elsevier Ltd. All rights reserved.

Radioprotection provides functional mechanics but delays healing of irradiated tendon allografts after ACL reconstruction in sheep.

PubMed

Seto, Aaron U; Culp, Brian M; Gatt, Charles J; Dunn, Michael

2013-12-01

Successful protection of tissue properties against ionizing radiation effects could allow its use for terminal sterilization of musculoskeletal allografts. In this study we functionally evaluate Achilles tendon allografts processed with a previously developed radioprotective treatment based on (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) crosslinking and free radical scavenging using ascorbate and riboflavin, for ovine anterior cruciate ligament reconstruction. Arthroscopic anterior cruciate ligament (ACL) reconstruction was performed using double looped allografts, while comparing radioprotected irradiated and fresh frozen allografts after 12 and 24 weeks post-implantation, and to control irradiated grafts after 12 weeks. Radioprotection was successful at preserving early subfailure mechanical properties comparable to fresh frozen allografts. Twelve week graft stiffness and anterior-tibial (A-T) translation for radioprotected and fresh frozen allografts were comparable at 30 % of native stiffness, and 4.6 and 5 times native A-T translation, respectively. Fresh frozen allograft possessed the greatest 24 week peak load at 840 N and stiffness at 177 N/mm. Histological evidence suggested a delay in tendon to bone healing for radioprotected allografts, which was reflected in mechanical properties. There was no evidence that radioprotective treatment inhibited intra-articular graft healing. This specific radioprotective method cannot be recommended for ACL reconstruction allografts, and data suggest that future efforts to improve allograft sterilization procedures should focus on modifying or eliminating the pre-crosslinking procedure.

In vivo assessment of bone healing following Piezotome® ultrasonic instrumentation.

PubMed

Reside, Jonathan; Everett, Eric; Padilla, Ricardo; Arce, Roger; Miguez, Patricia; Brodala, Nadine; De Kok, Ingeborg; Nares, Salvador

2015-04-01

This pilot study evaluated the molecular, histologic, and radiographic healing of bone to instrumentation with piezoelectric or high speed rotary (R) devices over a 3-week healing period. Fourteen Sprague-Dawley rats (Charles River Laboratories International, Inc., Wilmington, MA, USA) underwent bilateral tibial osteotomies prepared in a randomized split-leg design using Piezotome® (P1) (Satelec Acteon, Merignac, France), Piezotome 2® (P2) (Satelec Acteon), High-speed R instrumentation, or sham surgery (S). At 1 week, an osteogenesis array was used to evaluate differences in gene expression while quantitative analysis assessed percentage bone fill (PBF) and bone mineral density (BMD) in the defect, peripheral, and distant regions at 3 weeks. Qualitative histologic evaluation of healing osteotomies was also performed at 3 weeks. At 1 week, expression of 11 and 18 genes involved in bone healing was significantly (p < .05) lower following P1 and P2 instrumentation, respectively, relative to S whereas 16 and 4 genes were lower relative to R. No differences in PBF or BMD were detected between groups within the osteotomy defect. However, significant differences in PBF (p = .020) and BMD (p = .008) were noted along the peripheral region between P2 and R groups, being R the group with the lowest values. Histologically, smooth osteotomy margins were present following instrumentation using P1 or P2 relative to R. Piezoelectric instrumentation favors preservation of bone adjacent to osteotomies while variations in gene expression suggest differences in healing rates due to surgical modality. Bone instrumented by piezoelectric surgery appears less detrimental to bone healing than high-speed R device. © 2013 Wiley Periodicals, Inc.

Delayed healing of lower limb fractures with bisphosphonate therapy

PubMed Central

Ng, A; Tang, H; Joseph, S; Richardson, M

2015-01-01

Introduction Bisphosphonate therapy (BT) is used commonly in the management of osteoporosis. A systematic review was conducted investigating delayed union of lower limb, long bone fractures in patients on BT. We specifically assessed whether BT increases the risk of delayed union or non-union in lower limb, long bone fractures. Methods A literature search was conducted in the PubMed and Embase™ on 4 November 2014. Articles that investigated lower limb fractures, history of BT and fracture union were included in the review. Results A total of 9,809 papers were retrieved and 14 were deemed suitable for this review. The mean time to union in patients on BT was 8.5 months. A longer time to union was reported in a study investigating BT users versus controls (6.5 vs 4.8 months respectively). The mean rate of delayed or non-union for BT associated atypical fractures was 20% per fracture. Specifically in one study, delayed union was more common in the cohort with more than three years of BT (67%) than in the group with less than three years of BT (26%). Surgical fixation was associated with improved outcomes compared with non-operative management. Conclusions BT has been described to be associated with multiple adverse outcomes related to atypical fractures. Current evidence recommends operative management for this patient group. Further investigation is required to evaluate the exact effects of BT on lower limb fractures, in particular typical femoral fractures. PMID:26264082

The role of bone marrow-derived cells during the bone healing process in the GFP mouse bone marrow transplantation model.

PubMed

Tsujigiwa, Hidetsugu; Hirata, Yasuhisa; Katase, Naoki; Buery, Rosario Rivera; Tamamura, Ryo; Ito, Satoshi; Takagi, Shin; Iida, Seiji; Nagatsuka, Hitoshi

2013-03-01

Bone healing is a complex and multistep process in which the origin of the cells participating in bone repair is still unknown. The involvement of bone marrow-derived cells in tissue repair has been the subject of recent studies. In the present study, bone marrow-derived cells in bone healing were traced using the GFP bone marrow transplantation model. Bone marrow cells from C57BL/6-Tg (CAG-EGFP) were transplanted into C57BL/6 J wild mice. After transplantation, bone injury was created using a 1.0-mm drill. Bone healing was histologically assessed at 3, 7, 14, and 28 postoperative days. Immunohistochemistry for GFP; double-fluorescent immunohistochemistry for GFP-F4/80, GFP-CD34, and GFP-osteocalcin; and double-staining for GFP and tartrate-resistant acid phosphatase were performed. Bone marrow transplantation successfully replaced the hematopoietic cells into GFP-positive donor cells. Immunohistochemical analyses revealed that osteoblasts or osteocytes in the repair stage were GFP-negative, whereas osteoclasts in the repair and remodeling stages and hematopoietic cells were GFP-positive. The results indicated that bone marrow-derived cells might not differentiate into osteoblasts. The role of bone marrow-derived cells might be limited to adjustment of the microenvironment by differentiating into inflammatory cells, osteoclasts, or endothelial cells in immature blood vessels.

Effect of methotrexate on bone and wound healing.

PubMed

Pountos, Ippokratis; Giannoudis, Peter V

2017-05-01

Methotrexate (MTX) is one of the most commonly used disease modifying drugs administered for wide spectrum of conditions. Through the expansion of the indications of MTX use, an increasing number of patients nowadays attend orthopaedic departments receiving this pharmacological agent. The aim of this manuscript is to present our current understanding on the effect of MTX on bone and wound healing. Areas covered: The authors offer a comprehensive review of the existing literature on the experimental and clinical studies analysing the effect of MTX on bone and wound healing. The authors also analyse the available literature and describe the incidence of complications after elective orthopaedic surgery in patients receiving MTX. Expert opinion: The available experimental data and clinical evidence are rather inadequate to allow any safe scientific conclusions on the effect of MTX on bone healing. Regarding wound healing, in vitro and experimental animal studies suggest that MTX can adversely affect wound healing, whilst the clinical studies show that lose-dose MTX is safe and does not affect the incidence of postoperative wound complications.

Fracture healing in mice under controlled rigid and flexible conditions using an adjustable external fixator.

PubMed

Röntgen, Viktoria; Blakytny, Robert; Matthys, Romano; Landauer, Mario; Wehner, Tim; Göckelmann, Melanie; Jermendy, Philipp; Amling, Michael; Schinke, Thorsten; Claes, Lutz; Ignatius, Anita

2010-11-01

Mice are increasingly used to investigate mechanobiology in fracture healing. The need exists for standardized models allowing for adjustment of the mechanical conditions in the fracture gap. We introduced such a model using rigid and flexible external fixators with considerably different stiffness (axial stiffnesses of 18.1 and 0.82 N/mm, respectively). Both fixators were used to stabilize a 0.5 mm osteotomy gap in the femur of C57BL/6 mice (each n = 8). Three-point bending tests, µCT, and histomorphometry demonstrated a different healing pattern after 21 days. Both fixations induced callus formation with a mixture of intramembranous and enchondral ossification. Under flexible conditions, the bending stiffness of the callus was significantly reduced, and a larger but qualitatively inferior callus with a significantly lower fraction of bone but a higher fraction of cartilage and soft tissue was formed. Monitoring of the animal movement and the ground reaction forces demonstrated physiological loading with no significant differences between the groups, suggesting that the differences in healing were not based on a different loading behavior. In summary, flexible external fracture fixation of the mouse femur led to delayed fracture healing in comparison to a more rigid situation. © 2010 Orthopaedic Research Society.

Single-blind randomized clinical trial to evaluate clinical and radiological outcomes after one year of immediate versus delayed implant placement supporting full-arch prostheses

PubMed Central

Pellicer-Chover, Hilario; Peñarrocha-Oltra, David; Bagán, Leticia; Fichy-Fernandez, Antonio J.; Canullo, Luigi

2014-01-01

Purpose: To evaluate and compare peri-implant health, marginal bone loss and success of immediate and delayed implant placement for rehabilitation with full-arch fixed prostheses. Material and Methods: The present study was a prospective, randomized, single-blind, clinical preliminary trial. Patients were randomized into two treatment groups. In Group A implants were placed immediately post-extraction and in Group B six months after extraction. The following control time-points were established: one week, six months and twelve months after loading. Measurements were taken of peri-implant crevicular fluid volume, plaque index, gingival retraction, keratinized mucosa, probing depth, modified gingival index and presence of mucositis. Implant success rates were evaluated for the two groups. The study sample included fifteen patients (nine women and six men) with a mean average age of 63.7 years. One hundred and forty-four implants were placed: 76 placed in healed sites and 68 placed immediately. Results: At the moment of prosthetic loading, keratinized mucosa width and probing depth were higher in immediate implants than delayed implants, with statistically significant differences. However, after six and twelve months, differences between groups had disappeared. Bone loss was 0.54 ± 0.39 mm for immediate implants and 0.66 ± 0.25 mm for delayed implants (p=0.201). No implants failed in either group. Conclusions: The present study with a short follow-up and a small sample yielded no statistically significant differences in implant success and peri-implant marginal bone loss between immediate and delayed implants with fixed full-arch prostheses. Peri-implant health showed no statistically significant differences for any of the studied parameters (crevicular fluid volume, plaque index, gingival retraction, keratinized mucosa, probing depth, modified gingival index and presence of mucositis) at the twelve-month follow-up. Key words:Immediate implants, delayed implants, peri-implant health, success rate. PMID:24316712

Defective bone repair in mast cell-deficient Cpa3Cre/+ mice.

PubMed

Ramirez-GarciaLuna, Jose Luis; Chan, Daniel; Samberg, Robert; Abou-Rjeili, Mira; Wong, Timothy H; Li, Ailian; Feyerabend, Thorsten B; Rodewald, Hans-Reimer; Henderson, Janet E; Martineau, Paul A

2017-01-01

In the adult skeleton, cells of the immune system interact with those of the skeleton during all phases of bone repair to influence the outcome. Mast cells are immune cells best known for their pathologic role in allergy, and may be involved in chronic inflammatory and fibrotic disorders. Potential roles for mast cells in tissue homeostasis, vascularization and repair remain enigmatic. Previous studies in combined mast cell- and Kit-deficient KitW-sh/W-sh mice (KitW-sh) implicated mast cells in bone repair but KitW-sh mice suffer from additional Kit-dependent hematopoietic and non- hematopoietic deficiencies that could have confounded the outcome. The goal of the current study was to compare bone repair in normal wild type (WT) and Cpa3Cre/+ mice, which lack mast cells in the absence of any other hematopoietic or non- hematopoietic deficiencies. Repair of a femoral window defect was characterized using micro CT imaging and histological analyses from the early inflammatory phase, through soft and hard callus formation, and finally the remodeling phase. The data indicate 1) mast cells appear in healing bone of WT mice but not Cpa3Cre/+ mice, beginning 14 days after surgery; 2) re-vascularization of repair tissue and deposition of mineralized bone was delayed and dis-organised in Cpa3Cre/+ mice compared with WT mice; 3) the defects in Cpa3Cre/+ mice were associated with little change in anabolic activity and biphasic alterations in osteoclast and macrophage activity. The outcome at 56 days postoperative was complete bridging of the defect in most WT mice and fibrous mal-union in most Cpa3Cre/+ mice. The results indicate that mast cells promote bone healing, possibly by recruiting vascular endothelial cells during the inflammatory phase and coordinating anabolic and catabolic activity during tissue remodeling. Taken together the data indicate that mast cells have a positive impact on bone repair.

Defective bone repair in mast cell-deficient Cpa3Cre/+ mice

PubMed Central

Chan, Daniel; Samberg, Robert; Abou-Rjeili, Mira; Wong, Timothy H.; Li, Ailian; Feyerabend, Thorsten B.; Rodewald, Hans-Reimer; Henderson, Janet E.; Martineau, Paul A.

2017-01-01

In the adult skeleton, cells of the immune system interact with those of the skeleton during all phases of bone repair to influence the outcome. Mast cells are immune cells best known for their pathologic role in allergy, and may be involved in chronic inflammatory and fibrotic disorders. Potential roles for mast cells in tissue homeostasis, vascularization and repair remain enigmatic. Previous studies in combined mast cell- and Kit-deficient KitW-sh/W-sh mice (KitW-sh) implicated mast cells in bone repair but KitW-sh mice suffer from additional Kit-dependent hematopoietic and non- hematopoietic deficiencies that could have confounded the outcome. The goal of the current study was to compare bone repair in normal wild type (WT) and Cpa3Cre/+ mice, which lack mast cells in the absence of any other hematopoietic or non- hematopoietic deficiencies. Repair of a femoral window defect was characterized using micro CT imaging and histological analyses from the early inflammatory phase, through soft and hard callus formation, and finally the remodeling phase. The data indicate 1) mast cells appear in healing bone of WT mice but not Cpa3Cre/+ mice, beginning 14 days after surgery; 2) re-vascularization of repair tissue and deposition of mineralized bone was delayed and dis-organised in Cpa3Cre/+ mice compared with WT mice; 3) the defects in Cpa3Cre/+ mice were associated with little change in anabolic activity and biphasic alterations in osteoclast and macrophage activity. The outcome at 56 days postoperative was complete bridging of the defect in most WT mice and fibrous mal-union in most Cpa3Cre/+ mice. The results indicate that mast cells promote bone healing, possibly by recruiting vascular endothelial cells during the inflammatory phase and coordinating anabolic and catabolic activity during tissue remodeling. Taken together the data indicate that mast cells have a positive impact on bone repair. PMID:28350850

Evaluation of Guided Bone Regeneration around Oral Implants over Different Healing Times Using Two Different Bovine Bone Materials: A Randomized, Controlled Clinical and Histological Investigation.

PubMed

Kohal, Ralf Joachim; Straub, Lisa Marie; Wolkewitz, Martin; Bächle, Maria; Patzelt, Sebastian Berthold Maximilian

2015-10-01

To evaluate the potential of two bone substitute materials and the influence of different healing periods in guided bone regeneration therapy of osseous defects around implants. Twenty-four edentulous patients received implants in the region of the lost lower incisors. Around two standardized osseous defects were created, treated either with a 50:50 mixture of PepGen P-15® and OsteoGraf®/N-700 (test group) or with BioOss® (control group), and covered with titanium membranes. After healing periods of 2, 4, 6, or 9 months, the implants were removed together with the surrounding bone and subsequently prepared for histological evaluations. Defect depths in both groups showed a clinical reduction after intervention. The histologically measured distance from the implant shoulder to the first point of bone-implant contact (BIC) after treatment did not differ between the two groups. The healing time influenced the level of the first point of BIC, with a longer healing period producing a more coronal first point of BIC. A greater percentage BIC and a higher fraction of mineralized bone were found in the pristine bone area compared with the augmented defect area. It can be concluded that in the treatment of osseous defects around oral implants, both materials were equally effective bone substitute materials when used in combination with guided bone regeneration. © 2014 Wiley Periodicals, Inc.

Formononetin, a methoxy isoflavone, enhances bone regeneration in a mouse model of cortical bone defect.

PubMed

Singh, Krishna Bhan; Dixit, Manisha; Dev, Kapil; Maurya, Rakesh; Singh, Divya

2017-06-01

The bone regeneration and healing effect of formononetin was evaluated in a cortical bone defect model that predominantly heals by intramembranous ossification. For this study, female Balb/c mice were ovariectomised (OVx) and a drill-hole injury was generated in the midfemoral bones of all animals. Treatment with formononetin commenced the day after and continued for 21 d. Parathyroid hormone (PTH1-34) was used as a reference standard. Animals were killed at days 10 and 21. Femur bones were collected at the injury site for histomorphometry studies using microcomputed tomography (μCT) and confocal microscopy. RNA and protein were harvested from the region surrounding the drill-hole injury. For immunohistochemistry, 5 µm sections of decalcified femur bone adjoining the drill-hole site were cut. μCT analysis showed that formononetin promoted bone healing at days 10 and 21 and the healing effect observed was significantly better than in Ovx mice and equal to PTH treatment in many aspects. Formononetin also significantly enhanced bone regeneration as assessed by calcein-labelling studies. In addition, formononetin enhanced the expression of osteogenic markers at the injury site in a manner similar to PTH. Formononetin treatment also led to predominant runt-related transcription factor 2 and osteocalcin localisation at the injury site. These results support the potential of formononetin to be a bone-healing agent and are suggestive of its promising role in the fracture-repair process.

Orthobiologics in Pediatric Sports Medicine.

PubMed

Bray, Christopher C; Walker, Clark M; Spence, David D

2017-07-01

Orthobiologics are biological substances that allow injured muscles, tendons, ligaments, and bone to heal more quickly. They are found naturally in the body; at higher concentrations they can aid in the healing process. These substances include autograft bone, allograft bone, demineralized bone matrix, bone morphogenic proteins, growth factors, stem cells, plasma-rich protein, and ceramic grafts. Their use in sports medicine has exploded in efforts to increase graft incorporation, stimulate healing, and get athletes back to sport with problems including anterior cruciate ligament ruptures, tendon ruptures, cartilage injuries, and fractures. This article reviews orthobiologics and their applications in pediatric sports medicine. Copyright © 2017 Elsevier Inc. All rights reserved.

PREVALENCE OF HEALED LONG-BONE FRACTURES IN WILD CARNIVORES FROM THE NORTHEASTERN UNITED STATES.

PubMed

Argyros, George C; Roth, Aaron J

2016-09-01

Museum specimens representing 12 species of terrestrial carnivores from the northeastern United States were inspected for evidence of healed long-bone fractures. Of 413 individuals, 18 (4.4%) exhibited healed fractures. Thirteen (72.2%) occurred in hind limbs; five (27.8%) occurred in forelimbs. Mustelids had the highest prevalence of healed long-bone fractures (38.8%) of all observed fractures. Within family, 5.6% of Canidae and 2.8% of Mustelidae exhibited healed fractures. Bobcats had the highest taxon prevalence of fractures, 18%. Observational data to assess use of and behavior near roads could provide insight to causes of fracture. Capture in combination with noninvasive examination techniques could be employed to determine incidence of healed fractures in wild populations. Individuals with healed fractures could then be tracked via radio telemetry to determine if these animals behave differently than uninjured conspecifics, and assess long-term survivability and fitness.

End-threaded intramedullary positive profile screw ended self-tapping pin (Admit pin) - A cost-effective novel implant for fixing canine long bone fractures.

PubMed

Chanana, Mitin; Kumar, Adarsh; Tyagi, Som Prakash; Singla, Amit Kumar; Sharma, Arvind; Farooq, Uiase Bin

2018-02-01

The current study was undertaken to evaluate the clinical efficacy of end-threaded intramedullary pinning for management of various long bone fractures in canines. This study was conducted in two phases, managing 25 client-owned dogs presented with different fractures. The technique of application of end-threaded intramedullary pinning in long bone fractures was initially standardized in 6 clinical patients presented with long bone fractures. In this phase, end-threaded pins of different profiles, i.e., positive and negative, were used as the internal fixation technique. On the basis of results obtained from standardization phase, 19 client-owned dogs clinically presented with different fractures were implanted with end-threaded intramedullary positive profile screw ended self-tapping pin in the clinical application phase. The patients, allocated randomly in two groups, when evaluated postoperatively revealed slight pin migration in Group-I (negative profile), which resulted in disruption of callus site causing delayed union in one case and large callus formation in other two cases whereas no pin migration was observed in Group-II (positive profile). Other observations in Group-I was reduced muscle girth and delayed healing time as compared to Group-II. In clinical application, phase 21 st and 42 nd day post-operative radiographic follow-up revealed no pin migration in any of the cases, and there was no bone shortening or fragment collapse in end-threaded intramedullary positive profile screw ended self-tapping pin. The end-threaded intramedullary positive profile screw ended self-tapping pin used for fixation of long bone fractures in canines can resist pin migration, pin breakage, and all loads acting on the bone, i.e., compression, tension, bending, rotation, and shearing to an extent with no post-operative complications.

Biomechanical monitoring of healing bone based on acoustic emission technology.

PubMed

Hirasawa, Yasusuke; Takai, Shinro; Kim, Wook-Cheol; Takenaka, Nobuyuki; Yoshino, Nobuyuki; Watanabe, Yoshinobu

2002-09-01

Acoustic emission testing is a well-established method for assessment of the mechanical integrity of general construction projects. The purpose of the current study was to investigate the usefulness of acoustic emission technology in monitoring the yield strength of healing callus during external fixation. Thirty-five patients with 39 long bones treated with external fixation were evaluated for fracture healing by monitoring load for the initiation of acoustic emission signal (yield strength) under axial loading. The major criteria for functional bone union based on acoustic emission testing were (1) no acoustic emission signal on full weightbearing, and (2) a higher estimated strength than body weight. The yield strength monitored by acoustic emission testing increased with the time of healing. The external fixator could be removed safely and successfully in 97% of the patients. Thus, the acoustic emission method has good potential as a reliable method for monitoring the mechanical status of healing bone.

Injectable Reactive Biocomposites For Bone Healing In Critical-Size Rabbit Calvarial Defects

DTIC Science & Technology

2012-03-29

defects (i.e. be conformable), provide temporary protection to the brain until the bone heals, and enhance tissue regeneration with the delivery of...temporary protection to the brain until the bone heals, and enhance tissue regeneration with the delivery of biologics. In this study, we evaluated the...complex defects (i.e. be conformable), harden to provide temporary protection until tissue remodels (i.e. be settable), and enhance tissue regeneration

RhBMP-7 for the treatment of nonunion of fractures of long bones.

PubMed

Papanagiotou, M; Dailiana, Z H; Karachalios, T; Varitimidis, S; Vlychou, M; Hantes, M; Malizos, K N

2015-07-01

We report the outcome of 84 nonunions involving long bones which were treated with rhBMP-7, in 84 patients (60 men: 24 women) with a mean age 46 years (18 to 81) between 2003 and 2011. The patients had undergone a mean of three previous operations (one to 11) for nonunion which had been present for a mean of 17 months (4 months to 20 years). The nonunions involved the lower limb in 71 patients and the remainder involved the upper limb. A total of 30 nonunions were septic. Treatment was considered successful when the nonunion healed without additional procedures. The relationship between successful union and the time to union was investigated and various factors including age and gender, the nature of the nonunion (location, size, type, chronicity, previous procedures, infection, the condition of the soft tissues) and type of index procedure (revision of fixation, type of graft, amount of rhBMP-7) were analysed. The improvement of the patients' quality of life was estimated using the Short Form (SF) 12 score. A total of 68 nonunions (80.9%) healed with no need for further procedures at a mean of 5.4 months (3 to 10) post-operatively. Multivariate logistic regression analysis of the factors affecting union suggested that only infection significantly affected the rate of union (p = 0.004).Time to union was only affected by the number of previous failed procedures (p = 0.006). An improvement of 79% and 32.2% in SF-12 physical and mental score, respectively, was noted within the first post-operative year. Rh-BMP-7 combined with bone grafts, enabled healing of the nonunion and improved quality of life in about 80% of patients. Aseptic nonunions were much more likely to unite than septic ones. The number of previous failed operations significantly delayed the time to union. ©2015 The British Editorial Society of Bone & Joint Surgery.

Operative Treatment of Fifth Metatarsal Jones Fractures (Zones II and III) in the NBA.

PubMed

O'Malley, Martin; DeSandis, Bridget; Allen, Answorth; Levitsky, Matthew; O'Malley, Quinn; Williams, Riley

2016-05-01

Proximal fractures of the fifth metatarsal (zone II and III) are common in the elite athlete and can be difficult to treat because of a tendency toward delayed union, nonunion, or refracture. The purpose of this case series was to report our experience in treating 10 NBA players, determine the healing rate, return to play, refracture rate, and role of foot type in these athletes. The records of 10 professional basketball players were retrospectively reviewed. Seven athletes underwent standard percutaneous internal fixation with bone marrow aspirate concentrate (BMAC) whereas the other 3 had open bone grafting primarily in addition to fixation and BMAC. Radiographic features evaluated included fourth-fifth intermetatarsal, fifth metatarsal lateral deviation, calcaneal pitch, and metatarsus adductus angles. Radiographic healing was observed at an overall average of 7.5 weeks and return to play was 9.8 weeks. Three athletes experienced refractures. There were no significant differences in clinical features or radiographic measurements except that the refracture group had the highest metatatarsus adductus angles. Most athletes were pes planus and 9 of 10 had a bony prominence under the fifth metatarsal styloid. This is the largest published series of operatively treated professional basketball players who exemplify a specific patient population at high risk for fifth metatarsal fracture. These players were large and possessed a unique foot type that seemed to be associated with increased risk of fifth metatarsal fracture and refracture. This foot type had forefoot metatarsus adductus and a fifth metatarsal that was curved with a prominent base. We continue to use standard internal fixation with bone marrow aspirate but advocate additional prophylactic open bone grafting in patients with high fourth-to-fifth intermetatarsal, fifth metatarsal lateral deviation, and metatarsus adductus angles as well as prominent fifth metatarsal styloids in order to improve fracture healing and potentially decrease the risk of refracture. Level IV, case series. © The Author(s) 2016.

Preclinical and clinical studies on the use of growth factors for bone repair: a systematic review.

PubMed

Fisher, Daniel Mark; Wong, James Min-Leong; Crowley, Conor; Khan, Wasim S

2013-05-01

Bone healing is a complex process. Whilst the majority of fractures heal with conventional treatment, open fractures, large bone defects and non unions still provide great challenges to Orthopaedic Surgeons. Whilst autologous bone graft is seen as the gold standard, the use of growth factors is a growing area of research to find an effective alternative with lower side effects such as donor site morbidity and the finite amount available. This systematic review aims to summarize the pre clinical in-vivo studies and examine the clinical studies on the use of growth factors in bone healing. Databases: PubMed, Medline, OVID, and Cochrane library. The following key words and search terms were used: Growth Factors, Bone Healing, Bone Morphogenic Protein, Transforming Growth Factor Beta, Insulin Like Growth Factor, Platelet Derived Growth Factor, Fracture. All articles were screened based on title with abstracts and full text articles reviewed as appropriate. Reference lists were reviewed from relevant articles to ensure comprehensive and systematic review. Three tables of studies were constructed focussing on Bone Morphogenic Proteins, Platelet Rich Plasma and Growth Factors and Tissue Engineering. Bone Morphogenic Proteins and Platelet Rich Plasma, which contains multiple growth factors, have been shown in preclinical and clinical trials to be an effective alternative to autologous bone graft. Bone Morphogenic Proteins have been shown to be effective in fracture non union, and in open tibial fractures. Platelet Rich Plasma has shown promise in preclinical trials and some small clinical trials, however numbers are limited. Bone Morphogenic Proteins have been shown to be superior to Platelet Rich Protein in one trial. Combining these growth factors with tissue engineering techniques is the focus of ongoing research, and through further clinical trials the most effective techniques for enhancing bone healing will be revealed.

Peri-implant soft tissue and marginal bone adaptation on implant with non-matching healing abutments: micro-CT analysis.

PubMed

Finelle, Gary; Papadimitriou, Dimitrios E V; Souza, André B; Katebi, Negin; Gallucci, German O; Araújo, Mauricio G

2015-04-01

To assess (i) the outcome of changing the horizontal-offset dimension on the peri-implant soft tissues and the crestal bone and (ii) the effect of different healing abutments (flared vs. straight) on the marginal peri-implant soft tissues and crestal bone. Two-piece dental implants diameters of 3.5 and 4.5 mm were placed at least 1 mm subcrestal in five beagle dogs. Three different investigational groups: (i) 3.5-mm-diameter implant with narrow healing abutment (3.5N), (ii) 4.5-mm-diameter implant with narrow healing abutment (4.5N), and (iii) 3.5-mm-diameter implant with wide healing abutment (3.5W), were assessed. After 4 months of healing, the vertical distance from the marginal crestal bone (MB) to the implant shoulder (IS); the vertical distance from the IS to the first bone-to-implant contact; and the horizontal distance of bone ingrowth on the implant platform were measured with a high-resolution micro-CT (Xradia MicroXCT-200 system). Implants with a narrow healing caps showed an interproximal MB located between 0 and 1 mm above the implant shoulder, while the 3.5W group exhibits a mean value -0.50 mm. As all implants in group 3.5N presented a fBIC located at the level of the IS. For the 4.5N group, the mean fBIC-IS distance was -0.52 mm apically to the IS. For the 3.5WC group, the mean fBIC-IS distance was -1.42 mm. Horizontal bone apposition was only observed for the 3.5N group and the 4.5N group. The dimension of the horizontal offset would play a minimal role in reducing bone remodeling, whereas the configuration of the transmucosal component would directly influence marginal bone remodeling. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Comparison of bone healing and outcomes between allogenous bone chip and hydroxyapatite chip grafts in open wedge high tibial osteotomy.

PubMed

Lee, O-Sung; Lee, Kyung Jae; Lee, Yong Seuk

2017-11-03

Allogenous bone chips and hydroxyapatite (HA) chips have been known as good options for filling an inevitable void after open wedge high tibial osteotomy (OWHTO). However, there are concerns regarding bone healing after the use of these grafts. The purpose of this study was to compare the bone healing represented by the osteoconductivity and absorbability between allogenous bone chips and HA chips in OWHTO. The outcomes of bone healing of 53 patients who received an allogenous bone chip graft and 41 patients who received an HA chip graft were retrospectively evaluated, and the results were compared between the two groups. Osteoconductivity and absorbability were serially evaluated for the assessment of bone healing at 6 weeks, 3 months, 6 months, and 1 year postoperatively. The osteoconductivity of the allogenous bone chips was greater than that of the HA chips at 6 weeks postoperatively (p < 0.05). However, there were no statistically significant differences from 3 months to 1 year postoperatively. The absorbability showed no statistically significant differences 6 weeks and 3 months after OWHTO; however, the allogenous bone chip group showed a greater absorbability at 6 months and 1 year postoperatively (42.8 ± 14.2 vs. 34.6 ± 13.8, p = 0.006 at 6 months postoperatively; 54.6 ± 14.4 vs. 43.0 ± 14.0, p < 0.001 at 1 year postoperatively). However, the two graft materials showed similar results of HKA angle, WBL ratio, posterior tibial slope.

A comparative investigation of bone surface after cutting with mechanical tools and Er:YAG laser.

PubMed

Baek, Kyung-Won; Deibel, Waldemar; Marinov, Dilyan; Griessen, Mathias; Dard, Michel; Bruno, Alfredo; Zeilhofer, Hans-Florian; Cattin, Philippe; Juergens, Philipp

2015-07-01

Despite of the long history of medical application, laser ablation of bone tissue became successful only recently. Laser bone cutting is proven to have higher accuracy and to increase bone healing compared to conventional mechanical bone cutting. But the reason of subsequent better healing is not biologically explained yet. In this study we present our experience with an integrated miniaturized laser system mounted on a surgical lightweight robotic arm. An Erbium-doped Yttrium Aluminium Garnet (Er:YAG) laser and a piezoelectric (PZE) osteotome were used for comparison. In six grown up female Göttingen minipigs, comparative surgical interventions were done on the edentulous mandibular ridge. Our laser system was used to create different shapes of bone defects on the left side of the mandible. On the contralateral side, similar bone defects were created by PZE osteotome. Small bone samples were harvested to compare the immediate post-operative cut surface. The analysis of the cut surface of the laser osteotomy and conventional mechanical osteotomy revealed an essential difference. The scanning electron microscopy (SEM) analysis showed biologically open cut surfaces from the laser osteotomy. The samples from PZE osteotomy showed a flattened tissue structure over the cut surface, resembling the "smear layer" from tooth preparation. We concluded that our new finding with the mechanical osteotomy suggests a biological explanation to the expected difference in subsequent bone healing. Our hypothesis is that the difference of surface characteristic yields to different bleeding pattern and subsequently results in different bone healing. The analyses of bone healing will support our hypothesis. © 2015 Wiley Periodicals, Inc.

Assessment of Regeneration of Bone in the Extracted Third Molar Sockets Augmented Using Xenograft (CollaPlugTN Zimmer) in Comparison with the Normal Healing on the Contralateral Side.

PubMed

Ranganathan, Murugan; Balaji, M; Krishnaraj, R; Narayanan, Vivek; Thangavelu, Annamalai

2017-11-01

Alveolar bone resorption is a significant clinical problem. Bone loss in third molar region following extraction or surgical removal not only leads to periodontal problems in second molar region but also it may lead to some serious problems like increased incidence of angle fractures. In order to reduce the risks following third molar surgery, the socket should be augmented with bone grafts. In recent days guided tissue regeneration is the most accepted and successful technique followed many authors and its efficacy has been proved. Based upon our clinical experience, the use of bio absorbable collagen wound dressing such as CollaPlug TN has achieved quick healing and more primary wound coverage. Amongst the graft materials collagen is preferable due to its high biocompatibility and hemostatic ability. This study was done to assess the regeneration of bone in the extracted third molar sockets using xenograft (CollaPlug TN -Zimmer) which was compared with the normal healing on the contra lateral side. The assessment was done to analyze post-operative healing complications and to compare the bone density formed between control site and implant site radiologically. On this basis of this study, the use of collaplugTN appears to be beneficial to the patient in postoperative wound healing and also for better bone formation. The use of this material was advantageous because of its simplicity of application cost effectiveness and availability. There is enhanced wound healing and early bone formation.

Low-Intensity Vibration Improves Angiogenesis and Wound Healing in Diabetic Mice

PubMed Central

Weinheimer-Haus, Eileen M.; Judex, Stefan; Ennis, William J.; Koh, Timothy J.

2014-01-01

Chronic wounds represent a significant health problem, especially in diabetic patients. In the current study, we investigated a novel therapeutic approach to wound healing – whole body low-intensity vibration (LIV). LIV is anabolic for bone, by stimulating the release of growth factors, and modulating stem cell proliferation and differentiation. We hypothesized that LIV improves the delayed wound healing in diabetic mice by promoting a pro-healing wound environment. Diabetic db/db mice received excisional cutaneous wounds and were subjected to LIV (0.4 g at 45 Hz) for 30 min/d or a non-vibrated sham treatment (controls). Wound tissue was collected at 7 and 15 d post-wounding and wound healing, angiogenesis, growth factor levels and wound cell phenotypes were assessed. LIV increased angiogenesis and granulation tissue formation at day 7, and accelerated wound closure and re-epithelialization over days 7 and 15. LIV also reduced neutrophil accumulation and increased macrophage accumulation. In addition, LIV increased expression of pro-healing growth factors and chemokines (insulin-like growth factor-1, vascular endothelial growth factor and monocyte chemotactic protein-1) in wounds. Despite no evidence of a change in the phenotype of CD11b+ macrophages in wounds, LIV resulted in trends towards a less inflammatory phenotype in the CD11b− cells. Our findings indicate that LIV may exert beneficial effects on wound healing by enhancing angiogenesis and granulation tissue formation, and these changes are associated with increases in pro-angiogenic growth factors. PMID:24618702

Participation of GATA-3 in regulation of bone healing through transcriptional upregulation of bcl-xL expression

PubMed Central

Liao, Mei-Hsiu; Lin, Pei-I; Ho, Wei-Pin; Chan, Wing P; Chen, Ta-Liang; Chen, Ruei-Ming

2017-01-01

We have previously demonstrated the expression of GATA-DNA-binding protein (GATA)-3, a transcription factor, in osteoblasts and have verified its function in transducing cell survival signaling. This translational study was further designed to evaluate the roles of GATA-3 in regulating bone healing and to explore its possible mechanisms. A metaphyseal bone defect was created in the left femurs of male ICR mice. Analysis by micro-computed topography showed that the bone volume, trabecular bone number and trabecular thickness were augmented and that the trabecular pattern factor decreased. Interestingly, immunohistological analyses showed specific expression of GATA-3 in the defect area. In addition, colocalized expression of GATA-3 and alkaline phosphatase was observed at the wound site. As the fracture healed, the amounts of phosphorylated and non-phosphorylated GATA-3 concurrently increased. Separately, GATA-3 mRNA was induced during bone healing, and, levels of Runx2 mRNA and protein were also increased. The results of confocal microscopy and co-immunoprecipitation showed an association between nuclear GATA-3 and Runx2 in the area of insult. In parallel with fracture healing, Bcl-XL mRNA was significantly triggered. A bioinformatic search revealed the existence of a GATA-3-specific DNA-binding element in the promoter region of the bcl-xL gene. Analysis by chromatin immunoprecipitation assays further demonstrated transactivation activity by which GATA-3 regulated bcl-xL gene expression. Therefore, this study shows that GATA-3 participates in the healing of bone fractures via regulating bcl-xL gene expression, owing to its association with Runx2. In the clinic, GATA-3 may be used as a biomarker for diagnoses/prognoses or as a therapeutic target for bone diseases, such as bone fractures. PMID:29170477

Early experience and results of bone graft enriched with autologous platelet gel for recalcitrant nonunions of lower extremity.

PubMed

Chiang, Chao-Ching; Su, Chen-Yao; Huang, Ching-Kuei; Chen, Wei-Ming; Chen, Tain-Hsiung; Tzeng, Yun-Hsuan

2007-09-01

Refractory nonunions of the tibia or femur are physically and mentally devastating conditions for the patients, and the treatment is challenging for orthopedic surgeons. The goal of this study was to assess the feasibility and outcome of surgical treatment in recalcitrant nonunions of a lower extremity with bone graft enriched with autologous platelet gel (APG). Twelve patients with four femoral and eight tibial atrophic nonunions after multiple prior procedures were included. All of them were treated with the bone grafting procedures with autograft complex enriched with APG. They were evaluated with radiographs, bone mineral density for bony healing process, and the Short-Form 36 Health Survey for functional outcome. Of the 12 patients, 11 healed at an average of 19.7 weeks after the first attempt and 1 healed after the second attempt at 21 weeks. The bone mineral density continued to increase steadily from early healing to the remodeling phase. Functional status was greatly improved at an average follow-up of 32.4 months. The results of this preliminary study implied the possible potential of bone graft enriched with APG in the treatment of recalcitrant nonunions of the lower extremity. More research is necessary to clarify its role in augmentation of bone graft to enhance healing of nonunion.

Clinical factors affecting pathological fracture and healing of unicameral bone cysts

PubMed Central

2014-01-01

Background Unicameral bone cyst (UBC) is the most common benign lytic bone lesion seen in children. The aim of this study is to investigate clinical factors affecting pathological fracture and healing of UBC. Methods We retrospectively reviewed 155 UBC patients who consulted Nagoya musculoskeletal oncology group hospitals in Japan. Sixty of the 155 patients had pathological fracture at presentation. Of 141 patients with follow-up periods exceeding 6 months, 77 were followed conservatively and 64 treated by surgery. Results The fracture risk was significantly higher in the humerus than other bones. In multivariate analysis, ballooning of bone, cyst in long bone, male sex, thin cortical thickness and multilocular cyst were significant adverse prognostic factors for pathological fractures at presentation. The healing rates were 30% and 83% with observation and surgery, respectively. Multivariate analysis revealed that fracture at presentation and history of biopsy were good prognostic factors for healing of UBC in patients under observation. Conclusion The present results suggest that mechanical disruption of UBC such as fracture and biopsy promotes healing, and thus watchful waiting is indicated in these patients, whereas patients with poor prognostic factors for fractures should be considered for surgery. PMID:24884661

Clinical factors affecting pathological fracture and healing of unicameral bone cysts.

PubMed

Urakawa, Hiroshi; Tsukushi, Satoshi; Hosono, Kozo; Sugiura, Hideshi; Yamada, Kenji; Yamada, Yoshihisa; Kozawa, Eiji; Arai, Eisuke; Futamura, Naohisa; Ishiguro, Naoki; Nishida, Yoshihiro

2014-05-17

Unicameral bone cyst (UBC) is the most common benign lytic bone lesion seen in children. The aim of this study is to investigate clinical factors affecting pathological fracture and healing of UBC. We retrospectively reviewed 155 UBC patients who consulted Nagoya musculoskeletal oncology group hospitals in Japan. Sixty of the 155 patients had pathological fracture at presentation. Of 141 patients with follow-up periods exceeding 6 months, 77 were followed conservatively and 64 treated by surgery. The fracture risk was significantly higher in the humerus than other bones. In multivariate analysis, ballooning of bone, cyst in long bone, male sex, thin cortical thickness and multilocular cyst were significant adverse prognostic factors for pathological fractures at presentation. The healing rates were 30% and 83% with observation and surgery, respectively. Multivariate analysis revealed that fracture at presentation and history of biopsy were good prognostic factors for healing of UBC in patients under observation. The present results suggest that mechanical disruption of UBC such as fracture and biopsy promotes healing, and thus watchful waiting is indicated in these patients, whereas patients with poor prognostic factors for fractures should be considered for surgery.

Unicameral bone cysts: comparison of percutaneous curettage, steroid, and autologous bone marrow injections.

PubMed

Canavese, Federico; Wright, James G; Cole, William G; Hopyan, Sevan

2011-01-01

The purpose of this study was to compare the outcome of percutaneous curettage with intralesional injection of methylprednisolone and bone marrow for unicameral bone cysts (UBCs). This was a retrospective review of 46 children and adolescents with UBC treated with autologous bone marrow injection, methylprednisolone acetate injection or percutaneous curettage alone. Inclusion criteria were a radiological diagnosis of UBC and at least 24 months follow-up from the last procedure. Healing was determined using Neer/Cole 4-grades rating scale. The 3 treatment groups were comparable with regard to age, sex, location of the cyst, and the number of procedures undertaken. At 2 years follow-up, the proportion of patients with satisfactory healing (Neer/Cole grades I and II) was greatest among those who underwent percutaneous curettage (70%) compared with bone marrow injection (21%) and methylprednisolone acetate injection (41%) (P = 0.03). We found no association between healing and age (P = 0.80) nor between healing and sex (P = 0.61). These results suggest that mechanical disruption of the cyst membrane may be helpful in healing of cysts and that this technique may be preferred to simple intralesional injections. Level III.

