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Sample records for accelerate fracture healing

  1. Hyperbaric Hyperoxia Accelerates Fracture Healing in Mice

    PubMed Central

    Kawada, Shigeo; Wada, Eiji; Matsuda, Ryoichi; Ishii, Naokata

    2013-01-01

    Increased oxygen tension influences bone metabolism. This study comprised two main experiments: one aimed to determine the bone mineral apposition and bone formation rates in vivo under hyperbaric hyperoxia (HBO), and the other aimed to evaluate the effects of exposure to HBO on fracture healing. In experiment 1, male mice were exposed to HBO [90 min/day at 90% O2 at 2 atmospheres absolute (ATA) for 5 days]. In experiment 2, an open femur fracture model was created in mice, followed by exposure to HBO 5 times/week (90 min/day at 90% O2 at 2 ATA) for 6 weeks after surgery. In experiment 1, HBO treatment significantly increased the mineral apposition and bone formation rates in the lumbar vertebra and femur and type 1 collagen alpha 1 and alkaline phosphatase mRNA expression in the lumbar vertebra. In experiment 2, at 2 weeks after fracture, the fracture callus was significantly larger in the HBO group than in the non-HBO group. Furthermore, at 4 and 6 weeks after fracture, radiographic findings showed accelerated fracture healing in the HBO group. At 6 weeks after fracture, femur stiffness and maximum load were significantly higher in the HBO group than in the non-HBO group. Urinary 8-hydroxy-2′-deoxyguanosine and plasma calcium concentrations were not significantly different between groups. These results suggest that exposure to HBO enhances bone anabolism and accelerates fracture healing without causing oxidative DNA damage or disruption of plasma calcium homeostasis. PMID:23967323

  2. Stimulation of angiogenesis by cilostazol accelerates fracture healing in mice.

    PubMed

    Herath, Steven C; Lion, Thorsten; Klein, Moritz; Stenger, David; Scheuer, Claudia; Holstein, Jörg H; Mörsdorf, Philipp; Rollmann, Mika F R; Pohlemann, Tim; Menger, Michael D; Histing, Tina

    2015-12-01

    Cilostazol, a selective phosphodiesterase-3 inhibitor, is known to control cyclic adenosine monophosphate (c-AMP) and to stimulate angiogenesis through upregulation of pro-angiogenic factors. There is no information, however, whether cilostazol affects fracture healing. We, therefore, studied the effect of cilostazol on callus formation and biomechanics during fracture repair. Bone healing was analyzed in a murine femur fracture stabilized with an intramedullary screw. Radiological, biomechanical, histomorphometric, histochemical, and protein biochemical analyses were performed at 2 and 5 weeks after fracture. Twenty-five mice received 30 mg/kg body weight cilostazol p.o. daily. Controls (n=24) received equivalent amounts of vehicle. In cilostazol-treated animals radiological analysis at 2 weeks showed an improved healing with an accelerated osseous bridging compared to controls. This was associated with a significantly higher amount of bony tissue and a smaller amount of cartilage tissue within the callus. Western blot analysis showed a higher expression of cysteine-rich protein 61 (CYR61), bone morphogenetic protein (BMP)-4, and receptor activator of NF-kappaB ligand (RANKL). At 5 weeks, improved fracture healing after cilostazol treatment was indicated by biomechanical analyses, demonstrating a significant higher bending stiffness compared to controls. Thus, cilostazol improves fracture healing by accelerating both bone formation and callus remodeling.

  3. Role of platelet-rich plasma in acceleration of bone fracture healing.

    PubMed

    Simman, Richard; Hoffmann, Andrea; Bohinc, R Jordan; Peterson, Wylan C; Russ, Andrew J

    2008-09-01

    Platelet-rich plasma (PRP) is a common therapy for acceleration of maxillofacial and spinal fusion bone-graft healing. This study analyzes the therapeutic role of PRP during long-bone fracture healing evaluated Lewis rats. Following creation of unilateral open femur fractures, either 500 microL thrombin-activated PRP (PRP treated group) or 500 microL saline (control group) were applied once to the fracture site. Fracture healing was analyzed after 1 and 4 weeks. Following 4 weeks of fracture healing, radiographic analysis demonstrated higher callus to cortex width ratio (P < 0.05) in the PRP group (PRP: 1.65 +/- 0.06; control: 1.48 +/- 0.05). Three-point load bearing showed increased bone strength following PRP treatment (PRP: 60.85 +/- 6.06 Newton, control: 47.66 +/- 5.49 Newton). Fracture histology showed enhanced bone formation in the PRP group. Immunohistochemistry and Western-blotting demonstrated healing-associated changes in transforming growth factor (TGF)-beta1 and bone morphogenetic protein (BMP)-2. Our results suggest that PRP accelerates bone fracture healing of rat femurs via modulation of TGF-beta1 and BMP-2 growth factor expression.