Immediate Single-Tooth Implant Placement in Bony Defects in the Esthetic Zone: A 1-Year Randomized Controlled Trial.

PubMed

Slagter, Kirsten W; Meijer, Henny J A; Bakker, Nicolaas A; Vissink, Arjan; Raghoebar, Gerry M

2016-06-01

This study aims to assess, with regard to marginal bone level (MBL), whether the outcome of immediate implant placement in bony defects in the esthetic zone was non-inferior to delayed implant placement after 1 year. Forty patients with a failing tooth in the esthetic zone and a labial bony defect of ≥5 mm after removal of a tooth were randomly assigned for immediate (n = 20) or delayed (n = 20) implant placement. Second-stage surgery and provisionalization occurred after 3 months of healing. Follow-up was at 1 month and 1 year after definitive crown placement. The study was powered to detect a difference in MBL of >0.9 mm. Buccal bone thickness, soft tissue peri-implant parameters, esthetic indices, and patient satisfaction were also assessed. One year after definitive crown placement, MBL loss was 0.56 ± 0.39 mm mesially and 0.74 ± 0.51 mm distally for the immediate placement group and 0.51 ± 0.43 mesially and 0.54 ± 0.45 distally mm for the delayed placement group, respectively (not significant). Regarding differences in means, non-inferiority was observed after 1 year (difference in mean for immediate versus delayed: mesially 0.04 mm [95% confidence interval (CI) = -0.22 to 0.30 mm, P = 0.40]; distally 0.21 mm [95% CI = -0.10 to 0.51 mm, P = 0.58]). No significant differences in the other outcome variables were observed. Immediate implant placement with delayed provisionalization was non-inferior to delayed implant placement with delayed provisionalization in labial bony defects of ≥5 mm regarding change in MBL. Although not powered for other outcome variables, no clinically relevant differences were observed in these variables.

Fractures in geriatric mice show decreased callus expansion and bone volume.

PubMed

Lopas, Luke A; Belkin, Nicole S; Mutyaba, Patricia L; Gray, Chancellor F; Hankenson, Kurt D; Ahn, Jaimo

2014-11-01

Poor fracture healing in geriatric populations is a significant source of morbidity, mortality, and cost to individuals and society; however, a fundamental biologic understanding of age-dependent healing remains elusive. The development of an aged-based fracture model system would allow for a mechanistic understanding that could guide future biologic treatments. Using a small animal model of long-bone fracture healing based on chronologic age, we asked how aging affected (1) the amount, density, and proportion of bone formed during healing; (2) the amount of cartilage produced and the progression to bone during healing; (3) the callus structure and timing of the fracture healing; and (4) the behavior of progenitor cells relative to the observed deficiencies of geriatric fracture healing. Transverse, traumatic tibial diaphyseal fractures were created in 5-month-old (n=104; young adult) and 25-month-old (n=107; which we defined as geriatric, and are approximately equivalent to 70-85 year-old humans) C57BL/6 mice. Fracture calluses were harvested at seven times from 0 to 40 days postfracture for micro-CT analysis (total volume, bone volume, bone volume fraction, connectivity density, structure model index, trabecular number, trabecular thickness, trabecular spacing, total mineral content, bone mineral content, tissue mineral density, bone mineral density, degree of anisotropy, and polar moment of inertia), histomorphometry (total callus area, cartilage area, percent of cartilage, hypertrophic cartilage area, percent of hypertrophic cartilage area, bone and osteoid area, percent of bone and osteoid area), and gene expression quantification (fold change). The geriatric mice produced a less robust healing response characterized by a pronounced decrease in callus amount (mean total volume at 20 days postfracture, 30.08±11.53 mm3 versus 43.19±18.39 mm3; p=0.009), density (mean bone mineral density at 20 days postfracture, 171.14±64.20 mg hydroxyapatite [HA]/cm3 versus 210.79±37.60 mg HA/cm3; p=0.016), and less total cartilage (mean cartilage area at 10 days postfracture, 101,279±46,755 square pixels versus 302,167±137,806 square pixels; p=0.013) and bone content (mean bone volume at 20 days postfracture, 11.68±3.18 mm3 versus 22.34±10.59 mm3; p<0.001) compared with the young adult mice. However, the amount of cartilage and bone relative to the total callus size was similar between the adult and geriatric mice (mean bone volume fraction at 25 days postfracture, 0.48±0.10 versus 0.50±0.13; p=0.793), and the relative expression of chondrogenic (mean fold change in SOX9 at 10 days postfracture, 135+25 versus 90±52; p=0.221) and osteogenic genes (mean fold change in osterix at 20 days postfracture, 22.2±5.3 versus 18.7±5.2; p=0.324) was similar. Analysis of mesenchymal cell proliferation in the geriatric mice relative to adult mice showed a decrease in proliferation (mean percent of undifferentiated mesenchymal cells staining proliferating cell nuclear antigen [PCNA] positive at 10 days postfracture, 25%±6.8% versus 42%±14.5%; p=0.047). Our findings suggest that the molecular program of fracture healing is intact in geriatric mice, as it is in geriatric humans, but callus expansion is reduced in magnitude. Our study showed altered healing capacity in a relevant animal model of geriatric fracture healing. The understanding that callus expansion and bone volume are decreased with aging can help guide the development of targeted therapeutics for these difficult to heal fractures.

Effect of simvastatin versus low level laser therapy (LLLT) on bone regeneration in rabbit's tibia

NASA Astrophysics Data System (ADS)

Gheith, Mostafa E.; Khairy, Maggie A.

2014-02-01

Simvastatin is a cholesterol lowering drug which proved effective on promoting bone healing. Recently low level laser therapy (LLLT) proved its effect as a biostimulator promoting bone regeneration. This study aims to compare the effect of both Simvastatin versus low level laser on bone healing in surgically created bone defects in rabbit's tibia. Material and methods: The study included 12 New Zealand white rabbits. Three successive 3mm defects were created in rabbits tibia first defect was left as control, second defect was filled with Simvastatin while the third defect was acted on with Low Level Laser (optical fiber 320micrometer). Rabbits were sacrificed after 48 hours, 1 week and 2 weeks intervals. Histopathology was conducted on the three defects Results: The histopathologic studies showed that the bony defects treated with the Low Level Laser showed superior healing patterns and bone regeneration than those treated with Simvastatin. While the control defect showed the least healing pattern.

Osseointegration of Plateau Root Form Implants: Unique Healing Pathway Leading to Haversian-Like Long-Term Morphology.

PubMed

Coelho, Paulo G; Suzuki, Marcelo; Marin, Charles; Granato, Rodrigo; Gil, Luis F; Tovar, Nick; Jimbo, Ryo; Neiva, Rodrigo; Bonfante, Estevam A

2015-01-01

Endosteal dental implants have been utilized as anchors for dental and orthopedic rehabilitations for decades with one of the highest treatment success rates in medicine. Such success is due to the phenomenon of osseointegration where after the implant surgical placement, bone healing results into an intimate contact between bone and implant surface. While osseointegration is an established phenomenon, the route which osseointegration occurs around endosteal implants is related to various implant design factors including surgical instrumentation and implant macro, micro, and nanometer scale geometry. In an implant system where void spaces (healing chambers) are present between the implant and bone immediately after placement, its inherent bone healing pathway results in unique opportunities to accelerate the osseointegration phenomenon at the short-term and its maintenance on the long-term through a haversian-like bone morphology and mechanical properties.

The use of autologous blood-derived growth factors in bone regeneration

PubMed Central

Civinini, Roberto; Macera, Armando; Nistri, Lorenzo; Redl, Birgit; Innocenti, Massimo

2011-01-01

Platelet-rich plasma (PRP) is defined as a portion of the plasma fraction of autologous blood having platelet concentrations above baseline. When activated the platelets release growth factors that play an essential role in bone healing such as Platelet-derived Growth Factor, Transforming Growth Factor-β, Vascular Endothelial Growth Factor and others. Multiple basic science and in vivo animal studies agree that PRP has a role in the stimulation of the healing cascade in ligament, tendon, muscle cartilage and in bone regeneration in the last years PRP had a widespread diffusion in the treatment of soft tissue and bone healing. The purpose of this review is to describe the biological properties of platelets and its factors, the methods used for producing PRP, to provide a background on the underlying basic science and an overview of evidence based medicine on clinical application of PRP in bone healing. PMID:22461800

Oxygen as a critical determinant of bone fracture healing-a multiscale model.

PubMed

Carlier, Aurélie; Geris, Liesbet; van Gastel, Nick; Carmeliet, Geert; Van Oosterwyck, Hans

2015-01-21

A timely restoration of the ruptured blood vessel network in order to deliver oxygen and nutrients to the fracture zone is crucial for successful bone healing. Indeed, oxygen plays a key role in the aerobic metabolism of cells, in the activity of a myriad of enzymes as well as in the regulation of several (angiogenic) genes. In this paper, a previously developed model of bone fracture healing is further improved with a detailed description of the influence of oxygen on various cellular processes that occur during bone fracture healing. Oxygen ranges of the cell-specific oxygen-dependent processes were established based on the state-of-the art experimental knowledge through a rigorous literature study. The newly developed oxygen model is compared with previously published experimental and in silico results. An extensive sensitivity analysis was also performed on the newly introduced oxygen thresholds, indicating the robustness of the oxygen model. Finally, the oxygen model was applied to the challenging clinical case of a critical sized defect (3mm) where it predicted the formation of a fracture non-union. Further model analyses showed that the harsh hypoxic conditions in the central region of the callus resulted in cell death and disrupted bone healing thereby indicating the importance of a timely vascularization for the successful healing of a large bone defect. In conclusion, this work demonstrates that the oxygen model is a powerful tool to further unravel the complex spatiotemporal interplay of oxygen delivery, diffusion and consumption with the several healing steps, each occurring at distinct, optimal oxygen tensions during the bone repair process. Copyright © 2014 Elsevier Ltd. All rights reserved.

Immediate placement of endosseous implants into the extraction sockets

PubMed Central

Ebenezer, Vijay; Balakrishnan, K.; Asir, R. Vigil Dev; Sragunar, Banu

2015-01-01

Implant by definition “means any object or material, such as an alloplastic substance or other tissue, which is partial or completely inserted into the body for therapeutic, diagnostic, prosthetic, or experimental purpose.” The placement of a dental implant in an extraction socket at the time of extraction or explantation is known as immediate implant placement whereas delayed placement of implant signifies the implant placement in edentulous areas where healing has completed with new bone formation after the loss of tooth/teeth. Recent idea goes by “why late when it can be done immediately.” There are several advantages of immediate placement of implants, and lots of studies have been done. In this article, the advantages and disadvantages of immediate versus delayed placement of implants have been reviewed. PMID:26015721

Improvement of Bone Healing by Neutralization of microRNA-335-5p, but not by Neutralization of microRNA-92A in Bone Marrow Mononuclear Cells Transplanted into a Large Femur Defect of the Rat.

PubMed

Janko, Maren; Dietz, Konstantin; Rachor, Julia; Sahm, Julian; Schroder, Katrin; Schaible, Alexander; Nau, Christoph; Seebach, Caroline; Marzi, Ingo; Henrich, Dirk

2018-04-23

Transplanted bone marrow mononuclear cells (BMC) support the healing of large bone defects. Neutralization of microRNA (MiR) that negatively affects key processes of the reparative response in BMC might help to further improve the beneficial effect of transplanted BMC in bone healing. Hence, the aim of this study was to evaluate if the neutralization of MiR-92A (vascularization) and MiR-335-5p (osteogenic differentiation) in BMC using specific antiMiRs leads to a further improvement of the BMC-supported therapy of large bone defects. BMC transiently transfected with antiMiR- 92A, antiMiR-335, antiMiR-92A, and antiMiR-355 or control antiMiR were seeded on β-TCP (beta-tricalcium phosphate) and placed in a femoral large bone defect (5 mm) in Sprague-Dawley rats. Ultimate load as well as osseous integration of the β-TCP-scaffolds were significantly improved in the antiMiR-335 group compared to the control group after 8 weeks, whereas neutralization of antiMiR-92A lead to an improvement of early vascularization after 1 week, but not to enhanced bone healing after 8 weeks. We demonstrated that the targeted inhibition of MiRs in transplanted BMC is a new approach that enhances BMC-supported bone healing.

Two-stage open reduction and internal fixation versus limited internal fixation combined with external fixation: a meta-analysis of postoperative complications in patients with severe Pilon fractures.

PubMed

Cui, Xueliang; Chen, Hui; Rui, Yunfeng; Niu, Yang; Li, He

2018-01-01

Objectives Two-stage open reduction and internal fixation (ORIF) and limited internal fixation combined with external fixation (LIFEF) are two widely used methods to treat Pilon injury. However, which method is superior to the other remains controversial. This meta-analysis was performed to quantitatively compare two-stage ORIF and LIFEF and clarify which method is better with respect to postoperative complications in the treatment of tibial Pilon fractures. Methods We conducted a meta-analysis to quantitatively compare the postoperative complications between two-stage ORIF and LIFEF. Eight studies involving 360 fractures in 359 patients were included in the meta-analysis. Results The two-stage ORIF group had a significantly lower risk of superficial infection, nonunion, and bone healing problems than the LIFEF group. However, no significant differences in deep infection, delayed union, malunion, arthritis symptoms, or chronic osteomyelitis were found between the two groups. Conclusion Two-stage ORIF was associated with a lower risk of postoperative complications with respect to superficial infection, nonunion, and bone healing problems than LIFEF for tibial Pilon fractures. Level of evidence 2.

Hydroxyapatite-doped polycaprolactone nanofiber membrane improves tendon-bone interface healing for anterior cruciate ligament reconstruction.

PubMed

Han, Fei; Zhang, Peng; Sun, Yaying; Lin, Chao; Zhao, Peng; Chen, Jiwu

2015-01-01

Hamstring tendon autograft is a routine graft for anterior cruciate ligament (ACL) reconstruction. However, ways of improving the healing between the tendon and bone is often overlooked in clinical practice. This issue can be addressed by using a biomimetic scaffold. Herein, a biomimetic nanofiber membrane of polycaprolactone/nanohydroxyapatite/collagen (PCL/nHAp/Col) is fabricated that mimics the composition of native bone tissue for promoting tendon-bone healing. This membrane has good cytocompatibility, allowing for osteoblast cell adhesion and growth and bone formation. As a result, MC3T3 cells reveal a higher mineralization level in PCL/nHAp/Col membrane compared with PCL membrane alone. Further in vivo studies in ACL reconstruction in a rabbit model shows that PCL/nHAp/Col-wrapped tendon may afford superior tissue integration to nonwrapped tendon in the interface between the tendon and host bone as well as improved mechanical strength. This study shows that PCL/nHAp/Col nanofiber membrane wrapping of autologous tendon is effective for improving tendon healing with host bone in ACL reconstruction.

Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis

PubMed Central

Locatelli, Vittorio; Bianchi, Vittorio E.

2014-01-01

Background. Growth hormone (GH) and insulin-like growth factor (IGF-1) are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered. PMID:25147565

Serum leptin, bone mineral density and the healing of long bone fractures in men with spinal cord injury.

PubMed

Wang, Lei; Liu, Linjuan; Pan, Zhanpeng; Zeng, Yanjun

2015-11-16

Previously reported fracture rates in patients with spinal cord injury range from 1% to 20%. However, the exact role of spinal cord injury in bone metabolism has not yet been clarified. In order to investigate the effects of serum leptin and bone mineral density on the healing of long bone fractures in men with spinal cord injury, 15 male SCI patients and 15 matched controls were involved in our study. The outcome indicated that at 4 and 8 weeks after bone fracture, callus production in patients with spinal cord injury was lower than that in controls. Besides, bone mineral density was significantly reduced at 2, 4 and 8 weeks. In addition, it was found that at each time point, patients with spinal cord injury had significantly higher serum leptin levels than controls and no association was found between serum leptin level and bone mineral density of lumbar vertebrae. Moreover, bone mineral density was positively correlated with bone formation in both of the groups. These findings suggest that in early phases i.e. week 4 and 8, fracture healing was impaired in patients with spinal cord injury and that various factors participated in the complicated healing process, such as hormonal and mechanical factors.

Modeling the effects of inflammation in bone fracture healing

NASA Astrophysics Data System (ADS)

Kojouharov, H. V.; Trejo, I.; Chen-Charpentier, B. M.

2017-10-01

A new mathematical model is presented to study the early inflammatory effects in bone healing. It consists of a system of nonlinear ordinary differential equations that represents the interactions among macrophages, mesenchymal stem cells, and osteoblasts. A qualitative analysis of the model is performed to determine the equilibria and their corresponding stability properties. A set of numerical simulations is performed to support the theoretical results. The model is also used to numerically monitor the evolution of a broken bone for different types of fractures and to explore possible treatments to accelerate bone healing by administrating anti-inflammatory drugs.

Induced membrane technique combined with two-stage internal fixation for the treatment of tibial osteomyelitis defects.

PubMed

Luo, Fei; Wang, Xiaohua; Wang, Shulin; Fu, Jingshu; Xie, Zhao

2017-07-01

The purpose of this study was to observe the effects of induced membrane technique combined with two-stage internal fixation in the treatment of tibial osteomyelitis defects. A retrospective analyses for 67 cases of tibialosteomyelitis defects were admitted to our department between September 2012 to February 2015, which were treated with induced membrane technique. At the first stage, implanted with a PMMA cement spacer in the defects after radical debridement and fixed with reconstructive locked plate. Bone grafting and exchanged the plate with intramedullary nail at the second stage. In current study, all patients were followed up for 18-35 months. Sixty-six patients achieved bone union with the average radiographic and clinical healing times of 5.55±2.19 and 7.45±1.69months, respectively. Seven patients required a second debridement before grafting, while four patients experienced a recurrence of infection or a relapse following second stage treatment. Twelve patients experienced either knee or ankle dysfunctions and 2 patients faced delayed wound healing. Donor site complications includes pain and infection were found in 7 and 3 patients, respectively with delayed stress fracture in 1 patient only. Induced membrane technique for the treatment of tibial osteomyelitis defects, seems a reliable method. The use of reconstructive locked plate as a temporary internal fixation at the first stage and exchanged with intramedullary nail at the second stage, potentially achieves good clinical efficacy. Care should be taken to restore the joint function especially in distal tibia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Delayed wound healing after tooth extraction and self-reported kyphosis in Japanese men and women

PubMed Central

Taguchi, Akira; Kamimura, Mikio; Nakamura, Yukio; Sugino, Noriyuki; Ichinose, Akira; Maezumi, Hisayoshi; Fukuzawa, Takashi; Ashizawa, Ryouhei; Takahara, Kenji; Gushiken, Susumu; Mukaiyama, Keijiro; Ikegami, Shota; Uchiyama, Shigeharu; Kato, Hiroyuki

2016-01-01

It is unclear whether osteoporosis itself is a main risk factor for delayed wound healing after tooth extraction in humans. In this study, we evaluated the association between experience of delayed wound healing after last tooth extraction and self-reported kyphosis, with the possibility of having vertebral fractures, in Japanese patients. Among the 1,504 patients who responded to the structured questionnaire survey, 518 patients (134 men and 384 women) aged 55–97 years finally participated in this study. Patients who self-reported mild-moderate kyphosis were more likely to have problematic delayed wound healing after last tooth extraction than those who reported severe kyphosis (odds ratio [OR] 4.98; 95% confidence interval [CI], 1.86–13.38 and OR 2.30; 95% CI, 0.52–10.22, respectively) (p for trend = 0.005). Japanese patients with vertebral fractures may have a higher risk of having problematic delayed wound healing after tooth extraction. PMID:27848958

Delayed wound healing after tooth extraction and self-reported kyphosis in Japanese men and women.

PubMed

Taguchi, Akira; Kamimura, Mikio; Nakamura, Yukio; Sugino, Noriyuki; Ichinose, Akira; Maezumi, Hisayoshi; Fukuzawa, Takashi; Ashizawa, Ryouhei; Takahara, Kenji; Gushiken, Susumu; Mukaiyama, Keijiro; Ikegami, Shota; Uchiyama, Shigeharu; Kato, Hiroyuki

2016-11-16

It is unclear whether osteoporosis itself is a main risk factor for delayed wound healing after tooth extraction in humans. In this study, we evaluated the association between experience of delayed wound healing after last tooth extraction and self-reported kyphosis, with the possibility of having vertebral fractures, in Japanese patients. Among the 1,504 patients who responded to the structured questionnaire survey, 518 patients (134 men and 384 women) aged 55-97 years finally participated in this study. Patients who self-reported mild-moderate kyphosis were more likely to have problematic delayed wound healing after last tooth extraction than those who reported severe kyphosis (odds ratio [OR] 4.98; 95% confidence interval [CI], 1.86-13.38 and OR 2.30; 95% CI, 0.52-10.22, respectively) (p for trend = 0.005). Japanese patients with vertebral fractures may have a higher risk of having problematic delayed wound healing after tooth extraction.

Application of 3D printed customized external fixator in fracture reduction.

PubMed

Qiao, Feng; Li, Dichen; Jin, Zhongmin; Gao, Yongchang; Zhou, Tao; He, Jinlong; Cheng, Li

2015-01-01

Long bone fracture is common in traumatic osteopathic patients. Good reduction is beneficial for bone healing, preventing the complications such as delayed union, nonunion, malunion, but is hard to achieve. Repeated attempts during the surgery would increase the operation time, cause new damage to the fracture site and excessive exposure to radiation. Robotic and navigation techniques can help improve the reduction accuracy, however, the high cost and complexity of operation have limited their clinical application. We combined 3D printing with computer-assisted reduction technique to develop a customised external fixator with the function of fracture reduction. The original CT data obtained by scanning the fracture was imported to computer for reconstructing and reducing the 3D image of the fracture, based on which the external fixator (named as Q-Fixator) was designed and then fabricated by 3D printing techniques. The fracture reduction and fixation was achieved by connecting the pins inserted in the bones with the customised Q-Fixator. Experiments were conducted on three fracture models to demonstrate the reduction results. Good reduction results were obtained on all three fractured bone models, with an average rotation of 1.21°(± 0.24), angulation of 1.84°(± 0.28), and lateral displacement of 2.22 mm(± 0.62). A novel customised external fixator for long bone fracture reduction was readily developed using 3D printing technique. The customised external fixator had the advantages of easy manipulation, accurate reduction, minimally invasion and experience-independence. Future application of the customised external fixator can be extended to include the fixation function with stress adjustment and potentially optimise the fracture healing process. Copyright © 2015 Elsevier Ltd. All rights reserved.

Harnessing and Modulating Inflammation in Strategies for Bone Regeneration

PubMed Central

Mountziaris, Paschalia M.; Spicer, Patrick P.; Kasper, F. Kurtis

2011-01-01

Inflammation is an immediate response that plays a critical role in healing after fracture or injury to bone. However, in certain clinical contexts, such as in inflammatory diseases or in response to the implantation of a biomedical device, the inflammatory response may become chronic and result in destructive catabolic effects on the bone tissue. Since our previous review 3 years ago, which identified inflammatory signals critical for bone regeneration and described the inhibitory effects of anti-inflammatory agents on bone healing, a multitude of studies have been published exploring various aspects of this emerging field. In this review, we distinguish between regenerative and damaging inflammatory processes in bone, update our discussion of the effects of anti-inflammatory agents on bone healing, summarize recent in vitro and in vivo studies demonstrating how inflammation can be modulated to stimulate bone regeneration, and identify key future directions in the field. PMID:21615330

[Analysis of the results of bone healing in femurs lengthened by the gradual distraction method in children and adolescents].

PubMed

Jochymek, J; Skvaril, J; Ondrus, S

2009-10-01

Treatment of leg length inequality via lengthening of the shorter extremity is an infrequent orthopedic procedure due to the requirement of special distraction devices and possible serious complications. Essential qualitative changes in operative technique development are associated with the name of G. A. Ilizarov, who paved the way for the autoregenerate gradual distraction method in the 1950s. In the years 1990 through 2007 a total of 67 patients underwent femur lengthening via gradual distraction using various types of external fixators at the Department of Pediatric Surgery, Orthopedics, and Traumatology, Faculty Hospital in Brno. The quality of bone healing was monitored and a number of parameters followed and statistically evaluated using regularly scheduled X-ray examinations. In 13 cases we had to remove the external fixator following the distraction phase, perform an osteosynthesis via a splint and fill the distraction gap via spongioplasty. The bone healing was satisfactory in the remaining 54 patients and the lengthened bone required no other fixation method. The analysis showed statistically significant deceleration in bone healing following distraction in female patients over 12 years of age, and in boys over 14 years of age. Lack of periosteal callus five weeks after surgery always signified serious problems in further healing. Severe complications were recorded in 11 cases during the distraction phase, and in 12 cases after the removal of the distraction apparatus. Our results fully correspond with the data and experience of others cited authors. In addition our study showed deceleration in bone healing in girls over 12 years and in boys over 14 years of age and serious problem in healing when is lack of periostal callus five weeks after surgery. The aim of this report was to present the results of our study of distraction gap bone healing using the gradual lengthening approach. Key words: leg lengthening, gradual distraction, external fixation, leg discrepancy, complication.

Healing in the new millennium: bone stimulators: an overview of where we've been and where we may be heading.

PubMed

Cook, Jeremy J; Summers, N Jake; Cook, Emily A

2015-01-01

Electromagnetic fields and their uses in bone healing have been fairly well studied, with most results showing improvement in healing of both bone and cartilage. Most supportive data are found in relation to the spine, femur, and tibia, but there is increasing evidence for its use in the foot and ankle for treatment of nonunions and as an adjunctive device in arthrodeses, particularly in high-risk populations. There are varying data and a significant variety of quality in the current research and publications concerning the use of electrical bone stimulation in the treatment of the foot and ankle. Thus, there is a definite need for further investigation and high-quality study designs to determine the most effective treatment modalities and pathologies best used with bone stimulation. Bone stimulation should be viewed as an adjunctive procedure in which the surgeon optimizes the high-risk patient both medically or surgically whenever possible. But when used appropriately, bone stimulation has the potential to influence outcomes and aid in bone healing when complications arise and in high-risk populations. Copyright © 2015 Elsevier Inc. All rights reserved.

Promising role of ANGPTL4 gene in diabetic wound healing.

PubMed

Arya, Awadhesh K; Tripathi, Kamlakar; Das, Parimal

2014-03-01

Diabetes mellitus (DM) is one of the severe metabolic disorders of carbohydrate metabolism worldwide. Developing countries are at higher risk of DM, and there is significant evidence that it is epidemic in many economically developing and newly industrialized countries. Among all other complications associated with DM, delayed wound healing is a major concern in diabetic patients. Wound healing is a natural healing process that starts immediately after injury. This involves interaction of a complex cascade of cellular events that generates resurfacing, reconstitution, and restoration of the tensile strength of injured skin. There are multiple factors responsible for delayed wound healing among which the contribution of DM has been well documented. The wound healing process is also delayed by the metabolic, vascular, neurological, and inflammatory alterations, which are well known in both type 1 and type 2 diabetes. Keratinocytes are crucial for wound re-epithelialization, and defects in directed migration of keratinocytes due to DM are associated with the delayed wound healing process. Many factors responsible for re-epithelialization have been identified, characterized, and well described; however, the genes responsible for the healing process have only partially been illustrated. This article will therefore focus on the efficacy of ANGPTL4 (angiopoietin-like 4) gene, which plays a novel role in keratinocyte migration during wound healing.

Comparison of titanium elastic intramedullary nailing versus injection of bone marrow in treatment of simple bone cysts in children: a retrospective study.

PubMed

Li, Wenchao; Xu, Ruijiang; Du, Minghua; Chen, Hui

2016-08-15

Simple bone cysts are common benign lytic bone lesions in children. The main goals of treatment for bone cysts are to prevent pathological fractures, support the healing process, and prevent recurrence. This retrospective study compared fixation with titanium elastic intramedullary nailing (TEN) versus aspiration and injection of autogenous bone marrow (ABM) for the treatment of simple bone cysts in children. Forty-six patients (mean follow-up, 62 months; range, 34-71 months) who presented with bone cysts (30 in the humerus, 16 in the femur) from January 2006 to December 2012 were retrospectively evaluated. Patients were treated with either TEN or ABM injection. Radiographs were evaluated according to previously established criteria. Clinical evaluations of pain, infection, additional fractures, and range of motion were performed. After treatment, all patients were pain-free and had normal range of motion in adjacent joints. In the ABM group, 14 (60.9 %) bone cysts completely healed, six (26.1 %) healed with small residuals after two injections, and three (13.0 %) recurred. In the TEN group, 16 (69.6 %) bone cysts completely healed, four (17.4 %) healed with small residuals, and three (13.0 %) recurred. There were no significant differences in radiographic outcomes between groups at the final follow-up (P > 0.05). Three patients developed skin irritation as a result of the nail ends. Additional fractures occurred in four patients who underwent ABM injection and in two patients who underwent TEN. No significant associations were found between pathological fractures and cyst activity, location, or treatment outcomes in the patients studied. Both TEN and ABM injection are safe and effective treatment for bone cysts. ABM injection promotes osteogenic differentiation of bone marrow stromal cells; multiple injections can reduce the likelihood of recurrence. TEN stabilizes the affected bone and thus allows early limb mobilization. It also reduces pressure in the capsule wall by continuous decompression to promote cyst healing. ABM injections can be used to treat cyst recurrence after previous TEN, with favorable results.

Bone graft

MedlinePlus

... dry. Follow instructions about showering. DO NOT smoke. Smoking slows or prevents bone healing. If you smoke, the graft is more likely to fail. Be aware that nicotine patches slow healing just like smoking does.

Osteogenic effect of a gastric pentadecapeptide, BPC-157, on the healing of segmental bone defect in rabbits: a comparison with bone marrow and autologous cortical bone implantation.

PubMed

Sebecić, B; Nikolić, V; Sikirić, P; Seiwerth, S; Sosa, T; Patrlj, L; Grabarević, Z; Rucman, R; Petek, M; Konjevoda, P; Jadrijević, S; Perović, D; Slaj, M

1999-03-01

Gastrectomy often results in increased likelihood of osteoporosis, metabolic aberration, and risk of fracture, and there is a need for a gastric peptide with osteogenic activity. A novel stomach pentadecapeptide, BPC-157, improves wound and fracture healing in rats in addition to having an angiogenic effect. Therefore, in the present study, using a segmental osteoperiosteal bone defect (0.8 cm, in the middle of the left radius) that remained incompletely healed in all control rabbits for 6 weeks (assessed in 2 week intervals), pentadecapeptide BPC-157 was further studied (either percutaneously given locally [10 microg/kg body weight] into the bone defect, or applied intramuscularly [intermittently, at postoperative days 7, 9, 14, and 16 at 10 microg/kg body weight] or continuously [once per day, postoperative days 7-21 at 10 microg or 10 ng/kg body weight]). For comparison, rabbits percutaneously received locally autologous bone marrow (2 mL, postoperative day 7). As standard treatment, immediately after its formation, the bone defect was filled with an autologous cortical graft. Saline-treated (2 mL intramuscularly [i.m.] and 2 mL locally into the bone defect), injured animals were used as controls. Pentadecapeptide BPC-157 significantly improved the healing of segmental bone defects. For instance, upon radiographic assessment, the callus surface, microphotodensitometry, quantitative histomorphometry (10 microg/kg body weight i.m. for 14 days), or quantitative histomorphometry (10 ng/kg body weight i.m. for 14 days) the effect of pentadecapeptide BPC-157 was shown to correspond to improvement after local application of bone marrow or autologous cortical graft. Moreover, a comparison of the number of animals with unhealed defects (all controls) or healed defects (complete bony continuity across the defect site) showed that besides pentadecapeptide intramuscular application for 14 days (i.e., local application of bone marrow or autologous cortical graft), also following other pentadecapeptide BPC-157 regimens (local application, or intermittent intramuscular administration), the number of animals with healed defect was increased. Hopefully, in the light of the suggested stomach significance for bone homeostasis, the possible relevance of this pentadecapeptide BPC-157 effect (local or intramuscular effectiveness, lack of unwanted effects) could be a basis for methods of choice in the future management of healing impairment in humans, and requires further investigation.

Local strategies to prevent and treat osteoporosis.

PubMed

Torstrick, F Brennan; Guldberg, Robert E

2014-03-01

Despite advances in systemic osteoporosis therapeutic outcomes, management of fragility fractures and implant fixation in osteoporotic bone remain difficult clinical challenges. Low initial bone density and a prolonged healing response can lead to fracture nonunion and aseptic implant loosening. Local treatment strategies could be used to prevent fracture, accelerate healing, and increase implant fixation by locally stimulating anabolic pathways or inhibiting catabolic pathways. Local strategies under investigation include direct drug release from injectable materials or implant surface coatings. Common locally delivered drugs include bisphosphonates, parathyroid hormone, and bone morphogenetic proteins, yet additional compounds targeting novel pathways in bone biology are also being actively explored. Mechanical stimulation via low intensity pulsed ultrasound, alone or in combination with drug therapy, may also prove effective to promote local bone healing and implant fixation within osteoporotic bone.

Loss of transcription factor early growth response gene 1 results in impaired endochondral bone repair

PubMed Central

Reumann, Marie K.; Strachna, Olga; Yagerman, Sarah; Torrecilla, Daniel; Kim, Jihye; Doty, Steven B.; Lukashova, Lyudmila; Boskey, Adele L.; Mayer-Kuckuk, Philipp

2011-01-01

Transcription factors that play a role in ossification during development are expected to participate in postnatal fracture repair since the endochondral bone formation that occurs in embryos is recapitulated during fracture repair. However, inherent differences exist between bone development and fracture repair, including a sudden disruption of tissue integrity followed by an inflammatory response. This raises the possibility that repair-specific transcription factors participate in bone healing. Here, we assessed the consequence of loss of early growth response gene 1 (EGR-1) on endochondral bone healing because this transcription factor has been shown to modulate repair in vascularized tissues. Model fractures were created in ribs of wild type (wt) and EGR-1−/− mice. Differences in tissue morphology and composition between these two animal groups were followed over 28 post fracture days (PFDs). In wt mice, bone healing occurred in healing phases characteristic of endochondral bone repair. A similar healing sequence was observed in EGR-1−/− mice but was impaired by alterations. A persistent accumulation of fibrin between the disconnected bones was observed on PFD7 and remained pronounced in the callus on PFD14. Additionally, the PFD14 callus was abnormally enlarged and showed increased deposition of mineralized tissue. Cartilage ossification in the callus was associated with hyper-vascularity and -proliferation. Moreover, cell deposits located in proximity to the callus within skeletal muscle were detected on PFD14. Despite these impairments, repair in EGR-1−/− callus advanced on PFD28, suggesting EGR-1 is not essential for healing. Together, this study provides genetic evidence that EGR-1 is a pleiotropic regulator of endochondral fracture repair. PMID:21726677

Radiographic evaluation of marginal bone levels adjacent to parallel-screw cylinder machined-neck implants and rough-surfaced microthreaded implants using digitized panoramic radiographs.

PubMed

Nickenig, Hans-Joachim; Wichmann, Manfred; Schlegel, Karl Andreas; Nkenke, Emeka; Eitner, Stephan

2009-06-01

The purpose of this split-mouth study was to compare macro- and microstructure implant surfaces at the marginal bone level during a stress-free healing period and under functional loading. From January to February 2006, 133 implants (70 rough-surfaced microthreaded implants and 63 machined-neck implants) were inserted in the mandible of 34 patients with Kennedy Class I residual dentitions and followed until February 2008. The marginal bone level was radiographically determined, using digitized panoramic radiographs, at four time points: at implant placement (baseline level), after the healing period, after 6 months of functional loading, and at the end of follow-up. The median follow-up time was 1.9 (range: 1.9-2.1) years. The machined-neck group had a mean crestal bone loss of 0.5 mm (range: 0-2.3) after the healing period, 0.8 mm after 6 months (range: 0-2.4), and 1.1 mm (range: 0-3) at the end of follow-up. The rough-surfaced microthreaded implant group had a mean bone loss of 0.1 mm (range: -0.4-2) after the healing period, 0.4 mm (range: 0-2.1) after 6 months, and 0.5 mm (range: 0-2.1) at the end of follow-up. The two implant types showed significant differences in marginal bone levels (healing period: P=0.01; end of follow-up: P<0.01). Radiographic evaluation of marginal bone levels adjacent to machined-neck or rough-surfaced microthreaded implants showed that implants with the microthreaded design caused minimal changes in crestal bone levels during healing (stress-free) and under functional loading.

Loss of transcription factor early growth response gene 1 results in impaired endochondral bone repair.

PubMed

Reumann, Marie K; Strachna, Olga; Yagerman, Sarah; Torrecilla, Daniel; Kim, Jihye; Doty, Stephen B; Lukashova, Lyudmila; Boskey, Adele L; Mayer-Kuckuk, Philipp

2011-10-01

Transcription factors that play a role in ossification during development are expected to participate in postnatal fracture repair since the endochondral bone formation that occurs in embryos is recapitulated during fracture repair. However, inherent differences exist between bone development and fracture repair, including a sudden disruption of tissue integrity followed by an inflammatory response. This raises the possibility that repair-specific transcription factors participate in bone healing. Here, we assessed the consequence of loss of early growth response gene 1 (EGR-1) on endochondral bone healing because this transcription factor has been shown to modulate repair in vascularized tissues. Model fractures were created in ribs of wild type (wt) and EGR-1(-/-) mice. Differences in tissue morphology and composition between these two animal groups were followed over 28 post fracture days (PFDs). In wt mice, bone healing occurred in healing phases characteristic of endochondral bone repair. A similar healing sequence was observed in EGR-1(-/-) mice but was impaired by alterations. A persistent accumulation of fibrin between the disconnected bones was observed on PFD7 and remained pronounced in the callus on PFD14. Additionally, the PFD14 callus was abnormally enlarged and showed increased deposition of mineralized tissue. Cartilage ossification in the callus was associated with hyper-vascularity and -proliferation. Moreover, cell deposits located in proximity to the callus within skeletal muscle were detected on PFD14. Despite these impairments, repair in EGR-1(-/-) callus advanced on PFD28, suggesting EGR-1 is not essential for healing. Together, this study provides genetic evidence that EGR-1 is a pleiotropic regulator of endochondral fracture repair. Copyright © 2011 Elsevier Inc. All rights reserved.

Can platelet-rich plasma (PRP) improve bone healing? A comparison between the theory and experimental outcomes.

PubMed

Malhotra, Angad; Pelletier, Matthew H; Yu, Yan; Walsh, William R

2013-02-01

The increased concentration of platelets within platelet-rich plasma (PRP) provides a vehicle to deliver supra-physiologic concentrations of growth factors to an injury site, possibly accelerating or otherwise improving connective tissue regeneration. This potential benefit has led to the application of PRP in several applications; however, inconsistent results have limited widespread adoption in bone healing. This review provides a core understanding of the bone healing mechanisms, and corresponds this to the factors present in PRP. In addition, the current state of the art of PRP preparation, the key aspects that may influence its effectiveness, and treatment outcomes as they relate specifically to bone defect healing are presented. Although PRP does have a sound scientific basis, its use for bone healing appears only beneficial when used in combination with osteoconductive scaffolds; however, neither allograft nor autograft appear to be appropriate carriers. Aggressive processing techniques and very high concentrations of PRP may not improve healing outcomes. Moreover, many other variables exist in PRP preparation and use that influence its efficacy; the effect of these variables should be understood when considering PRP use. This review includes the essentials of what has been established, what is currently missing in the literature, and recommendations for future directions.

Milk thistle: a future potential anti-osteoporotic and fracture healing agent.

PubMed

Mohd Fozi, Nur Farhana; Mazlan, Mazliadiyana; Shuid, Ahmad Nazrun; Isa Naina, Mohamed

2013-12-01

Osteoporosis is a progressive disease of the skeleton characterised by bone fragility due to a reduction in bone mass and possibly to alteration in bone architecture that lead to a propensity to fracture with minimum trauma. Most osteoporotic fractures occur at locations rich in trabecular or cancellous bone and usually related to post menopausal women. Recently, silymarin received attention due to its alternative beneficial effect on bone formation. It is a mixture of flavonoids with powerful antioxidant properties. This review focuses on the use of milk thistle or silymarin for the treatment of osteoporosis that may be related to fracture bone. Silymarin shows potent antioxidant herb that may modulate multiple genes in favour of helping to build bone and prevent bone loss. In the mouse fracture healing model, silymarin supplementation improved tibial healing with elevated BMD and serum levels of ALP and osteocalcin. Silymarin also demonstrated clear estrogenic antiosteoporotic effects in bone structure. Silymarin appears to play a crucial role to prevent bone loss and might regulate osteogenesis and may be beneficial for fracture healing. If silymarin is considered for the use of post menopausal women, it may be used for the treatment of osteoporosis. It would be of great benefit to postmenopausal women to develop an oestrogen antagonist that is as potent and efficacious as oestrogen in preventing bone loss without the major side effect associated with HRT.

Periodontal healing in one-wall intra-bony defects in dogs following implantation of autogenous bone or a coral-derived biomaterial.

PubMed

Kim, Chang-Sung; Choi, Seong-Ho; Cho, Kyoo-Sung; Chai, Jung-Kiu; Wikesjö, Ulf M E; Kim, Chong-Kwan

2005-06-01

Autogenous bone grafts and bone biomaterials are being used as part of protocols aiming at reconstruction of periodontal defects. There is a limited biologic information on the effect of such materials on periodontal healing, in particular aberrant healing events that may prevent their general use. The objective of this study was, using histological techniques, to evaluate periodontal healing with focus on root resorption and ankylosis following implantation of autogenous bone and a coral-derived biomaterial into intra-bony defects in dogs. One-wall intra-bony periodontal defects were surgically created at the distal aspect of the second and the mesial aspect of the fourth mandibular premolars in either right or left jaw quadrants in four Beagle dogs. Each animal received particulated autogenous bone and the resorbable calcium carbonate biomaterial into discrete one-wall intra-bony defects. The mucoperiosteal flaps were positioned and sutured to their pre-surgery position. The animals were euthanized 8 weeks post-surgery when block sections of the defect sites were collected and prepared for qualitative histological analysis. There were no significant differences in periodontal healing between sites receiving autograft bone and the coral-derived biomaterial. A well-organized periodontal ligament bridging new bone and cementum regeneration was observed extending coronal to a notch prepared to delineate the apical extent of the defect. Osteoid and bone with enclosed osteocytes were formed onto the surface of both autograft and coral particles. Although small resorption pits were evident in most teeth, importantly none of the biomaterials provoked marked root resorption. Ankylosis was not observed. Particulated autogenous bone and the coral-derived biomaterial may be implanted into periodontal defects without significant healing aberrations such as root resorption and ankylosis. The histopathological evaluation suggests that the autogenous bone graft has a limited osteogenic potential as demonstrated in this study model.

Analysis of fracture healing in osteopenic bone caused by disuse: experimental study.

PubMed

Paiva, A G; Yanagihara, G R; Macedo, A P; Ramos, J; Issa, J P M; Shimano, A C

2016-03-01

Osteoporosis has become a serious global public health issue. Hence, osteoporotic fracture healing has been investigated in several previous studies because there is still controversy over the effect osteoporosis has on the healing process. The current study aimed to analyze two different periods of bone healing in normal and osteopenic rats. Sixty, 7-week-old female Wistar rats were randomly divided into four groups: unrestricted and immobilized for 2 weeks after osteotomy (OU2), suspended and immobilized for 2 weeks after osteotomy (OS2), unrestricted and immobilized for 6 weeks after osteotomy (OU6), and suspended and immobilized for 6 weeks after osteotomy (OS6). Osteotomy was performed in the middle third of the right tibia 21 days after tail suspension, when the osteopenic condition was already set. The fractured limb was then immobilized by orthosis. Tibias were collected 2 and 6 weeks after osteotomy, and were analyzed by bone densitometry, mechanical testing, and histomorphometry. Bone mineral density values from bony calluses were significantly lower in the 2-week post-osteotomy groups compared with the 6-week post-osteotomy groups (multivariate general linear model analysis, P<0.000). Similarly, the mechanical properties showed that animals had stronger bones 6 weeks after osteotomy compared with 2 weeks after osteotomy (multivariate general linear model analysis, P<0.000). Histomorphometry indicated gradual bone healing. Results showed that osteopenia did not influence the bone healing process, and that time was an independent determinant factor regardless of whether the fracture was osteopenic. This suggests that the body is able to compensate for the negative effects of suspension.

Bone-to-bone Fixation Enhances Functional Healing of the Porcine Anterior Cruciate Ligament Using a Collagen-Platelet Composite

PubMed Central

Murray, Martha M.; Magarian, Elise; Zurakowski, David; Fleming, Braden C.

2010-01-01

Purpose The purpose of this study was to determine if providing bony stabilization between the tibia and femur would improve the structural properties of an “enhanced” ACL repair using a collagen-platelet composite when compared to the traditional (Marshall) suture technique. Methods Twelve pigs underwent unilateral ACL transection and were treated with sutures connecting the bony femoral ACL attachment site to the distal ACL stump (LIGAMENT group), or to the tibia via a bone tunnel (TIBIA group). A collagen-platelet composite was placed around the sutures to enhance the biologic repair in both groups. Anteroposterior (AP) knee laxity and the graft structural properties were measured after 15 weeks of healing in both the ACL-repaired and contralateral ACL-intact joints. Results Enhanced ACL repair with bone-to-bone fixation significantly improved yield load and linear stiffness of the ACL repairs (p<0.05) after 15 weeks of healing. However, laxity values of the knees were similar in both groups of repaired knees (p>0.10). Conclusions Using an enhanced ACL suture repair technique that includes bone-to-bone fixation to protect the repair in the initial healing stages resulted in an ACL with improved structural properties after 15 weeks in the porcine model. Clinical Relevance The healing response of an ACL suture repair using a collagen-platelet composite can be enhanced by providing bony stabilization between the tibia and femur to protect the graft during the initial healing process in a translational model. PMID:20810092

[Surgical treatment of tibial nonunion after wounding by high velocity missile and external fixators: a case report].

PubMed

Golubović, Ivan; Vukašinović, Zoran; Stojiljković, Predrag; Golubović, Zoran; Stojiljković, Danilo; Radovanović, Zoran; Ilić, Nenad; Najman, Stevo; Višnjić, Aleksandar; Arsić, Stojanka

2012-01-01

The missiles of modern firearms can cause severe fractures of the extremity. High velocity missile fractures of the tibia are characterized by massive tissue destruction and primary contamination with polymorphic bacteria. Treatment of these fractures is often complicated by delayed healing, poor position healing, nonhealing and bone tissue infection. We present the management of tibial nonunion after wounding by high velocity missile and primary treatment by external fixation in a 25-year-old patient. The patient was primarily treated with external fixation and reconstructive operations of the soft tissue without union of the fracture. Seven months after injury we placed a compression-distraction external fixator type Mitkovic and started with compression and distraction in the fracture focus after osteotomy of the fibula and autospongioplasty. We recorded satisfactory fracture healing and good functional outcome. Contamination and devitalization of the soft-tissue envelope increase the risk of infection and nonunion in fractures after wounding by high velocity missile. The use of the compression-distraction external fixator type Mitkovic may be an effective method in nonunions of the tibia after this kind of injury.

GM-CSF produced by non-hematopoietic cells is required for early epithelial cell proliferation and repair of injured colonic mucosa1,2

PubMed Central

Egea, Laia; McAllister, Christopher S.; Lakhdari, Omar; Minev, Ivelina; Shenouda, Steve; Kagnoff, Martin F.

2012-01-01

GM-CSF is a growth factor that promotes the survival and activation of macrophages and granulocytes, and dendritic cell (DC) differentiation and survival in vitro. The mechanism by which exogenous GM-CSF ameliorates the severity of Crohn’s disease in humans and colitis in murine models has been considered mainly to reflect its activity on myeloid cells. We used GM-CSF deficient (GM-CSF−/−) mice to probe the functional role of endogenous host-produced GM-CSF in a colitis model induced after injury to the colon epithelium. Dextran sodium sulfate (DSS) at doses that resulted in little epithelial damage and mucosal ulceration in wild type (WT) mice resulted in marked colon ulceration and delayed ulcer healing in GM-CSF−/− mice. Colon crypt epithelial cell proliferation in vivo was significantly decreased in GM-CSF−/− mice at early times after DSS injury. This was paralleled by decreased expression of crypt epithelial cell genes involved in cell cycle, proliferation, and wound healing. Decreased crypt cell proliferation and delayed ulcer healing in GM-CSF−/− mice were rescued by exogenous GM-CSF, indicating the lack of a developmental abnormality in the epithelial cell proliferative response in those mice. Non-hematopoietic cells and not myeloid cells produced the GM-CSF important for colon epithelial proliferation after DSS-induced injury as revealed by bone marrow chimera and DC depletion experiments, with colon epithelial cells being the cellular source of GM-CSF. Endogenous epithelial cell produced GM-CSF has a novel non-redundant role in facilitating epithelial cell proliferation and ulcer healing in response to injury of the colon crypt epithelium. PMID:23325885

External fixation combined with delayed internal fixation in treatment of tibial plateau fractures with dislocation

PubMed Central

Tao, Xingguang; Chen, Nong; Pan, Fugen; Cheng, Biao

2017-01-01

Abstract The aim of this study was to evaluate the clinical efficacy of external fixation, delayed open reduction, and internal fixation in treating tibial plateau fracture with dislocation. Clinical data of 34 patients diagnosed with tibial plateau fracture complicated with dislocation between January 2009 and May 2015 were retrospectively analyzed. Fifteen patients in group A underwent early calcaneus traction combined with open reduction and internal fixation and 19 in group B received early external fixation combined with delayed open reduction and internal fixation. Operation time, postoperative complication, bone healing time, knee joint range of motion, initial weight-bearing time, Rasmussen tibial plateau score, and knee function score (HSS) were statistically compared between 2 groups. The mean follow-up time was 18.6 months (range: 5–24 months). The mean operation time in group A was 96 minutes, significantly longer than 71 minutes in group B (P < .05). In group A, 5 cases had postoperative complications and 1 in group B (P < .05). The mean bone healing time in group A was 6.9 months (range: 5–9 months) and 6.0 months (range: 5–8 months) in group B (P > .05). In group A, initial weight-bearing time in group A was (14.0 ± 3.6) weeks, significantly differing from (12.9 ± 2.8) weeks in group B (P < 0.05). In group A, the mean knee joint range of motion was 122° (range: 95°–150°) and 135° (range: 100°–160°) in group B (P > 0.05). Rasmussen tibial plateau score in group A was slightly lower than that in group B (P > .05). The excellent rate of knee joint function in group A was 80% and 84.21% in group B (P > .05). External fixation combined with delayed open reduction and internal fixation is a safer and more efficacious therapy of tibial plateau fracture complicated with dislocation compared with early calcaneus traction and open reduction and internal fixation. PMID:29019890

External fixation combined with delayed internal fixation in treatment of tibial plateau fractures with dislocation.

PubMed

Tao, Xingguang; Chen, Nong; Pan, Fugen; Cheng, Biao

2017-10-01

The aim of this study was to evaluate the clinical efficacy of external fixation, delayed open reduction, and internal fixation in treating tibial plateau fracture with dislocation.Clinical data of 34 patients diagnosed with tibial plateau fracture complicated with dislocation between January 2009 and May 2015 were retrospectively analyzed. Fifteen patients in group A underwent early calcaneus traction combined with open reduction and internal fixation and 19 in group B received early external fixation combined with delayed open reduction and internal fixation. Operation time, postoperative complication, bone healing time, knee joint range of motion, initial weight-bearing time, Rasmussen tibial plateau score, and knee function score (HSS) were statistically compared between 2 groups.The mean follow-up time was 18.6 months (range: 5-24 months). The mean operation time in group A was 96 minutes, significantly longer than 71 minutes in group B (P < .05). In group A, 5 cases had postoperative complications and 1 in group B (P < .05). The mean bone healing time in group A was 6.9 months (range: 5-9 months) and 6.0 months (range: 5-8 months) in group B (P > .05). In group A, initial weight-bearing time in group A was (14.0 ± 3.6) weeks, significantly differing from (12.9 ± 2.8) weeks in group B (P < 0.05). In group A, the mean knee joint range of motion was 122° (range: 95°-150°) and 135° (range: 100°-160°) in group B (P > 0.05). Rasmussen tibial plateau score in group A was slightly lower than that in group B (P > .05). The excellent rate of knee joint function in group A was 80% and 84.21% in group B (P > .05).External fixation combined with delayed open reduction and internal fixation is a safer and more efficacious therapy of tibial plateau fracture complicated with dislocation compared with early calcaneus traction and open reduction and internal fixation.

Evaluation of osteoblastic activity in extraction sockets treated with platelet-rich fibrin

PubMed Central

Tumer, Celal; Ugur, Omer; Vatankulu, Betul

2015-01-01

Objective: The aim of this study was to determine whether the use of platelet rich fibrin (PRF) improved the healing of extraction sockets. Study Design: A total of 20 patients with bilateral soft tissue impacted mandibular third molars were included in this study. The left and right third molars were extracted during the same session. Subsequently, the PRF membrane was randomly administered to one of the extraction sockets, whereas the contra lateral sockets were left without treatment. On postoperative 30. and 90. days, panoramic images and bone scintigrams were taken to evaluate the bone healing between PRF-treated and non-PRF-treated sockets. Also, periodontal evaluation was performed in the same control sessions. Dependent group t test for paired samples was used for statistical analysis. Results: The average increase in technetium-99m methylene diphosphonate uptake as an indication of enhanced bone healing did not differ significantly between PRF-treated and non-PRF-treated sockets 30 and 90 days post operatively. Radio opacity that can show the bone healing on panoramic images were measured by Image J programmer and they did not differ significantly. Also periodontal values did not differ significantly. Conclusions: PRF might not lead to enhanced bone healing in impacted mandibular third molar extraction sockets 30 and 90 days after surgery. It is thought that PRF has the potential characteristics of an autologous fibrin matrix and can accelerate the healing. To better understand the effects of PRF on healing, further research is warranted with larger sample sizes. Key words:PRF, scintigraphy, healing, extraction sockets. PMID:25475771

Efficacy of Various Analgesics on Shoulder Function and Rotator Cuff Tendon-to-Bone Healing in a Rat (Rattus norvegicus) Model

PubMed Central

Caro, Adam C; Tucker, Jennica J; Yannascoli, Sarah M; Dunkman, Andrew A; Thomas, Stephen J; Soslowsky, Louis J

2014-01-01

Although relief of postoperative pain is an imperative aspect of animal welfare, analgesics that do not interfere with the scientific goals of the study must be used. Here we compared the efficacy of different analgesic agents by using an established rat model of supraspinatus tendon healing and a novel gait-analysis system. We hypothesized that different analgesic agents would all provide pain relief in this model but would cause differences in tendon-to-bone healing and gait parameters. Buprenorphine, ibuprofen, tramadol–gabapentin, and acetaminophen were compared with a no-analgesia control group. Gait measures (stride length and vertical force) on the operative forelimb differed between the control group and both the buprenorphine (2 and 4 d postsurgery) and ibuprofen (2 d postsurgery) groups. Step length was different in the control group as compared with the tramadol–gabapentin (2 d after surgery), buprenorphine (2 and 4 d after surgery), and ibuprofen (2 d after surgery) groups. Regarding tendon-to-bone healing, the ibuprofen group showed less stiffness at the insertion site; no other differences in tendon-to-bone healing were detected. In summary, the analgesics evaluated were associated with differences in both animal gait and tendon-to-bone healing. This information will be useful for improving the management of postsurgical pain without adversely affecting tissue healing. Given its ability to improve gait without impeding healing, we recommend use of buprenorphine for postsurgical pain management in rats. In addition, our gait-analysis system can be used to evaluate new analgesics. PMID:24602546

Dynamic Fixation of Humeral Shaft Fractures Using Active Locking Plates: A Prospective Observational Study.

PubMed

Madey, Steven M; Tsai, Stanley; Fitzpatrick, Daniel C; Earley, Kathleen; Lutsch, Michael; Bottlang, Michael

2017-01-01

Rigid locked plating constructs can suppress fracture healing by inhibiting interfragmentary motion required to stimulate natural bone healing by callus formation. Dynamic fixation with active locking plates reduces construct stiffness, enables controlled interfragmentary motion, and has been shown to induce faster and stronger bone healing in vivo compared to rigid locking plates. This prospective observational study represents the first clinical use of active locking plates. It documents our early clinical experience with active plates for stabilization of humeral shaft fractures to assess their durability and understand potential complications. Eleven consecutive patients with humeral shaft fractures (AO/OTA types 12 A-C) were prospectively enrolled at a level I and a level II trauma center. Fractures were stabilized by using active locking plates without supplemental bone graft or bone morphogenic proteins. The screw holes of active locking plates are elastically suspended in elastomer envelopes inside the plate, enabling up to 1.5 mm of controlled interfragmentary motion. Progression of fracture healing and integrity of implant fixation was assessed radiographically at 3, 6, 12, and 24 weeks post surgery. Patient-reported functional outcome measures were obtained at 6, 12, and 24 weeks post surgery. The primary endpoint of this study was plate durability in absence of plate bending or breakage, or failure of the elastically suspended locking hole mechanism. Secondary endpoints included fracture healing, complications requiring revision surgery, and functional outcome scores. The eleven patients had six simple AO/ OTA type 12A fractures, three wedge type 12B fractures, and two comminuted type 12C fracture, including one open fracture. All active locking plates endured the 6-month loading period without any signs of fatigue or failure. Ten of eleven fractures healed at 10.9 ± 5.2 weeks, as evident by bridging callus and pain-free function. One fracture required revision surgery 37 weeks post surgery due to late fixation failure at the screwbone interface in the presence of a atrophic delayed union. The average Disability of the Arm, Shoulder and Hand (DASH) score improved from 31 ± 22 at week 6 to 13 ± 15 by week 24, approaching that of the normal, healthy population (DASH = 10.1). By week 12, the difference between Constant shoulder scores, expressed as the difference between the affected and contralateral arm (8 ± 8), was considered excellent. By week 24, the SF-12 physical health score (44 ± 9) and mental health score (48 ± 11) approached the mean value of 50 that represents the norm for the general U.S. population. Absence of failure of the plate and locking holes suggests that dynamic fixation of humeral shaft fractures with active plates provides safe and effective fixation. Moreover, early callus bridging and excellent functional outcome scores suggest that dynamic fixation with active locking plates may promote increased fracture healing over standard locked plating.

Sequential healing of open extraction sockets. An experimental study in monkeys.

PubMed

Scala, Alessandro; Lang, Niklaus P; Schweikert, Michael T; de Oliveira, José Américo; Rangel-Garcia, Idelmo; Botticelli, Daniele

2014-03-01

To describe the sequential healing of open extraction sockets at which no attempts to obtain a primary closure of the coronal access to the alveolus have been made. The third mandibular premolar was extracted bilaterally in 12 monkeys, and no sutures were applied to close the wound. The healing after 4, 10, 20, 30, 90 and 180 days was morphometrically studied. After 4 days of healing, a blood clot mainly occupied the extraction sockets, with the presence of an inflammatory cells' infiltrate. A void was confined in the central zones of the coronal and middle regions, in continuity with the entrance of the alveoli. At 10 days, the alveolus was occupied by a provisional matrix, with new bone formation lining the socket bony walls. At 20 days, the amount of woven bone was sensibly increasing. At 30 days, the alveolar socket was mainly occupied by mineralized immature bone at different stages of healing. At 90 and 180 days, the amount of mineralized bone decreased and substituted by trabecular bone and bone marrow. Bundle bone decreased from 95.5% at 4 days to 7.6% at 180 days, of the whole length of the inner alveolar surface. Modeling processes start from the lateral and apical walls of the alveolus, leading to the closure of the socket with newly formed bone within a month from extraction. Remodeling processes will follow the previous stages, resulting in trabecular and bone marrow formation and in a corticalization of the socket access. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

The biomechanical behavior on the interface of tumor arthrosis/allograft prosthetic composite by finite element analysis

NASA Astrophysics Data System (ADS)

Chen, H. Z.; Jiang, W.; Zou, W.; Luo, J. M.; Chen, J. Y.; Tu, C. Q.; Xing, B. B.; Gu, Z. W.; Zhang, X. D.

2008-11-01

The biomechanical behavior of the uniting interface between the allograft bone and the autogenetic bone plays an important role in the treatment of the proximal femur massive defects with artificial tumor arthrosis/allograft prosthetic composite (TAAPC). According to the CT data of a patient, a 3D medical treatment model of TAAPC was established. Under the loads of 1.5 and 2.5 times standard body weight (70 kg), the mechanical behavior of the treatment model was analyzed by finite element analysis (FEA) for three typical healing periods. The results show that there are significant differences in the stress values and distribution in different healing periods. With healing of osteotomy, the hardness of the tissue of the uniting interface increases, the stress in uniting area was increased greatly and the stress concentration decreased. After cured the stress almost reached the level of normal bone. In the initial stage of healing, the healing training is not encouraged because there is an obvious risk of fracture of prosthesis and bone cement. In addition, porous hydroxyapatite (HA) ceramic used as bone tissue scaffold for this case, not only facilitates the generation of new bone, but also can avoid this risk caused by the non-uniting interface.

Dissolution behavior and early bone apposition of calcium phosphate-coated machined implants

PubMed Central

Hwang, Ji-Wan; Lee, Eun-Ung; Lee, Jung-Seok; Jung, Ui-Won; Lee, In-Seop

2013-01-01

Purpose Calcium phosphate (CaP)-coated implants promote osseointegration and survival rate. The aim of this study was to (1) analyze the dissolution behavior of the residual CaP particles of removed implants and (2) evaluate bone apposition of CaP-coated machined surface implants at the early healing phase. Methods Mandibular premolars were extracted from five dogs. After eight weeks, the implants were placed according to drilling protocols: a nonmobile implant (NI) group and rotational implant (RI) group. For CaP dissolution behavior analysis, 8 implants were removed after 0, 1, 2, and 4 weeks. The surface morphology and deposition of the coatings were observed. For bone apposition analysis, block sections were obtained after 1-, 2-, and 4-week healing periods and the specimens were analyzed. Results Calcium and phosphorus were detected in the implants that were removed immediately after insertion, and the other implants were composed mainly of titanium. There were no notable differences between the NI and RI groups in terms of the healing process. The bone-to-implant contact and bone density in the RI group showed a remarkable increase after 2 weeks of healing. Conclusions It can be speculated that the CaP coating dissolves early in the healing phase and chemically induces early bone formation regardless of the primary stability. PMID:24455442

Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance

PubMed Central

Ma, Li; del Soldato, Piero; Wallace, John L.

2002-01-01

Delayed gastric ulcer healing is a well recognized problem associated with the use of cyclooxygenase (COX) inhibitors. In contrast, NO-releasing COX inhibitors do not interfere with ulcer healing. These divergent effects may in part be due to differences in their effects on platelets, which are known to influence ulcer healing. Therefore, we compared the effects of a nonselective COX inhibitor (flurbiprofen), a nitric oxide-releasing COX inhibitor (HCT-1026), and a selective COX-2 inhibitor (celecoxib) on gastric ulcer healing, angiogenesis, and platelet/serum levels of vascular endothelial growth factor (VEGF) and endostatin. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily treatment with the test drugs was started 3 days later and continued for 1 week. Celecoxib and flurbiprofen impaired angiogenesis and delayed ulcer healing, as well as increasing serum endostatin levels relative to those of VEGF. HCT-1026 did not delay ulcer healing nor impair angiogenesis, and also did not change the ratio of serum endostatin to VEGF. Incubation of human umbilical vein endothelial cells with serum from celecoxib- or flurbiprofen-treated rats resulted in suppressed proliferation and increased apoptosis, effects that were reversed by an antiendostatin antibody. These results demonstrate a previously unrecognized mechanism through which nonsteroidal antiinflammatory drugs can delay ulcer healing, namely, through altering the balance of anti- and proangiogenic factors in the serum. The absence of a delaying effect of HCT-1026 on ulcer healing may be related to the maintenance of a more favorable balance in serum levels of pro- and antiangiogenic growth factors. PMID:12232050

Histomorphometric evaluation of a calcium-phosphosilicate putty bone substitute in extraction sockets.

PubMed

Kotsakis, Georgios A; Joachim, Frederic P C; Saroff, Stephen A; Mahesh, Lanka; Prasad, Hari; Rohrer, Michael D

2014-01-01

The objective of this study was to evaluate bone regeneration in 24 sockets grafted with a calcium phosphosilicate putty alloplastic bone substitute. A core was obtained from 17 sockets prior to implant placement for histomorphometry at 5 to 6 months postextraction. Radiographic analysis during the same postextraction healing period showed radiopaque tissue in all sockets. Histomorphometric analysis revealed a mean vital bone content of 31.76% (± 14.20%) and residual graft content of 11.47% (± 8.99%) after a mean healing period of 5.7 months. The high percentage of vital bone in the healed sites in combination with its timely absorption rate suggest that calcium phosphosilicate putty can be a reliable choice for osseous regeneration in extraction sockets.

Evaluation of bone healing in femurs lengthened via the gradual distraction method.

PubMed

Jochymek, Jiri; Gal, Petr

2007-06-01

Treatment of leg length inequality via lengthening of the shorter extremity is an infrequent orthopedic procedure due to the requirement of special distraction devices and possible serious complications. Essential qualitative changes in operative technique development are associated with the name of G. A. Ilizarov, who paved the way for the autoregenerate gradual distraction method in the 1950s. In the years 1990 through 2006 a total of 57 patients underwent femur lengthening via gradual distraction using various types of external fixators at the Department of Pediatric Surgery, Orthopedics, and Traumatology, Faculty Hospital in Brno. The quality of bone healing was monitored and a number of parameters followed and statistically evaluated using regularly scheduled X-ray examinations. In 11 cases we had to remove the external fixator following the distraction phase, perform an osteosynthesis via a splint and fill the distraction gap via spongioplasty. The bone healing was satisfactory in the remaining 46 patients and the lengthened bone required no other fixation method. The analysis showed statistically significant deceleration in bone healing following distraction in female patients over 12 years of age, and in boys over 14 years of age. Lack of periosteal callus five weeks after surgery always signified serious problems in further healing. Severe complications were recorded in 11 cases during the distraction phase, and in 9 cases after the removal of the distraction apparatus. The aim of this report was to present the results of our study of distraction gap bone healing using the gradual lengthening approach.

Effects of pulsed electromagnetic fields on postmenopausal osteoporosis.

PubMed

Zhu, Siyi; He, Hongchen; Zhang, Chi; Wang, Haiming; Gao, Chengfei; Yu, Xijie; He, Chengqi

2017-09-01

Postmenopausal osteoporosis (PMOP) is considered to be a well-defined subject that has caused high morbidity and mortality. In elderly women diagnosed with PMOP, low bone mass and fragile bone strength have been proven to significantly increase risk of fragility fractures. Currently, various anabolic and anti-resorptive therapies have been employed in an attempt to retain healthy bone mass and strength. Pulsed electromagnetic fields (PEMFs), first applied in treating patients with delayed fracture healing and nonunions, may turn out to be another potential and effective therapy for PMOP. PEMFs can enhance osteoblastogenesis and inhibit osteoclastogenesis, thus contributing to an increase in bone mass and strength. However, accurate mechanisms of the positive effects of PEMFs on PMOP remain to be further elucidated. This review attempts to summarize recent advances of PEMFs in treating PMOP based on clinical trials, and animal and cellular studies. Possible mechanisms are also introduced, and the future possibility of application of PEMFs on PMOP are further explored and discussed. Bioelectromagnetics. 38:406-424, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Surgical complications associated with primary closure in patients with diabetic foot osteomyelitis

PubMed Central

García-Morales, Esther; Lázaro-Martínez, José Luis; Aragón-Sánchez, Javier; Cecilia-Matilla, Almudena; García-Álvarez, Yolanda; Beneit-Montesinos, Juan Vicente

2012-01-01

Background The aim of this study was to determine the incidence of complications associated with primary closure in surgical procedures performed for diabetic foot osteomyelitis compared to those healed by secondary intention. In addition, further evaluation of the surgical digital debridement for osteomyelitis with primary closure as an alternative to patients with digital amputation was also examined in our study. Methods Comparative study that included 46 patients with diabetic foot ulcerations. Surgical debridement of the infected bone was performed on all patients. Depending on the surgical technique used, primary surgical closure was performed on 34 patients (73.9%, Group 1) while the rest of the 12 patients were allowed to heal by secondary intention (26.1%, Group 2). During surgical intervention, bone samples were collected for both microbiological and histopathological analyses. Post-surgical complications were recorded in both groups during the recovery period. Results The average healing time was 9.9±SD 8.4 weeks in Group 1 and 19.1±SD 16.9 weeks in Group 2 (p=0.008). The percentage of complications was 61.8% in Group 1 and 58.3% in Group 2 (p=0.834). In all patients with digital ulcerations that were necessary for an amputation, a primary surgical closure was performed with successful outcomes. Discussion Primary surgical closure was not associated with a greater number of complications. Patients who received primary surgical closure had faster healing rates and experienced a lower percentage of exudation (p=0.05), edema (p<0.001) and reinfection, factors that determine the delay in wound healing and affect the prognosis of the surgical outcome. Further research with a greater number of patients is required to better define the cases for which primary surgical closure may be indicated at different levels of the diabetic foot. PMID:23050062

The osteo-inductive activity of bone-marrow-derived mononuclear cells resides within the CD14+ population and is independent of the CD34+ population.

PubMed

Henrich, D; Seebach, C; Verboket, R; Schaible, A; Marzi, I; Bonig, H

2018-03-06

Bone marrow mononuclear cells (BMC) seeded on a scaffold of β-tricalcium phosphate (β-TCP) promote bone healing in a critical-size femur defect model. Being BMC a mixed population of predominantly mature haematopoietic cells, which cell type(s) is(are) instrumental for healing remains elusive. Although clinical therapies using BMC are often dubbed as stem cell therapies, whether stem cells are relevant for the therapeutic effects is unclear and, at least in the context of bone repair, seems dubious. Instead, in light of the critical contribution of monocytes and macrophages to tissue development, homeostasis and injury repair, in the current study it was hypothesised that BMC-mediated bone healing derived from the stem cell population. To test this hypothesis, bone remodelling studies were performed in an established athymic rats critical-size femoral defect model, with β-TCP scaffolds augmented with complete BMC or BMC immunomagnetically depleted of stem cells (CD34+) or monocytes/macrophages (CD14+). Bone healing was assessed 8 weeks after transplantation. Compared to BMC-augmented controls, when CD14- BMC, but not CD34- BMC were transplanted into the bone defect, femora possessed dramatically decreased biomechanical stability and new bone formation was markedly reduced, as measured by histology. The degree of vascularisation did not differ between the two groups. It was concluded that the monocyte fraction within the BMC provided critical osteo-inductive cues during fracture healing. Which factors were responsible at the molecular levels remained elusive. However, this study marked a significant progress towards elucidating the mechanisms by which BMC elicit their therapeutic effects, at least in bone regeneration.

Evaluation of osteoblastic activity in extraction sockets treated with platelet-rich fibrin.

PubMed

Baslarli, Ozgur; Tumer, Celal; Ugur, Omer; Vatankulu, Betul

2015-01-01

The aim of this study was to determine whether the use of platelet rich fibrin (PRF) improved the healing of extraction sockets. A total of 20 patients with bilateral soft tissue impacted mandibular third molars were included in this study. The left and right third molars were extracted during the same session. Subsequently, the PRF membrane was randomly administered to one of the extraction sockets, whereas the contralateral sockets were left without treatment. On postoperative 30. and 90. days, panoramic images and bone scintigrams were taken to evaluate the bone healing between PRF-treated and non-PRF-treated sockets. Also, periodontal evaluation was performed in the same control sessions. Dependent group t test for paired samples was used for statistical analysis. The average increase in technetium-99m methylene diphosphonate uptake as an indication of enhanced bone healing did not differ significantly between PRF-treated and non-PRF-treated sockets 30 and 90 days postoperatively. Radio-opacity that can show the bone healing on panoramic images were measured by Image J programme and they did not differ significantly. Also periodontal values did not differ significantly. PRF might not lead to enhanced bone healing in impacted mandibular third molar extraction sockets 30 and 90 days after surgery. It is thought that PRF has the potential characteristics of an autologous fibrin matrix and can accelerate the healing. To better understand the effects of PRF on healing, further research is warranted with larger sample sizes.

Bone tissue engineering: the role of interstitial fluid flow

NASA Technical Reports Server (NTRS)

Hillsley, M. V.; Frangos, J. A.

1994-01-01

It is well established that vascularization is required for effective bone healing. This implies that blood flow and interstitial fluid (ISF) flow are required for healing and maintenance of bone. The fact that changes in bone blood flow and ISF flow are associated with changes in bone remodeling and formation support this theory. ISF flow in bone results from transcortical pressure gradients produced by vascular and hydrostatic pressure, and mechanical loading. Conditions observed to alter flow rates include increases in venous pressure in hypertension, fluid shifts occurring in bedrest and microgravity, increases in vascularization during the injury-healing response, and mechanical compression and bending of bone during exercise. These conditions also induce changes in bone remodeling. Previously, we hypothesized that interstitial fluid flow in bone, and in particular fluid shear stress, serves to mediate signal transduction in mechanical loading- and injury-induced remodeling. In addition, we proposed that a lack or decrease of ISF flow results in the bone loss observed in disuse and microgravity. The purpose of this article is to review ISF flow in bone and its role in osteogenesis.

Mandibular Third Molar Extraction Wound Healing With and Without Platelet Rich Plasma: A Comparative Prospective Study.

PubMed

Dutta, Shubha Ranjan; Singh, Purnima; Passi, Deepak; Patter, Pradeep

2015-09-01

To evaluate the efficacy of autologous platelet rich plasma (PRP) in regeneration of bone and to assess clinical compatibility of the material in mandibular third molar extraction socket. To compare the healing of mandibular third molar extraction wounds with and without PRP. Group A consists of the 30 patients where PRP will be placed in the extraction socket before closure of the socket. Group B consists of 30 patients who will be the control group where the extraction sockets will be closed without any intra socket medicaments. The patients would be allocated to the groups randomly. Soft tissue healing was better in study site compared to control site. The result of the study shows rapid bone regeneration in the extraction socket treated with PRP when compared with the socket without PRP. Evaluation for bone blending and trabecular bone formation started earlier in PRP site compared to control, non PRP site. Also there was less postoperative discomfort on the PRP treated side. Autologous PRP is biocompatible and has significant improved soft tissue healing, bone regeneration and increase in bone density in extraction sockets.

Present status and future potential of enhancing bone healing using nanotechnology.

PubMed

Stylios, George; Wan, Taoyu; Giannoudis, Peter

2007-03-01

An overview of the current state of tissue engineering material systems used in bone healing is presented. A variety of fabrication processes have been developed that have resulted in porous implant substrates that can address unresolved clinical problems. The merits of these biomaterial systems are evaluated in the context of the mechanical properties and biomedical performances most suitable for bone healing. An optimal scaffold for bone tissue engineering applications should be biocompatible and act as a 3D template for in vitro and in vivo bone growth; in addition, its degradation products should be non-toxic and easily excreted by the body. To achieve these features, scaffolds must consist of an interconnected porous network of micro- and nanoscale to allow extensive body fluid transport through the pores, which will trigger bone ingrowth, cell migration, tissue ingrowth, and eventually vascularization.

Effect of Electromagnetic Wave on Bone Healing in Fixed and Unfixed Conditions.

PubMed

Onger, Mehmet Emin; Göçer, Hasan; Çirakli, Alper; Büyükceran, Ismail; Kiliç, Mesut; Kaplan, Süleyman

2016-09-01

Mobile phones have come into daily life and are now one of the most frequently used devices for communication. The aim of this study was to evaluate possible effect of electromagnetic wave (EMW) with and without fixation material on bone healing.Forty male rats were exposed to fracture on tibia bone and were randomly divided into 4 groups as E(+)K(+), E(+)K(-), E(-)K(+), and E(-)K(-) where E(+) means EMW exposure and K(+) means Kirschner wire fixation. At the end of study tibia samples were taken from all the groups for the quantitative evaluation of regeneration.Significant difference was found between Group E(+)K(+) and E(-)K(+) in terms of both new bone and capillary volume.Electromagnetic wave may be harmful for bone healing with fixation whereas it has no same effect on bone regeneration without fixation.

Nanotechnology and bone healing.

PubMed

Harvey, Edward J; Henderson, Janet E; Vengallatore, Srikar T

2010-03-01

Nanotechnology and its attendant techniques have yet to make a significant impact on the science of bone healing. However, the potential benefits are immediately obvious with the result that hundreds of researchers and firms are performing the basic research needed to mature this nascent, yet soon to be fruitful niche. Together with genomics and proteomics, and combined with tissue engineering, this is the new face of orthopaedic technology. The concepts that orthopaedic surgeons recognize are fabrication processes that have resulted in porous implant substrates as bone defect augmentation and medication-carrier devices. However, there are dozens of applications in orthopaedic traumatology and bone healing for nanometer-sized entities, structures, surfaces, and devices with characteristic lengths ranging from 10s of nanometers to a few micrometers. Examples include scaffolds, delivery mechanisms, controlled modification of surface topography and composition, and biomicroelectromechanical systems. We review the basic science, clinical implications, and early applications of the nanotechnology revolution and emphasize the rich possibilities that exist at the crossover region between micro- and nanotechnology for developing new treatments for bone healing.

Bilateral first rib anomalous articulations with pseudarthroses mimicking healing fractures in an infant with abusive head injury.

PubMed

Pasquale-Styles, Melissa A; Crowder, Christian M; Fridie, Jeannette; Milla, Sarah S

2014-11-01

Bilateral symmetric bone nodules were observed in the anterolateral first ribs of an infant with shaking injuries at autopsy. The location prompted diagnostic considerations of healing fractures versus anomalous articulations with pseudarthroses. The forensic pathologist worked with forensic anthropologists and pediatric radiologists to evaluate autopsy findings and compare premortem and postmortem X-rays. Gross examination of the bones by the pathologist and anthropologists confirmed bilateral, callus-like bone nodules in first-rib locations associated with pseudarthroses. Histologic examination of one of the bones further showed features most consistent with pseudarthrosis, not a healing fracture. Radiologists then compared multiple premortem and postmortem radiographs that showed no remodeling of the bone over a 2-week interval between the time of injury and death, which would be unexpected for a healing fracture in an infant. This multidisciplinary approach resulted in the appropriate diagnosis of pseudarthroses due to anomalous articulations, an uncommon finding in forensic pathology. © 2014 American Academy of Forensic Sciences.

Role of FGFs/FGFRs in skeletal development and bone regeneration.

PubMed

Du, Xiaolan; Xie, Yangli; Xian, Cory J; Chen, Lin

2012-12-01

Fibroblast growth factor (FGF)/FGF (FGFR) signaling is an important pathway involved in skeletal development. Missense mutations in FGFs and FGFRs were found clinically to cause multiple congenital skeleton diseases including chondrodysplasia, craniosynostosis, syndromes with dysregulated phosphate metabolism. FGFs/FGFRs also have crucial roles in bone fracture repair and bone regeneration. Understanding the molecular mechanisms for the role of FGFs/FGFRs in the regulation of skeletal development, genetic skeletal diseases, and fracture healing will ultimately lead to better treatment of skeleton diseases caused by mutations of FGFs/FGFRs and fracture. This review summarizes the major findings on the role of FGF signaling in skeletal development, genetic skeletal diseases and bone healing, and discusses issues that remain to be resolved in applying FGF signaling-related measures to promote bone healing. This review has also provided a perspective view on future work for exploring the roles and action mechanisms of FGF signaling in skeletal development, genetic skeletal diseases, and fracture healing. Copyright © 2012 Wiley Periodicals, Inc.

Microgrooved Polymer Substrates Promote Collective Cell Migration To Accelerate Fracture Healing in an in Vitro Model.

PubMed

Zhang, Qing; Dong, Hua; Li, Yuli; Zhu, Ye; Zeng, Lei; Gao, Huichang; Yuan, Bo; Chen, Xiaofeng; Mao, Chuanbin

2015-10-21

Surface topography can affect cell adhesion, morphology, polarity, cytoskeleton organization, and osteogenesis. However, little is known about the effect of topography on the fracture healing in repairing nonunion and large bone defects. Microgrooved topography on the surface of bone implants may promote cell migration into the fracture gap to accelerate fracture healing. To prove this hypothesis, we used an in vitro fracture (wound) healing assay on the microgrooved polycaprolactone substrates to study the effect of microgroove widths and depths on the osteoblast-like cell (MG-63) migration and the subsequent healing. We found that the microgrooved substrates promoted MG-63 cells to migrate collectively into the wound gap, which serves as a fracture model, along the grooves and ridges as compared with the flat substrates. Moreover, the groove widths did not show obvious influence on the wound healing whereas the smaller groove depths tended to favor the collective cell migration and thus subsequent healing. The microgrooved substrates accelerated the wound healing by facilitating the collective cell migration into the wound gaps but not by promoting the cell proliferation. Furthermore, microgrooves were also found to promote the migration of human mesenchymal stem cells (hMSCs) to heal the fracture model. Though osteogenic differentiation of hMSCs was not improved on the microgrooved substrate, collagen I and minerals deposited by hMSCs were organized in a way similar to those in the extracellular matrix of natural bone. These findings suggest the necessity in using microgrooved implants in enhancing fracture healing in bone repair.

Mesenchymal stem cells ameliorate impaired wound healing through enhancing keratinocyte functions in diabetic foot ulcerations on the plantar skin of rats.

PubMed

Kato, Jiro; Kamiya, Hideki; Himeno, Tatsuhito; Shibata, Taiga; Kondo, Masaki; Okawa, Tetsuji; Fujiya, Atsushi; Fukami, Ayako; Uenishi, Eita; Seino, Yusuke; Tsunekawa, Shin; Hamada, Yoji; Naruse, Keiko; Oiso, Yutaka; Nakamura, Jiro

2014-01-01

Although the initial healing stage involves a re-epithelialization in humans, diabetic foot ulceration (DFU) has been investigated using rodent models with wounds on the thigh skin, in which a wound contraction is initiated. In this study, we established a rodent model of DFU on the plantar skin and evaluated the therapeutic efficacy of bone-marrow-derived mesenchymal stem cells (BM-MSCs) in this model. The wounds made on the hind paws or thighs of streptozotocin induced diabetic or control rats were treated with BM-MSCs. Expression levels of phosphorylated focal adhesion kinase (pFAK), matrix metaroprotease (MMP)-2, EGF, and IGF-1, were evaluated in human keratinocytes, which were cultured in conditioned media of BM-MSCs (MSC-CM) with high glucose levels. Re-epithelialization initiated the healing process on the plantar, but not on the thigh, skin. The therapy utilizing BM-MSCs ameliorated the delayed healing in diabetic rats. In the keratinocytes cultured with MSC-CM, the decreased pFAK levels in the high glucose condition were restored, and the MMP2, EGF, and IGF-1 levels increased. Our study established a novel rat DFU model. The impaired healing process in diabetic rats was ameliorated by transplantation of BM-MSCs. This amelioration might be accounted for by the modification of keratinocyte functions. Copyright © 2014 Elsevier Inc. All rights reserved.

Selection of animal models for pre-clinical strategies in evaluating the fracture healing, bone graft substitutes and bone tissue regeneration and engineering.

PubMed

Bigham-Sadegh, Amin; Oryan, Ahmad

2015-06-01

In vitro assays can be useful in determining biological mechanism and optimizing scaffold parameters, however translation of the in vitro results to clinics is generally hard. Animal experimentation is a better approximation than in vitro tests, and usage of animal models is often essential in extrapolating the experimental results and translating the information in a human clinical setting. In addition, usage of animal models to study fracture healing is useful to answer questions related to the most effective method to treat humans. There are several factors that should be considered when selecting an animal model. These include availability of the animal, cost, ease of handling and care, size of the animal, acceptability to society, resistance to surgery, infection and disease, biological properties analogous to humans, bone structure and composition, as well as bone modeling and remodeling characteristics. Animal experiments on bone healing have been conducted on small and large animals, including mice, rats, rabbits, dogs, pigs, goats and sheep. This review also describes the molecular events during various steps of fracture healing and explains different means of fracture healing evaluation including biomechanical, histopathological and radiological assessments.

Smoking and Bone Healing - A Risky Surgical Combination

MedlinePlus

... Risky Surgical Combination A A A | Print | Share Smoking and Bone Healing – A Risky Surgical Combination Imagine ... saying that they'd prefer patients to quit smoking. There hasn't been a great deal of ...

Antibiotic-loaded bone void filler accelerates healing in a femoral condylar rat model.

PubMed

Shiels, S M; Cobb, R R; Bedigrew, K M; Ritter, G; Kirk, J F; Kimbler, A; Finger Baker, I; Wenke, J C

2016-08-01

Demineralised bone matrix (DBM) is rarely used for the local delivery of prophylactic antibiotics. Our aim, in this study, was to show that a graft with a bioactive glass and DBM combination, which is currently available for clinical use, can be loaded with tobramycin and release levels of antibiotic greater than the minimum inhibitory concentration for Staphylococcus aureus without interfering with the bone healing properties of the graft, thus protecting the graft and surrounding tissues from infection. Antibiotic was loaded into a graft and subsequently evaluated for drug elution kinetics and the inhibition of bacterial growth. A rat femoral condylar plug model was used to determine the effect of the graft, loaded with antibiotic, on bone healing. We found that tobramycin loaded into a graft composed of bioglass and DBM eluted antibiotic above the minimum inhibitory concentration for three days in vitro. It was also found that the antibiotic loaded into the graft produced no adverse effects on the bone healing properties of the DBM at a lower level of antibiotic. This antibiotic-loaded bone void filler may represent a promising option for the delivery of local antibiotics in orthopaedic surgery. Cite this article: Bone Joint J 2016;98-B:1126-31. ©2016 The British Editorial Society of Bone & Joint Surgery.