  4. 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.

  5. Low-intensity pulsed ultrasound accelerates rat femoral fracture healing by acting on the various cellular reactions in the fracture callus.

    PubMed

    Azuma, Y; Ito, M; Harada, Y; Takagi, H; Ohta, T; Jingushi, S

    2001-04-01

    Low-intensity pulsed ultrasound (LIPUS) has been shown to accelerate fracture healing in both animal models and clinical trials, but the mechanism of action remains unclear. In fracture healing, various consecutive cellular reactions occurred until repair. We investigated whether the advanced effects of LIPUS depended on the duration and timing of LIPUS treatment in a rat closed femoral fracture model to determine the target of LIPUS in the healing process. Sixty-nine Long-Evans male rats that have bilateral closed femoral fractures were used. The right femur was exposed to LIPUS (30 mW/cm2 spatial and temporal average [SATA], for 20 minutes/day), and the left femur was used as a control. Rats were divided into four groups according to timing and duration of treatment (Ph-1, days 1-8; Ph-2, days 9-16; Ph-3, days 17-24; throughout [T], days 1-24 after the fracture). Animals were killed on day 25. After radiographs and microfocus X-ray computed tomography (muCT) tomograms were taken, the hard callus area (HCA), bone mineral content (BMC) at the fracture site, and mechanical torsion properties were measured, and histological analysis was conducted. Interestingly, the maximum torque of the LIPUS-treated femur was significantly greater than that of the controls in all groups without any changes in HCA and BMC. The multiviewing of three-dimensional (3D) muCT reconstructions and histology supported our findings that the partial LIPUS treatment time was able to accelerate healing, but longer treatment was more effective. These results suggest that LIPUS acts on some cellular reactions involved in each phase of the healing process such as inflammatory reaction, angiogenesis, chondrogenesis, intramembranous ossification, endochondral ossification, and bone remodeling.

  6. Fracture healing and lipid mediators.

    PubMed

    O'Connor, J Patrick; Manigrasso, Michaele B; Kim, Brian D; Subramanian, Sangeeta

    2014-01-01

    Lipid mediators regulate bone regeneration during fracture healing. Prostaglandins and leukotrienes are well-known lipid mediators that regulate inflammation and are synthesized from the Ω-6 fatty acid, arachidonic acid. Cyclooxygenase (COX-1 or COX-2) and 5-lipoxygenase (5-LO) catalyze the initial enzymatic steps in the synthesis of prostaglandins and leukotrienes, respectively. Inhibition or genetic ablation of COX-2 activity impairs fracture healing in animal models. Genetic ablation of COX-1 does not affect the fracture callus strength in mice, suggesting that COX-2 activity is primarily responsible for regulating fracture healing. Inhibition of cyclooxygenase activity with nonsteroidal anti-inflammatory drugs (NSAIDs) is performed clinically to reduce heterotopic ossification, although clinical evidence that NSAID treatment impairs fracture healing remains controversial. In contrast, inhibition or genetic ablation of 5-LO activity accelerates fracture healing in animal models. Even though prostaglandins and leukotrienes regulate inflammation, loss of COX-2 or 5-LO activity appears to primarily affect chondrogenesis during fracture healing. Prostaglandin or prostaglandin analog treatment, prostaglandin-specific synthase inhibition and prostaglandin or leukotriene receptor antagonism also affect callus chondrogenesis. Unlike the Ω-6-derived lipid mediators, lipid mediators derived from Ω-3 fatty acids, such as resolvin E1 (RvE1), have anti-inflammatory activity. In vivo, RvE1 can inhibit osteoclastogenesis and limit bone resorption. Although Ω-6 and Ω-3 lipid mediators have clear-cut effects on inflammation, the role of these lipid mediators in bone regeneration is more complex, with apparent effects on callus chondrogenesis and bone remodeling. PMID:24795811

  7. Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells.