Investigation of a pre-clinical mandibular bone notch defect model in miniature pigs: clinical computed tomography, micro-computed tomography, and histological evaluation.

PubMed

Carlisle, Patricia L; Guda, Teja; Silliman, David T; Lien, Wen; Hale, Robert G; Brown Baer, Pamela R

2016-02-01

To validate a critical-size mandibular bone defect model in miniature pigs. Bilateral notch defects were produced in the mandible of dentally mature miniature pigs. The right mandibular defect remained untreated while the left defect received an autograft. Bone healing was evaluated by computed tomography (CT) at 4 and 16 weeks, and by micro-CT and non-decalcified histology at 16 weeks. In both the untreated and autograft treated groups, mineralized tissue volume was reduced significantly at 4 weeks post-surgery, but was comparable to the pre-surgery levels after 16 weeks. After 16 weeks, CT analysis indicated that significantly greater bone was regenerated in the autograft treated defect than in the untreated defect (P=0.013). Regardless of the treatment, the cortical bone was superior to the defect remodeled over 16 weeks to compensate for the notch defect. The presence of considerable bone healing in both treated and untreated groups suggests that this model is inadequate as a critical-size defect. Despite healing and adaptation, the original bone geometry and quality of the pre-injured mandible was not obtained. On the other hand, this model is justified for evaluating accelerated healing and mitigating the bone remodeling response, which are both important considerations for dental implant restorations.

Effects of Particle Size and Porosity on In Vivo Remodeling of Settable Allograft Bone/Polymer Composites

PubMed Central

Prieto, Edna M.; Talley, Anne D.; Gould, Nicholas R.; Zienkiewicz, Katarzyna J.; Drapeau, Susan J.; Kalpakci, Kerem N.

2014-01-01

Established clinical approaches to treat bone voids include the implantation of autograft or allograft bone, ceramics, and other bone void fillers (BVFs). Composites prepared from lysine-derived polyurethanes and allograft bone can be injected as a reactive liquid and set to yield BVFs with mechanical strength comparable to trabecular bone. In this study, we investigated the effects of porosity, allograft particle size, and matrix mineralization on remodeling of injectable and settable allograft/polymer composites in a rabbit femoral condyle plug defect model. Both low viscosity (LV) and high viscosity (HV) grafts incorporating small (<105 μm) particles only partially healed at 12 weeks, and the addition of 10% demineralized bone matrix did not enhance healing. In contrast, composite grafts with large (105 – 500 μm) allograft particles healed at 12 weeks post-implantation, as evidenced by radial μCT and histomorphometric analysis. This study highlights particle size and surface connectivity as influential parameters regulating the remodeling of composite bone scaffolds. PMID:25581686

Bone regeneration by implantation of adipose-derived stromal cells expressing BMP-2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Huiwu; Health and Science Center, SIBS CAS and SSMU, 225 South Chongqing Road, Shanghai 200025; Dai Kerong

2007-05-18

In this study, we reported that the adipose-derived stromal cells (ADSCs) genetically modified by bone morphogenetic protein 2 (BMP-2) healed critical-sized canine ulnar bone defects. First, the osteogenic and adipogenic differentiation potential of the ADSCs derived from canine adipose tissue were demonstrated. And then the cells were modified by the BMP-2 gene and the expression and bone-induction ability of BMP-2 were identified. Finally, the cells modified by BMP-2 gene were applied to a {beta}-tricalcium phosphate (TCP) carrier and implanted into ulnar bone defects in the canine model. After 16 weeks, radiographic, histological, and histomorphometry analysis showed that ADSCs modified bymore » BMP-2 gene produced a significant increase of newly formed bone area and healed or partly healed all of the bone defects. We conclude that ADSCs modified by the BMP-2 gene can enhance the repair of critical-sized bone defects in large animals.« less

Octacalcium phosphate collagen composite facilitates bone regeneration of large mandibular bone defect in humans.

PubMed

Kawai, Tadashi; Suzuki, Osamu; Matsui, Keiko; Tanuma, Yuji; Takahashi, Tetsu; Kamakura, Shinji

2017-05-01

Recently it was reported that the implantation of octacalcium phosphate (OCP) and collagen composite (OCP-collagen) was effective at promoting bone healing in small bone defects after cystectomy in humans. In addition, OCP-collagen promoted bone regeneration in a critical-sized bone defect of a rodent or canine model. In this study, OCP-collagen was implanted into a human mandibular bone defect with a longer axis of approximately 40 mm, which was diagnosed as a residual cyst with apical periodontitis. The amount of OCP-collagen implanted was about five times greater than the amounts implanted in previous clinical cases. Postoperative wound healing was satisfactory and no infection or allergic reactions occurred. The OCP-collagen-treated lesion was gradually filled with radio-opaque figures, and the alveolar region occupied the whole of the bone defect 12 months after implantation. This study suggests that OCP-collagen could be a useful bone substitute material for repairing large bone defects in humans that might not heal spontaneously. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Bone regenerative medicine: classic options, novel strategies, and future directions

PubMed Central

2014-01-01

This review analyzes the literature of bone grafts and introduces tissue engineering as a strategy in this field of orthopedic surgery. We evaluated articles concerning bone grafts; analyzed characteristics, advantages, and limitations of the grafts; and provided explanations about bone-tissue engineering technologies. Many bone grafting materials are available to enhance bone healing and regeneration, from bone autografts to graft substitutes; they can be used alone or in combination. Autografts are the gold standard for this purpose, since they provide osteogenic cells, osteoinductive growth factors, and an osteoconductive scaffold, all essential for new bone growth. Autografts carry the limitations of morbidity at the harvesting site and limited availability. Allografts and xenografts carry the risk of disease transmission and rejection. Tissue engineering is a new and developing option that had been introduced to reduce limitations of bone grafts and improve the healing processes of the bone fractures and defects. The combined use of scaffolds, healing promoting factors, together with gene therapy, and, more recently, three-dimensional printing of tissue-engineered constructs may open new insights in the near future. PMID:24628910

In vivo study of magnesium plate and screw degradation and bone fracture healing.

PubMed

Chaya, Amy; Yoshizawa, Sayuri; Verdelis, Kostas; Myers, Nicole; Costello, Bernard J; Chou, Da-Tren; Pal, Siladitya; Maiti, Spandan; Kumta, Prashant N; Sfeir, Charles

2015-05-01

Each year, millions of Americans suffer bone fractures, often requiring internal fixation. Current devices, like plates and screws, are made with permanent metals or resorbable polymers. Permanent metals provide strength and biocompatibility, but cause long-term complications and may require removal. Resorbable polymers reduce long-term complications, but are unsuitable for many load-bearing applications. To mitigate complications, degradable magnesium (Mg) alloys are being developed for craniofacial and orthopedic applications. Their combination of strength and degradation make them ideal for bone fixation. Previously, we conducted a pilot study comparing Mg and titanium devices with a rabbit ulna fracture model. We observed Mg device degradation, with uninhibited healing. Interestingly, we observed bone formation around degrading Mg, but not titanium, devices. These results highlighted the potential for these fixation devices. To better assess their efficacy, we conducted a more thorough study assessing 99.9% Mg devices in a similar rabbit ulna fracture model. Device degradation, fracture healing, and bone formation were evaluated using microcomputed tomography, histology and biomechanical tests. We observed device degradation throughout, and calculated a corrosion rate of 0.40±0.04mm/year after 8 weeks. In addition, we observed fracture healing by 8 weeks, and maturation after 16 weeks. In accordance with our pilot study, we observed bone formation surrounding Mg devices, with complete overgrowth by 16 weeks. Bend tests revealed no difference in flexural load of healed ulnae with Mg devices compared to intact ulnae. These data suggest that Mg devices provide stabilization to facilitate healing, while degrading and stimulating new bone formation. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Acceleration of hard and soft tissue healing in the oral cavity by a single transmucosal injection of fluvastatin-impregnated poly (lactic-co-glycolic acid) microspheres. An in vitro and rodent in vivo study.

PubMed

Yasunami, Noriyuki; Ayukawa, Yasunori; Furuhashi, Akihiro; Atsuta, Ikiru; Rakhmatia, Yunia Dwi; Moriyama, Yasuko; Masuzaki, Tomohiro; Koyano, Kiyoshi

2015-12-23

Antihyperlipidemic drug statins reportedly promote both bone formation and soft tissue healing. We examined the effect of sustained-release, fluvastatin-impregnated poly(lactic-co-glycolic acid) (PLGA) microspheres on the promotion of bone and gingival healing at an extraction socket in vivo, and the effect of fluvastatin on epithelial cells and fibroblasts in vitro. The maxillary right first molar was extracted in rats, then one of the following was immediately injected, as a single dose, into the gingivobuccal fold: control (no administration), PLGA microspheres without a statin (active control), or PLGA microspheres containing 20 or 40 μg kg(-1) of fluvastatin. At days 1, 3, 7, 14, and 28 after injection, bone and soft tissue healing were histologically evaluated. Cell proliferation was measured under the effect of fluvastatin at dosages of 0, 0.01, 0.1, 1.0, 10, and 50 μM. Cell migration and morphology were observed at dosages of 0 and 0.1 μM. Following tooth extraction, the statin significantly enhanced bone volume and density, connective tissue volume, and epithelial wound healing. In the in vitro study, it promoted significant proliferation and migration of epithelial cells and fibroblasts. A single dose of topically administered fluvastatin-impregnated PLGA microspheres promoted bone and soft tissue healing at the extraction site.

Salvage of infected craniotomy bone flaps with the wash-in, wash-out indwelling antibiotic irrigation system. Technical note and case series of 12 patients.

PubMed

Auguste, Kurtis I; McDermott, Michael W

2006-10-01

When complicated by infection, craniotomy bone flaps are commonly removed, discarded, and delayed cranioplasty is performed. This treatment paradigm is costly, carries the risks associated with additional surgery, and may cause cosmetic deformities. The authors present their experience with an indwelling antibiotic irrigation system used for the sterilization and salvage of infected bone flaps as an alternative to their removal and replacement. The authors retrospectively reviewed the medical records for 12 patients with bone flap infections following craniotomy who received treatment with the wash-in, wash-out indwelling antibiotic irrigation system. Infected flaps were removed and scrubbed with povidone-iodine solution and soaked in 1.5% hydrogen peroxide while the wound was debrided. The bone flaps were returned to the skull and the irrigation system was installed. Antibiotic medication was infused through the system for a mean of 5 days. Intravenous antibiotic therapy was continued for 2 weeks and oral antibiotics for 3 months postoperatively. Wound checks were performed at clinic follow-up visits, and there was a mean follow-up period of 13 months. Eleven of the 12 patients who had undergone placement of the bone flap irrigation system experienced complete resolution of the infection. In five patients there was involvement of the nasal sinus cavities, and in four there was a history of radiation treatment. In the one patient whose infection recurred, there was both involvement of the nasal sinuses and a history of extensive radiation treatment. Infected bone flaps can be salvaged, thus avoiding the cost, risk, and possible disfigurement associated with flap removal and delayed cranioplasty. Although prior radiation treatment and involvement of the nasal sinuses may interfere with wound healing and clearance of the infection, these factors should not preclude the use of irrigation with antibiotic agents for bone flap salvage.

Treatment of unicameral bone cyst: systematic review and meta analysis.

PubMed

Kadhim, Muayad; Thacker, Mihir; Kadhim, Amjed; Holmes, Laurens

2014-03-01

Different treatment modalities have been utilized to treat unicameral bone cyst (UBC), but evidence has not been fully described to support one treatment over another and the optimal treatment is controversial. The aim of this quantitative systematic review was to assess the effectiveness of different UBC treatment modalities. We utilized Pubmed to isolate retrospective studies on patients with UBC who received any kind of treatment. The included studies needed to have a minimum sample size of 15 patients, and have provided data on radiographic healing outcome. Sixty-two articles were selected for the meta-analysis from a total of 463 articles. The cumulative sample size was 3,211 patients with 3,217 UBC, and male to female ratio was 2.2:1. The summary or pool estimate of methylprednisolone acetate (MPA) injection resulted in a healing rate of (77.4 %) that was comparable to bone marrow injection (77.9 %). A higher healing rate was observed with MPA injection when inner wall disruption was performed. The pool estimate of bone marrow with demineralized bone matrix injection was high (98.7 %). UBC healing rate after surgical curettage was comparable whether autograft or allograft was utilized (90 %). UBC treatment with flexible intramedullary nails without curettage provided almost 100% healing rate, while continuous decompression with cannulated screws provided 89 % healing rate. Conservative treatment indicated a healing rate of 64.2, 95 % CI (26.7-101.8). Active treatment for UBC provided variable healing rates and the outcomes were favorable relative to conservative treatment. Due to the heterogeneity of the studies and reporting bias, the interpretation of these findings should be handled with caution.

Review of techniques for monitoring the healing fracture of bones for implementation in an internally fixated pelvis.

PubMed

Wong, Lydia Chwang Yuh; Chiu, Wing Kong; Russ, Matthias; Liew, Susan

2012-03-01

Sacral fractures from high-impact trauma often cause instability in the pelvic ring structure. Treatment is by internal fixation which clamps the fractured edges together to promote healing. Healing could take up to 12 weeks whereby patients are bedridden to avoid hindrances to the fracture from movement or weight bearing activities. Immobility can lead to muscle degradation and longer periods of rehabilitation. The ability to determine the time at which the fracture is stable enough to allow partial weight-bearing is important to reduce hospitalisation time. This review looks into different techniques used for monitoring the fracture healing of bones which could lead to possible methods for in situ and non-invasive assessment of healing fracture in a fixated pelvis. Traditional techniques being used include radiology and CT scans but were found to be unreliable at times and very subjective in addition to being non in situ. Strain gauges have proven to be very effective for accurate assessment of fracture healing as well as stability for long bones with external fixators but may not be suitable for an internally fixated pelvis. Ultrasound provides in situ monitoring of stiffness recovery but only assesses local fracture sites close to the skin surface and has only been tested on long bones. Vibration analysis can detect non-uniform healing due to its assessment of the overall structure but may suffer from low signal-to-noise ratio due to damping. Impedance techniques have been used to assess properties of non-long bones but recent studies have only been conducted on non-biological materials and more research needs to be done before it can be applicable for monitoring healing in the fixated pelvis. Copyright © 2011 IPEM. Published by Elsevier Ltd. All rights reserved.

Low dose PTH improves metaphyseal bone healing more when muscles are paralyzed.

PubMed

Sandberg, Olof; Macias, Brandon R; Aspenberg, Per

2014-06-01

Stimulation of bone formation by PTH is related to mechanosensitivity. The response to PTH treatment in intact bone could therefore be blunted by unloading. We studied the effects of mechanical loading on the response to PTH treatment in bone healing. Most fractures occur in the metaphyses, therefor we used a model for metaphyseal bone injury. One hind leg of 20 male SD rats was unloaded via intramuscular botulinum toxin injections. Two weeks later, the proximal unloaded tibia had lost 78% of its trabecular contents. At this time-point, the rats received bilateral proximal tibiae screw implants. Ten of the 20 rats were given daily injections of 5 μg/kg PTH (1-34). After two weeks of healing, screw fixation was measured by pull-out, and microCT of the distal femur cancellous compartment was performed. Pull-out force provided an estimate for cancellous bone formation after trauma. PTH more than doubled the pull-out force in the unloaded limbs (from 14 to 30 N), but increased it by less than half in the loaded ones (from 30 to 44 N). In relative terms, PTH had a stronger effect on pull-out force in unloaded bone than in loaded bone (p=0.03). The results suggest that PTH treatment for stimulation of bone healing does not require simultaneous mechanical stimulation. Copyright © 2014 Elsevier Inc. All rights reserved.

SDF-1 promotes endochondral bone repair during fracture healing at the traumatic brain injury condition.

PubMed

Liu, Xiaoqi; Zhou, Changlong; Li, Yanjing; Ji, Ye; Xu, Gongping; Wang, Xintao; Yan, Jinglong

2013-01-01

The objective of this study was to investigate the role of stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, on bone healing and whether SDF-1 contributes to accelerating bone repair in traumatic brain injury (TBI)/fracture model. Real-time polymerase chain reaction and immunohistochemical analysis were used to detect the expression of SDF-1 during the repair of femoral bone in TBI/fracture model. The TBI/fracture model was treated with anti-SDF-1 neutralizing antibody or AMD3100, an antagonist for CXCR4, and evaluated by histomorphometry. In vitro and in vivo migration assays were used to evaluate the functional effect of SDF-1 on primary mesenchymal stem cells. The expression of SDF1 and CXCR4 messenger RNA was increased during the bone healing in TBI/fracture model but was less increased in fracture only model. High expression of SDF-1 protein was observed in the surrounding tissue of the damaged bone. Treated with anti-SDF-1 antibody or AMD3100 could inhibit new bone formation. SDF-1 increased mesenchymal stem cell chemotaxis in vitro in a dose-dependent manner. The in vivo migration study demonstrated that mesenchymal stem cells recruited by SDF-1 participate in endochondral bone repair. The SDF-1/CXCR4 axis plays a crucial role in the accelerating fracture healing under the condition of TBI and contributes to endochondral bone repair.

Laser for bone healing after oral surgery: systematic review.

PubMed

Noba, Claudio; Mello-Moura, Anna Carolina Volpi; Gimenez, Thais; Tedesco, Tamara Kerber; Moura-Netto, Cacio

2018-04-01

The purpose of this study is to perform a systematic review on the use of lasers in oral surgery for bone healing. Selection of articles was carried out by two evaluators in Pubmed and Web of Science databases for published articles and OpenGray for gray literature. Search strategy was developed based on the PICO Question "Does the use of lasers after oral surgery improve bone healing?". Eligibility criteria were: being on laser; evaluate bone healing; involve oral surgery; do not be about implant, periodontics, orthodontics, osteonecrosis or radiotherapy, nor revisions, clinical cases, etc. Data were collected from each article in a structured spreadsheet and a descriptive analysis was performed. Risk assessment of bias of the articles was carried out through the tool elaborated by the Cochrane collaboration. A total of 827 potentially relevant references were identified. No articles were found in OpenGray. Eleven articles met the eligibility criteria and were included in the systematic review. Most of studies were in vivo and in jaw, being conducted with low-power lasers which were applied immediately after the surgical procedure of extraction. Neoformation and bone density were the outcomes of choice and there was a tendency of increase in bone density, neoformation, regeneration, mineralization, or bone condensation when laser was applied. Regarding the bias risk assessment, studies were not clear in reporting most of the parameters. Low-power laser therapy seems to reduce time of bone healing in oral surgery, although there are no defined protocols and the level of evidence is still considered weak.

Microdialysis Sampling from Wound Fluids Enables Quantitative Assessment of Cytokines, Proteins, and Metabolites Reveals Bone Defect-Specific Molecular Profiles.

PubMed

Förster, Yvonne; Schmidt, Johannes R; Wissenbach, Dirk K; Pfeiffer, Susanne E M; Baumann, Sven; Hofbauer, Lorenz C; von Bergen, Martin; Kalkhof, Stefan; Rammelt, Stefan

2016-01-01

Bone healing involves a variety of different cell types and biological processes. Although certain key molecules have been identified, the molecular interactions of the healing progress are not completely understood. Moreover, a clinical routine for predicting the quality of bone healing after a fracture in an early phase is missing. This is mainly due to a lack of techniques to comprehensively screen for cytokines, growth factors and metabolites at their local site of action. Since all soluble molecules of interest are present in the fracture hematoma, its in-depth assessment could reveal potential markers for the monitoring of bone healing. Here, we describe an approach for sampling and quantification of cytokines and metabolites by using microdialysis, combined with solid phase extractions of proteins from wound fluids. By using a control group with an isolated soft tissue wound, we could reveal several bone defect-specific molecular features. In bone defect dialysates the neutrophil chemoattractants CXCL1, CXCL2 and CXCL3 were quantified with either a higher or earlier response compared to dialysate from soft tissue wound. Moreover, by analyzing downstream adaptions of the cells on protein level and focusing on early immune response, several proteins involved in the immune cell migration and activity could be identified to be specific for the bone defect group, e.g. immune modulators, proteases and their corresponding inhibitors. Additionally, the metabolite screening revealed different profiles between the bone defect group and the control group. In summary, we identified potential biomarkers to indicate imbalanced healing progress on all levels of analysis.

Microdialysis Sampling from Wound Fluids Enables Quantitative Assessment of Cytokines, Proteins, and Metabolites Reveals Bone Defect-Specific Molecular Profiles

PubMed Central

Wissenbach, Dirk K.; Pfeiffer, Susanne E. M.; Baumann, Sven; Hofbauer, Lorenz C.; von Bergen, Martin; Kalkhof, Stefan; Rammelt, Stefan

2016-01-01

Bone healing involves a variety of different cell types and biological processes. Although certain key molecules have been identified, the molecular interactions of the healing progress are not completely understood. Moreover, a clinical routine for predicting the quality of bone healing after a fracture in an early phase is missing. This is mainly due to a lack of techniques to comprehensively screen for cytokines, growth factors and metabolites at their local site of action. Since all soluble molecules of interest are present in the fracture hematoma, its in-depth assessment could reveal potential markers for the monitoring of bone healing. Here, we describe an approach for sampling and quantification of cytokines and metabolites by using microdialysis, combined with solid phase extractions of proteins from wound fluids. By using a control group with an isolated soft tissue wound, we could reveal several bone defect-specific molecular features. In bone defect dialysates the neutrophil chemoattractants CXCL1, CXCL2 and CXCL3 were quantified with either a higher or earlier response compared to dialysate from soft tissue wound. Moreover, by analyzing downstream adaptions of the cells on protein level and focusing on early immune response, several proteins involved in the immune cell migration and activity could be identified to be specific for the bone defect group, e.g. immune modulators, proteases and their corresponding inhibitors. Additionally, the metabolite screening revealed different profiles between the bone defect group and the control group. In summary, we identified potential biomarkers to indicate imbalanced healing progress on all levels of analysis. PMID:27441377

Exogenous PTHrP Repairs the Damaged Fracture Healing of PTHrP+/− Mice and Accelerates Fracture Healing of Wild Mice

PubMed Central

Wang, Yinhe; Fang, Xin; Wang, Chun; Ding, Congzhu; Lin, Hua; Liu, Anlong; Wang, Lei; Cao, Yang

2017-01-01

Bone fracture healing is a complicated physiological regenerative process initiated in response to injury and is similar to bone development. To demonstrate whether an exogenous supply of parathyroid hormone–related protein (PTHrP) helps in bone fracture healing, closed mid-diaphyseal femur fractures were created and stabilized with intramedullary pins in eight-week-old wild-type (WT) PTHrP+/+ and PTHrP+/− mice. After administering PTHrP for two weeks, callus tissue properties were analyzed at one, two, and four weeks post-fracture (PF) by various methods. Bone formation–related genes and protein expression levels were evaluated by real-time reverse transcriptase–polymerase chain reaction and Western blots. At two weeks PF, mineral density of callus, bony callus areas, mRNA levels of alkaline phosphatase (ALP), type I collagen, Runt-related transcription factor 2 (Runx-2), and protein levels of Runx-2 and insulin-like growth factor-1 decreased in PTHrP+/− mice compared with WT mice. At four weeks PF, total collagen-positive bony callus areas, osteoblast number, ALP-positive areas, and type I collagen-positive areas all decreased in PTHrP+/− mice. At both two and four weeks PF, tartrate-resistant acid phosphatase–positive osteoclast number and surface decreased a little in PTHrP+/− mice. The study indicates that exogenous PTHrP provided by subcutaneous injection could redress impaired bone fracture healing, leading to mutation of activated PTHrP by influencing callus areas, endochondral bone formation, osteoblastic bone formation, and bone turnover. PMID:28178186

Rapid identification of slow healing wounds.

PubMed

Jung, Kenneth; Covington, Scott; Sen, Chandan K; Januszyk, Michael; Kirsner, Robert S; Gurtner, Geoffrey C; Shah, Nigam H

2016-01-01

Chronic nonhealing wounds have a prevalence of 2% in the United States, and cost an estimated $50 billion annually. Accurate stratification of wounds for risk of slow healing may help guide treatment and referral decisions. We have applied modern machine learning methods and feature engineering to develop a predictive model for delayed wound healing that uses information collected during routine care in outpatient wound care centers. Patient and wound data was collected at 68 outpatient wound care centers operated by Healogics Inc. in 26 states between 2009 and 2013. The dataset included basic demographic information on 59,953 patients, as well as both quantitative and categorical information on 180,696 wounds. Wounds were split into training and test sets by randomly assigning patients to training and test sets. Wounds were considered delayed with respect to healing time if they took more than 15 weeks to heal after presentation at a wound care center. Eleven percent of wounds in this dataset met this criterion. Prognostic models were developed on training data available in the first week of care to predict delayed healing wounds. A held out subset of the training set was used for model selection, and the final model was evaluated on the test set to evaluate discriminative power and calibration. The model achieved an area under the curve of 0.842 (95% confidence interval 0.834-0.847) for the delayed healing outcome and a Brier reliability score of 0.00018. Early, accurate prediction of delayed healing wounds can improve patient care by allowing clinicians to increase the aggressiveness of intervention in patients most at risk. © 2015 by the Wound Healing Society.

Recent biological trends in management of fracture non-union

PubMed Central

Emara, Khaled M; Diab, Ramy Ahmed; Emara, Ahmed Khaled

2015-01-01

Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. Currently, there is a plethora of different strategies to augment the impaired or “insufficient” bone-regeneration process, including the “gold standard” autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. Improved “local” strategies in terms of tissue engineering and gene therapy, or even “systemic” enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible, to accelerate the overall regeneration process, or even to address systemic conditions, such as skeletal disorders and osteoporosis. An improved understanding of the molecular and cellular events that occur during bone repair and remodeling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Orthobiologics, including stem cells, osteoinductive growth factors, osteoconductive matrices, and anabolic agents, are available clinically for accelerating fracture repair and treatment of compromised bone repair situations like delayed unions and nonunions. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use, and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications. PMID:26396938

Rapid identification of slow healing wounds

PubMed Central

Jung, Kenneth; Covington, Scott; Sen, Chandan K.; Januszyk, Michael; Kirsner, Robert S.; Gurtner, Geoffrey C.; Shah, Nigam H.

2016-01-01

Chronic nonhealing wounds have a prevalence of 2% in the United States, and cost an estimated $50 billion annually. Accurate stratification of wounds for risk of slow healing may help guide treatment and referral decisions. We have applied modern machine learning methods and feature engineering to develop a predictive model for delayed wound healing that uses information collected during routine care in outpatient wound care centers. Patient and wound data was collected at 68 outpatient wound care centers operated by Healogics Inc. in 26 states between 2009 and 2013. The dataset included basic demographic information on 59,953 patients, as well as both quantitative and categorical information on 180,696 wounds. Wounds were split into training and test sets by randomly assigning patients to training and test sets. Wounds were considered delayed with respect to healing time if they took more than 15 weeks to heal after presentation at a wound care center. Eleven percent of wounds in this dataset met this criterion. Prognostic models were developed on training data available in the first week of care to predict delayed healing wounds. A held out subset of the training set was used for model selection, and the final model was evaluated on the test set to evaluate discriminative power and calibration. The model achieved an area under the curve of 0.842 (95% confidence interval 0.834–0.847) for the delayed healing outcome and a Brier reliability score of 0.00018. Early, accurate prediction of delayed healing wounds can improve patient care by allowing clinicians to increase the aggressiveness of intervention in patients most at risk. PMID:26606167

The mechanical heterogeneity of the hard callus influences local tissue strains during bone healing: a finite element study based on sheep experiments.

PubMed

Vetter, A; Liu, Y; Witt, F; Manjubala, I; Sander, O; Epari, D R; Fratzl, P; Duda, G N; Weinkamer, R

2011-02-03

During secondary fracture healing, various tissue types including new bone are formed. The local mechanical strains play an important role in tissue proliferation and differentiation. To further our mechanobiological understanding of fracture healing, a precise assessment of local strains is mandatory. Until now, static analyses using Finite Elements (FE) have assumed homogenous material properties. With the recent quantification of both the spatial tissue patterns (Vetter et al., 2010) and the development of elastic modulus of newly formed bone during healing (Manjubala et al., 2009), it is now possible to incorporate this heterogeneity. Therefore, the aim of this study is to investigate the effect of this heterogeneity on the strain patterns at six successive healing stages. The input data of the present work stemmed from a comprehensive cross-sectional study of sheep with a tibial osteotomy (Epari et al., 2006). In our FE model, each element containing bone was described by a bulk elastic modulus, which depended on both the local area fraction and the local elastic modulus of the bone material. The obtained strains were compared with the results of hypothetical FE models assuming homogeneous material properties. The differences in the spatial distributions of the strains between the heterogeneous and homogeneous FE models were interpreted using a current mechanobiological theory (Isakson et al., 2006). This interpretation showed that considering the heterogeneity of the hard callus is most important at the intermediate stages of healing, when cartilage transforms to bone via endochondral ossification. Copyright © 2010 Elsevier Ltd. All rights reserved.

An ultrasound wearable system for the monitoring and acceleration of fracture healing in long bones.

PubMed

Protopappas, Vasilios C; Baga, Dina A; Fotiadis, Dimitrios I; Likas, Aristidis C; Papachristos, Athanasios A; Malizos, Konstantinos N

2005-09-01

An ultrasound wearable system for remote monitoring and acceleration of the healing process in fractured long bones is presented. The so-called USBone system consists of a pair of ultrasound transducers, implanted into the fracture region, a wearable device and a centralized unit. The wearable device is responsible to carry out ultrasound measurements using the axial-transmission technique and initiate therapy sessions of low-intensity pulsed ultrasound. The acquired measurements and other data are wirelessly transferred from the patient-site to the centralized unit, which is located in a clinical setting. The evaluation of the system on an animal tibial osteotomy model is also presented. A dataset was constructed for monitoring purposes consisting of serial ultrasound measurements, follow-up radiographs, quantitative computed tomography-based densitometry and biomechanical data. The animal study demonstrated the ability of the system to collect ultrasound measurements in an effective and reliable fashion and participating orthopaedic surgeons accepted the system for future clinical application. Analysis of the acquired measurements showed that the pattern of evolution of the ultrasound velocity through healing bones over the postoperative period monitors a dynamic healing process. Furthermore, the ultrasound velocity of radiographically healed bones returns to 80% of the intact bone value, whereas the correlation coefficient of the velocity with the material and mechanical properties of the healing bone ranges from 0.699 to 0.814. The USBone system constitutes the first telemedicine system for the out-hospital management of patients sustained open fractures and treated with external fixation devices.

Bone and gallium scanning in the pre-op evaluation of the infected dysvascular foot

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stewart, C.; Sakimura, I.; Dillon, A.

1984-01-01

The purpose of this study is to determine the value of bone and gallium scans in predicting healing levels in the dysvascular foot with an infection requiring amputation. Healing requires amputation at a level both free of infection and with adequate blood flow. Forty-one such patients had bone and gallium scans and Doppler studies prior to amputation at a level selected by the surgeon. Eight patients required multiple surgeries before healing was obtained. Bone and soft tissue infections were determined from scans and healing levels predicted (SPHL) as the most distal amputation level free from infection: toectomy, Reye's, transmetatarsal, calcanectomy,more » Syme's, below knee. Doppler healing levels (DPHL) were predicted using a standard ischemic index. Doppler alone predicted the final healing level (FHL) in 41% with 59% needing more proximal amputation. Scans alone predicted FHL in 64% with 26% needing more proximal amputation. Ten percent were distal to the SPHL and all healed. These scans showed infection at transition sites between amputation levels, and the more proximal level had been predicted. Using the more proximal of the DPHL and SPHL the FHL was predicted in 78% with another 12% having more proximal amputation for nursing reasons. In 10% amputation was performed between DPHL and SPHL or at the more distal level. In no case was successful surgery performed distal to the more distal SPHL or DPHL. Bone and gallium scans used with Doppler studies are useful in optimizing the choice of amputation level in the infected, dysvascular foot.« less

Osteoimmune Mechanisms of Segmental Bone Fracture Healing and Therapy

DTIC Science & Technology

2016-09-01

to civilians. Despite efforts involving allografts , surgery and fixators, intramedullary nailing and invasive plate fixing to heal segmental...efforts are focused on: tissue engineering approaches aimed at developing osteoconductive scaffolds, better quality synthetic bone grafts, and use of

Juvenile Swine Surgical Alveolar Cleft Model to Test Novel Autologous Stem Cell Therapies

PubMed Central

Caballero, Montserrat; Morse, Justin C.; Halevi, Alexandra E.; Emodi, Omri; Pharaon, Michael R.; Wood, Jeyhan S.

2015-01-01

Reconstruction of craniofacial congenital bone defects has historically relied on autologous bone grafts. Engineered bone using mesenchymal stem cells from the umbilical cord on electrospun nanomicrofiber scaffolds offers an alternative to current treatments. This preclinical study presents the development of a juvenile swine model with a surgically created maxillary cleft defect for future testing of tissue-engineered implants for bone generation. Five-week-old pigs (n=6) underwent surgically created maxillary (alveolar) defects to determine critical-sized defect and the quality of treatment outcomes with rib, iliac crest cancellous bone, and tissue-engineered scaffolds. Pigs were sacrificed at 1 month. Computed tomography scans were obtained at days 0 and 30, at the time of euthanasia. Histological evaluation was performed on newly formed bone within the surgical defect. A 1 cm surgically created defect healed with no treatment, the 2 cm defect did not heal. A subsequently created 1.7 cm defect, physiologically similar to a congenitally occurring alveolar cleft in humans, from the central incisor to the canine, similarly did not heal. Rib graft treatment did not incorporate into adjacent normal bone; cancellous bone and the tissue-engineered graft healed the critical-sized defect. This work establishes a juvenile swine alveolar cleft model with critical-sized defect approaching 1.7 cm. Both cancellous bone and tissue engineered graft generated bridging bone formation in the surgically created alveolar cleft defect. PMID:25837453

Concise review: Insights from normal bone remodeling and stem cell-based therapies for bone repair.

PubMed

Khosla, Sundeep; Westendorf, Jennifer J; Mödder, Ulrike I

2010-12-01

There is growing interest in the use of mesenchymal stem cells for bone repair. As a major reason for normal bone remodeling is the removal of fatigue microcracks, advances in our understanding of this process may inform approaches to enhance fracture healing. Increasing evidence now indicates that physiological bone remodeling occurs in close proximity to blood vessels and that these vessels carry perivascular stem cells that differentiate into osteoblasts. Similarly, fracture healing is critically dependent on the ingrowth of blood vessels not only for a nutrient supply but also for the influx of osteoblasts. A number of animal and human studies have now shown the potential benefit of bone marrow-derived mesenchymal stem cells in enhancing bone repair. However, as in other tissues, the question of whether these cells improve fracture healing directly by differentiating into osteoblasts or indirectly by secreting paracrine factors that recruit blood vessels and the accompanying perivascular stem cells remains a major unresolved issue. Moreover, CD34+ cells, which are enriched for endothelial/hematopoietic cells, have also shown efficacy in various bone repair models, at least in part due to the induction of angiogenesis and recruitment of host progenitor cells. Thus, mesenchymal and nonmesenchymal stem/progenitor cells are attractive options for bone repair. It is possible that they contribute directly to bone repair, but it is also likely that they express paracrine factors in the appropriate amounts and combinations that promote and sustain the healing process.

Enhanced Healing of Rat Calvarial Defects with MSCs Loaded on BMP-2 Releasing Chitosan/Alginate/Hydroxyapatite Scaffolds

PubMed Central

He, Xiaoning; Liu, Yang; Yuan, Xue; Lu, Li

2014-01-01

In this study, we designed a chitosan/alginate/hydroxyapatite scaffold as a carrier for recombinant BMP-2 (CAH/B2), and evaluated the release kinetics of BMP-2. We evaluated the effect of the CAH/B2 scaffold on the viability and differentiation of bone marrow mesenchymal stem cells (MSCs) by scanning electron microscopy, MTS, ALP assay, alizarin-red staining and qRT-PCR. Moreover, MSCs were seeded on scaffolds and used in a 8 mm rat calvarial defect model. New bone formation was assessed by radiology, hematoxylin and eosin staining 12 weeks postoperatively. We found the release kinetics of BMP-2 from the CAH/B2 scaffold were delayed compared with those from collagen gel, which is widely used for BMP-2 delivery. The BMP-2 released from the scaffold increased MSC differentiation and did not show any cytotoxicity. MSCs exhibited greater ALP activity as well as stronger calcium mineral deposition, and the bone-related markers Col1α, osteopontin, and osteocalcin were upregulated. Analysis of in vivo bone formation showed that the CAH/B2 scaffold induced more bone formation than other groups. This study demonstrates that CAH/B2 scaffolds might be useful for delivering osteogenic BMP-2 protein and present a promising bone regeneration strategy. PMID:25084008

Delayed administration of recombinant human parathyroid hormone improves early biomechanical strength in a rat rotator cuff repair model.

PubMed

Duchman, Kyle R; Goetz, Jessica E; Uribe, Bastian U; Amendola, Andrew M; Barber, Joshua A; Malandra, Allison E; Fredericks, Douglas C; Hettrich, Carolyn M

2016-08-01

Despite advances in intraoperative techniques, rotator cuff repairs frequently do not heal. Recombinant human parathyroid hormone (rhPTH) has been shown to improve healing at the tendon-to-bone interface in an established acute rat rotator cuff repair model. We hypothesized that administration of rhPTH beginning on postoperative day 7 would result in improved early load to failure after acute rotator cuff repair in an established rat model. Acute rotator cuff repairs were performed in 108 male Sprague-Dawley rats. Fifty-four rats received daily injections of rhPTH beginning on postoperative day 7 until euthanasia or a maximum of 12 weeks postoperatively. The remaining 54 rats received no injections and served as the control group. Animals were euthanized at 2 and 16 weeks postoperatively and evaluated by gross inspection, biomechanical testing, and histologic analysis. At 2 weeks postoperatively, rats treated with rhPTH demonstrated significantly higher load to failure than controls (10.9 vs. 5.2 N; P = .003). No difference in load to failure was found between the 2 groups at 16 weeks postoperatively, although control repairs more frequently failed at the tendon-to-bone interface (45.5% vs. 22.7%; P = .111). Blood vessel density appeared equivalent between the 2 groups at both time points, but increased intracellular and extracellular vascular endothelial growth factor expression was noted in the rhPTH-treated group at 2 weeks. Delayed daily administration of rhPTH resulted in increased early load to failure and equivalent blood vessel density in an acute rotator cuff repair model. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Socket Preservation using Enzyme-treated Equine Bone Granules and an Equine Collagen Matrix: A Case Report with Histological and Histomorphometrical Assessment.

PubMed

Leonida, Alessandro; Todeschini, Giovanni; Lomartire, Giovanni; Cinci, Lorenzo; Pieri, Laura

2016-11-01

To histologically assess the effectiveness of a socket-preservation technique using enzyme-treated equine bone granules as a bone-graft material in combination with an equine collagen matrix as a scaffold for soft-tissue regeneration. Enzyme-treated equine bone granules and equine collagen matrix recently have been developed to help overcome alveolar bone deficiencies that develop in the wake of edentulism. The patient had one mandibular molar extracted and the socket grafted with equine bone granules. The graft was covered with the equine collagen matrix, placed in a double layer. No flap was prepared, and the gingival margins were stabilized with a single stitch, leaving the matrix partially exposed and the site to heal by secondary intention. The adjacent molar was extracted 1 month later, and that socket was left to heal by secondary intention without any further treatment. Three months after each surgery, an implant was placed and a biopsy was collected. The two biopsies underwent histological processing and qualitative evaluation. Histomorphometric analysis was also performed to calculate the percentage of newly formed bone (NFB) in the two cores. Healing at both sites was uneventful, and no inflammation or other adverse reactions were observed in the samples. Soft-tissue healing by secondary intention appeared to occur faster at the grafted site. The corresponding core showed a marked separation between soft and hard tissue that was not observed in the core from the nongrafted site, where soft-tissue hypertrophy could be observed. Newly formed bone at the grafted and nongrafted sites was not significantly different (27.2 ± 7.1 and 29.4 ± 6.2% respectively, p = 0.45). The surgical technique employed in this case appeared to facilitate postextraction soft-tissue healing by second intention and simplify soft-tissue management. Using a collagen-based matrix to cover a postextraction grafted site may facilitate second intention soft-tissue healing and proper soft-tissue growth.

Periodontal regeneration using an injectable bone cement combined with BMP-2 or FGF-2.

PubMed

Oortgiesen, Daniël A W; Walboomers, X Frank; Bronckers, Antonius L J J; Meijer, Gert J; Jansen, John A

2014-03-01

Periodontitis is a frequently diagnosed oral disease characterized by bone resorption and soft tissue loss around teeth. Unfortunately, currently available therapies only slow or arrest progress of the disease. Ideally, treatment of periodontal defects should be focused on complete regeneration of the lost tissues [(bone and periodontal ligament (PDL)]. As a result, this study used intrabony defects to evaluate the regenerative potential of an injectable macroporous calcium phosphate cement (CaP) in combination with bone morphogenetic protein-2 (BMP-2) or fibroblast growth factor-2 (FGF-2). After creating 30 periodontal defects in 15 Wistar rats, three treatment strategies were conducted: application of CaP only, CaP + BMP-2 and CaP + FGF-2. Animals were euthanized after 12 weeks and processed for histology and histomorphometry. Using CaP alone resulted in limited effects on PDL and bone healing. CaP + BMP-2 showed a good response for bone healing; a significant 2.4 fold increase in bone healing score was observed compared to CaP. However, for PDL healing, CaP + BMP-2 treatment showed no difference compared to the CaP group. The best results were observed with the combined treatment of CaP + FGF-2, which showed a significant 3.3 fold increase in PDL healing score compared to CaP + BMP-2 and a significant 2.6 fold increase compared to CaP. For bone healing, CaP +  FGF-2 showed a significant 1.9 fold increase compared to CaP but no significant difference was noted compared to the CaP + BMP-2 group. The combination of a topical application of FGF-2 and an injectable CaP seems to be a promising treatment modality for periodontal regeneration. Copyright © 2012 John Wiley & Sons, Ltd.

Characteristics of bone turnover in the long bone metaphysis fractured patients with normal or low Bone Mineral Density (BMD).

PubMed

Wölfl, Christoph; Schweppenhäuser, Daniela; Gühring, Thorsten; Takur, Caner; Höner, Bernd; Kneser, Ulrich; Grützner, Paul Alfred; Kolios, Leila

2014-01-01

The incidence of osteoporotic fractures increases as our population ages. Until now, the exact biochemical processes that occur during the healing of metaphyseal fractures remain unclear. Diagnostic instruments that allow a dynamic insight into the fracture healing process are as yet unavailable. In the present matched pair analysis, we study the time course of the osteoanabolic markers bone specific alkaline phosphatase (BAP) and transforming growth factor β1 (TGFβ1), as well as the osteocatabolic markers crosslinked C-telopeptide of type-I-collagen (β-CTX) and serum band 5 tartrate-resistant acid phosphatase (TRAP5b), during the healing of fractures that have a low level of bone mineral density (BMD) compared with fractures that have a normal BMD. Between March 2007 and February 2009, 30 patients aged older than 50 years who suffered a metaphyseal fracture were included in our study. BMDs were verified by dual energy Xray absorptiometry (DXEA) scans. The levels of BTMs were examined over an 8-week period. Osteoanabolic BAP levels in those with low levels of BMD were significantly different from the BAP levels in those with normal BMD. BAP levels in the former group increased constantly, whereas the latter group showed an initial strong decrease in BAP followed by slowly rising values. Osteocatabolic β-CTX increased in the bone of the normal BMD group constantly, whereas these levels decreased significantly in the bone of the group with low BMD from the first week. TRAP5b was significantly reduced in the low level BMD group. With this work, we conduct first insights into the molecular biology of the fracture healing process in patients with low levels of BMD that explains the mechanism of its fracture healing. The results may be one reason for the reduced healing qualities in bones with low BMD.

Microcracks induce osteoblast alignment and maturation on hydroxyapatite scaffolds

NASA Astrophysics Data System (ADS)

Shu, Yutian

Physiological bone tissue is a mineral/collagen composite with a hierarchical structure. The features in bone, such as mineral crystals, fibers, and pores can range from the nanometer to the centimeter in size. Currently available bone tissue scaffolds primarily address the chemical composition, pore size, and pore size distribution. While these design parameters are extensively investigated for mimicking bone function and inducing bone regeneration, little is known about microcracks, which is a prevalent feature found in fractured bone in vivo and associated with fracture healing and repair. Since the purpose of bone tissue engineering scaffold is to enhance bone regeneration, the coincidence of microcracks and bone densification should not be neglected but rather be considered as a potential parameter in bone tissue engineering scaffold design. The purpose of this study is to test the hypothesis that microcracks enhance bone healing. In vitro studies were designed to investigate the osteoblast (bone forming cells) response to microcracks in dense (94%) hydroxyapatite substrates. Microcracks were introduced using a well-established Vickers indentation technique. The results of our study showed that microcracks induced osteoblast alignment, enhanced osteoblast attachment and more rapid maturation. These findings may provide insight into fracture healing mechanism(s) as well as improve the design of bone tissue engineering orthopedic scaffolds for more rapid bone regeneration.

Autonomic healing of acrylic bone cement.

PubMed

Gladman, A Sydney; Celestine, Asha-Dee N; Sottos, Nancy R; White, Scott R

2015-01-28

Self-healing in orthopedic bone cement is demonstrated with a novel thermoplastic solvent-bonding approach. Low toxicity solvent-filled microcapsules, embedded in a commercial acrylic bone cement matrix, enable recovery of up to 80% of the virgin fracture toughness of the cement at room and body temperature conditions without external stimuli or human intervention. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A theoretical analysis and finite element simulation of fixator-bone system stiffness on healing progression.

PubMed

Li, Jianfeng; Zhao, Xia; Hu, Xiaojie; Tao, Chunjing; Ji, Run

2018-03-01

The unilateral external fixator has become a quick and easy application for fracture stabilization of the extremities; the main value for evaluation of mechanical stability of the external fixator is stiffness. The stiffness property of the external fixator affects the local biomechanical environment of fractured bone. In this study, a theoretical model with changing Young's modulus of the callus is established by using the Castigliano's theory, investigating compression stiffness, torsional stiffness and bending stiffness of the fixator-bone system during the healing process. The effects of pin deviation angle on three stiffness methods are also investigated. In addition, finite element simulation is discussed regarding the stress distribution between the fixator and bone. The results reveal the three stiffness evaluation methods are similar for the fixator-bone system. Finite element simulation shows that with increased healing time, the transmission of the load between the fixator and bone are different. In addition, the finite element analyses verify the conclusions obtained from the theoretical model. This work helps orthopedic doctors to monitor the progression of fracture healing and determine the appropriate time for removal of a fixation device and provide important theoretical methodology.

Biological Evaluation of Implant Drill Made from Zirconium Dioxide.

PubMed

Akiba, Yosuke; Eguchi, Kaori; Akiba, Nami; Uoshima, Katsumi

2017-04-01

Zirconia is a good candidate material in the dental field. In this study, we evaluated biological responses against a zirconia drill using a bone cavity healing model. Zirconia drills, stainless steel drills, and the drilled bone surface were observed by scanning electron microscopy (SEM), before and after cavity preparation. For the bone cavity healing model, the upper first and second molars of Wistar rats were extracted. After 4 weeks, cavities were prepared with zirconia drills on the left side. As a control, a stainless steel drill was used on the right side. At 3, 7, and 14 days after surgery, micro-CT images were taken. Samples were prepared for histological staining. SEM images revealed that zirconia drills maintained sharpness even after 30 drilling procedures. The bone surface was smoother with the zirconia drill. Micro-CT images showed faster and earlier bone healing in the zirconia drill cavity. On H-E staining, at 7 days, the zirconia drill defect had a smaller blank lacunae area. At 14 days, the zirconia drill defect was filled with newly formed bone. The zirconia drill induces less damage during cavity preparation and is advantageous for bone healing. (197 words). © 2016 The Authors Clinical Implant Dentistry and Related Research Published by Wiley Periodicals, Inc.

Delayed cutaneous wound healing in aged rats compared to younger ones.

PubMed

Soybir, Onur C; Gürdal, Sibel Ö; Oran, Ebru Ş; Tülübaş, Feti; Yüksel, Meral; Akyıldız, Ayşenur İ; Bilir, Ayhan; Soybir, Gürsel R

2012-10-01

Delayed wound healing in elderly males is a complex process in which the factors responsible are not fully understood. This study investigated the hormonal, oxidative and angiogenic factors affecting wound healing in aged rats. Two groups consisting of eight healthy male Wistar Albino rats [young (30 ± 7 days) and aged (360 ± 30 days)], and a cutaneous incision wound healing model were used. Scar tissue samples from wounds on the 7th, 14th and 21st days of healing were evaluated for hydroxyproline and vascular endothelial growth factor content. Macrophage, lymphocyte, fibroblast and polymorphonuclear cell infiltration; collagen formation and vascularization were assessed by light and electron microscopy. The free oxygen radical content of the wounds was measured by a chemiluminescence method. Blood sample analysis showed that the hydroxyproline and total testosterone levels were significantly higher, and the oxygen radical content was significantly lower in young rats. Histopathological, immunohistochemical and ultrastructural evaluations revealed higher amounts of fibroblasts and collagen fibers, and more vascularization in young rats. These results are indicative of the delayed wound healing in aged rats. A combination of multiple factors including hormonal regulation, free oxygen radicals and impaired angiogenesis appears to be the cause of delayed cutaneous healing. © 2011 The Authors. International Wound Journal © 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc.

Unicameral Bone Cysts in the Humerus: Treatment Outcomes.

PubMed

Kadhim, Muayad; Sethi, Samir; Thacker, Mihir M

2016-06-01

Several treatment modalities have been described for the treatment of unicameral bone cysts (UBC). The aim of this study was to examine the outcome of various treatment modalities of UBC in a specific anatomic location, the humerus. This study is a retrospective case-only study of patients with humeral UBC with minimum follow-up of 1 year. Medical records and radiographs were assessed and UBC healing status was determined based on most recent follow-up radiographs and divided into 3 groups (healed, partially healed, and not healed). Descriptive statistics were utilized to summarize study outcome. Sixty-eight patients (54 boys and 14 girls) with humeral UBC comprised the study population. Sixty-four cases (94.1%) presented with a pathologic fracture. Fifty-one cases were in the proximal metaphysis and 17 were in the diaphysis. Mean age at diagnosis was 9.2±3.7 years, and mean follow-up was 4.0±2.6 years. Twenty-five patients were treated with observation, 38 by injection (27 with steroids and 11 with bone marrow), and 5 by open surgery. Patients who underwent open surgery had relatively larger cyst length, width, and cyst index, and all healed or partially healed at last follow-up. UBC persistence was observed in 29% of diaphyseal and 27.5% of metaphyseal cysts. Of the 19 patients with persistence, 8 were treated with observation, 9 with steroid injection, and 2 with bone marrow injection. Inner wall disruption before injection was performed in 17 patients (24% did not heal), whereas 21 patients did not have inner wall disruption (33% did not heal). Twenty patients received >1 injection. Eleven patients complained of pain at the last visit (8 had a persistent cyst, 2 were partially healed, and 1 had a healed UBC). Complete healing of humeral UBC is challenging to achieve irrespective of treatment modality. UBCs treated with open surgery tended to heal better. Unhealed cysts were more likely to be associated with pain. Level III-a retrospective comparative study.

Surface modification of biomedical and dental implants and the processes of inflammation, wound healing and bone formation.

PubMed

Stanford, Clark M

2010-01-25

Bone adaptation or integration of an implant is characterized by a series of biological reactions that start with bone turnover at the interface (a process of localized necrosis), followed by rapid repair. The wound healing response is guided by a complex activation of macrophages leading to tissue turnover and new osteoblast differentiation on the implant surface. The complex role of implant surface topography and impact on healing response plays a role in biological criteria that can guide the design and development of future tissue-implant surface interfaces.

Effects of salmon calcitonin on fracture healing in ovariectomized rats.

PubMed

Li, Xiaolin; Luo, Xinle; Yu, Nansheng; Zeng, Bingfang

2007-01-01

To explore the effects of salmon calcitonin on the healing process of osteoporotic fractures in ovariectomized rats. We performed this study in The First Affiliated Hospital of Guangzhou Medical College, Guangzhou, China, during the period March 2002 to December 2004. We used 120 female adult Wistar rats in this experiment, among which 90 underwent ovariectomy (OVX) and the other 30 had sham-operation. All rats had their left tibias fractured 3 months later. The 90 OVX rats were randomly divided into 3 groups with 30 in each, while the 30 sham-operated rats served as control group. After the fracture the rats had subcutaneous injection of normal saline, salmon calcitonin and estrogen, respectively. X-ray film, histological examination, bone mineral density (BMD) measurement and biomechanics testing were carried out to evaluate the fracture healing. Compared with OVX rats treated with normal saline, the rats with salmon calcitonin had significantly higher BMD values in the left tibia, higher max torque, shear stress of the left tibia 8 weeks after fracture (p<0.05), and presented with stronger callus formation, shorter fracture healing time and faster normalization of microstructure of bone trabeculae. Salmon calcitonin can, not only increase BMD in osteoporotic bone, but also enhance the bone biomechanical properties and improve the process of fracture healing in fractured osteoporotic bone.

Spatially offset raman spectroscopy for non-invasive assessment of fracture healing

NASA Astrophysics Data System (ADS)

Ding, Hao; Lu, Guijin; West, Christopher; Gogola, Gloria; Kellam, James; Ambrose, Catherine; Bi, Xiaohong

2016-02-01

Fracture non-unions and bone re-fracture are common challenges for post-fracture management. To achieve better prognosis and treatment evaluation, it is important to be able to assess the quality of callus over the time course of healing. This study evaluated the potential of spatially offset Raman spectroscopy for assessing the fracture healing process in situ. We investigated a rat model of fracture healing at two weeks and 4 weeks post fracture with a fractured femur and a contralateral control in each animal. Raman spectra were collected from the depilated thighs on both sides transcutaneously in situ with various source/detection offsets. Bone signals were recovered from SORS spectra, and then compared with those collected from bare bones. The relative intensity of mineral from fractured bone was markedly decreased compared to the control. The fractured bones demonstrated lower mineral and carbonate level and higher collagen content in the callus at the early time point. Compared to week 2, collagen mineralization and mineral carbonation increased at 4 weeks post fracture. Similarly, the material properties of callus determined by reference point indentation also increased in the 4-week group, indicating improved callus quality with time. The results from Raman analysis are in agreement with radiographic and material testing, indicating the potential of this technique in assessing fracture healing in vivo.

Tendon Reattachment to Bone in an Ovine Tendon Defect Model of Retraction Using Allogenic and Xenogenic Demineralised Bone Matrix Incorporated with Mesenchymal Stem Cells.

PubMed

Thangarajah, Tanujan; Shahbazi, Shirin; Pendegrass, Catherine J; Lambert, Simon; Alexander, Susan; Blunn, Gordon W

2016-01-01

Tendon-bone healing following rotator cuff repairs is mainly impaired by poor tissue quality. Demineralised bone matrix promotes healing of the tendon-bone interface but its role in the treatment of tendon tears with retraction has not been investigated. We hypothesized that cortical demineralised bone matrix used with minimally manipulated mesenchymal stem cells will result in improved function and restoration of the tendon-bone interface with no difference between xenogenic and allogenic scaffolds. In an ovine model, the patellar tendon was detached from the tibial tuberosity and a complete distal tendon transverse defect measuring 1 cm was created. Suture anchors were used to reattach the tendon and xenogenic demineralised bone matrix + minimally manipulated mesenchymal stem cells (n = 5), or allogenic demineralised bone matrix + minimally manipulated mesenchymal stem cells (n = 5) were used to bridge the defect. Graft incorporation into the tendon and its effect on regeneration of the enthesis was assessed using histomorphometry. Force plate analysis was used to assess functional recovery. Compared to the xenograft, the allograft was associated with significantly higher functional weight bearing at 6 (P = 0.047), 9 (P = 0.028), and 12 weeks (P = 0.009). In the allogenic group this was accompanied by greater remodeling of the demineralised bone matrix into tendon-like tissue in the region of the defect (p = 0.015), and a more direct type of enthesis characterized by significantly more fibrocartilage (p = 0.039). No failures of tendon-bone healing were noted in either group. Demineralised bone matrix used with minimally manipulated mesenchymal stem cells promotes healing of the tendon-bone interface in an ovine model of acute tendon retraction, with superior mechanical and histological results associated with use of an allograft.

Soft Tissue Alterations in Esthetic Postextraction Sites: A 3-Dimensional Analysis.

PubMed

Chappuis, V; Engel, O; Shahim, K; Reyes, M; Katsaros, C; Buser, D

2015-09-01

Dimensional alterations of the facial soft and bone tissues following tooth extraction in the esthetic zone play an essential role to achieve successful outcomes in implant therapy. This prospective study is the first to investigate the interplay between the soft tissue dimensions and the underlying bone anatomy during an 8-wk healing period. The analysis is based on sequential 3-dimensional digital surface model superimpositions of the soft and bone tissues using digital impressions and cone beam computed tomography during an 8-wk healing period. Soft tissue thickness in thin and thick bone phenotypes at extraction was similar, averaging 0.7 mm and 0.8 mm, respectively. Interestingly, thin bone phenotypes revealed a 7-fold increase in soft tissue thickness after an 8-wk healing period, whereas in thick bone phenotypes, the soft tissue dimensions remained unchanged. The observed spontaneous soft tissue thickening in thin bone phenotypes resulted in a vertical soft tissue loss of only 1.6 mm, which concealed the underlying vertical bone resorption of 7.5 mm. Because of spontaneous soft tissue thickening, no significant differences were detected in the total tissue loss between thin and thick bone phenotypes at 2, 4, 6, and 8 wk. More than 51% of these dimensional alterations occurred within 2 wk of healing. Even though the observed spontaneous soft tissue thickening in thin bone phenotypes following tooth extraction conceals the pronounced underlying bone resorption pattern by masking the true bone deficiency, spontaneous soft tissue thickening offers advantages for subsequent bone regeneration and implant therapies in sites with high esthetic demand (Clinicaltrials.gov NCT02403700). © International & American Associations for Dental Research.

Proteomic Analysis of Gingival Tissue and Alveolar Bone during Alveolar Bone Healing*

PubMed Central

Yang, Hee-Young; Kwon, Joseph; Kook, Min-Suk; Kang, Seong Soo; Kim, Se Eun; Sohn, Sungoh; Jung, Seunggon; Kwon, Sang-Oh; Kim, Hyung-Seok; Lee, Jae Hyuk; Lee, Tae-Hoon

2013-01-01

Bone tissue regeneration is orchestrated by the surrounding supporting tissues and involves the build-up of osteogenic cells, which orchestrate remodeling/healing through the expression of numerous mediators and signaling molecules. Periodontal regeneration models have proven useful for studying the interaction and communication between alveolar bone and supporting soft tissue. We applied a quantitative proteomic approach to analyze and compare proteins with altered expression in gingival soft tissue and alveolar bone following tooth extraction. For target identification and validation, hard and soft tissue were extracted from mini-pigs at the indicated times after tooth extraction. From triplicate experiments, 56 proteins in soft tissue and 27 proteins in alveolar bone were found to be differentially expressed before and after tooth extraction. The expression of 21 of those proteins was altered in both soft tissue and bone. Comparison of the activated networks in soft tissue and alveolar bone highlighted their distinct responsibilities in bone and tissue healing. Moreover, we found that there is crosstalk between identified proteins in soft tissue and alveolar bone with respect to cellular assembly, organization, and communication. Among these proteins, we examined in detail the expression patterns and associated networks of ATP5B and fibronectin 1. ATP5B is involved in nucleic acid metabolism, small molecule biochemistry, and neurological disease, and fibronectin 1 is involved in cellular assembly, organization, and maintenance. Collectively, our findings indicate that bone regeneration is accompanied by a profound interaction among networks regulating cellular resources, and they provide novel insight into the molecular mechanisms involved in the healing of periodontal tissue after tooth extraction. PMID:23824910

Healing at the Interface Between Autologous Block Bone Grafts and Recipient Sites Using n-Butyl-2-Cyanoacrylate Adhesive as Fixation: Histomorphometric Study in Rabbits.

PubMed

De Santis, Enzo; Silva, Erick Ricardo; Martins, Evandro Neto Carneiro; Favero, Riccardo; Botticelli, Daniele; Xavier, Samuel Porfirio

2017-12-01

The aim of the present split-mouth (split-plot) study was to describe the sequential healing in the interface between autologous bone grafts and recipient parent bone, fixed using an n-butyl-2-cyanoacrylate adhesive with or without an additional titanium fixation screw. Bone grafts were collected from the calvaria and fixed to the lateral aspect of the mandible in 24 rabbits. The cortical layers of the recipient sites were perforated, and the grafts were randomly fixed using an n-butyl-2-cyanocrylate adhesive, either alone or in conjunction with a 1.5 mm × 6.0 mm titanium fixation screw. The animals were sacrificed after 3, 7, 20, and 40 days, and histomorphometric evaluations of the interface between graft and parent bone were performed. Only 2 of 6 grafts in each group were partially incorporated to the parent bone after 40 days of healing. The remaining grafts were separated from the parent bone by adhesive and connective tissue. It was concluded that the use of n-butyl-2-cyanoacrylate as fixation of an autologous bone graft to the lateral aspect of the mandible was able to maintain the fixation over time but did not incorporate the graft to the recipient sites. Use of fixation screws did not improve the healing.

The effects of nail rigidity on fracture healing in rats with osteoporosis

PubMed Central

Sha, Mo; Fu, Jun; Li, Jing; Fan Yuan, Chao; Shi, Lei; Jun Li, Shu

2009-01-01

Background and purpose Stress shielding from rigid internal fixation may lead to refracture after removal of the osteosynthesis material. We investigated the effect of a low-rigidity (Ti-24Nb-4Zr-7.9Sn) intramedullary nail regarding stress shielding and bone healing of osteoporotic fractures in the rat. Methods 40 female Sprague-Dawley rats, aged 3 months, were divided into the following groups: sham-operation (SHAM) (n = 10), ovariectomized (OVX) (n = 10) and OVX-fracture (n = 20). 10 SHAM rats and 10 OVX rats were killed after 12 weeks to provide biomechanical data. Ovariectomy was performed 12 weeks before fracturing both femurs in 20 rats. The left fracture was stabilized with a high-rigidity titanium alloy pin (Ti-6Al-4V; elastic modulus 110 GPa) and the right with a low-rigidity (Ti-24Nb-4Zr-7.9Sn; elastic modulus 33 GPa). The bony calluses were examined by micro-CT at 6 and 12 weeks after fracture, bone volume (BV) and total volume (TV) were determined at the callus region (ROI1) and the total femur (ROI2). Subsequently, the bones were tested mechanically by a three-point bending test. Results In the low-rigidity group, TV (ROI1) increased at 6 weeks, but BV (ROI1), BV (ROI2) were similar but maximum load increased. At 12 weeks, the maximum load and also BV (ROI1, ROI2) were increased in the low-rigidity group. Interpretation The low-rigidity nail manufactured from Ti-24Nb-4Zr-7.9Sn showed better external callus formation, seemed to reduce effects of stress shielding, and reduced bone resorption better than the stiffer nail. The low-rigidity nail was strong enough to maintain alignment of the fracture in the osteoporotic rat model without delayed union. PMID:19297794

The effects of the Er:YAG laser on trabecular bone micro-architecture: Comparison with conventional dental drilling by micro-computed tomographic and histological techniques

PubMed Central

Zeitouni, Jihad; Clough, Bret; Zeitouni, Suzanne; Saleem, Mohammed; Al Aisami, Kenan; Gregory, Carl

2017-01-01

Background: The use of lasers has become increasingly common in the field of medicine and dentistry, and there is a growing need for a deeper understanding of the procedure and its effects on tissue. The aim of this study was to compare the erbium-doped yttrium aluminium garnet (Er:YAG) laser and conventional drilling techniques, by observing the effects on trabecular bone microarchitecture and the extent of thermal and mechanical damage. Methods: Ovine femoral heads were employed to mimic maxillofacial trabecular bone, and cylindrical osteotomies were generated to mimic implant bed preparation. Various laser parameters were tested, as well as a conventional dental drilling technique. The specimens were then subjected to micro-computed tomographic (μCT) histomorphometic analysis and histology. Results: Herein, we demonstrate that mCT measurements of trabecular porosity provide quantitative evidence that laser-mediated cutting preserves the trabecular architecture and reduces thermal and mechanical damage at the margins of the cut. We confirmed these observations with histological studies. In contrast with laser-mediated cutting, conventional drilling resulted in trabecular collapse, reduction of porosity at the margin of the cut and histological signs of thermal damage. Conclusions: This study has demonstrated, for the first time, that mCT and quantification of porosity at the margin of the cut provides a quantitative insight into damage caused by bone cutting techniques. We further show that with laser-mediated cutting, the marrow remains exposed to the margins of the cut, facilitating cellular infiltration and likely accelerating healing. However, with drilling, trabecular collapse and thermal damage is likely to delay healing by restricting the passage of cells to the site of injury and causing localized cell death. PMID:29416849

Mixing implants of differing metallic composition in the treatment of upper-extremity fractures.

PubMed

Acevedo, Daniel; Loy, Bo Nasmyth; Loy, Bo Nasymuth; Lee, Brian; Omid, Reza; Itamura, John

2013-09-01

Mixing implants with differing metallic compositions has been avoided for fear of galvanic corrosion and subsequent failure of the implants and of bone healing. The purpose of this study was to evaluate upper-extremity fractures treated with open reduction and internal fixation with metallic implants that differed in metallic composition placed on the same bone. The authors studied the effects of using both stainless steel and titanium implants on fracture healing, implant failure, and other complications associated with this method of fixation. Their hypothesis was that combining these metals on the same bone would not cause clinically significant nonunions or undo clinical effects from galvanic corrosion. A retrospective review was performed of 17 patients with upper-extremity fractures fixed with metal implants of differing metallic compositions. The primary endpoint was fracture union. Eight clavicles, 2 proximal humeri, 3 distal humeri, 3 olecranons, and 1 glenoid fracture with an average follow-up 10 months were reviewed. All fractures healed. One patient experienced screw backout, which did not affect healing. This study implies that mixing implants with differing metallic compositions on the same bone for the treatment of fractures does not adversely affect bone healing. No evidence existed of corrosion or an increase in complications with this method of treatment. Contrary to prior belief, small modular hand stainless steel plates can be used to assist in reduction of smaller fracture fragments in combination with anatomic titanium plates to obtain anatomic reduction of the fracture without adversely affecting healing. Copyright 2013, SLACK Incorporated.

Smoking cessation and bone healing: optimal cessation timing.

PubMed

Truntzer, Jeremy; Vopat, Bryan; Feldstein, Michael; Matityahu, Amir

2015-02-01

Smoking is a worldwide epidemic. Complications related to smoking behavior generate an economic loss around $193 billion annually. In addition to impacting chronic health conditions, smoking is linked to increased perioperative complications in those with current or previous smoking history. Numerous studies have demonstrated more frequent surgical complications including higher rates of infection, poor wound healing, heightened pain complaints, and increased pulmonary morbidities in patients with a smoking history. Longer preoperative cessation periods also seem to correlate with reduced rates. At roughly 4 weeks of cessation prior to surgery, complication rates more closely reflect individuals without a smoking history in comparison with those that smoke within 4 weeks of surgery. In the musculoskeletal system, a similar trend has been observed in smokers with higher rates of fractures, nonunions, malunions, infections, osteomyelitis, and lower functional scores compared to non-smoking patients. Unfortunately, the present literature lacks robust data suggesting a temporal relationship between smoking cessation and bone healing. In our review, we analyze pseudoarthrosis rates following spinal fusion to suggest that bone healing in the context of smoking behavior follows a similar time sequence as observed in wound healing. We also discuss the implications for further clarity on bone healing and smoking cessation within orthopedics including improved risk stratification and better identification of circumstances where adjunct therapy is appropriate.

Chitosan nanofiber scaffold improves bone healing via stimulating trabecular bone production due to upregulation of the Runx2/osteocalcin/alkaline phosphatase signaling pathway

PubMed Central

Ho, Ming-Hua; Yao, Chih-Jung; Liao, Mei-Hsiu; Lin, Pei-I; Liu, Shing-Hwa; Chen, Ruei-Ming

2015-01-01

Osteoblasts play critical roles in bone formation. Our previous study showed that chitosan nanofibers can stimulate osteoblast proliferation and maturation. This translational study used an animal model of bone defects to evaluate the effects of chitosan nanofiber scaffolds on bone healing and the possible mechanisms. In this study, we produced uniform chitosan nanofibers with fiber diameters of approximately 200 nm. A bone defect was surgically created in the proximal femurs of male C57LB/6 mice, and then the left femur was implanted with chitosan nanofiber scaffolds for 21 days and compared with the right femur, which served as a control. Histological analyses revealed that implantation of chitosan nanofiber scaffolds did not lead to hepatotoxicity or nephrotoxicity. Instead, imaging analyses by X-ray transmission and microcomputed tomography showed that implantation of chitosan nanofiber scaffolds improved bone healing compared with the control group. In parallel, microcomputed tomography and bone histomorphometric assays further demonstrated augmentation of the production of new trabecular bone in the chitosan nanofiber-treated group. Furthermore, implantation of chitosan nanofiber scaffolds led to a significant increase in the trabecular bone thickness but a reduction in the trabecular parameter factor. As to the mechanisms, analysis by confocal microscopy showed that implantation of chitosan nanofiber scaffolds increased levels of Runt-related transcription factor 2 (Runx2), a key transcription factor that regulates osteogenesis, in the bone defect sites. Successively, amounts of alkaline phosphatase and osteocalcin, two typical biomarkers that can simulate bone maturation, were augmented following implantation of chitosan nanofiber scaffolds. Taken together, this translational study showed a beneficial effect of chitosan nanofiber scaffolds on bone healing through stimulating trabecular bone production due to upregulation of Runx2-mediated alkaline phosphatase and osteocalcin gene expressions. Our results suggest the potential of chitosan nanofiber scaffolds for therapy of bone diseases, including bone defects and bone fractures. PMID:26451104

Poly-ADP-ribose polymerase inhibition enhances ischemic and diabetic wound healing by promoting angiogenesis.

PubMed

Zhou, Xin; Patel, Darshan; Sen, Sabyasachi; Shanmugam, Victoria; Sidawy, Anton; Mishra, Lopa; Nguyen, Bao-Ngoc

2017-04-01

Chronic nonhealing wounds are a major health problem for patients in the United States and worldwide. Diabetes and ischemia are two major risk factors behind impaired healing of chronic lower extremity wounds. Poly-ADP-ribose polymerase (PARP) is found to be overactivated with both ischemic and diabetic conditions. This study seeks a better understanding of the role of PARP in ischemic and diabetic wound healing, with a specific focus on angiogenesis and vasculogenesis. Ischemic and diabetic wounds were created in FVB/NJ mice and an in vitro scratch wound model. PARP inhibitor PJ34 was delivered to the animals at 10 mg/kg/d through implanted osmotic pumps or added to the culture medium, respectively. Animal wound healing was assessed by daily digital photographs. Animal wound tissues, peripheral blood, and bone marrow cells were collected at different time points for further analysis with Western blot and flow cytometry. Scratch wound migration and invasion angiogenesis assays were performed using human umbilical vein endothelial cells (HUVECs). Measurements were reported as mean ± standard deviation. Continuous measurements were compared by t-test. P < .05 was considered statistically significant. A significant increase in PARP activity was observed under ischemic and diabetic conditions that correlated with delayed wound healing and slower HUVEC migration. The beneficial effect of PARP inhibition with PJ34 on ischemic and diabetic wound healing was observed in both animal and in vitro models. In the animal model, the percentage of wound healing was significantly enhanced from 43% ± 6% to 71% ± 9% (P < .05) by day 7 with the addition of PJ34. PARP inhibition promoted angiogenesis at the ischemic and diabetic wound beds as evidenced by significantly higher levels of endothelial cell markers (vascular endothelial growth factor receptor 2 [VEGFR2] and endothelial nitric oxide synthase) in mice treated with PJ34 compared with controls. Flow cytometry analysis of peripheral blood mononuclear cells showed that PARP inhibition increased mobilization of endothelial progenitor cells (VEGFR2 + /CD133 + and VEGFR2 + /CD34 + ) into the systemic circulation. Furthermore, under in vitro hyperglycemia and hypoxia conditions, PARP inhibition enhanced HUVEC migration and invasion in Boyden chamber assays by 80% and 180% (P < .05), respectively. Delayed healing in ischemic and diabetic wounds is caused by PARP hyperactivity, and PARP inhibition significantly enhanced ischemic and diabetic wound healing by promoting angiogenesis. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Human Bone-Forming Chondrocytes Cultured in the Hydrodynamic Focusing Bioreactor Retain Matrix Proteins: Similarities to Spaceflight Results

NASA Technical Reports Server (NTRS)

Duke, P. J.; Hecht, J.; Montufar-Solis, D.

2006-01-01

Fracture healing, crucial to a successful Mars mission, involves formation of a cartilaginous fracture callus which differentiates, mineralizes, ossifies and remodels via the endochondral process. Studies of spaceflown and tailsuspended rats found that, without loading, fracture callus formation and cartilage differentiation within the callus were minimal. We found delayed differentiation of chondrocytes within the rat growth plate on Cosmos 1887, 2044, and Spacelab 3. In the current study, differentiation of human bone-forming chondrocytes cultured in the hydrodynamic focusing bioreactor (HFB) was assessed. Human costochondral chondrocytes in suspension were aggregated overnight, then cultured in the HFB for 25 days. Collagen Type II, aggrecan and unsulfated chondroitin were found extracellularly and chondroitin sulfates 4 and 6 within the cell. Lack of secretion was also found in pancreatic cells of spaceflown rats, and in our SL3 studies. The HFB can be used to study cartilage differentiation in simulated microgravity.

The Role of the Progressive Ankylosis Protein (ANK) in Adipogenic/Osteogenic Fate Decision of Precursor Cells

PubMed Central

Minashima, Takeshi; Quirno, Martin; Lee, You Jin; Kirsch, Thorsten

2017-01-01

The progressive ankylosis protein (ANK) is a transmembrane protein that transports intracellular pyrophosphate (PPi) to the extracellular milieu. In this study we show increased fatty degeneration of the bone marrow of adult ank/ank mice, which lack a functional ANK protein. In addition, isolated bone marrow stromal cells (BMSCs) isolated from ank/ank mice showed a decreased proliferation rate and osteogenic differentiation potential, and an increased adipogenic differentiation potential compared to BMSCs isolated from wild type (WT) littermates. Wnt signaling pathway PCR array analysis revealed that Wnt ligands, Wnt receptors and Wnt signaling proteins that stimulate osteoblast differentiation were expressed at markedly lower levels in ank/ank BMSCs than in WT BMSCs. Lack of ANK function also resulted in impaired bone fracture healing, as indicated by a smaller callus formed and delayed bone formation in the callus site. Whereas 5 weeks after fracture, the fractured bone in WT mice was further remodeled and restored to original shape, the fractured bone in ank/ank mice was not fully restored and remodeled to original shape. In conclusion, our study provides evidence that ANK plays a critical role in the adipogenic/osteogenic fate decision of adult mesenchymal precursor cells. ANK functions in precursor cells are required for osteogenic differentiation of these cells during adult bone homeostasis and repair, whereas lack of ANK functions favors adipogenic differentiation. PMID:28286238

An animal model of co-existing sarcopenia and osteoporotic fracture in senescence accelerated mouse prone 8 (SAMP8).

PubMed

Zhang, Ning; Chow, Simon Kwoon Ho; Leung, Kwok Sui; Lee, Ho Hin; Cheung, Wing Hoi

2017-10-15

Sarcopenia and osteoporotic fracture are common aging-related musculoskeletal problems. Recent evidences report that osteoporotic fracture patients showed high prevalence of sarcopenia; however, current clinical practice basically does not consider sarcopenia in the treatment or rehabilitation of osteoporotic fracture. There is almost no report studying the relationship of the co-existing of sarcopenia and osteoporotic fracture healing. In this study, we validated aged senescence accelerated mouse prone 8 (SAMP8) and senescence accelerated mouse resistant 1 (SAMR1) as animal models of senile osteoporosis with/without sarcopenia. Bone mineral density (BMD) at the 5th lumbar and muscle testing of the two animal strains were measured to confirm the status of osteoporosis and sarcopenia, respectively. Closed fracture was created on the right femur of 8-month-old animals. Radiographs were taken weekly post-fracture. MicroCT and histology of the fractured femur were performed at week 2, 4 and 6 post-fracture, while mechanical test of both femora at week 4 and 6 post-fracture. Results showed that the callus of SAMR1 was significantly larger at week 2 but smaller at week 6 post-fracture than SAMP8. Mechanical properties were significantly better at week 4 post-fracture in SAMR1 than SAMP8, indicating osteoporotic fracture healing was delayed in sarcopenic SAMP8. This study validated an animal model of co-existing sarcopenia and osteoporotic fracture, where a delayed fracture healing might be resulted in the presence of sarcopenia. Copyright © 2017 Elsevier Inc. All rights reserved.

Enhanced Bone Formation in Segmental Defects with BMP2 in a Biologically Relevant Molecular Context

DTIC Science & Technology

2016-10-16

gun shots . These do not heal on their own once a ‘critical size’ segment of bone is missing. One strategy to induce healing is to use bone-inducing...accelerate BMP2-induced bone formation by presenting the growth factor in a more biologically relevant context. This is based on our observation...that manganese increases the binding of BMP2 to COMP. The next steps are to validate these observations using BMP2:COMP on HA/PLG scaffolds in-vitro

[Mechanobiology and bone metabolism: Clinical relevance for fracture treatment].

PubMed

Haffner-Luntzer, M; Liedert, A; Ignatius, A

2015-12-01

Mechanical stimuli are known to significantly influence bone metabolism and fracture healing. Various studies have demonstrated the involvement of complex molecular mechanotransduction pathways, such as the Wnt/beta-catenin, bone morphogenetic protein (BMP) and estrogen receptor signaling pathways in mechanotransduction. Mechanotransduction is influenced by aging and the comorbidities of the patient. Pharmacological modulation of signal transduction influences bone formation and the mechanosensitivity of skeletal tissue. The combination of pharmacological and biomechanical therapies may be useful for the treatment of fractures with impaired healing.

Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice.

PubMed

Bentzon, Jacob F; Sondergaard, Claus S; Kassem, Moustapha; Falk, Erling

2007-10-30

Signs of preceding episodes of plaque rupture and smooth muscle cell (SMC)-mediated healing are common in atherosclerotic plaques, but the source of the healing SMCs is unknown. Recent studies suggest that activated platelets adhering to sites of injury recruit neointimal SMCs from circulating bone marrow-derived progenitor cells. Here, we analyzed the contribution of this mechanism to plaque healing after spontaneous and mechanical plaque disruption in apolipoprotein E knockout (apoE-/-) mice. To determine the origin of SMCs after spontaneous plaque disruption, irradiated 18-month-old apoE-/- mice were reconstituted with bone marrow cells from enhanced green fluorescent protein (eGFP) transgenic apoE-/- mice and examined when they died up to 9 months later. Plaque hemorrhage, indicating previous plaque disruption, was widely present, but no bone marrow-derived eGFP+ SMCs were detected. To examine the origin of healing SMCs in a model that recapitulates more features of human plaque rupture and healing, we developed a mechanical technique that produced consistent plaque disruption, superimposed thrombosis, and SMC-mediated plaque healing in apoE-/- mice. Mechanical plaque disruption was produced in irradiated apoE-/- mice reconstituted with eGFP+ apoE-/- bone marrow cells and in carotid bifurcations cross-grafted between apoE-/- and eGFP+ apoE-/- mice. Apart from few non-graft-derived SMCs near the anastomosis site in 1 transplanted carotid bifurcation, no SMCs originating from outside the local arterial segment were detected in healed plaques. Healing SMCs after atherosclerotic plaque disruption are derived entirely from the local arterial wall and not circulating progenitor cells in apoE-/- mice.

Bioelectric modulation of wound healing in a 3D in vitro model of tissue-engineered bone.

PubMed

Sundelacruz, Sarah; Li, Chunmei; Choi, Young Jun; Levin, Michael; Kaplan, David L

2013-09-01

Long-standing interest in bioelectric regulation of bone fracture healing has primarily focused on exogenous stimulation of bone using applied electromagnetic fields. Endogenous electric signals, such as spatial gradients of resting potential among non-excitable cells in vivo, have also been shown to be important in cell proliferation, differentiation, migration, and tissue regeneration, and may therefore have as-yet unexplored therapeutic potential for regulating wound healing in bone tissue. To study this form of bioelectric regulation, there is a need for three-dimensional (3D) in vitro wound tissue models that can overcome limitations of current in vivo models. We present a 3D wound healing model in engineered bone tissue that serves as a pre-clinical experimental platform for studying electrophysiological regulation of wound healing. Using this system, we identified two electrophysiology-modulating compounds, glibenclamide and monensin, that augmented osteoblast mineralization. Of particular interest, these compounds displayed differential effects in the wound area compared to the surrounding tissue. Several hypotheses are proposed to account for these observations, including the existence of heterogeneous subpopulations of osteoblasts that respond differently to bioelectric signals, or the capacity of the wound-specific biochemical and biomechanical environment to alter cell responses to electrophysiological treatments. These data indicate that a comprehensive characterization of the cellular, biochemical, biomechanical, and bioelectrical components of in vitro wound models is needed to develop bioelectric strategies to control cell functions for improved bone regeneration. Copyright © 2013 Elsevier Ltd. All rights reserved.

Micromotion-induced strain fields influence early stages of repair at bone-implant interfaces

PubMed Central

Wazen, Rima M.; Currey, Jennifer A.; Guo, Hongqiang; Brunski, John B.; Helms, Jill A.; Nanci, Antonio

2013-01-01

Implant loading can create micromotion at the bone-implant interface. The interfacial strain associated with implant micromotion could contribute to regulating the tissue healing response. Excessive micromotion can lead to fibrous encapsulation and implant loosening. Our objective was to characterize the influence of interfacial strain on bone regeneration around implants in mouse tibiae. A micromotion system was used to create strain under conditions of (1) no initial contact between implant and bone, and (2) a direct bone-implant contact. Pin- and screw-shaped implants were subjected to displacements of 150 μm or 300 μm, 60 cycles/day, for 7 days. Pin-shaped implants placed in 5 animals were subjected to 3 sessions of 150 μm displacement per day, with 60 cycles per session. Control implants in both types of interfaces were stabilized throughout the healing period. Experimental strain analyses, microtomography, image-based displacement mapping, and finite element simulations were used to characterize interfacial strain fields. Calcified tissue sections were prepared and stained with Goldner to evaluate tissue reaction in higher and lower strain regions. In stable implants, bone formation occurred consistently around the implants. In implants subjected to micromotion, bone regeneration was disrupted in areas of high strain concentrations (e.g. > 30%), whereas lower strain values were permissive of bone formation. Increasing implant displacement or number of cycles per day also changed the strain distribution and disturbed bone healing. These results indicate that not only implant micromotion but also the associated interfacial strain field contributes to regulating the interfacial mechanobiology at healing bone-implant interfaces. PMID:23337705

Bone compositional study during healing of subcritical calvarial defects in rats by Raman spectroscopy

NASA Astrophysics Data System (ADS)

Ahmed, Rafay; Wing Lun Law, Alan; Cheung, Tsz Wing; Lau, Condon

2017-07-01

Subcritical calvarial defects are important to study bone regeneration during healing. In this study 1mm calvarial defects were created using trephine in the parietal bones of Sprague-Dawley rats (n=7) that served as in vivo defects. Subjects were sacrificed after 7 days and the additional defects were created on the harvested skull with the same method to serve as control defects. Raman spectroscopy is established to investigate mineral/matrix ratio, carbonate/phosphate ratio and crystallinity of three different surfaces; in vivo defects, control defects and normal surface. Results show 21% and 23% decrease in mineral/matrix after 7 days of healing from surface to in vivo and control to in vivo defects, respectively. Carbonate to phosphate ratio was found to be increased by 39% while crystallinity decreased by 26% in both surface to in vivo and control to in vivo defects. This model allows to study the regenerated bone without mechanically perturbing healing surface.

T-Lymphocytes Enable Osteoblast Maturation via IL-17F during the Early Phase of Fracture Repair

PubMed Central

Nam, Diane; Mau, Elaine; Wang, Yufa; Wright, David; Silkstone, David; Whetstone, Heather; Whyne, Cari; Alman, Benjamin

2012-01-01

While it is well known that the presence of lymphocytes and cytokines are important for fracture healing, the exact role of the various cytokines expressed by cells of the immune system on osteoblast biology remains unclear. To study the role of inflammatory cytokines in fracture repair, we studied tibial bone healing in wild-type and Rag1−/− mice. Histological analysis, µCT stereology, biomechanical testing, calcein staining and quantitative RNA gene expression studies were performed on healing tibial fractures. These data provide support for Rag1−/− mice as a model of impaired fracture healing compared to wild-type. Moreover, the pro-inflammatory cytokine, IL-17F, was found to be a key mediator in the cellular response of the immune system in osteogenesis. In vitro studies showed that IL-17F alone stimulated osteoblast maturation. We propose a model in which the Th17 subset of T-lymphocytes produces IL-17F to stimulate bone healing. This is a pivotal link in advancing our current understanding of the molecular and cellular basis of fracture healing, which in turn may aid in optimizing fracture management and in the treatment of impaired bone healing. PMID:22768215

Healing of the bone with anti-fracture drugs.