    PubMed

    Collette, Nicole M; Yee, Cristal S; Hum, Nicholas R; Murugesh, Deepa K; Christiansen, Blaine A; Xie, LiQin; Economides, Aris N; Manilay, Jennifer O; Robling, Alexander G; Loots, Gabriela G

    2016-07-01

    Loss of Sostdc1, a growth factor paralogous to Sost, causes the formation of ectopic incisors, fused molars, abnormal hair follicles, and resistance to kidney disease. Sostdc1 is expressed in the periosteum, a source of osteoblasts, fibroblasts and mesenchymal progenitor cells, which are critically important for fracture repair. Here, we investigated the role of Sostdc1 in bone metabolism and fracture repair. Mice lacking Sostdc1 (Sostdc1(-/-)) had a low bone mass phenotype associated with loss of trabecular bone in both lumbar vertebrae and in the appendicular skeleton. In contrast, Sostdc1(-/-) cortical bone measurements revealed larger bones with higher BMD, suggesting that Sostdc1 exerts differential effects on cortical and trabecular bone. Mid-diaphyseal femoral fractures induced in Sostdc1(-/-) mice showed that the periosteal population normally positive for Sostdc1 rapidly expands during periosteal thickening and these cells migrate into the fracture callus at 3days post fracture. Quantitative analysis of mesenchymal stem cell (MSC) and osteoblast populations determined that MSCs express Sostdc1, and that Sostdc1(-/-) 5day calluses harbor >2-fold more MSCs than fractured wildtype controls. Histologically a fraction of Sostdc1-positive cells also expressed nestin and α-smooth muscle actin, suggesting that Sostdc1 marks a population of osteochondral progenitor cells that actively participate in callus formation and bone repair. Elevated numbers of MSCs in D5 calluses resulted in a larger, more vascularized cartilage callus at day 7, and a more rapid turnover of cartilage with significantly more remodeled bone and a thicker cortical shell at 21days post fracture. These data support accelerated or enhanced bone formation/remodeling of the callus in Sostdc1(-/-) mice, suggesting that Sostdc1 may promote and maintain mesenchymal stem cell quiescence in the periosteum.

  8. 5. Accelerated Fracture Healing Targeting Periosteal Cells: Possibility of Combined Therapy of Low-Intensity Pulsed Ultrasound (LIPUS), Bone Graft, and Growth Factor (bFGF).

    PubMed

    Uchida, Kentaro; Urabe, Ken; Naruse, Koji; Mikuni-Takagaki, Yuko; Inoue, Gen; Takaso, Masashi

    2016-08-01

    We have studied the mechanism of fracture healing, and the effect of LIPUS, bone graft and growth factor on accelerating fracture healing. We present here the results of our research. To examine callus formation cells in fracture healing, we made marrow GFP chimera mice and a fracture model of marrow mesenchymal stem cell GFP chimera mice. It was demonstrated that periosteal cells were essential for callus formation. We focused on periosteal cells and examined the effect of LIPUS. In an in vitro experiment using a cultured part of the femur, LIPUS promoted ossification of the periosteal tissue. Further, LIPUS accelerated VEGF expression in the experiment using the femoral fracture model of mice. From these results, it was suggested that activation of periosteal cells might play a role in the fracture healing mechanism of LIPUS. Next, we discussed the possibility of combined therapy of LIPUS, bone graft and growth factor. Therapy involving the topical administration of bFGF using a controlled release system and bone graft could promote callus formation. In addition, LIPUS was able to promote membranaceous ossification after the bone graft. It was suggested that combined therapy of LIPUS, bone graft and bFGF could be a new option for treating fractures. PMID:27441766

  9. Current medical treatment strategies concerning fracture healing.

    PubMed

    Giannotti, Stefano; Bottai, Vanna; Dell'osso, Giacomo; Pini, Erica; De Paola, Gaia; Bugelli, Giulia; Guido, Giulio