PubMed

Vannucci, Letizia; Brandi, Maria Luisa

2016-12-01

Fracture healing is a complex physiological process. As impaired fracture healing is more frequent in osteoporotic subjects, anti-osteoporotic drugs could have some impact on this process. Areas covered: We reviewed the current literature to evaluate the effects of these drugs on fracture healing and their potential role in supporting this process, especially when impaired. A PubMed/Medline search was undertaken combining the terms 'fracture healing', 'anti-resorptive drugs', 'anabolic agents', 'anti-osteoporotic drugs'. Expert opinion: As clinical evidence on the role of anti-osteoporotic drugs in the process of fracture healing consists mainly of case reports or studies with a relatively small number of patients, large randomized clinical trials are needed in order to extend to the human setting the promising results on these agents as inductors or co-adjuvants of bone healing derived from animal studies.

A 5-year comparison of marginal bone level following immediate loading of single-tooth implants placed in healed alveolar ridges and extraction sockets in the maxilla.

PubMed

Berberi, Antoine N; Sabbagh, Joseph M; Aboushelib, Moustafa N; Noujeim, Ziad F; Salameh, Ziad A

2014-01-01

The aim of present investigation was to evaluate marginal bone level after 5-year follow-up of implants placed in healed ridges and fresh extraction sockets in maxilla with immediate loading protocol. Thirty-six patients in need of a single-tooth replacement in the anterior maxilla received 42 Astra Tech implants (Astra Tech Implant system™, Dentsply Implants, Mölndal, Sweden). Implants were placed either in healed ridges (group I) or immediately into fresh extraction sockets (group II). Implants were restored and placed into functional loading immediately by using a prefabricated abutment. Marginal bone level relative to the implant reference point was recorded at implant placement, crown cementation, 12, 36, and 60 months following loading using intra-oral radiographs. Measurements were made on the mesial and distal sides of each implant. Overall, two implants were lost from the group II, before final crown cementation: they were excluded from the study. The mean change in marginal bone loss (MBL) after implant placement was 0.26 ± 0.161 mm for 1 year, and 0.26 ± 0.171 mm for 3 years, and 0.21 ± 0.185 mm for 5 years in extraction sockets and was 0.26 ± 0.176 mm for 1 year and 0.21 ± 0.175 mm for 3 years, and 0.19 ± 0.172 mm for 5 years in healed ridges group. Significant reduction of marginal bone was more pronounced in implants inserted in healed ridges (P < 0.041) compared to fresh surgical extraction sockets (P < 0.540). Significant MBL was observed on the mesial side of the implant after cementation of the provisional (P < 0.007) and after 12 months (P < 0.034) compared to the distal side which remained stable for 3 and 5 years observation period. Within the limitations of this study, responses of local bone to immediately loaded implants placed either in extraction sockets or healed ridges were similar. Functional loading technique by using prefabricated abutment placed during the surgery time seems to maintain marginal bone around implant in both healed and fresh extraction sites.

[Intramedullary nailing of the distal tibia illustrated with the Expert(TM) tibia nail].

PubMed

El Attal, R; Hansen, M; Rosenberger, R; Smekal, V; Rommens, P M; Blauth, M

2011-12-01

Restoration of axis, length, and rotation of the lower leg. Sufficient primary stability of the osteosynthesis for functional aftercare and to maintain joint mobility. Good bony healing in closed and open fractures. Closed and open fractures of the tibia and complete lower leg fractures distal to the isthmus (AO 42), extraarticular fractures of the distal tibia (AO 43 A1/A2/A3), segmental fractures of the tibia with a fracture in the distal tibia, and certain intraarticular fractures of the distal tibia without impression of the joint line with the use of additional implants (AO 43 C1) Patient in reduced general condition (e.g., bed ridden), flexion of the knee of less than 90°, patients with knee arthroplasty of the affected leg, infection in the area of the nail's insertion, infection of the tibial cavity, complex articular fractures of the proximal or distal tibia with joint depression. Closed reduction of the fracture preferably on a fracture table or using a distractor or an external fixation frame. If necessary, use pointed reduction clamps or sterile drapery. In some cases, additional implants like percutaneous small fragment screws, poller screws or k-wires are helpful. Open reduction is rarely necessary and must be avoided. Opening of the proximal tibia in line with the medullary canal. Canulated insertion of the Expert(TM) tibia nail (ETN; Synthes GmbH, Oberdorf, Switzerland) with reaming of the medullary canal. Control of axis, length, and rotation. Distal interlocking with the radiolucent drill and proximal interlocking with the targeting device. Immediate mobilization of ankle and knee joint. Mobilization with 20 kg weight-bearing with crutches. X-ray control 6 weeks postoperatively and increased weight-bearing depending on the fracture status. In cases with simple fractures, good bony contact, or transverse fracture pattern, full weight-bearing at the end of week 6 is targeted. Between July 2004 and May 2005, 180 patients were included in a multicenter study. The follow-up rate was 81% after 1 year. Of these, 91 fractures (50.6%) were located in the distal third of the tibia. In this segment, the rate of delayed union was 10.6%. Malalignment of > 5° was observed in 5.4%. A secondary malalignment after initial good reduction was detected in only 1.1% of all cases. The implant-specific risk for screw breakage was 3.2%. One patient sustained a deep infection. If additional fibula plating was performed an 8-fold higher risk for delayed bone healing was observed (95%CI: 2.9-21.2, p< 0.001). If the fracture of the fibula was at the same height as on the tibia, the risk for delayed healing was even 14-fold (95% CI: 3.4-62.5, p< 0.001). Biomechanically plating of the fibula does not increase stability in suprasyndesmal distal tibia-fibular fractures treated with an intramedullary nail. Using the ETN with its optimized locking options, fibula plating is not recommended, thus, avoiding soft tissue problems and potentially delayed bone healing.

Current Options for Determining Fracture Union

PubMed Central

2014-01-01

Determining whether a bone fracture is healed is one of the most important and fundamental clinical determinations made in orthopaedics. However, there are currently no standardized methods of assessing fracture union, which in turn has created significant disagreement among orthopaedic surgeons in both clinical and research settings. An extensive amount of research has been dedicated to finding novel and reliable ways of determining healing with some promising results. Recent advancements in imaging techniques and introduction of new radiographic scores have helped decrease the amount of disagreement on this topic among physicians. The knowledge gained from biomechanical studies of bone healing has helped us refine our tools and create more efficient and practical research instruments. Additionally, a deeper understanding of the molecular pathways involved in the bone healing process has led to emergence of serologic markers as possible candidates in assessment of fracture union. In addition to our current physician centered methods, patient-centered approaches assessing quality of life and function are gaining popularity in assessment of fracture union. Despite these advances, assessment of union remains an imperfect practice in the clinical setting. Therefore, clinicians need to draw on multiple modalities that directly and indirectly measure or correlate with bone healing when counseling patients. PMID:26556422

Fracture bone healing and biodegradation of AZ31 implant in rats.

PubMed

Iglesias, C; Bodelón, O G; Montoya, R; Clemente, C; Garcia-Alonso, M C; Rubio, J C; Escudero, M L

2015-04-17

The ideal temporary implant should offer enough mechanical support to allow healing of the fracture and then biodegrade and be resorbed by metabolic mechanisms without causing any toxic effect. The aim of this research has been to simultaneously study in situ bone healing and the biodegradation of AZ31 Mg alloy as an osteosynthesis material. The in vivo study was carried out in AZ31 implants with and without Mg-fluoride coating inserted in un-fractured and fractured femurs of Wistar rats for long experimentation time, from 1 to 13 months, by means of computed tomography, histological and histomorphometric analysis. Tomography analysis showed the bone healing and biodegradation of AZ31 implants. The fracture is healed in 100% of the animals, and AZ31 maintains its mechanical integrity throughout the healing process. Biodegradation was monitored, quantifying the evolution of gas over time by 3D composition of tomography images. In all the studied groups, gas pockets disappear with time as a result of the diffusion process through soft tissues. Histomorphometric studies reveal that after 13 months the 46.32% of AZ31 alloy has been resorbed. The resorption of the coated and uncoated AZ31 implants inserted in fractured femurs after 1, 9 and 13 months does not have statistically significant differences. There is a balance between the biodegradation of AZ31 and bone healing which allows the use of AZ31 to be proposed as an osteosynthesis material.

The effect of layer-by-layer chitosan-hyaluronic acid coating on graft-to-bone healing of a poly(ethylene terephthalate) artificial ligament.

PubMed

Li, Hong; Ge, Yunsheng; Zhang, Pengyun; Wu, Lingxiang; Chen, Shiyi

2012-01-01

Surface coating with an organic layer-by-layer self-assembled template of chitosan and hyaluronic acid on a poly(ethylene terephthalate) (PET) artificial ligament was designed for the promotion and enhancement of graft-to-bone healing after artificial ligament implantation in a bone tunnel. The results of in vitro culturing of MC3T3-E1 mouse osteoblastic cells supported the hypothesis that the layer-by-layer coating of chitosan and hyaluronic acid could promote the cell compatibility of grafts and could promote osteoblast proliferation. A rabbit extra-articular tendon-to-bone healing model was used to evaluate the effect of this kind of surface-modified stainless artificial ligament in vivo. The final results proved that this organic compound coating could significantly promote and enhance new bone formation at the graft-bone interface histologically and, correspondingly, the experimental group with coating had significantly higher biomechanical properties compared with controls at 8 weeks (P < 0.05).

Improved Mobilization of Exogenous Mesenchymal Stem Cells to Bone for Fracture Healing and Sex Difference

PubMed Central

Yao, Wei; Evan Lay, Yu-An; Kot, Alexander; Liu, Ruiwu; Zhang, Hongliang; Chen, Haiyan; Lam, Kit; Lane, Nancy E.

2017-01-01

Mesenchymal stem cell (MSC) transplantation has been tested in animal and clinical fracture studies. We have developed a bone-seeking compound, LLP2A-Alendronate (LLP2A-Ale) that augments MSC homing to bone. The purpose of this study was to determine whether treatment with LLP2A-Ale or a combination of LLP2A-Ale and MSCs would accelerate bone healing in a mouse closed fracture model and if the effects are sex dependent. A right mid-femur fracture was induced in two-month-old osterix-mCherry (Osx-mCherry) male and female reporter mice. The mice were subsequently treated with placebo, LLP2A-Ale (500 µg/kg, IV), MSCs derived from wild-type female Osx-mCherry adipose tissue (ADSC, 3 × 105, IV) or ADSC + LLP2A-Ale. In phosphate buffered saline-treated mice, females had higher systemic and surface-based bone formation than males. However, male mice formed a larger callus and had higher volumetric bone mineral density and bone strength than females. LLP2A-Ale treatment increased exogenous MSC homing to the fracture gaps, enhanced incorporation of these cells into callus formation, and stimulated endochondral bone formation. Additionally, higher engraftment of exogenous MSCs in fracture gaps seemed to contribute to overall fracture healing and improved bone strength. These effects were sex-independent. There was a sex-difference in the rate of fracture healing. ADSC and LLP2A-Ale combination treatment was superior to on callus formation, which was independent of sex. Increased mobilization of exogenous MSCs to fracture sites accelerated endochondral bone formation and enhanced bone tissue regeneration. PMID:27334693

Nerve growth factor and associated nerve sprouting contribute to local mechanical hyperalgesia in a rat model of bone injury.

PubMed

Yasui, M; Shiraishi, Y; Ozaki, N; Hayashi, K; Hori, K; Ichiyanagi, M; Sugiura, Y

2012-08-01

To clarify the mechanism of tenderness after bone injury, we investigated changes in the withdrawal threshold to mechanical stimuli, nerve distribution and nerve growth factor (NGF)-expression in a rat model of bone injury without immobilization for bone injury healing. Rats were divided into three groups as follows: (1) rats incised in the skin and periosteum, followed by drilling a hole in the tibia [bone lesion group (BLG)]; (2) those incised in the skin and periosteum without bone drilling [periosteum lesion group (PLG)]; and (3) those incised in the skin [skin lesion group (SLG)]. Mechanical hyperalgesia continued for 28 days at a lesion in the BLG, 21 days in PLG and 5 days in SLG after treatments, respectively. Endochondral ossification was observed on days 5-28 in BLG and on days 5-21 in PLG. Nerve growth appeared in deep connective tissue (DCT) at day 28 in BLG. Nerve fibres increased in both cutaneous tissue and DCT at day 7 in PLG, but they were not found at day 28. Mechanical hyperalgesia accompanied with endochondral ossification and nerve fibres increasing at the lesion in both BLG and PLG. NGF was expressed in bone-regenerating cells during the bone injury healing. Anti-NGF and trk inhibitor K252a inhibited hyperalgesia in the different time course. This study shows that localized tenderness coincides with the bone healing and involves NGF expression and nerve sprouting after bone injury. The findings present underlying mechanisms and provide pathophysiological relevance of local tenderness to determination of bone fracture and its healing. © 2011 European Federation of International Association for the Study of Pain Chapters.

Healing bone lesion defects using injectable CaSO4 /CaPO4 -TCP bone graft substitute compared to cancellous allograft bone chips in a canine model.

PubMed

Hall, Deborah J; Turner, Thomas M; Urban, Robert M

2018-04-16

CaSO 4 /CaPO 4 -TCP bone graft substitute has been shown to be effective for treatment of bone lesion defects, but its mechanical, histological, and radiographic characteristics have not been studied in direct comparison with a conventional treatment such as cancellous allograft bone. Thirteen canines had a critical-size axial defect created bilaterally into the proximal humerus. CaSO 4 /CaPO 4 -TCP bone graft substitute (PRO-DENSE™, Wright Medical Technology) was injected into the defect in one humerus, and an equal volume of freeze-dried cancellous allograft bone chips was placed in the contralateral defect. The area fraction of new bone, residual graft, and fibrous tissue and the compressive strength and elastic modulus of bone within the defects were determined after 6, 13, or 26 weeks and correlated with radiographic changes. The data were analyzed using Friedman and Mann-Whitney tests. There was more bone in defects treated with the CaSO 4 /CaPO 4 -TCP bone graft substitute compared to defects treated with cancellous bone allograft at all three time points, and the difference at 13 weeks was significant (p = 0.025). The new bone was significantly stronger and stiffer in defects treated with the CaSO 4 /CaPO 4 -TCP bone graft substitute compared to defects treated with cancellous bone allograft at 13 (p = 0.046) and 26 weeks (p = 0.025). At 26 weeks, all defects treated with CaSO 4 /CaPO 4 -TCP bone graft substitute demonstrated complete healing with new bone, whereas healing was incomplete in all defects treated with cancellous allograft chips. The CaSO 4 /CaPO 4 -TCP bone graft substitute could provide faster and significantly stronger healing of bone lesions compared to the conventional treatment using freeze-dried cancellous allograft bone. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. © 2018 Wiley Periodicals, Inc.

Enhanced Healing of Segmental Bone Defects by Modulation of the Mechanical Environment

DTIC Science & Technology

2013-10-01

Employment opportunities received based upon experience/ training supported by this award Partly based upon her research during the completion of...School, Coventry CV4 7AL, United Kingdom References 1. Stevenson S. Enhancement of fracture healing with autogenous and allogeneic bone grafts. Clin

Skeletal Complications in Neurofibromatosis Type 1: The Role of Neurofibromin Haploinsufficiency in Defective Skeletal Remodeling and Bone Healing in NF1

DTIC Science & Technology

2007-01-01

including scoliosis and pseudoarthrosis, which are compounded by osteoporosis and poor bone healing. Corrective orthopaedic intervention often fails...3 - Introduction: A large proportion of patients with Neurofibromatosis Type 1 display skeletal abnormalities including scoliosis and...abnormalities including alterations in bone size and shape, the presence of scoliosis , and a tendency to develop pseudoarthrosis. These skeletal

Bone modelling at fresh extraction sockets: immediate implant placement versus spontaneous healing: an experimental study in the beagle dog.

PubMed

Vignoletti, Fabio; Discepoli, Nicola; Müller, Anna; de Sanctis, Massimo; Muñoz, Fernando; Sanz, Mariano

2012-01-01

The purpose of this investigation is to describe histologically the undisturbed healing of fresh extraction sockets when compared to immediate implant placement. In eight beagle dogs, after extraction of the 3P3 and 4P4, implants were inserted into the distal sockets of the premolars, while the mesial sockets were left to heal spontaneously. Each animal provided four socket sites (control) and four implant sites (test). After 6 weeks, animals were sacrificed and tissue blocks were dissected, prepared for ground sectioning. The relative vertical buccal bone resorption in relation to the lingual bone was similar in both test and control groups. At immediate implant sites, however, the absolute buccal bone loss observed was 2.32 (SD 0.36) mm, what may indicate that while an apical shift of both the buccal and lingual bone crest occurred at the implant sites, this may not happen in naturally healing sockets. The results from this investigation showed that after tooth extraction the buccal socket wall underwent bone resorption at both test and control sites. This resorption appeared to be more pronounced at the implant sites, although the limitations of the histological evaluation method utilized preclude a definite conclusion. © 2011 John Wiley & Sons A/S.

Monitoring of bone healing by piezoelectric-EMI method

NASA Astrophysics Data System (ADS)

Mazlina, M. H.; Sarpinah, Bibi; Tawie, Rudy; Daho, Claira Dalislone; Annuar, Ishak

2016-02-01

Smart Piezoelectric devices which have excellent piezoelectric properties have been employed for various sensor and actuators applications. The work presented here is an attempt to demonstrate the feasibility of bone healing monitoring by using piezoelectric-electromechanical impedance (EMI) method that have several advantages such as low cost, portable, light weight and simplicity in measurement. A Piezoelectric sensor (PZT) has been widely used in damage detection of various structures including concrete, pipes and bones due to their unique sensing and actuating properties. The EMI technique has emerged as a universal Structural Health Monitoring (SHM) tool suitable for almost all engineering materials and structures. The method used for this proposed study consists of put healing agent in the host structure in particular cracks bone to be monitored by PZT-needle sensor which is embedded to the host structure. The measurements were taken in the frequency range between 0.04 to 100 kHz at 1 kHz interval using AD5933 evaluation board. The signals retrieved from the AD5933 evaluation board, were quantify and analyse to obtain Root Mean Square Deviation (RMSD) percentage value. Measurements were taken every hour for 12 hours. The result from the study shows the feasibility of the piezoelectric-EMI method to effectively detect changes during bone-cracks healing process until the cracks bone is fully recovered.

Healing of ungrafted and grafted extraction sockets after 12 weeks: a prospective clinical study.

PubMed

Heberer, Susanne; Al-Chawaf, Bassem; Jablonski, Carlo; Nelson, John J; Lage, Hermann; Nelson, Katje

2011-01-01

In this prospective study, bone formation in human extraction sockets augmented with Bio-Oss Collagen after a 12-week healing period was quantified and compared to bone formation in unaugmented extraction sockets. Selected patients with four-walled extraction sockets were included in this prospective study. After extraction, the sockets were randomly augmented using Bio-Oss Collagen or left to heal unfilled without raising a mucoperiosteal flap. At the time of implant placement, histologic specimens were obtained from the socket and analyzed. Statistical analysis was performed using the Wilcoxon signed-rank test. Twenty-five patients with a total of 39 sockets (20 augmented, 19 unaugmented) were included in the study and the histologic specimens analyzed. All specimens were free of inflammatory cells. The mean overall new bone formation in the augmented sites was 25% (range, 8%-41%) and in the unaugmented sockets it was 44% (range, 3%-79%). There was a significant difference in the rate of new bone formation between the grafted and ungrafted sockets and a significant difference in the bone formation rate in the apical compared to the coronal regions of all sockets, independent of the healing mode. This descriptive study demonstrated that bone formation in Bio-Oss Collagen-grafted human extraction sockets was lower than bone formation in ungrafted sockets. Bone formation occurred in all specimens with varying degrees of maturation independent of the grafting material and was initiated from the apical region.

Extended fatigue life of a catalyst-free self-healing acrylic bone cement using microencapsulated 2-octyl cyanoacrylate

PubMed Central

Brochu, Alice B.W.; Matthys, Oriane B.; Craig, Stephen L.; Reichert, William M.

2014-01-01

The tissue adhesive 2-octyl cyanoacrylate (OCA) was encapsulated in polyurethane microshells and incorporated into bone cement to form a catalyst free, self-healing bone cement comprised of all clinically approved components. The bending strength, modulus, and fatigue lifetime were investigated in accordance with ASTM and ISO standards for the testing of PMMA bone cement. The bending strength of bone cement specimens decreased with increasing wt% capsules content for capsules without or with OCA, with specimens of < 5 wt% capsule content showing minimal effect. In contrast, bone cement bending modulus was insensitive to capsule content. Load controlled fatigue testing was performed in air at room temperature on capsule free bone cement (0 wt%), bone cement with 5 wt% OCA-free capsules (5 wt% No OCA), and 5 wt% OCA-containing capsules (5 wt% OCA). Specimens were tested at a frequency of 5 Hz at maximum stresses of 90%, 80%, 70% and 50% of each specimen's bending strength until failure. The 5 wt% OCA exhibited significant self-healing at 70% and 50% of its reference strength (p < 0.05). Fatigue testing of all three specimen types in air at 22 MPa (50% of reference strength of the 5 wt% OCA specimens) showed that the cycles to failure of OCA-containing specimens was increased by two-fold compared to the OCA-free and capsule-free specimens. This study represents the first demonstration of dynamic, catalyst-free self-healing in a biomaterial formulation. PMID:24825796

Effect of insertion torque on titanium implant osseointegration: an animal experimental study.

PubMed

Duyck, Joke; Roesems, Rutger; Cardoso, Marcio V; Ogawa, Toru; De Villa Camargos, Germana; Vandamme, Katleen

2015-02-01

To evaluate the effect of implant insertion torque on the peri-implant bone healing and implant osseointegration. Bilaterally in the tibia of five adult New Zealand white rabbits, 20 implants were installed, subdivided into four groups, corresponding to two insertion torque conditions (low, < 10 Ncm vs. high > 50 Ncm) and 2 experimental periods (2 weeks vs. 4 weeks of healing). The implant insertion torque was determined by the surgical drill diameter relative to the implant diameter. Implant osseointegration was evaluated by quantitative histology (bone-to-implant contact with host bone [BIC-host], with neoformed bone [BIC-de novo], with both bone types [BIC-total], and peri-implant bone [BA/TA]). Every response was modelled over time using GEE (general estimation equation) with an unstructured variance-covariance matrix to correct for dependency between the measurements from one animal. The statistical significance level of α = 0.05 was applied. Significantly, more BIC-host and BIC-total were recorded for H implants compared with L implants after 2 week of healing (P = 0.010 and P = 0.0001, respectively). However, this result was no longer found for the extended healing period. Furthermore, BIC-total significantly increased over time for L implants (P < 0.00001). In contrast, the significant increase in BA/TA over time was found for H implants (P < 0.01). Finally, H insertion torque led to an increased BA/TA after 4 week of healing (P < 0.02) compared with the L insertion protocol. L insertion torque implants installed in the rabbit tibial bone osseointegrate with considerable de novo bone formation. This bone neoformation enables L implants to catch up, already during the early osseointegration stage, the initial inferior amount BIC contact compared with that of H implants. A negative impact of the created strain environment accompanying H insertion torque implant installation on the biological process of osseointegration could not be observed, at least not at tissue level. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Distinctive Tooth-Extraction Socket Healing: Bisphosphonate Versus Parathyroid Hormone Therapy

PubMed Central

Kuroshima, Shinichiro; Mecano, Rodan B.; Tanoue, Ryuichiro; Koi, Kiyono; Yamashita, Junro

2014-01-01

Background Patients with osteoporosis who receive tooth extractions are typically on either oral bisphosphonate or parathyroid hormone (PTH) therapy. Currently, the consequence of these therapies on hard- and soft-tissue healing in the oral cavity is not clearly defined. The aim of this study is to determine the differences in the therapeutic effect on tooth-extraction wound healing between bisphosphonate and PTH therapies. Methods Maxillary second molars were extracted in Sprague Dawley rats (n = 30), and either bisphosphonate (zoledronate [Zol]), PTH, or saline (vehicle control [VC]) was administered for 10 days (n = 10 per group). Hard-tissue healing was evaluated by microcomputed tomography and histomorphometric analyses. Collagen, blood vessels, inflammatory cell infiltration, and cathepsin K expression were assessed in soft tissue using immunohistochemistry, quantitative polymerase chain reaction, and immunoblotting. Results Both therapies significantly increased bone fill and suppressed vertical bone loss. However, considerably more devital bone was observed in the sockets of rats on Zol versus VC. Although Zol increased the numbers of blood vessels, the total blood vessel area in soft tissue was significantly smaller than in VC. PTH therapy increased osteoblastic bone formation and suppressed osteoclasts. PTH therapy promoted soft-tissue maturation by suppressing inflammation and stimulating collagen deposition. Conclusion Zoledronate therapy deters whereas PTH therapy promotes hard- and soft-tissue healing in the oral cavity, and both therapies prevent vertical bone loss. PMID:23688101

Imunohistological aspects of the tissue around dental implants

NASA Astrophysics Data System (ADS)

Nimigean, Victor; Nimigean, Vanda R.; Sǎlǎvǎstru, Dan I.; Moraru, Simona; BuÅ£incu, Lavinia; Ivaşcu, Roxana V.; Poll, Alexandru

2016-03-01

Objectives: study of soft and hard tissues around implants. Material and methods: For the immunohistochemical and histological study of the implant/soft tissue interface, we examined pieces of peri-implant mucosa harvested from 35 patients. The implant/bone interface was assessed using histologic and histomorphometric examination of hard tissues around unloaded, early loaded or delayed loaded dental implants with pre-established design, with a sandblasted and acid-etched surface, placed both in extraction sockets, or after bone healing following tooth removal. This study was performed on 9 common race dogs. Results: The histological study of the implant/soft tissue interface showed regenerative modifications and moderate chronic subepithelial inflammatory reactions. Immunohistochemical evaluation of the soft tissue biopsies revealed the presence of specific immunocompetent cells and proteins of the matrix metalloproteinase (MMP) expression. Bone-implants contacts were more obvious in the apical half of the implants and at the edges of the threads, than between them. A mature, lamelliform bone containing lacunae with osteocytes and lack of connective tissue were noticed around implants that were late placed and loaded. The new-formed bone was also abundant in the crestal zone, not only in the apical part of the implants. Conclusions: A thorough understanding of the microstructure of dental implant/soft and hard tissue interface will improve the longevity of osseointegrated implants.

[Bone fracture and the healing mechanisms. The role of BMP signaling in fracture healing].

PubMed

Imai, Yuuki; Takaoka, Kunio

2009-05-01

When bone tissue, which plays a central role in locomotive organs, is broken by trauma and decreased in its own function of support, it is lead to be remarkable decline in the activity of daily life (ADL). Recently, in a clinical situation, various treatments have been tried for prophylaxis of fractures, and these treatments have been rewarded with good results. However, fractures would be occurred in a certain amount and there would be serious problems in ADL if the treatment fails to repair fractures. Furthermore, fractures could spontaneously heal in several weeks, it can be achieved in early rehabilitation and improvement of ADL, if we can accelerate fracture healing. Bone morphogenetic proteins, which were advocated by Dr. Urist, would be expected to be a key to establish much better society especially for the old.

Marginal and apical bone stability after staged sinus floor augmentation using bone condensing implants with variable-thread design: a two-dimensional analysis.

PubMed

Younes, F; Eghbali, A; De Troyer, S; De Bruyckere, T; Cleymaet, R; Cosyn, J

2016-09-01

Studies on the vertical stability of augmented bone after sinus lifting differ substantially. In addition, long healing periods are usually advocated prior to implant installation. The purpose of this case series study was to evaluate the changes in bone height after sinus lifting with a bovine-derived xenograft and to evaluate the clinical outcome of bone condensing implants installed after a short healing period. Patients treated during the years 2010-2013 were re-examined using peri-apical radiographs to evaluate the changes in augmented bone height (BH) and marginal bone loss (BL). Fifty-seven of 70 eligible subjects (28 male and 29 female, mean age 56 years) attended for reassessment. Data were available for 53 sinus lifts and 105 implants installed after a mean healing period of 4.6±1.5 months. Implant survival was 99% after a mean time in function of 19±9 months. Baseline BH, BH at implant placement, and final BH were on average 3.87±1.74mm, 13.75±2.12mm, and 13.11±2.12mm, respectively (P<0.001). Mean BL was 0.51±0.65mm. Only limited resorption is to be expected after sinus lifting in the short term. A bone condensing implant can be used in the early healing phase with successful outcomes in terms of implant survival and bone adaptation. Copyright © 2016 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Multiscale mechanobiology of de novo bone generation, remodeling and adaptation of autograft in a common ovine femur model.

PubMed

Knothe Tate, Melissa L; Dolejs, Scott; McBride, Sarah H; Matthew Miller, R; Knothe, Ulf R

2011-08-01

The link between mechanics and biology in the generation and the adaptation of bone has been studied for more than a century in the context of skeletal development and fracture healing. However, the interplay between mechanics and biology in de novo generation of bone in postnatal defects as well as healing of morcellized bone graft or massive cortical bone autografts is less well understood. To address this, here we integrate insights from our previously published studies describing the mechanobiology on both de novo bone generation and graft healing in a common ovine femoral defect model. Studying these effects in a common experimental model provides a unique opportunity to elucidate factors conducive to harnessing the regenerative power of the periosteum, and ultimately, to provide mechanistic insights into the multiscale mechanobiology of bone generation, remodeling and adaptation. Taken together, the studies indicate that, as long as adequate, directional transport of cells and molecules can be insured (e.g. with periosteum in situ or a delivery device), biological factors intrinsic to the periosteum suffice to bridge critical sized bone defects, even in the absence of a patent blood supply. Furthermore, mechanical stimuli are crucial for the success of periosteal bone generation and bone graft healing. Interestingly, areas of highest periosteal strain around defects correlate with greatest amounts albeit not greatest mineralization of newly generated bone. This may indicate a role for convection enhanced transport of cells and molecules in modulation of tissue generation by pluripotent cells that ingress into the defect center, away from the periosteum and toward the surface of the intramedullary nail that fills the medullary cavity. These insights bring us much closer to understanding the mechanobiological environment and stimuli that stimulate the proliferation and differentiation of periosteum-derived progenitor cells and ultimately drive the generation of new bone tissue. Furthermore, these insights provide a foundation to create virtual predictive computational models of bone mechanophysiology, to develop cell seeding protocols for scale up and manufacture of engineered tissues, to optimize surgical procedures, and to develop post-surgical therapies with the ultimate goal of achieving the best possible healing outcomes for treatment and/or reconstruction of postnatal bone defects. Copyright © 2011 Elsevier Ltd. All rights reserved.

Periosteal BMP2 activity drives bone graft healing.

PubMed

Chappuis, Vivianne; Gamer, Laura; Cox, Karen; Lowery, Jonathan W; Bosshardt, Dieter D; Rosen, Vicki

2012-10-01

Bone graft incorporation depends on the orchestrated activation of numerous growth factors and cytokines in both the host and the graft. Prominent in this signaling cascade is BMP2. Although BMP2 is dispensable for bone formation, it is required for the initiation of bone repair; thus understanding the cellular mechanisms underlying bone regeneration driven by BMP2 is essential for improving bone graft therapies. In the present study, we assessed the role of Bmp2 in bone graft incorporation using mice in which Bmp2 has been removed from the limb prior to skeletal formation (Bmp2(cKO)). When autograft transplantations were performed in Bmp2cKO mice, callus formation and bone healing were absent. Transplantation of either a vital wild type (WT) bone graft into a Bmp2(cKO) host or a vital Bmp2(cKO) graft into a WT host also resulted in the inhibition of bone graft incorporation. Histological analyses of these transplants show that in the absence of BMP2, periosteal progenitors remain quiescent and healing is not initiated. When we analyzed the expression of Sox9, a marker of chondrogenesis, on the graft surface, we found it significantly reduced when BMP2 was absent in either the graft itself or the host, suggesting that local BMP2 levels drive periosteal cell condensation and subsequent callus cell differentiation. The lack of integrated healing in the absence of BMP2 was not due to the inability of periosteal cells to respond to BMP2. Healing was achieved when grafts were pre-soaked in rhBMP2 protein, indicating that periosteal progenitors remain responsive in the absence of BMP2. In contrast to the requirement for BMP2 in periosteal progenitor activation in vital bone grafts, we found that bone matrix-derived BMP2 does not significantly enhance bone graft incorporation. Taken together, our data show that BMP2 signaling is not essential for the maintenance of periosteal progenitors, but is required for the activation of these progenitors and their subsequent differentiation along the osteo-chondrogenic pathway. These results indicate that BMP2 will be among the signaling molecules whose presence will determine success or failure of new bone graft strategies. Copyright © 2012 Elsevier Inc. All rights reserved.

T and B cells participate in bone repair by infiltrating the fracture callus in a two-wave fashion.

PubMed

Könnecke, Ireen; Serra, Alessandro; El Khassawna, Thaqif; Schlundt, Claudia; Schell, Hanna; Hauser, Anja; Ellinghaus, Agnes; Volk, Hans-Dieter; Radbruch, Andreas; Duda, Georg N; Schmidt-Bleek, Katharina

2014-07-01

Fracture healing is a regenerative process in which bone is restored without scar tissue formation. The healing cascade initiates with a cycle of inflammation, cell migration, proliferation and differentiation. Immune cells invade the fracture site immediately upon bone damage and contribute to the initial phase of the healing process by recruiting accessory cells to the injury site. However, little is known about the role of the immune system in the later stages of fracture repair, in particular, whether lymphocytes participate in soft and hard callus formation. In order to answer this question, we analyzed femoral fracture healing in mice by confocal microscopy. Surprisingly, after the initial inflammatory phase, when soft callus developed, T and B cells withdrew from the fracture site and were detectable predominantly at the femoral neck and knee. Thereafter lymphocytes massively infiltrated the callus region (around day 14 after injury), during callus mineralization. Interestingly, lymphocytes were not found within cartilaginous areas of the callus but only nearby the newly forming bone. During healing B cell numbers seemed to exceed those of T cells and B cells progressively underwent effector maturation. Both, osteoblasts and osteoclasts were found to have direct cell-cell contact with lymphocytes, strongly suggesting a regulatory role of the immune cells specifically in the later stages of fracture healing. Copyright © 2014 Elsevier Inc. All rights reserved.

The effect of lysophosphatidic acid using a hydrogel or collagen sponge carrier on bone healing in dogs.

PubMed

Might, Kelly R; Martinez, Steven A; Karin, Norman; Lin, Genyao; Tarasevich, Barbara; Pool, Roy R

2016-07-19

The purposes of this study were to determine: 1) the efficacy of polycaprolactone-g-polyethylene glycol (PCL-g-PEG) and polylactic-co-glycolic acid (PLGA-g-PEG) hydrogels and an absorbable collagen sponge (ACS) as carriers for lysophosphatidic acid (LPA), 2) the effect of LPA on bone healing in dogs, and 3) the ideal dose of LPA to maximally stimulate bone healing. Bilateral ulnar ostectomies were performed on purpose bred dogs. Control defects were filled with a PCL-g-PEG or PLGA-g-PEG hydrogel, or a saline soaked ACS. Contralateral defects were filled with a PCL-g-PEG or PLGA-g-PEG hydrogel, or an ACS with each carrying differing concentrations of an LPA solution. Dual-energy X-ray absorptiometry (DXA) was performed. Total bone area (TBA), mineral density (BMD), and mineral content (BMC) were determined at each time point. Relationships between the effect of treatment over time on TBA, BMC and BMD were determined. Phase 1 - There was no significant difference in DXA-based TBA (p = 0.09), BMC (p = 0.33), or BMD (p = 0.74) over time between LPA treatments, or between the LPA treated and control groups TBA (p = 0.95), BMC (p = 0.99), or BMD (p = 0.46). Phase 2 - There was no significant difference over time between LPA treatments in DXA-based TBA (p = 0.33), BMC (p = 0.45), or BMD (p = 0.43), or between the LPA treated and control groups TBA (p = 0.94), BMC (p = 0.38), or BMD (p = 0.17). Phase 3 - There was no significant difference over time between LPA treatments in DXA-based TBA (p = 0.78), BMC (p = 0.88), or BMD (p = 0.35), or between the LPA treated and control groups TBA (p = 0.07), BMC (p = 0.85), or BMD (p = 0.06). There was a significant increase in TBA (p <0.0001) and BMC (p = 0.0014), but a significant decrease in BMD (p <0.0001) was noted over time when all groups were combined. Although LPA has shown promise as an osteoinductive agent in research, its performance as a bone graft substitute, as utilized in this study, is unsupported. Further studies are necessary to determine the incorporation and elution kinetics of LPA from the PLGA-g-PEG hydrogel and from an ACS. Hydrogels may have clinical applications for delaying or preventing bone formation.

Occurrence of a 'bad' split and success of initial mandibular healing: a review of 524 sagittal ramus osteotomies in 262 patients.

PubMed

Posnick, J C; Choi, E; Liu, S

2016-10-01

The purpose of this study was to assess the prevalence of a 'bad' split after sagittal ramus osteotomies (SRO) and report the results of initial mandibular healing. A retrospective cohort study derived from patients treated by a single surgeon at one institution between 2004 and 2013 was performed. An index group consisting of a series of subjects with a spectrum of bimaxillary dentofacial deformities also involving the chin and symptomatic chronic obstructive nasal breathing was identified. The SRO design, bicortical screw fixation technique, and perioperative management were consistent. Outcome variables included the occurrence of a 'bad' split and the success of initial SRO healing. Two hundred sixty-two subjects undergoing 524 SROs met the inclusion criteria. Their average age was 25 years (range 13-63 years) and 134 were female (51%). Simultaneous removal of a third molar was performed during 209 of the SROs (40%). There were no 'bad' splits. All subjects achieved successful bone union, the planned occlusion, and return to a chewing diet and physical activities by 5 weeks after surgery. The presence of a third molar removed during SRO was not associated with an increased frequency of a 'bad' split or delayed mandibular healing. Copyright © 2016 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Bone Regeneration Using Bone Morphogenetic Proteins and Various Biomaterial Carriers

PubMed Central

Sheikh, Zeeshan; Javaid, Mohammad Ahmad; Hamdan, Nader; Hashmi, Raheel

2015-01-01

Trauma and disease frequently result in fractures or critical sized bone defects and their management at times necessitates bone grafting. The process of bone healing or regeneration involves intricate network of molecules including bone morphogenetic proteins (BMPs). BMPs belong to a larger superfamily of proteins and are very promising and intensively studied for in the enhancement of bone healing. More than 20 types of BMPs have been identified but only a subset of BMPs can induce de novo bone formation. Many research groups have shown that BMPs can induce differentiation of mesenchymal stem cells and stem cells into osteogenic cells which are capable of producing bone. This review introduces BMPs and discusses current advances in preclinical and clinical application of utilizing various biomaterial carriers for local delivery of BMPs to enhance bone regeneration. PMID:28788032

Effect of microthreads on coronal bone healing of narrow-diameter implants with reverse-tapered design in beagle dogs.

PubMed

Chang, Yun-Young; Kim, Su-Hwan; Park, Keun-Oh; Yun, Jeong-Ho

2017-12-01

The objective of this study was to investigate the effect of microthreads on the coronal bone healing of narrow-diameter implants with reverse-tapered design. A total of 52 implants were classified into two groups according to presence or absence of coronal microthreads, the reverse-tapered narrow-diameter implant (RTN) group, and the reverse-tapered narrow-diameter implant with microthreads (RTNM) group. The implants were installed in split-mouth design in the edentulous mandible of six dogs. Three animals were sacrificed at 4 weeks and three at 8 weeks. Resonance frequency analysis, bone measurement using microcomputed tomography (micro-CT), removal torque test, and histometric analysis were performed. No significant differences in implant stability quotient value were observed between the groups at baseline, 4 weeks, or 8 weeks. Bone measurement using micro-CT showed that bone-implant contact volume (BICV) and bone-implant contact volume ratio (BICVR) in the coronal part of RTNM were statistically higher than those in RTN at 4 and 8 weeks. Histometric analysis showed statistically higher bone-implant contact length (BICL) in the coronal part of RTNM than in RTN at 4 weeks; however, bone-implant contact ratio (BICR) was not significantly different between the groups. At 8 weeks, the BICL and BICR did not differ significantly between the groups. Removal torque test showed no significant differences between the groups at 4 and 8 weeks. The microthreads might facilitate more coronal bone-implant contact due to increased surface areas at an early healing phase; however, they did not significantly affect coronal bone healing at 8 weeks. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Enhanced Bone Bonding to Nanotextured Implant Surfaces at a Short Healing Period: A Biomechanical Tensile Testing in the Rat Femur.

PubMed

Coelho, Paulo G; Zavanelli, Ricardo A; Salles, Marcos B; Yeniyol, Sinem; Tovar, Nick; Jimbo, Ryo

2016-06-01

To compare the bone bonding capabilities of 2 different surface treatments at an early healing period. Titanium alloy (Ti6Al4V) custom-made rectangular plates (1.4 × 2.4 × 4 mm) were either dual acid etched (Ti6Al4V-DAE) or DAE/nanotextured blasted (Ti6Al4V-NTB). Implants were placed in the distal femurs of 10 Wistar rats and were allowed to heal for 9 days. After euthanasia, the bone immediately proximal and distal to the implant was removed to test the bone bonding force with a universal testing machine. Ultrastructure of the bone/implant interface was assessed by scanning electron microscopy. Ti6Al4V-NTB samples exhibited significantly greater bond strength than Ti6Al4V-DAE samples. Morphologically, the Ti6Al4V-NTB surfaces presented intimate interaction with bone, whereas little interaction between the Ti6Al4V-DAE surface and bone was observed. The results of this study indicated a significant increase in bone bonding for the DAE/nanotextured blasted surface, which is suggested to be the outcome of the nanotexturing.

Novel Therapy for Bone Regeneration in Large Segmental Defects

DTIC Science & Technology

2017-12-01

HC, Giannoudis PV. Fat embolism and IM nailing. Injury. 2006;37(Suppl 4):S1–2. 38. Wenda K, Ritter G, Degreif J, Rudigier J. Pathogenesis of pul...morphogenetic protein (BMP), thrombopoietin (TPO), therapy, fracture healing, bone regeneration, minipig, pig 16. SECURITY CLASSIFICATION OF: 17... fracture healing, bone regeneration, minipig, pig 3. OVERALL PROJECT SUMMARY: Project start date 30/09/2013 Project end date 29/09/2017 (with 1 year NCE

The characterization of a full-thickness excision open foot wound model in n5-streptozotocin (STZ)-induced type 2 diabetic rats that mimics diabetic foot ulcer in terms of reduced blood circulation, higher C-reactive protein, elevated inflammation, and reduced cell proliferation.

PubMed

Yu, Caroline Oi-Ling; Leung, Kwok-Sui; Fung, Kwok-Pui; Lam, Francis Fu-Yuen; Ng, Ethel Sau-Kuen; Lau, Kit-Man; Chow, Simon Kwoon-Ho; Cheung, Wing-Hoi

2017-08-05

Delayed foot wound healing is a major complication attributed to hyperglycemia in type 2 diabetes mellitus (DM) patients, and these wounds may develop into foot ulcers. There are at least two types of DM wound models used in rodents to study delayed wound healing. However, clinically relevant animal models are not common. Most models use type 1 DM rodents or wounds created on the back rather than on the foot. An open full-thickness excision wound on the footpad of type 2 DM rats is more clinically relevant, but such a model has not yet been characterized systematically. The objective of this study was to investigate and characterize how DM affected a full-thickness excision open foot wound in n5-streptozotocin (n5-STZ)-induced type 2 DM rats. We hypothesized that elevated inflammation, reduced blood circulation, and cell proliferation due to hyperglycemia could delay the wound healing of DM rats. The wounds of DM rats were compared with those of non-DM rats (Ctrl) at Days 1 and 8 post wounding. The wound healing process of the DM rats was significantly delayed compared with that of the Ctrl rats. The DM rats also had higher C-reactive protein (CRP) and lower blood circulation and proliferating cell nuclear antigen (PCNA) in DM wounds. This confirmed that elevated inflammation and reduced blood flow and cell proliferation delayed foot wound healing in the n5-STZ rats. Hence, this open foot wound animal model provides a good approach to study the process of delayed wound healing.

The characterization of a full-thickness excision open foot wound model in n5-streptozotocin (STZ)-induced type 2 diabetic rats that mimics diabetic foot ulcer in terms of reduced blood circulation, higher C-reactive protein, elevated inflammation, and reduced cell proliferation

PubMed Central

Yu, Caroline Oi-Ling; Leung, Kwok-Sui; Fung, Kwok-Pui; Lam, Francis Fu-Yuen; Ng, Ethel Sau-Kuen; Lau, Kit-Man; Chow, Simon Kwoon-Ho; Cheung, Wing-Hoi

2017-01-01

Delayed foot wound healing is a major complication attributed to hyperglycemia in type 2 diabetes mellitus (DM) patients, and these wounds may develop into foot ulcers. There are at least two types of DM wound models used in rodents to study delayed wound healing. However, clinically relevant animal models are not common. Most models use type 1 DM rodents or wounds created on the back rather than on the foot. An open full-thickness excision wound on the footpad of type 2 DM rats is more clinically relevant, but such a model has not yet been characterized systematically. The objective of this study was to investigate and characterize how DM affected a full-thickness excision open foot wound in n5-streptozotocin (n5-STZ)-induced type 2 DM rats. We hypothesized that elevated inflammation, reduced blood circulation, and cell proliferation due to hyperglycemia could delay the wound healing of DM rats. The wounds of DM rats were compared with those of non-DM rats (Ctrl) at Days 1 and 8 post wounding. The wound healing process of the DM rats was significantly delayed compared with that of the Ctrl rats. The DM rats also had higher C-reactive protein (CRP) and lower blood circulation and proliferating cell nuclear antigen (PCNA) in DM wounds. This confirmed that elevated inflammation and reduced blood flow and cell proliferation delayed foot wound healing in the n5-STZ rats. Hence, this open foot wound animal model provides a good approach to study the process of delayed wound healing. PMID:28413186

Botulinum Toxin Induces Muscle Paralysis and Inhibits Bone Regeneration in Zebrafish

PubMed Central

Recidoro, Anthony M.; Roof, Amanda C.; Schmitt, Michael; Worton, Leah E.; Petrie, Timothy; Strand, Nicholas; Ausk, Brandon J.; Srinivasan, Sundar; Moon, Randall T.; Gardiner, Edith M.; Kaminsky, Werner; Bain, Steven D.; Allan, Christopher H.; Gross, Ted S.; Kwon, Ronald Y.

2016-01-01

Intramuscular administration of Botulinum toxin (BTx) has been associated with impaired osteogenesis in diverse conditions of bone formation (e.g., development, growth, and healing), yet the mechanisms of neuromuscular-bone crosstalk underlying these deficits have yet to be identified. Motivated by the emerging utility of zebrafish (Danio rerio) as a rapid, genetically tractable, and optically transparent model for human pathologies (as well as the potential to interrogate neuromuscular-mediated bone disorders in a simple model that bridges in vitro and more complex in vivo model systems), in this study we developed a model of BTx-induced muscle paralysis in adult zebrafish, and examined its effects on intramembranous ossification during tail fin regeneration. BTx administration induced rapid muscle paralysis in adult zebrafish in a manner that was dose-dependent, transient, and focal, mirroring the paralytic phenotype observed in animal and human studies. During fin regeneration, BTx impaired continued bone ray outgrowth, morphology, and patterning, indicating defects in early osteogenesis. Further, BTx significantly decreased mineralizing activity and crystalline mineral accumulation, suggesting delayed late-stage osteoblast differentiation and/or altered secondary bone apposition. Bone ray transection proximal to the amputation site focally inhibited bone outgrowth in the affected ray, implicating intra- and/or inter-ray nerves in this process. Taken together, these studies demonstrate the potential to interrogate pathological features of BTx-induced osteoanabolic dysfunction in the regenerating zebrafish fin, define the technological toolbox for detecting bone growth and mineralization deficits in this process, and suggest that pathways mediating neuromuscular regulation of osteogenesis may be conserved beyond established mammalian models of bone anabolic disorders. PMID:24806738

Improved Healing of Large, Osseous, Segmental Defects by Reverse Dynamization: Evaluation in a Sheep Model

DTIC Science & Technology

2015-10-01

IFM ) through the separated bone cortices (fracture gap). In research funded by a CDMRP Idea Development Award, we used a rat segmental defect...491, 2011. [3] V. Glatt, M . Miller, a Ivkovic, F. Liu, N. Parry, D. Griffin, M . Vrahas, and C. Evans, “Improved healing of large segmental defects...2012. [4] M . Mehta, S . Checa, J. Lienau, D. Hutmacher, and G. N. Duda, “In vivo tracking of segmental bone defect healing reveals that callus

[Early application of the antibiotic-laden bone cement (ALBC) combined with the external fixation support in treating the open fractures of lower limbs complicated with bone defect].

PubMed

Xiao, Jian; Mao, Zhao-Guang; Zhu, Hui-Hua; Guo, Liang

2017-03-25

To discuss the curative effect of the early application of the antibiotic-laden bone cement (ALBC) combined with the external fixation support in treating the open fractures of lower limbs complicated with bone defect. From December 2013 to January 2015, 36 cases of lower limb open comminuted fractures complicated with bone defects were treated by the vancomycin ALBC combined with the external fixation support, including 26 males and 10 females with an average age of 38.0 years old ranging from 19 to 65 years old. The included cases were all open fractures of lower limbs complicated with bone defects with different degree of soft tissue injuries. Among them, 25 cases were tibial fractures, 11 cases were femoral fractures. The radiographs indicated a presence of bone defects, which ranged from 3.0 to 6.1 cm with an average of 4.0 cm. The Gustilo classification of open fractures:24 cases were type IIIA, 12 cases were typr IIIB. The percentage of wound infection, bone grafting time, fracture healing time and postoperative joint function of lower limb were observed. The function of injured limbs was evaluated at 1 month after the clinical healing of fracture based on Paley evaluation criterion. All cases were followed up for 3 to 24 months with an average of (6.0±3.0) months. The wound surface was healed well, neither bone infections nor unhealed bone defects were presented. The reoperation of bone grafting was done at 6 weeks after the patients received an early treatment with ALBC, some of them were postponed to 8 weeks till the approximate healing of fractures, the treatment course lasted for 4 to 8 months with an average of(5.5±1.5) months. According to Paley and other grading evaluations of bone and function, there were 27 cases as excellent, 5 cases as good, 3 cases as ordinary. The ALBC combined with external fixation support was an effective method for early treatment to treat the traumatic lower limb open fractures complicated with bone defects. This method was typified with the advantages such as easy operation, short operation time, overwhelming superiority in controlling infection and provision of good bone grafting bed, a good bone healing can be realized by the use of membrane induction technology for bone grafting.

Tendon healing in a bone tunnel. Part II: Histologic analysis after biodegradable interference fit fixation in a model of anterior cruciate ligament reconstruction in sheep.

PubMed

Weiler, Andreas; Hoffmann, Reinhard F G; Bail, Hermann J; Rehm, Oliver; Südkamp, Norbert P

2002-02-01

Tendon-to-bone healing of soft-tissue grafts has been described to progress by the development of a fibrous interzone that undergoes a maturation process leading to the development of an indirect type of ligament insertion. Previous studies used extra-articular models or fixation far away from the joint line; thus, no data are available investigating tendon-to-bone healing of a soft-tissue graft fixed anatomically. Therefore, we studied the tendon-to-bone healing of the anatomic soft-tissue graft interference fit fixation in a model of anterior cruciate ligament (ACL) reconstruction in sheep. Animal study. Thirty-five mature sheep underwent ACL reconstruction with an autologous Achilles tendon split graft. Grafts were directly fixed with biodegradable poly-(D,L-lactide) interference screws. Animals were euthanized after 6, 9, 12, 24, and 52 weeks and histologic evaluations were performed. Undecalcified specimens were evaluated under normal and polarized light. Additionally, animals received a polychrome sequential labeling (tetracycline, xylenol orange, and calcein green) to determine bone growth per time under fluorescent light. Intratunnel histologic findings at 6 weeks showed a tendon-bone junction with only a partial fibrous interzone between the graft tissue and the surrounding bone. A mature intratunnel tendon-bone junction with a zone of fibrocartilage was found at 9 to 12 weeks. At the tunnel entrance site a wide regular ligamentous insertion site was seen in all specimens after 24 weeks. This insertion showed regular patterns such as the direct type of insertion of a normal ligament with a dense basophilic transition zone consisting of mineralized cartilage. A fibrous interzone between the graft tissue and the bone tunnel was only partially developed, which is in contrast to all previous studies in which nonanatomic fixation was used. Thus, it is reasonable to assume that the tendon-to-bone healing in the present study may progress partially by direct-contact healing without the development of a fibrous interzone. To our knowledge, this is the first report describing the development of a direct type of ligament insertion after ACL replacement with a soft-tissue graft. This is in contrast to previous studies reporting the development of an indirect type of insertion when using nonanatomic fixation far away from the joint line. Thus, histologic data strongly indicate that anatomic interference fit fixation is beneficial for tendon-to-bone incorporation by leading to the development of a direct type of ligament insertion.

[Tuberculous otomastoiditis: advantage of MRI in the treatment survey].

PubMed

Moya, Plana A; Malinvaud, D; Mimoun, M; Huart, J; Bonfils, P

2008-01-01

Mycobacterium tuberculosis is a rare cause of otomastoiditis, accounting for less than a percent of chronic otitis media. The diagnosis is difficult and typically delayed because most physicians are unfamiliar with its presenting features and special laboratory requirements. Such delayed diagnosis leads to delayed treatment onset, and thus, increases complications frequency as irreversible hearing loss, facial palsy or meningo-encephalitis complications. Moreover non specific CT findings do not allow any accurate evaluation of inner ear lesions initially and under treatment. We described the first case of MRI of tuberculous mastoiditis and the evolution over a 2-years follow-up period. A patient with a clinical history of chronic otorrhea, resistant to conventional therapy, was referred to our department. CT and MRI permitted to describe the initial lesions and to appreciate the medical treatment efficiency (in order to perform surgery in case of failure or complications). Under medical treatment, MRI showed abscess volume decrease at three months while CT was still unchanged. Remineralization only was observed on CT at 12 months. The patient's healing was obtained after 15 months of antituberculous medication. MRI has the advantage over CT to demonstrate directly abscess collections that superimposed to areas of bone destructions within the temporal bone. Initially, MRI allows an accurate evaluation of abscess collections and possible meningo-encephalitis complications. Moreover, MRI precises earlier than CT the improvement of lesions and the efficacy of medical treatment, and thus, permitting us to postpone surgery where it is unnecessary.

[Polarized microscopic observation of the collagen change in bone healing during bone lengthening].

PubMed

Zou, Pei; Li, Junhui; Li, Zhuyi

2006-01-01

To investigate the feature and regularity of the collagen change in bone healing during bone lengthening. Bone lengthening model was made in the middle segment of the rabbit tibia. Five days after the model was established, the bone was lengthened 1.5 mm per day for 14 days. The rabbits were put to death after elongation, 7, 14, 21, 30, 40, 50, 60 and 70 days after elongation. The distracted area of the bone was imbedded with paraffin. After being stained by the picric acid-sirius red staining, the slice was observed under polarized microscope. The features of the collagen change in the distracted bone were as follows: (1) In the fibrous tissue of the distracted area during lengthening period and the early stage after lengthening, there was not only collagen III but also much collagen I. (2) Collagen I , II and III were observed in the cartilage. (3) Collagen I, II and III were also observed in the pseudo-growth plate. (4) Collagen I took the dominance during lengthening period and the late stage after lengthening. New bone formation in bone lengthening is under the distracted force, so the collagen changes have different features compared with that in fracture healing. Collagen I, II and III can be identified by picric acid-sirius red staining and polarized microscope, so a new method for studying the collagen typing in bone repairing is provided.

Influence of Healing Period Upon Bone Turn Over on Maxillary Sinus Floor Augmentation Grafted Solely with Deproteinized Bovine Bone Mineral: A Prospective Human Histological and Clinical Trial.

PubMed

Wang, Feng; Zhou, Wenjie; Monje, Alberto; Huang, Wei; Wang, Yueping; Wu, Yiqun

2017-04-01

To investigate the influence of maturation timing upon histological, histomorphometric and clinical outcomes when deproteinized bovine bone mineral (DBBM) was used as a sole biomaterial for staged maxillary sinus floor augmentation (MSFA). Patients with a posterior edentulous maxillary situation and a vertical bone height ≤ 4 mm were included in this study. A staged MSFA was carried out. After MSFA with DBBM as a sole grafting material, biopsy cores were harvested with simultaneous implant placement followed by a healing period of 5, 8, and 11 months, respectively. Micro-CT, histologic and histomorphometric analyses were performed. Forty-one patients were enrolled and 38 bone core biopsies were harvested. Significantly greater BV/TV was observed between 5- and 8-month healing from micro-CT analysis. Histomorphometric analyses showed the ratio of mineralized newly formed bone increased slightly from 5 to 11 months; however, no statistically significant difference was reached (p = .409). Residual bone substitute decreased from 37.3 ± 5.04% to 20.6 ± 7.45%, achieving a statistical significant difference from of 5 up to 11 months (p < .01). Moreover, no implant failure, biological or technical complication occurred after 12-month follow-up of functional loading. DBBM utilized as sole grafting material in staged MSFA demonstrated to be clinically effective regardless of the healing period. Histomorphometrical and micro-CT assessments revealed that at later stages of healing (8 and 11 months) there is a higher proportion of newly-bone formation compared to earlier stages (5 months). Moreover, the longer the maturation period, the substantially lesser remaining biomaterial could be expected. Even though, these facts did not seem to negatively impact on the implant prognosis 1-year after loading. © 2016 Wiley Periodicals, Inc.

The effects of photobiomodulation on healing of bone defects in streptozotocin induced diabetic rats

NASA Astrophysics Data System (ADS)

Martinez Costa Lino, Maíra D.; Bastos de Carvalho, Fabíola; Ferreira Moraes, Michel; Augusto Cardoso, José; Pinheiro, Antônio L. B.; Maria Pedreira Ramalho, Luciana

2011-03-01

Previous studies have shown positive effects of Low level laser therapy (LLLT) on the repair of bone defects, but there are only a few that associates bone healing in the presence of a metabolic disorder as Diabetes Melitus and LLLT. The aim of this study was to assess histologically the effect of LLLT (AsGaAl), 780nm, 70mW, CW, Ø~0.4mm, 16J/cm2 per session) on the repair of surgical defects created in the femur of diabetic and non-diabetic Wistar Albinus rats. Surgical bone defects were created in 60 animals divided into four groups of 15 animals each: Group C (non-diabetic - control); Group CL (non-diabetic + LLLT); Group CD (diabetic); Group CDL (diabetic + LLLT). The animals on the irradiated group received 16 J/cm2 per session divided into four points around the defect, being the first irradiation immediately after surgery and repeated every 48h for 14 days. The animals were killed 15, 21 and 30 days after surgery. The results of the present investigation showed histological evidence of improved amount of collagen fibers at early stages of the bone healing (15 days) and increased amount of well organized bone trabeculae at the end of the experimental period (30 days) on irradiated animals, (diabetic and non-diabetic) compared to non irradiated ones. It is concluded that LLLT has a positive biomodulative effect on the healing process of bone defects, even when diabetes mellitus was present.

Nonsurgical Clinical Management of Periapical Lesions Using Calcium Hydroxide-Iodoform-Silicon-Oil Paste

PubMed Central

Al Khasawnah, Qusai; Hassan, Fathi; Malhan, Deeksha; Engelhardt, Markus; Daghma, Diaa Eldin S.; Obidat, Dima; Lips, Katrin S.; Heiss, Christian

2018-01-01

Background The study aim is to avoid tooth extraction by nonsurgical treatment of periapical lesion. It assesses healing progress in response to calcium hydroxide-iodoform-silicon oil paste (CHISP). Numeric Pain Rating Scale was used to validate the approach. Furthermore, CHISP was used to treat cystic lesions secondary to posttraumatic avulsion of permanent teeth. Materials and Methods Over 200 patients with radicular cysts were treated with CHISP through the root canal. Radiographs were used to verify lesion size and position, ensure correct delivery to the site, and monitor the progress of bone healing in the lesion area. Ten males and 10 females were randomly selected for statistical assessment. Results No severe pain, complications, or failure in cyst healing was reported. Complete healing was achieved in an average of 75 days. Furthermore, healing of radicular cyst secondary to posttraumatic tooth avulsion was successful. Conclusion CHISP indicated an antiseptic effect, which enhanced and shortened healing time of periapical lesions. The less invasive procedure avoids tooth extraction and reduces bone resorption. Cyst management with CHISP can remedy failed root canal treatments. The results show a bone regenerative capacity of CHISP suggested in first rapid phase and a second slow phase. PMID:29619378

Potential osteogenic activity of ethanolic extract and oxoflavidin isolated from Pholidota articulata Lindley.

PubMed

Sharma, Chetan; Dixit, Manisha; Singh, Rohit; Agrawal, Manali; Mansoori, Mohd Nizam; Kureel, Jyoti; Singh, Divya; Narender, Tadigoppula; Arya, Kamal Ram

2015-07-21

Pholidota articulata Lindley (PA) locally known as Hadjojen (bone jointer) belongs to family Orchidaceae is used for healing fractures in folklore tradition of Kumaon region of Uttarakhand, Himalaya, India. Bone is a dynamic organ and is constantly being remodeled in order to facilitate growth and repair. This process requires the involvement of bone forming osteoblast and bone resorbing osteoclast cells, which function in generating and mineralizing bone, giving strength and rigidity to the skeletal system. Present study was aimed to determine the therapeutic potential of ethanolic extract of PA and its isolated compound oxoflavidin, by characterizing their fracture healing properties. Ovariectomized (Ovx) estrogen deficient adult female Balb/c mice were used for in vivo evaluation of osteogenic or bone healing potential of ethanolic extract of PA. Further, its isolated compounds were tested for their osteogenic efficacy using alkaline phosphatase assay and mineralization assay in vitro in mice calvarial osteoblasts. The ethanolic extract of PA exhibited significant restoration of trabecular micro-architecture in both femoral and tibial bones. Additionally, treatment with PA extract led to better bone quality and devoid of any uterine estrogenicity in ovariectomized estrogen deficient mice. One of the isolated compound, oxoflavidin enhanced ALP activity (a marker of osteoblast differentiation), mineral nodule formation and mRNA levels of osteogenic markers like BMP-2, Type 1 Collagen, RUNX-2 and osteocalcin. These results warrant that ethanolic extract of PA and it's pure compound oxoflavidin have fracture healing properties. The extract and oxoflavidin exhibit a strong threapeutical potential for the treatment and management of postmenopausal osteoporosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Dkk1 haploinsufficiency requires expression of Bmp2 for bone anabolic activity.

PubMed

Intini, Giuseppe; Nyman, Jeffry S

2015-06-01

Bone fractures remain a serious health burden and prevention and enhanced healing of fractures have been obtained by augmenting either BMP or Wnt signaling. However, whether BMP and Wnt signaling are both required or are self-sufficient for anabolic and fracture healing activities has never been fully elucidated. Mice haploinsufficient for Dkk1 (Dkk1(+/-)) exhibit a high bone mass phenotype due to an up-regulation of canonical Wnt signaling while mice lacking Bmp2 expression in the limbs (Bmp2(c/c);Prx1::cre) succumb to spontaneous fracture and are unable to initiate fracture healing; combined, these mice offer an opportunity to examine the requirement for activated BMP signaling on the anabolic and fracture healing activity of Wnts. When Dkk1(+/-) mice were crossed with Bmp2(c/c);Prx1::cre mice, the offspring bearing both genetic alterations were unable to increase bone mass and heal fractures, indicating that increased canonical Wnt signaling is unable to exploit its activity in absence of Bmp2. Thus, our data suggest that BMP signaling is required for Wnt-mediated anabolic activity and that therapies aimed at preventing fractures and fostering fracture repair may need to target both pathways for maximal efficacy. Copyright © 2015 Elsevier Inc. All rights reserved.

Dkk1 haploinsufficiency requires expression of Bmp2 for bone anabolic activity

PubMed Central

Intini, Giuseppe; Nyman, Jeffry S.

2015-01-01

Bone fractures remain a serious health burden and prevention and enhanced healing of fractures has been obtained by augmenting either BMP or Wnt signaling. However, whether BMP and Wnt signaling are both required or are self-sufficient for anabolic and fracture healing activities has never been fully elucidated. Mice haploinsufficient for Dkk1 (Dkk1+/−) exhibit a high bone mass phenotype due to an up-regulation of canonical Wnt signaling while mice lacking Bmp2 expression in the limbs (Bmp2c/c;Prx1::cre) succumb to spontaneous fracture and are unable to initiate fracture healing; combined, these mice offer an opportunity to examine the requirement for activated BMP signaling on the anabolic and fracture healing activity of Wnts. When Dkk1+/− mice were crossed with Bmp2c/c;Prx1::cre mice, the offspring bearing both genetic alterations were unable to increase bone mass and heal fractures, indicating that increased canonical Wnt signaling is unable to exploit its activity in absence of Bmp2. Thus, our data suggest that BMP signaling is required for Wnt-mediated anabolic activity and that therapies aimed at preventing fractures and fostering fracture repair may need to target both pathways for maximal efficacy. PMID:25603465

The effects of different nutritional measurements on delayed wound healing after hip fracture in the elderly.

PubMed

Guo, Jiong Jiong; Yang, Huilin; Qian, Haixin; Huang, Lixin; Guo, Zhongxing; Tang, Tiansi

2010-03-01

It has been well recognized that malnutrition causes wounds to heal inadequately and incompletely. Malnutrition is often observed in the elderly, and it appears to be more severe in patients with hip fracture than in the general aging population. Few prospective studies give a detailed account of the identification and classification of nutritional status in the elderly. The objective of this study was to evaluate the effects of different nutritional measurements on wound healing status after hip fracture in the elderly. From September 2002 to December 2007, 207 hip fracture patients older than 60 y treated surgically were reviewed for preoperative nutritional status. There were 81 males and 126 females with an average age of 75.93 y (62-91 y); 131 cases with femoral neck fractures, 76 cases with intertrochanteric fractures. Parameters indicative of nutritional status (serum albumin, serum transferrin, serum pre-albumin, and total lymphocyte count levels) at the time of admission were assessed, along with anthropometric measurements, Rainey MacDonald nutritional index, and MNA tool. Suture removal was performed on postoperative day 14. Delayed wound healing complicated 46 (22.2%) of the 207 cases. The preoperative serum transferring total lymphocyte count levels, MNA total score, and Rainey MacDonald nutritional index were significantly lower for patients who subsequently had delayed wound healing. When all variables were subjected to multivariate analysis, only total lymphocyte count levels and MNA total score showed significant value in predicting which patients would have delayed wound healing. Through prophylactic antibiotics and adherence to strict aseptic precautions, on follow-up, wound healing was normal in all patients. Patients at risk for delayed wound healing problems after hip fracture can be identified using relatively inexpensive laboratory test such as TLC and MNA tool. The clinician must be aware of the risk values of both measurements. We believe this information is particularly important before planning procedures of hip fractures in the elderly. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair.

PubMed

Baht, Gurpreet S; Nadesan, Puviindran; Silkstone, David; Alman, Benjamin A

2017-05-01

Patients with Neurofibromatosis type 1 display delayed fracture healing and the increased deposition of fibrous tissue at the fracture site. Severe cases can lead to non-union and even congenital pseudarthrosis. Neurofibromatosis type 1 is caused by a mutation in the NF1 gene and mice lacking the Nf1 gene show a fracture repair phenotype similar to that seen in patients. Tissue from the fracture site of patients with Neurofibromatosis type 1 and from mice deficient in the Nf1 gene both show elevated levels of β-catenin protein and activation of β-catenin mediated signaling. Constitutively elevated β-catenin leads to a delayed and fibrous fracture repair process, and (RS)-5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine (Nefopam, a centrally-acting, non-narcotic analgesic agent) inhibits β-catenin mediated signaling during skin wound repair. Here we investigate Nefopam's potential as a modulator of bone repair in mice deficient in Nf1. Mice were treated with Nefopam and investigated for bone fracture repair. Bone marrow stromal cells flushed from the long bones of unfractured mice were treated with Nefopam and investigated for osteogenic potential. Treatment with Nefopam was able to lower the β-catenin level and the Axin2 transcript level in the fracture calluses of Nf1 deficient mice. Cultures from the bone marrow of Nf1 -/- mice had significantly lower osteoblastic colonies and mineralized nodules, which was increased when cells were cultured in the presence of Nefopam. Fracture calluses were harvested and analyzed 14days and 21days after injury. Nf1 -/- calluses had less bone, less cartilage, and higher fibrous tissue content than control calluses. Treatment with Nefopam increased the bone and cartilage content and decreased the fibrous tissue content in Nf1 -/- calluses. These findings present a potential treatment for patients with Neurofibromatosis 1 in the context of bone repair. Since Nefopam is already in use in patient care, it could be rapidly translated to the clinical setting. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of the Effects of Photobiomodulation on Partial Osteotomy in Streptozotocin-Induced Diabetes in Rats.

PubMed

Mostafavinia, Ataroalsadat; Masteri Farahani, Reza; Abdollahifar, Mohammad-Amin; Ghatrehsamani, Mahdi; Ghoreishi, Seyed Kamran; Hajihossainlou, Behnam; Chien, Sufan; Dadras, Sara; Rezaei, Fatemehalsadat; Bayat, Mohammad

2018-05-31

We examined the effects of photobiomodulation (PBM) on stereological parameters, and gene expression of Runt-related transcription factor 2 (RUNX2), osteocalcin, and receptor activator of nuclear factor kappa-B ligand (RANKL) in repairing tissue of tibial bone defect in streptozotocin (STZ)-induced type 1 diabetes mellitus (TIDM) in rats during catabolic response of fracture healing. There were conflicting results regarding the efficacy of PBM on bone healing process in healthy and diabetic animals. Forty-eight rats have been distributed into four groups: group 1 (healthy control, no TIDM and no PBM), group 2 (healthy test, no TIDM and PBM), group 3 (diabetic control, TIDM and no PBM), and group 4 (diabetic test, no TIDM and PBM). TIDM was induced in the groups 3 and 4. A partial bone defect in tibia was made in all groups. The bone defects of groups second and fourth were irradiated by a laser (890 nm, 80 Hz, 1.5 J/cm 2 ). Thirty days after the surgery, all bone defects were extracted and were submitted to stereological examination and real-time polymerase chain reaction (RT-PCR). PBM significantly increased volumes of total callus, total bone, bone marrow, trabecular bone, and cortical bone, and the numbers of osteocytes and osteoblasts of callus in TIDM rats compared to those of callus in diabetic control. In addition, TIDM increased RUNX2, and osteocalcin in callus of tibial bone defect compared to healthy group. PBM significantly decreased osteocalcin gene expression in TIDM rats. PBM significantly increased many stereological parameters of bone repair in an STZ-induced TIDM during catabolic response of fracture healing. Further RT-PCR test demonstrated that bone repair was modulated in diabetic rats during catabolic response of fracture healing by significant increase in mRNA expression of RUNX2, and osteocalcin compared to healthy control rats. PBM also decreased osteocalcin mRNA expression in TIDM rats.

The use of a magnesium-based bone adhesive for flexor tendon-to-bone healing

PubMed Central

Stavros, Thomopoulos; Emmanouil, Zampiakis; Rosalina, Das; Hyun-Min, Kim; J., Silva, Matthew; Necat, Havlioglu; H., Gelberman, Richard

2010-01-01

Purpose Our previous studies in a canine animal model demonstrated that the flexor tendon-to-bone insertion site has a poor capacity to heal. Magnesium based adhesives have the potential to improve tendon-to-bone healing. Therefore, we hypothesized that magnesium based bone adhesive (MBA) will improve the tendon-to-bone biomechanical properties initially and in the early period after repair. Methods Flexor digitorum profundus tendons were injured and repaired into bone tunnels in the distal phalanges of dogs. The bone tunnels were either filled with MBA prior to completing the repair or left empty (CTL). Histologic appearance, tensile properties, range of motion, and bone density were examined at time zero and 21 days after the repair. Results There was no histologic evidence of acute inflammation. There appeared to be more mast cells in the MBA group than in the CTL group. Chronic inflammatory infiltrate and fibrosis was slightly higher in the MBA group compared to the CTL group. Tensile properties at time zero were significantly higher in the MBA group compared to the CTL group. However, tensile properties were significantly lower in the MBA group compared to the CTL group at 21 days. Range of motion and bone density were significantly lower in the MBA and CTL groups compared to normal (i.e., uninjured) at 21 days; no differences were seen when comparing MBA to CTL. Conclusions We found that the initial biomechanical properties of flexor tendon-to-bone repairs can be improved with MBA. However, MBA use in vivo led to a decrease in the biomechanical properties of the repair. There was no effect of MBA on bone density or range of motion in the early period after repair. Our histologic analysis suggests that the poor healing in the MBA group may have been due to an allergic response or to increased chronic inflammation due to the foreign material. PMID:19643291

Healing of Postextraction Sockets Preserved With Autologous Platelet Concentrates. A Systematic Review and Meta-Analysis.

PubMed

Del Fabbro, Massimo; Bucchi, Cristina; Lolato, Alessandra; Corbella, Stefano; Testori, Tiziano; Taschieri, Silvio

2017-08-01

The true benefit of autologous platelet concentrates (APCs) for enhancing the healing of postextraction sites is still a matter of debate, and in recent years several clinical trials have addressed this issue. The purpose of this study was to determine the effectiveness of an APC adjunct in the preservation of fresh extraction sockets. An electronic search was performed on Medline, Embase, Scopus, and the Cochrane Central Register of Controlled Trials. Only controlled clinical trials or randomized clinical trials were included. Selected articles underwent risk-of-bias assessment. The outcomes were complications and adverse events, discomfort and quality of life, bone healing and remodeling assessed by histologic and radiographic techniques, and soft tissue healing. Thirty-three comparative studies were included. Nine articles had a parallel design and 24 had a split-mouth design. Twenty studies were considered to have a low risk of bias and 13 were considered to have a high risk. Overall, 1,193 teeth were extracted from 911 patients. Meta-analysis showed that soft tissue healing, probing depth at 3 months, and bone density at 1, 3, and 6 months were statistically better for the APC group. Qualitative analysis suggested that APCs might be associated with a decrease in swelling and trismus. However, no relevant difference among groups was found for probing depth at 1 month, incidence of alveolar osteitis, acute inflammation or infection, percentage of new bone, and indirect measurement of bone metabolism. APCs should be used in postextraction sites to improve clinical and radiographic outcomes such as bone density and soft tissue healing and postoperative symptoms. The actual benefit of APCs on decreasing pain in extraction sockets is still not quantifiable. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Dura Mater Stimulates Human Adipose-Derived Stromal Cells to Undergo Bone Formation in Mouse Calvarial Defects

PubMed Central

Levi, Benjamin; Nelson, Emily R.; Li, Shuli; James, Aaron W.; Hyun, Jeong S.; Montoro, Daniel T.; Lee, Min; Glotzbach, Jason P.; Commons, George W.; Longaker, Michael T.

2015-01-01

Human adipose-derived stromal cells (hASCs) have a proven capacity to aid in osseous repair of calvarial defects. However, the bone defect microenvironment necessary for osseous healing is not fully understood. In this study, we postulated that the cell-cell interaction between engrafted ASCs and host dura mater (DM) cells is critical for the healing of calvarial defects. hASCs were engrafted into critical sized calvarial mouse defects. The DM-hASC interaction was manipulated surgically by DM removal or by insertion of a semipermeable or nonpermeable membrane between DM and hASCs. Radiographic, histologic, and gene expression analyses were performed. Next, the hASC-DM interaction is assessed by conditioned media (CM) and coculture assays. Finally, bone morphogenetic protein (BMP) signaling from DM was investigated in vivo using novel BMP-2 and anti-BMP-2/4 slow releasing scaffolds. With intact DM, osseous healing occurs both from host DM and engrafted hASCs. Interference with the DM-hASC interaction dramatically reduced calvarial healing with abrogated BMP-2–Smad-1/5 signaling. Using CM and coculture assays, mouse DM cells stimulated hASC osteogenesis via BMP signaling. Through in vivo manipulation of the BMP-2 pathway, we found that BMP-2 plays an important role in DM stimulation of hASC osteogenesis in the context of calvarial bone healing. BMP-2 supplementation to a defect with disrupted DM allowed for bone formation in a nonhealing defect. DM is an osteogenic cell type that both participates in and stimulates osseous healing in a hASC-engrafted calvarial defect. Furthermore, DM-derived BMP-2 paracrine stimulation appears to play a key role for hASC mediated repair. PMID:21656608

FLUOXETINE INHIBITS OSTEOBLAST DIFFERENTIATION & MINERALIZATION IN FRACTURE HEALING

PubMed Central

Bradaschia-Correa, Vivian; Josephson, Anne M; Mehta, Devan; Mizrahi, Matthew; Neibart, Shane S; Liu, Chao; Kennedy, Oran; Castillo, Alesha B; Egol, Kenneth A; Leucht, Philipp

2016-01-01

Chronic use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression has been linked to osteoporosis. In this study, we investigated the effect of chronic SSRI use on fracture healing in two murine models of bone regeneration. First, we performed a comprehensive analysis of endochondral bone healing in a femur fracture model. C57/BL6 mice treated with fluoxetine, the most commonly prescribed SSRI, developed a normal cartilaginous soft-callus at 14 days after fracture and demonstrated a significantly smaller and biomechanically weaker bony hard-callus at 28 days. In order to further dissect the mechanism that resulted in a smaller bony regenerate, we used an intramembranous model of bone healing and revealed that fluoxetine treatment resulted in a significantly smaller bony callus at 7 and 14 days postinjury. In order to test whether the smaller bony regenerate following fluoxetine treatment was caused by an inhibition of osteogenic differentiation and/or mineralization, we employed in vitro experiments, which established that fluoxetine treatment decreases osteogenic differentiation and mineralization and that this effect is serotonin-independent. Finally, in a translational approach, we tested whether cessation of the medication would result in restoration of the regenerative potential. However, histologic and µCT analysis revealed non-union formation in these animals with fibrous tissue interposition within the callus. In conclusion, fluoxetine exerts a direct, inhibitory effect on osteoblast differentiation and mineralization, shown in two disparate murine models of bone repair. Discontinuation of the drug did not result in restoration of the healing potential, but rather led to complete arrest of the repair process. Besides the well-established effect of SSRIs on bone homeostasis, our study provides strong evidence that fluoxetine use negatively impacts fracture healing. PMID:27869327

Alveolar socket preservation with demineralised bovine bone mineral and a collagen matrix

PubMed Central

2017-01-01

Purpose The aim of the present study was to evaluate the healing of post-extraction sockets following alveolar ridge preservation clinically, radiologically, and histologically. Methods Overall, 7 extraction sockets in 7 patients were grafted with demineralised bovine bone mineral and covered with a porcine-derived non-crosslinked collagen matrix (CM). Soft tissue healing was clinically evaluated on the basis of a specific healing index. Horizontal and vertical ridge dimensional changes were assessed clinically and radiographically at baseline and 6 months after implant placement. For histological and histomorphometric analysis, bone biopsies were harvested from the augmented sites during implant surgery 6 months after the socket preservation procedure. Results Clinically, healing proceeded uneventfully in all the sockets. A trend towards reduced horizontal and vertical socket dimensions was observed from baseline to the final examination. The mean width and height of resorption were 1.21 mm (P=0.005) and 0.46 mm (P=0.004), respectively. Histologically, residual xenograft particles (31.97%±3.52%) were surrounded by either newly formed bone (16.02%±7.06%) or connective tissue (50.67%±8.42%) without fibrous encapsulation. The CM underwent a physiological substitution process in favour of well-vascularised collagen-rich connective tissue. Conclusions Socket preservation using demineralised bovine bone mineral in combination with CM provided stable dimensional changes of the alveolar ridge associated with good re-epithelialisation of the soft tissues during a 6-month healing period. PMID:28861284

Management strategy for unicameral bone cyst.

PubMed

Chuo, Chin-Yi; Fu, Yin-Chih; Chien, Song-Hsiung; Lin, Gau-Tyan; Wang, Gwo-Jaw

2003-06-01

The management of a unicameral bone cyst varies from percutaneous needle biopsy, aspiration, and local injection of steroid, autogenous bone marrow, or demineralized bone matrix to the more invasive surgical procedures of conventional curettage and grafting (with autogenous or allogenous bone) or subtotal resection with bone grafting. The best treatment for a unicameral bone cyst is yet to be identified. Better understanding of the pathology will change the concept of management. The aim of treatment is to prevent pathologic fracture, to promote cyst healing, and to avoid cyst recurrence and re-fracture. We retrospectively reviewed 17 cases of unicameral bone cysts (12 in the humerus, 3 in the femur, 2 in the fibula) managed by conservative observation, curettage and bone grafting with open reduction and internal fixation, or continuous decompression and drainage with a cannulated screw. We suggest percutaneous cannulated screw insertion to promote cyst healing and prevent pathologic fracture. We devised a protocol for the management of unicameral bone cysts.

Treatment of Unicameral Bone Cysts of the Proximal Femur With Internal Fixation Lessens the Risk of Additional Surgery.

PubMed

Wilke, Benjamin; Houdek, Matthew; Rao, Rameshwar R; Caird, Michelle S; Larson, A Noelle; Milbrandt, Todd

2017-09-01

Little data exist to guide the treatment of unicameral bone cysts in the proximal femur. Methods of treatment include corticosteroid injections, curettage and bone grafting, and internal fixation. The authors completed a multi-institutional, retrospective review to evaluate their experience with proximal femoral unicameral bone cysts. They posed the following questions: (1) Does internal fixation reduce the risk of further procedures for the treatment of a unicameral bone cyst? (2) Is radiographic healing faster with internal fixation? Following institutional review board approval, the authors conducted a retrospective review of 36 patients treated for a unicameral bone cyst of the proximal femur at their institutions between 1974 and 2014. Medical records and radiographs were reviewed to identify patient demographics and treatment outcomes. Tumor locations included femoral neck (n=13), intertrochanteric (n=16), and subtrochanteric (n=7). Initial treatment included steroid injection (n=2), curettage and bone grafting (n=9), and internal fixation with curettage and bone grafting (n=25). Mean time was 9 months to radiographic healing and 15 months to return to full activity. The number of patients requiring additional surgeries was increased among those who did not undergo internal fixation. There was no difference in time to radiographic healing. However, time to return to normal activities was reduced if patients had received internal fixation. A significant reduction in additional procedures was observed when patients had been treated with internal fixation. Although this did not influence time to radiographic healing, patients did return to normal activities sooner. Internal fixation should be considered in the treatment of proximal femoral unicameral bone cysts. [Orthopedics. 2017; 40(5):e862-e867.]. Copyright 2017, SLACK Incorporated.

Ozone Therapy Enhances Osseous Healing in Rats With Diabetes With Calvarial Defects: A Morphometric and Immunohistochemical Study.

PubMed

Alpan, Aysan Lektemur; Toker, Hülya; Ozer, Hatice

2016-08-01

Bone healing is impaired in diabetes mellitus (DM) cases. The aim of this study is to investigate, both morphometrically and immunohistochemically, the effect of gaseous ozone on bone healing in diabetic rat calvarial defects treated with xenografts. DM was induced with 50 mg/kg intraperitoneal streptozotocin in 56 male Wistar rats. Study groups were as follows: 1) empty defect (control, n = 14); 2) xenograft (XG, n = 14); 3) empty defect treated with ozone therapy (control + ozone, n = 14); and 4) xenograft and ozone application (XG + ozone, n = 14). Critical-size defects were created in all rats. Bovine-derived xenograft was applied to XG groups. Gaseous ozone was applied on the operation day and daily for 2 weeks (140 ppm at 2 L/d, 2.24 mg). Rats were sacrificed at 4 or 8 weeks post-surgery. Total bone area, newly formed bone, and residual graft material were measured histomorphometrically. Osteocalcin and bone morphogenic protein (BMP)-2 expression was evaluated immunohistochemically. Osteoclast numbers in the XG + ozone group were higher than the other groups at week 4 (P <0.05). XG + ozone group revealed more total bone area and new bone area than the XG group at weeks 4 (P <0.05) and 8 (P >0.05). Residual graft materials were decreased in the XG + ozone group and the same group revealed more BMP-2 positivity compared with other groups. Osteocalcin positivity in XG groups was higher than in control groups. Within the limitations of this DM animal study, gaseous ozone application accelerates xenograft resorption and enhances bone regeneration, especially in the early stages of bone healing.

Growth factors and cytokines in patients with long bone fractures and associated spinal cord injury.

PubMed

Khallaf, Fathy G; Kehinde, Elijah O; Mostafa, Ahmed

2016-06-01

The aim of the study was to test the effect of acute traumatic spinal cord injury of quadriplegia or paraplegia on bone healing in patients with associated long bone fractures and to investigate the molecular and cellular events of the underlying mechanism for a possible acceleration. Healing indicators of long bone fractures and growth factors, IGF-II, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), Activin-A, and cytokine I-L-1, in the patients' blood were calculated and measured for 21 patients with spinal cord injuries and associated long bone fractures in prospective controlled study and compared to 20 patients with only spinal cord injuries, 30 patients with only long bone fractures, and 30 healthy volunteers. The study results showed that long bone fractures in patients with associated acute traumatic spinal cord injury of quadriplegia or paraplegia heal more expectedly, faster, and with exuberant florid union callus (P > 0.001) and show statistically significant higher levels of growth factors like PDGF, VEGF, Activin-A, and cytokine I-L-1, along the 3 weeks of follow-up (P > 0.005). I-IGF-II showed statistically significant subnormal level along the whole follow-up period in the same patients (P > 0.005). We concluded that long bone fractures in spinal cord injury patients heal more expectedly, faster, and with exuberant and florid callus formation; growth factors like IGF-II, PDGF, VEGF, Activin-A, and cytokine I-L-I have roles as mediators, in molecular events and as byproducts of the subtle mechanism of accelerated osteogenesis in these patients and may represent therapeutic potentials to serve as agents to enhance bone repair.

Histopathological and biomechanical evaluation of bone healing properties of DBM and DBM-G90 in a rabbit model.

PubMed

Meimandi Parizi, Abdolhamid; Oryan, Ahmad; Haddadi, Shahram; Bigham Sadegh, Amin

2015-01-01

The present study was designed to investigate the effects of DBM and DBM-G90 on bone healing in a rabbit model. Thirty male white albino rabbits were used in this study. An incision was made in all rabbits under general anesthesia directly over the radius in order to expose it. A 10-mm segmental defect was created on the middle portion of each radius. The defects of 10 rabbits (Group I) were filled with DBM Block and Strip (Zimmer, Inc., Warsaw, IN, USA), the defects of 10 rabbits (Group II) were filled with DBM soaked in G90, and the defects of 10 rabbits (Group III/control) were left empty. The rabbits were euthanized at 60 days postoperatively for histopathological and biomechanical evaluation. At the histopathologic level, the defects of the animals in the DBM and DBM-G90 groups showed more advanced healing criteria than those of the control group. In biomechanical findings, there was a statistically significant difference between the injured bones and contralateral normal bones of the control group in terms of measured strength. There was not a statistically significant difference between the treated bones of the DBM and DBM-G90 groups with contralateral normal bones, nor was there a statistically significant difference between the treated bones of the DBM and DBM-G90 groups with the treated bones of the control group, in terms of other biomechanical tests. Based on the histopathological and biomechanical findings, the DBM and DBM-G90 groups demonstrated superior osteogenic potential; however, G90 shows no superiority over DBM on bone healing.

Pathological fractures in children

PubMed Central

De Mattos, C. B. R.; Binitie, O.; Dormans, J. P.

2012-01-01

Pathological fractures in children can occur as a result of a variety of conditions, ranging from metabolic diseases and infection to tumours. Fractures through benign and malignant bone tumours should be recognised and managed appropriately by the treating orthopaedic surgeon. The most common benign bone tumours that cause pathological fractures in children are unicameral bone cysts, aneurysmal bone cysts, non-ossifying fibromas and fibrous dysplasia. Although pathological fractures through a primary bone malignancy are rare, these should be recognised quickly in order to achieve better outcomes. A thorough history, physical examination and review of plain radiographs are crucial to determine the cause and guide treatment. In most benign cases the fracture will heal and the lesion can be addressed at the time of the fracture, or after the fracture is healed. A step-wise and multidisciplinary approach is necessary in caring for paediatric patients with malignancies. Pathological fractures do not have to be treated by amputation; these fractures can heal and limb salvage can be performed when indicated. PMID:23610658

Study on osteogenesis promoted by low sound pressure level infrasound in vivo and some underlying mechanisms.

PubMed

Long, Hua; Zheng, Liheng; Gomes, Fernando Cardoso; Zhang, Jinhui; Mou, Xiang; Yuan, Hua

2013-09-01

To clarify the effects of low sound pressure level (LSPL) infrasound on local bone turnover and explore its underlying mechanisms, femoral defected rats were stabilized with a single-side external fixator. After exposure to LSPL infrasound for 30min twice everyday for 6 weeks, the pertinent features of bone healing were assessed by radiography, peripheral quantitative computerized tomography (pQCT), histology and immunofluorescence assay. Infrasound group showed a more consecutive and smoother process of fracture healing and modeling in radiographs and histomorphology. It also showed significantly higher average bone mineral content (BMC) and bone mineral density (BMD). Immunofluorescence showed increased expression of calcitonin gene related peptide (CGRP) and decreased Neuropeptide Y (NPY) innervation in microenvironment. The results suggested the osteogenesis promotion effects of LSPL infrasound in vivo. Neuro-osteogenic network in local microenvironment was probably one target mediating infrasonic osteogenesis, which might provide new strategy to accelerate bone healing and remodeling. Copyright © 2013 Elsevier B.V. All rights reserved.

Analogous cellular contribution and healing mechanisms following digit amputation and phalangeal fracture in mice

PubMed Central

Dawson, Lindsay A.; Simkin, Jennifer; Sauque, Michelle; Pela, Maegan; Palkowski, Teresa

2016-01-01

Abstract Regeneration of amputated structures is severely limited in humans and mice, with complete regeneration restricted to the distal portion of the terminal phalanx (P3). Here, we investigate the dynamic tissue repair response of the second phalangeal element (P2) post amputation in the adult mouse, and show that the repair response of the amputated bone is similar to the proximal P2 bone fragment in fracture healing. The regeneration‐incompetent P2 amputation response is characterized by periosteal endochondral ossification resulting in the deposition of new trabecular bone, corresponding to a significant increase in bone volume; however, this response is not associated with bone lengthening. We show that cells of the periosteum respond to amputation and fracture by contributing both chondrocytes and osteoblasts to the endochondral ossification response. Based on our studies, we suggest that the amputation response represents an attempt at regeneration that ultimately fails due to the lack of a distal organizing influence that is present in fracture healing. PMID:27499878

New bone formation and trabecular bone microarchitecture of highly porous tantalum compared to titanium implant threads: A pilot canine study.

PubMed

Lee, Jin Whan; Wen, Hai Bo; Gubbi, Prabhu; Romanos, Georgios E

2018-02-01

This study evaluated new bone formation activities and trabecular bone microarchitecture within the highly porous region of Trabecular Metal™ Dental Implants (TM) and between the threads of Tapered Screw-Vent® Dental Implants (TSV) in fresh canine extraction sockets. Eight partially edentulated dogs received four implants (4.1 mmD × 13 mmL) bilaterally in mandibular fresh extraction sockets (32 TM, 32 TSV implants), and allowed to heal for 2, 4, 8, and 12 weeks. Calcein was administered to label mineralizing bone at 11 and 4 days before euthanasia for dogs undergoing all four healing periods. Biopsies taken at each time interval were examined histologically. Histomorphometric assay was conducted for 64 unstained and 64 stained slides at the region of interest (ROI) (6 mm long × 0.35 mm deep) in the midsections of the implants. Topographical and chemical analyses were also performed. Histomorphometry revealed significantly more new bone in the TM than in the TSV implants at each healing time (p = .0014, .0084, .0218, and .0251). Calcein-labeled data showed more newly mineralized bone in the TM group than in the TSV group at 2, 8, and 12 weeks (p = .045, .028, .002, respectively) but not at 4 weeks (p = .081). Histologically TM implants exhibited more bone growth and dominant new immature woven bone at an earlier time point than TSV implants. The parameters representing trabecular bone microarchitecture corroborated faster new bone formation in the TM implants when compared to the TSV implants. TM exhibited an irregular faceted topography compared to a relatively uniform microtextured surface for TSV. Chemical analysis showed peaks associated with each implant's composition material, and TSV also showed peaks reflecting the elements of the calcium phosphate blasting media. Results suggest that the healing pathway associated with the highly porous midsection of TM dental implant could enable faster and stronger secondary implant stability than conventional osseointegration alone; however, prospective clinical studies are needed to confirm these potential benefits in patients with low bone density, compromised healing, or prior implant failure. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Flexible intramedullary nailing for the treatment of unicameral bone cysts in long bones.

PubMed

Roposch, A; Saraph, V; Linhart, W E

2000-10-01

Unicameral bone cyst is characterized by its tenacity and risk of recurrence. Pathological fracture is common and is often the presenting symptom. The objective of the present study was to evaluate the results of flexible intramedullary nailing for the treatment of a unicameral bone cyst with or without a pathological fracture. Flexible intramedullary nailing for the treatment of a unicameral bone cyst was performed in thirty-two patients. Thirty of these patients presented with a pathological fracture; twenty-four were managed immediately with intramedullary nailing, and the other six had been managed conservatively at other clinics before they were referred to our department. The remaining two cysts were detected incidentally. The cyst was located in the humerus in twenty-one patients, in the femur in nine, and in the radius in two. The mean age of the patients at the time of surgery was 9.8 years, and the mean duration of follow-up was 53.7 months. Radiographic evaluation was performed according to the criteria of Capanna et al., and the cyst was classified as completely healed, healed with residual radiolucency (osteolysis), recurred, or having no response. The healing period ranged from three to 105 months. Fourteen cysts healed completely, and sixteen healed with residual radiolucent areas visible on radiographs. There was recurrence of two cysts that had healed with residual radiolucency. All of the cysts in the present study responded to treatment. A change of nails was necessary in nine patients, as the nails had become too short after bone growth. No major complications were observed. Flexible intramedullary nailing provides early stability, which allows early mobilization and thus obviates the need for a plaster cast and decreases the prevalence of the most common complication: a pathological fracture. This method of treatment also allows for an early return to normal activity.

Immediate provisionalization of dental implants placed in healed alveolar ridges and extraction sockets: a 5-year prospective evaluation.

PubMed

Cooper, Lyndon F; Reside, Glenn J; Raes, Filiep; Garriga, Joan Soliva; Tarrida, Luis Giner; Wiltfang, Jörg; Kern, Matthias; De Bruyn, Hugo

2014-01-01

This 5-year prospective multicenter study compared implant survival and success, peri-implant health and soft tissue responses, crestal bone level stability, and complication rates following immediate loading of single OsseoSpeed implants placed in anterior maxillary healed ridges or extraction sockets. Individuals requiring anterior tooth replacement with single implants were treated and immediately provisionalized. Definitive all-ceramic crowns were placed at 12 weeks. Implant survival, bone levels, soft tissue levels, and peri-implant health were monitored for 5 years. One hundred thirteen patients received implants in fresh sockets (55) and healed ridges (58). After 5 years, 45 and 49 patients remained for evaluation, respectively. During the first year, three implants failed in the extraction socket group (94.6% survival) and one implant failed in the healed ridge group (98.3% survival); this difference was not significant. No further implant failures were recorded. After 5 years, the interproximal crestal bone levels were located a mean of 0.43 ± 0.63 mm and 0.38 ± 0.62 mm from the reference points of implants in sockets and healed ridges (not a significant difference). In both groups, papillae increased over time and peri-implant mucosal zenith positions were stable from the time of definitive crown placement in sockets and healed ridges. Compared to flap surgery for implants in healed ridges, flapless surgery resulted in increased peri-implant mucosal tissue dimension (average, 0.78 ± 1.34 mm vs 0.19 ± 0.79 mm). After 5 years, the bone and soft tissue parameters that characterize implant success and contribute to dental implant esthetics were similar following the immediate provisionalization of implants in sockets and healed ridges. The overall tissue responses and reported implant survival support the immediate provisionalization of dental implants in situations involving healed ridges and, under ideal circumstances, extraction sockets.

Reverse Dynamization: Influence of Fixator Stiffness on the Mode and Efficiency of Large-Bone-Defect Healing at Different Doses of rhBMP-2.

PubMed

Glatt, Vaida; Bartnikowski, Nicole; Quirk, Nicholas; Schuetz, Michael; Evans, Christopher

2016-04-20

Reverse dynamization is a technology for enhancing the healing of osseous defects. With use of an external fixator, the axial stiffness across the defect is initially set low and subsequently increased. The purpose of the study described in this paper was to explore the efficacy of reverse dynamization under different conditions. Rat femoral defects were stabilized with external fixators that allowed the stiffness to be modulated on living animals. Recombinant human bone morphogenetic protein-2 (rhBMP-2) was implanted into the defects on a collagen sponge. Following a dose-response experiment, 5.5 μg of rhBMP-2 was placed into the defect under conditions of very low (25.4-N/mm), low (114-N/mm), medium (185-N/mm), or high (254-N/mm) stiffness. Reverse dynamization was evaluated with 2 different starting stiffnesses: low (114 N/mm) and very low (25.4 N/mm). In both cases, high stiffness (254 N/mm) was imposed after 2 weeks. Healing was assessed with radiographs, micro-computed tomography (μCT), histological analysis, and mechanical testing. In the absence of dynamization, the medium-stiffness fixators provided the best healing. Reverse dynamization starting with very low stiffness was detrimental to healing. However, with low initial stiffness, reverse dynamization considerably improved healing with minimal residual cartilage, enhanced cortication, increased mechanical strength, and smaller callus. Histological analysis suggested that, in all cases, healing provoked by rhBMP-2 occurred by endochondral ossification. These data confirm the potential utility of reverse dynamization as a way of improving bone healing but indicate that the stiffness parameters need to be selected carefully. Reverse dynamization may reduce the amount of rhBMP-2 needed to induce healing of recalcitrant osseous lesions, reduce the time to union, and decrease the need for prolonged external fixation. Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated.

Is sonic Hedgehog involved in human fracture healing? --a prospective study on local and systemic concentrations of SHH.

PubMed

Eipeldauer, Stefan; Thomas, Anita; Hoechtl-Lee, Leonard; Kecht, Mathias; Binder, Harald; Koettstorfer, Julia; Gregori, Markus; Sarahrudi, Kambiz

2014-01-01

Sonic Hedgehog (SHH) is a new signalling pathway in bone repair. Evidence exist that SHH pathway plays a significant role in vasculogenesis and limb development during embryogenesis. Some in vitro and animal studies has already proven its potential for bone regeneration. However, no data on the role of SHH in the human fracture healing have been published so far. Seventy-five patients with long bone fractures were included into the study and divided in 2 groups. First group contained 69 patients with normal fracture healing. Four patients with impaired fracture healing formed the second group. 34 volunteers donated blood samples as control. Serum samples were collected over a period of 1 year following a standardized time schedule. In addition, SHH levels were measured in fracture haematoma and serum of 16 patients with bone fractures. Fracture haematoma and patients serum both contained lower SHH concentrations compared to control serum. The comparison between the patients' serum SHH level and the control serum revealed lower levels for the patients at all measurement time points. Significantly lower concentrations were observed at weeks 1 and 2 after fracture. SHH levels were slightly decreased in patients with impaired fracture healing without statistical significance. This is the first study to report local and systemic concentration of SHH in human fracture healing and SHH serum levels in healthy adults. A significant reduction of the SHH levels during the inflammatory phase of fracture healing was found. SHH concentrations in fracture haematoma and serum were lower than the concentration in control serum for the rest of the healing period. Our findings indicate that there is no relevant involvement of SHH in human fracture healing. Fracture repair process seem to reduce the SHH level in human. Further studies are definitely needed to clarify the underlying mechanisms.

Knockdown of SVCT2 impairs in-vitro cell attachment, migration and wound healing in bone marrow stromal cells.

PubMed

Sangani, Rajnikumar; Pandya, Chirayu D; Bhattacharyya, Maryka H; Periyasamy-Thandavan, Sudharsan; Chutkan, Norman; Markand, Shanu; Hill, William D; Hamrick, Mark; Isales, Carlos; Fulzele, Sadanand

2014-03-01

Bone marrow stromal cell (BMSC) adhesion and migration are fundamental to a number of pathophysiologic processes, including fracture and wound healing. Vitamin C is beneficial for bone formation, fracture repair and wound healing. However, the role of the vitamin C transporter in BMSC adhesion, migration and wound healing is not known. In this study, we knocked-down the sodium-dependent vitamin C transporter, SVCT2, the only known transporter of vitamin C in BMSCs, and performed cell adhesion, migration, in-vitro scratch wound healing and F-actin re-arrangement studies. We also investigated the role of oxidative stress on the above processes. Our results demonstrate that both oxidative stress and down-regulation of SVCT2 decreased cell attachment and spreading. A trans-well cell migration assay showed that vitamin C helped in BMSC migration and that knockdown of SVCT2 decreased cell migration. In the in-vitro scratch wound healing studies, we established that oxidative stress dose-dependently impairs wound healing. Furthermore, the supplementation of vitamin C significantly rescued the BMSCs from oxidative stress and increased wound closing. The knockdown of SVCT2 in BMSCs strikingly decreased wound healing, and supplementing with vitamin C failed to rescue cells efficiently. The knockdown of SVCT2 and induction of oxidative stress in cells produced an alteration in cytoskeletal dynamics. Signaling studies showed that oxidative stress phosphorylated members of the MAP kinase family (p38) and that vitamin C inhibited their phosphorylation. Taken together, these results indicate that both the SVCT2 transporter and oxidative stress play a vital role in BMSC attachment, migration and cytoskeletal re-arrangement. BMSC-based cell therapy and modulation of SVCT2 could lead to a novel therapeutic approach that enhances bone remodeling, fracture repair and wound healing in chronic disease conditions. Published by Elsevier B.V.

A 5-year comparison of marginal bone level following immediate loading of single-tooth implants placed in healed alveolar ridges and extraction sockets in the maxilla

PubMed Central

Berberi, Antoine N.; Sabbagh, Joseph M.; Aboushelib, Moustafa N.; Noujeim, Ziad F.; Salameh, Ziad A.

2014-01-01

Purpose: The aim of present investigation was to evaluate marginal bone level after 5-year follow-up of implants placed in healed ridges and fresh extraction sockets in maxilla with immediate loading protocol. Materials and Methods: Thirty-six patients in need of a single-tooth replacement in the anterior maxilla received 42 Astra Tech implants (Astra Tech Implant system™, Dentsply Implants, Mölndal, Sweden). Implants were placed either in healed ridges (group I) or immediately into fresh extraction sockets (group II). Implants were restored and placed into functional loading immediately by using a prefabricated abutment. Marginal bone level relative to the implant reference point was recorded at implant placement, crown cementation, 12, 36, and 60 months following loading using intra-oral radiographs. Measurements were made on the mesial and distal sides of each implant. Results: Overall, two implants were lost from the group II, before final crown cementation: they were excluded from the study. The mean change in marginal bone loss (MBL) after implant placement was 0.26 ± 0.161 mm for 1 year, and 0.26 ± 0.171 mm for 3 years, and 0.21 ± 0.185 mm for 5 years in extraction sockets and was 0.26 ± 0.176 mm for 1 year and 0.21 ± 0.175 mm for 3 years, and 0.19 ± 0.172 mm for 5 years in healed ridges group. Significant reduction of marginal bone was more pronounced in implants inserted in healed ridges (P < 0.041) compared to fresh surgical extraction sockets (P < 0.540). Significant MBL was observed on the mesial side of the implant after cementation of the provisional (P < 0.007) and after 12 months (P < 0.034) compared to the distal side which remained stable for 3 and 5 years observation period. Conclusions: Within the limitations of this study, responses of local bone to immediately loaded implants placed either in extraction sockets or healed ridges were similar. Functional loading technique by using prefabricated abutment placed during the surgery time seems to maintain marginal bone around implant in both healed and fresh extraction sites. PMID:24550840

Ceramic-polylactide composite material used in a model of healing of osseous defects in rabbits.

PubMed

Myciński, Paweł; Zarzecka, Joanna; Skórska-Stania, Agnieszka; Jelonek, Agnieszka; Okoń, Krzysztof; Wróbel, Maria

The growing demand for various kinds of bone regeneration material has in turn increased the desire to find materials with optimal physical, chemical, and biological properties. The objective of the present study was to identify the proportions of ceramic and polylactide components in a bone substitute material prepared in collaboration with the Crystal Chemistry of Drugs Team of the Faculty of Chemistry at the Jagiellonian University, which would be optimal for bone regeneration processes. Another goal was to provide a histological analysis of the influence of a ceramic-polylactide composite on the healing of osseous defects in rabbits. The study was performed on laboratory animals (18 New Zealand White rabbits). The following study groups were formed: - group A (study group, 9 animals) - in this group we performed a histological analysis of healing with a ceramic-polylactide composite based on an 80/20 mix of hydroxyapatite and polylactide; - group B (study group, 9 animals) - in this group we performed a histological analysis of healing with a ceramic-polylactide composite with a reduced amount of hydroxyapatite compared to the previous group, i.e. in a ratio of 61/39; - group K (control, 18 animals) - the control group comprised self-healing, standardised osseous defects prepared in the calvarial bone of the rabbits on the contralateral side. In the assessment of histological samples, we were also able to eliminate individual influences that might have led to differentiation in wound healing. The material used in the histological analysis took the form of rabbit bone tissue samples, containing both defects, with margins of around 0.5 cm, taken 1, 3, and 6 months after the experiment. The osseous defects from groups A and B filled with ceramic-polylactide material healed with less inflammatory infiltration than was the case with control group K. They were also characterised by faster regression, and no resorption or osteonecrosis, which allowed for better regeneration of the bone tissue. A statistical analysis of the study results revealed the increased resorptive activity of the composite in group B, which may have been due to its higher polylactide content. Simultaneously, we observed that healing of osseous defects filled with ceramic-polylactide composites in 80/20 and 61/39 ratios was comparable.

Allergies in orthopaedic and trauma surgery.

PubMed

Lohmann, C H; Hameister, R; Singh, G

2017-02-01

Hypersensitivity reactions to implants in orthopaedic and trauma surgery are a rare but devastating complication. They are considered as a delayed-type of hypersensitivity reaction (type IV), characterized by an antigen activation of sensitized T-lymphocytes releasing various cytokines and may result in osteoclast activation and bone resorption. Potential haptens are originated from metal alloys or bone-cement. A meta-analysis has confirmed a higher probability of developing a metal hypersensitivity postoperatively and noted a greater risk of failed replacements compared to stable implants. Hypersensitivity to implants may present with a variety of symptoms such as pain, joint effusion, delayed wound/bone healing, persistent secretion, allergic dermatitis (localized or systemic), clicking noises, loss of joint function, instability and failure of the implant. Various diagnostic options have been offered, including patch testing, metal alloy patch testing, histology, lymphocyte transformation test (LTT), memory lymphocyte immunostimulation assay (MELISA), leukocyte migration inhibition test (LIF) and lymphocyte activation test (LAT). No significant differences between in vivo and in vitro methods have been found. Due to unconvincing evidence for screening methods, predictive tests are not recommended for routine performance. Infectious aetiology always needs to be excluded. As there is a lack of evidence on large-scale studies with regards to the optimal treatment option, management currently relies on individual case-by-case decisions. Several options for patients with (suspected) metal-related hypersensitivity exist and may include materials based on ceramic, titanium or oxinium or modified surfaces. Promising results have been reported, but long-term experience is lacking. More large-scaled studies are needed in this context. In patients with bone-cement hypersensitivity, the component suspected for hypersensitivity should be avoided. The development of (predictive) biomarkers is considered as a major contribution for the future. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Treatment of malreduced pilon fracture: A case report and the result in the long-term follow-up.

PubMed

Balioğlu, Mehmet Bulent; Akman, Yunus Emre; Bahar, Hakan; Albayrak, Akif

2016-01-01

The risk for post-traumatic osteoarthritis (POA) following tibial plafond joint trauma has been reported to be as high as 70-75%. In the treatment of more severe joint pathologies, with incongruity and intra-articular defects, internal or external fixations techniques may be required. We report the orthopedic management of a pilon fracture in a 30-year-old male with malunion and implant failure after initial mal-reduction of the fracture 9-months earlier. Tricortical iliac crest autologous bone grafting (TCG) was used in combination with internal fixation to restore distal tibial articular. The procedure resulted in a pain free ankle, sufficient range of motion for function and patient satisfaction. Early surgical intervention and anatomical reduction with appropriate fixation are recommended for intra-articular tibial pilon fractures. Autogenous bone grafting is a reliable treatment option to augment structural stability, bone defects and bone-healing. Indications for bone grafting include delayed union or nonunion, malunion, arthrodesis, limb salvage, and reconstruction of bone voids or defects. The application of TCG in the management of a malreduced tibial plafond fracture has not been described before. We performed TCG with internal fixation in order to restore stability, congruency and alignment in a young patient in whom a biological restoration was feasible due to good bone quality. In suitable cases, TCG might provide an alternative to arthrodesis or arthroplasty. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Treatment of malreduced pilon fracture: A case report and the result in the long-term follow-up

PubMed Central

Balioğlu, Mehmet Bulent; Akman, Yunus Emre; Bahar, Hakan; Albayrak, Akif

2015-01-01

Introduction The risk for post-traumatic osteoarthritis (POA) following tibial plafond joint trauma has been reported to be as high as 70–75%. In the treatment of more severe joint pathologies, with incongruity and intra-articular defects, internal or external fixations techniques may be required. Presentation of case We report the orthopedic management of a pilon fracture in a 30-year-old male with malunion and implant failure after initial mal-reduction of the fracture 9-months earlier. Tricortical iliac crest autologous bone grafting (TCG) was used in combination with internal fixation to restore distal tibial articular. The procedure resulted in a pain free ankle, sufficient range of motion for function and patient satisfaction. Discussion Early surgical intervention and anatomical reduction with appropriate fixation are recommended for intra-articular tibial pilon fractures. Autogenous bone grafting is a reliable treatment option to augment structural stability, bone defects and bone-healing. Indications for bone grafting include delayed union or nonunion, malunion, arthrodesis, limb salvage, and reconstruction of bone voids or defects. The application of TCG in the management of a malreduced tibial plafond fracture has not been described before. Conclusion We performed TCG with internal fixation in order to restore stability, congruency and alignment in a young patient in whom a biological restoration was feasible due to good bone quality. In suitable cases, TCG might provide an alternative to arthrodesis or arthroplasty. PMID:26724734

Repair of segmental radial defect with autologous bone marrow aspirate and hydroxyapatite in rabbit radius: A clinical and radiographic evaluation

PubMed Central

Yassine, Kalbaza Ahmed; Mokhtar, Benchohra; Houari, Hemida; Karim, Amara; Mohamed, Melizi

2017-01-01

Aim: Finding an ideal bone substitute to treat large bone defects, delayed union and nonunions remain a challenge for orthopedic surgeons and researchers. Several studies have been conducted on bone regeneration; each has its own advantages and disadvantages. The aim of this study was to evaluate the effect of a combination of hydroxyapatite (HA) powder with autologous bone marrow (BM) aspirate on the repair of segmental radial defect in a rabbit model. Materials and Methods: A total of 36 male and adult New Zealand rabbit with a mean weight of 2.25 kg were used in this study. Approximately, 5 mm defect was created in the mid-shaft of the radius to be filled with HA powder in the control group “HA” (n=18) and with a combination of HA powder and autologous BM aspirate in the test group “HA+BM” (n=18). Animals were observed daily for healing by inspection of the surgical site, and six rabbits of each group were sacrificed at 30, 60, and 90 post-operative days to perform a radiographic evaluation of defect site. Results: Obtained results revealed a better and more rapid bone regeneration in the test group: Since the defect was rapidly and completely filled with mature bone tissue after 90 days. Conclusion: Based on these findings, we could infer that adding a BM aspirate to HA is responsible of a better regeneration process leading to a complete filling of the defect. PMID:28831217

Articular Cartilage Increases Transition Zone Regeneration in Bone-tendon Junction Healing

PubMed Central

Qin, Ling; Lee, Kwong Man; Leung, Kwok Sui

2008-01-01

The fibrocartilage transition zone in the direct bone-tendon junction reduces stress concentration and protects the junction from failure. Unfortunately, bone-tendon junctions often heal without fibrocartilage transition zone regeneration. We hypothesized articular cartilage grafts could increase fibrocartilage transition zone regeneration. Using a goat partial patellectomy repair model, autologous articular cartilage was harvested from the excised distal third patella and interposed between the residual proximal two-thirds bone fragment and tendon during repair in 36 knees. We evaluated fibrocartilage transition zone regeneration, bone formation, and mechanical strength after repair at 6, 12, and 24 weeks and compared them with direct repair. Autologous articular cartilage interposition resulted in more fibrocartilage transition zone regeneration (69.10% ± 14.11% [mean ± standard deviation] versus 8.67% ± 7.01% at 24 weeks) than direct repair at all times. There was no difference in the amount of bone formation and mechanical strength achieved. Autologous articular cartilage interposition increases fibrocartilage transition zone regeneration in bone-tendon junction healing, but additional research is required to ascertain the mechanism of stimulation and to establish the clinical applicability. PMID:18987921

Delayed Wound Healing in Heat Stable Antigen (HSA/CD24)-Deficient Mice

PubMed Central

Shapira, Shiran; Ben-Amotz, Oded; Sher, Osnat; Kazanov, Dina; Mashiah, Jacob; Kraus, Sarah; Gur, Eyal; Arber, Nadir

2015-01-01

Background Healthy individuals rarely have problems with wound healing. Most skin lesions heal rapidly and efficiently within one to two weeks. However, many medical and surgical complications can be attributed to deficiencies in wound repair. Open wounds have lost the barrier that protects tissues from bacterial invasion and allows the escape of vital fluids. Without expeditious healing, infections become more frequent. The CD24 gene encodes a heavily-glycosylated cell surface protein anchored to the membrane by phosphatidylinositol. CD24 plays an important role in the adaptive immune response and controls an important genetic checkpoint for homeostasis and autoimmune diseases in both mice and humans. We have previously shown that overexpression of CD24 results in increased proliferation and migration rates. Aim To examine the role of CD24 in the wound healing process. Methods An excisional model of wound healing was used and delayed wound healing was studied in genetically modified heat stable antigen (HSA/CD24)-deficient mice (HSA -/-) compared to wild-type (WT) mice. Results Large full-thickness skin wounds, excised on the back of mice, exhibited a significant delay in the formation of granulation tissue, and in wound closure when compared to their WTHSA +/+ littermates. Wounds were histologically analyzed and scored, based on the degree of cellular invasion, granulation tissue formation, vascularity, and re-epithelialization. Additionally, in stitched wounds, the HSA -/- mice failed to maintain their stitches; they did not hold and fell already 24 hours, revealing erythematous wound fields. Re-expression of HSA, delivered by lentivirus, restored the normal healing phenotype, within 24 hours post-injury, and even improved the healing in WT, and in BalbC mice. Conclusions Delayed wound-healing in the absence of HSA/CD24 suggests that CD24 plays an important role in this process. Increased expression of CD24, even in the normal state, may be used to enhance wound repair. PMID:26440795

Delayed Wound Healing in Heat Stable Antigen (HSA/CD24)-Deficient Mice.

PubMed

Shapira, Shiran; Ben-Amotz, Oded; Sher, Osnat; Kazanov, Dina; Mashiah, Jacob; Kraus, Sarah; Gur, Eyal; Arber, Nadir

2015-01-01

Healthy individuals rarely have problems with wound healing. Most skin lesions heal rapidly and efficiently within one to two weeks. However, many medical and surgical complications can be attributed to deficiencies in wound repair. Open wounds have lost the barrier that protects tissues from bacterial invasion and allows the escape of vital fluids. Without expeditious healing, infections become more frequent. The CD24 gene encodes a heavily-glycosylated cell surface protein anchored to the membrane by phosphatidylinositol. CD24 plays an important role in the adaptive immune response and controls an important genetic checkpoint for homeostasis and autoimmune diseases in both mice and humans. We have previously shown that overexpression of CD24 results in increased proliferation and migration rates. To examine the role of CD24 in the wound healing process. An excisional model of wound healing was used and delayed wound healing was studied in genetically modified heat stable antigen (HSA/CD24)-deficient mice (HSA-/-) compared to wild-type (WT) mice. Large full-thickness skin wounds, excised on the back of mice, exhibited a significant delay in the formation of granulation tissue, and in wound closure when compared to their WTHSA+/+ littermates. Wounds were histologically analyzed and scored, based on the degree of cellular invasion, granulation tissue formation, vascularity, and re-epithelialization. Additionally, in stitched wounds, the HSA-/- mice failed to maintain their stitches; they did not hold and fell already 24 hours, revealing erythematous wound fields. Re-expression of HSA, delivered by lentivirus, restored the normal healing phenotype, within 24 hours post-injury, and even improved the healing in WT, and in BalbC mice. Delayed wound-healing in the absence of HSA/CD24 suggests that CD24 plays an important role in this process. Increased expression of CD24, even in the normal state, may be used to enhance wound repair.

Clinical and Radiologic Outcomes of Submerged and Nonsubmerged Bone-Level Implants with Internal Hexagonal Connections in Immediate Implantation: A 5-Year Retrospective Study.

PubMed

Wu, Shiyu; Wu, Xiayi; Shrestha, Rachana; Lin, Jinying; Feng, Zhicai; Liu, Yudong; Shi, Yunlin; Huang, Baoxin; Li, Zhipeng; Liu, Quan; Zhang, Xiaocong; Hu, Mingxuan; Chen, Zhuofan

2018-02-01

To evaluate the 5-year clinical and radiologic outcome of immediate implantation using submerged and nonsubmerged techniques with bone-level implants and internal hexagonal connections and the effects of potential influencing factors. A total of 114 bone-level implants (XiVE S plus) with internal hexagonal connections inserted into 72 patients were included. Patients were followed up for 5 years. A t-test was used to statistically evaluate the marginal bone loss between the submerged and nonsubmerged groups. The cumulative survival rate (CSR) was calculated according to the life table method and illustrated with Kaplan-Meier survival curves. Comparisons of the CSR between healing protocols, guided bone regeneration, implants with different sites, lengths, and diameters were performed using log-rank tests. The 5-year cumulative implant survival rates with submerged and nonsubmerged healing were 94% and 96%, respectively. No statistically significant differences in terms of marginal bone loss, healing protocol, application of guided bone regeneration, implant site, or length were observed. High CSRs and good marginal bone levels were achieved 5 years after immediate implantation of bone-level implants with internal hexagonal connections using both the submerged and nonsubmerged techniques. Factors such as implant length, site, and application of guided bone regeneration did not have an impact on the long-term success of the implants. © 2017 by the American College of Prosthodontists.

Coating with a Modular Bone Morphogenetic Peptide Promotes Healing of a Bone-Implant Gap in an Ovine Model

PubMed Central

Lu, Yan; Lee, Jae Sung; Nemke, Brett; Graf, Ben K.; Royalty, Kevin; Illgen, Richard; Vanderby, Ray; Markel, Mark D.; Murphy, William L.

2012-01-01

Despite the potential for growth factor delivery strategies to promote orthopedic implant healing, there is a need for growth factor delivery methods that are controllable and amenable to clinical translation. We have developed a modular bone growth factor, herein termed “modular bone morphogenetic peptide (mBMP)”, which was designed to efficiently bind to the surface of orthopedic implants and also stimulate new bone formation. The purpose of this study was to coat a hydroxyapatite-titanium implant with mBMP and evaluate bone healing across a bone-implant gap in the sheep femoral condyle. The mBMP molecules efficiently bound to a hydroxyapatite-titanium implant and 64% of the initially bound mBMP molecules were released in a sustained manner over 28 days. The results demonstrated that the mBMP-coated implant group had significantly more mineralized bone filling in the implant-bone gap than the control group in C-arm computed tomography (DynaCT) scanning (25% more), histological (35% more) and microradiographic images (50% more). Push-out stiffness of the mBMP group was nearly 40% greater than that of control group whereas peak force did not show a significant difference. The results of this study demonstrated that mBMP coated on a hydroxyapatite-titanium implant stimulates new bone formation and may be useful to improve implant fixation in total joint arthroplasty applications. PMID:23185610

Effect of diet-induced vitamin D deficiency on rotator cuff healing in a rat model.

PubMed

Angeline, Michael E; Ma, Richard; Pascual-Garrido, Cecilia; Voigt, Clifford; Deng, Xiang Hua; Warren, Russell F; Rodeo, Scott A

2014-01-01

Few studies have considered hormonal influences, particularly vitamin D, on healing. Vitamin D deficiency would have a negative effect on the structure of the healing tendon-bone interface in a rat model and would result in decreased tendon attachment strength. Controlled laboratory study. Vitamin D deficiency was induced in 28 male Sprague-Dawley rats using a specialized vitamin D-deficient diet and ultraviolet light restriction. Serum levels of vitamin D were measured after 6 weeks. These vitamin D-deficient animals (experimental group) plus 32 rats with normal vitamin D levels (controls) underwent unilateral detachment of the right supraspinatus tendon from the greater tuberosity of the humerus, followed by immediate repair using bone tunnel suture fixation. The animals were sacrificed at 2- and 4-week intervals after surgery for biomechanical analysis. A paired t test was used to compare serum vitamin D levels at day 0 and at 6 weeks. A nonparametric Mann-Whitney U test was used to compare load-to-failure and stiffness values between the experimental group and controls. Bone density and new bone formation at the tendon insertion site on the greater tuberosity were assessed with micro-computed tomography (CT). The organization of collagen tissue, new bone formation, vascularity at the tendon-bone interface, fibrocartilage at the tendon-bone interface, and collagen fiber continuity between the tendon and bone tissue were evaluated with safranin O and picrosirius red staining. Blood draws confirmed vitamin D deficiency at 6 weeks compared with time zero/baseline for rats in the experimental group (10.9 ng/mL vs 6.5 ng/mL, respectively; P < .001). Biomechanical testing demonstrated a significant decrease in load to failure in the experimental group compared with controls at 2 weeks (5.8 ± 2.0 N vs 10.5 ± 4.4 N, respectively; P < .006). There was no difference in stiffness at 2 weeks between the control and experimental groups. At 4 weeks, there was no significant difference in load to failure or stiffness between the control and experimental groups. Histological analysis showed less bone formation and less collagen fiber organization in the vitamin D-deficient specimens at 4 weeks as compared with controls. Micro-CT analysis showed no significant difference between groups for total mineral density and bone volume fraction of cortical, whole, or trabecular bone at 4 weeks. The biomechanical and histological data from this study suggest that low vitamin D levels may negatively affect early healing at the rotator cuff repair site. It is estimated that 1 billion people worldwide are vitamin D deficient. In the deficient state, acutely injured rotator cuffs may have a reduced ability for tendon healing. Further studies are needed to determine the exact mechanism by which vitamin D affects tendon healing and whether vitamin D supplementation can improve rotator cuff tendon healing and reduce the incidence of retears.

Enhancement of healing in osteochondral defects by collagen sponge implants.

PubMed

Speer, D P; Chvapil, M; Volz, R G; Holmes, M D

1979-10-01

Implants of porous, highly cross-linked collagen sponge (CS) were tested for their capacity to enhance the healing of osteochondral defects in rabbits. Comparison was made to the healing of similar defects with polyvinyl alcohol sponge (PVAS) implants and with no implants (CONT). Evaluation was carried out up to 44 weeks following implantation and included observation of host cellular response, biodegradability of implant, gross appearance of restored joint surface, collagenous architecture of repair tissue, and properties of the junctions of implants and host articular cartilage, subchondral bone, and medullary bone. Collagen sponge proved most effective in promoting healing of osteochondral defects with fibrous and fibrocartilaginous tissue over restored subchondral bone. Collagen sponge showed many desirable properties as a potential material for biologic resurfacing of damaged joints. These properties included porosity, biodegradability, biocompatability, ability to mechanically protect cells and matrix while directing cell ingrowth, and an available chemical technology for modifying its biomechanical and biological properties. Comparative analysis of results of healing of CS, PVAS, and CONT osteochondral defects suggest rational design criteria for implant materials to improve their effectiveness in restoration of articular surfaces.

Defect nonunion of a metatarsal bone fracture in a cow: successful management with bone plating and autogenous cancellous bone graft.

PubMed

Raghunath, M; Singh, N; Singh, T; Gopinathan, A; Mohindroo, J; Atri, K

2013-01-01

A two-and-half-year-old cow was presented with a defect nonunion of the right metatarsal III/IV bone following a severely comminuted open fracture two months previously. The animal underwent open fixation using a 4.5 mm, broad, 10-hole, dynamic compression plate and autogenous cancellous bone graft collected from the contralateral iliac shaft. The animal started partial weight bearing after the third postoperative day and resumed complete weight bearing after the 10th day. Fracture healing was complete and the implants were removed after the 120th postoperative day. Stable fixation by means of a bone plate in conjunction with a cancellous bone graft facilitated complete healing and restoration of the bone column of the defect and the metatarsal fracture. The animal made a complete recovery.

Combination of platelet-rich plasma with degradable bioactive borate glass for segmental bone defect repair.

PubMed

Zhang, Ya-Dong; Wang, Gang; Sun, Yan; Zhang, Chang-Qing

2011-02-01

Porous scaffold biomaterials may offer a clinical alternative to bone grafts; however, scaffolds alone are typically insufficient to heal large bone defects. Numerous studies have demonstrated that osteoinductive growth factor significantly improves bone repair. In this study, a strategy combining degradable bioactive borate glass (BG) scaffolds with platelet-rich plasma (PRP) was tested. The bone defect was filled with BG alone, BG combined with autologous PRP or left empty. Bone formation was analyzed at 4, 8 and 12 weeks using both histology and radiology. The PRP treated group yielded better bone formation than the pure BG scaffold as determined by both histology and microcomputer tomography after 12 weeks. In conclusion, PRP improved bone healing in a diaphyseal rabbit model on BG. The combination of PRP and BG may be an effective approach to repair critical defects.

Stem cell-mediated accelerated bone healing observed with in vivo molecular and small animal imaging technologies in a model of skeletal injury.

PubMed

Lee, Sheen-Woo; Padmanabhan, Parasuraman; Ray, Pritha; Gambhir, Sanjiv Sam; Doyle, Timothy; Contag, Christopher; Goodman, Stuart B; Biswal, Sandip

2009-03-01

Adult stem cells are promising therapeutic reagents for skeletal regeneration. We hope to validate by molecular imaging technologies the in vivo life cycle of adipose-derived multipotent cells (ADMCs) in an animal model of skeletal injury. Primary ADMCs were lentivirally transfected with a fusion reporter gene and injected intravenously into mice with bone injury or sham operation. Bioluminescence imaging (BLI), [(18)F]FHBG (9-(fluoro-hydroxy-methyl-butyl-guanine)-micro-PET, [(18)F]Fluoride ion micro-PET and micro-CT were performed to monitor stem cells and their effect. Bioluminescence microscopy and immunohistochemistry were done for histological confirmation. BLI showed ADMC's traffic from the lungs then to the injury site. BLI microscopy and immunohistochemistry confirmed the ADMCs in the bone defect. Micro-CT measurements showed increased bone healing in the cell-injected group compared to the noninjected group at postoperative day 7 (p < 0.05). Systemically administered ADMC's traffic to the site of skeletal injury and facilitate bone healing, as demonstrated by molecular and small animal imaging. Molecular imaging technologies can validate the usage of adult adipose tissue-derived multipotent cells to promote fracture healing. Imaging can in the future help establish therapeutic strategies including dosage and administration route. (c) 2008 Orthopaedic Research Society.