    2013-05-01

    The morbidity and socioeconomic costs associated with bone healing are considerable. A number of fractures are complicated by impaired healing. This is prevalent in certain risk groups such as elderly, osteoporotics, post-menopausal women, and in people with malnutrition. The biologic process of fracture healing is complex and impacted by multiple factors. Some of them, such as the nutritional and health conditions, are patient-dependent, while others depend on the trauma experienced and stability of the fracture. Fracture healing disorders negatively affect the patient's quality of life and result in high health-care costs, as a second surgery is required to stabilize the fracture and stimulate bone biology. Future biotechnologies that accelerate fracture healing may be useful tools, which might also prevent the onset of these disorders. We list the characteristics of the drugs used for osteoporosis, but we point out in particular the use of strontium ranelate and teriparatide in our clinical practice in elderly patients, especially females, who reported fractures with risk of nonunion. This medical treatment could impaired fracture healing however, most of the evidence is obtained in animal studies and very few studies have been done in humans. Thus one could hypothesize the possibility of a medical treatment both as a preventive and as support to the synthesis. However, no clinical studies are available so far, and such studies are warranted before any conclusions can be drawn. A positive effect of osteoporosis treatments on bone healing is an interesting possibility and merits further clinical research. PMID:24133528

  10. Current medical treatment strategies concerning fracture healing.

    PubMed

    Giannotti, Stefano; Bottai, Vanna; Dell'osso, Giacomo; Pini, Erica; De Paola, Gaia; Bugelli, Giulia; Guido, Giulio

    2013-05-01

    The morbidity and socioeconomic costs associated with bone healing are considerable. A number of fractures are complicated by impaired healing. This is prevalent in certain risk groups such as elderly, osteoporotics, post-menopausal women, and in people with malnutrition. The biologic process of fracture healing is complex and impacted by multiple factors. Some of them, such as the nutritional and health conditions, are patient-dependent, while others depend on the trauma experienced and stability of the fracture. Fracture healing disorders negatively affect the patient's quality of life and result in high health-care costs, as a second surgery is required to stabilize the fracture and stimulate bone biology. Future biotechnologies that accelerate fracture healing may be useful tools, which might also prevent the onset of these disorders. We list the characteristics of the drugs used for osteoporosis, but we point out in particular the use of strontium ranelate and teriparatide in our clinical practice in elderly patients, especially females, who reported fractures with risk of nonunion. This medical treatment could impaired fracture healing however, most of the evidence is obtained in animal studies and very few studies have been done in humans. Thus one could hypothesize the possibility of a medical treatment both as a preventive and as support to the synthesis. However, no clinical studies are available so far, and such studies are warranted before any conclusions can be drawn. A positive effect of osteoporosis treatments on bone healing is an interesting possibility and merits further clinical research.

  11. Accelerated fracture healing in the geriatric, osteoporotic rat with recombinant human platelet-derived growth factor-BB and an injectable beta-tricalcium phosphate/collagen matrix.

    PubMed

    Hollinger, Jeffrey O; Onikepe, Andrew O; MacKrell, Jim; Einhorn, Thomas; Bradica, Gino; Lynch, Samuel; Hart, Charles E

    2008-01-01

    Aging and osteoporosis contribute to decreased bone mass and bone mineral density as well as compromised fracture healing rates and bone repair quality. Consequently, the purpose of this study was to determine if recombinant human platelet-derived growth factor-BB (rhPDGF-BB) delivered in an injectable beta-tricalcium phosphate/collagen matrix would enhance tibial fracture healing in geriatric (>2 years of age), osteoporotic rats. A total of 80 rats were divided equally among four groups: Fracture alone; Fracture plus matrix; Fracture plus matrix and either 0.3 mg/mL or 1.0 mg/mL rhPDGF-BB. At 3 and 5 weeks, rats were euthanized and treatment outcome was assessed histologically, radiographically, biomechanically, and by micro-CT. Results indicated rhPDGF-BB-treated fractures in osteoporotic, geriatric rats caused a statistically significant time-dependent increase in torsional strength 5 weeks after treatment. The healed fractures were equivalent in torsional strength to the contralateral, unoperated tibiae. Data from the study are the first, to our knowledge, to underscore rhPDGF-BB efficacy in an injectable beta-tricalcium phosphate/collagen matrix accelerated fracture repair in a geriatric, osteoporotic rat model.

  12. Effect of osteoporosis medications on fracture healing.

    PubMed

    Hegde, V; Jo, J E; Andreopoulou, P; Lane, J M

    2016-03-01

    Antiosteoporotic medications are often used to concurrently treat a patient's fragility fractures and underlying osteoporosis. This review evaluates the existing literature from animal and clinical models to determine these drugs' effects on fracture healing. The data suggest that these medications may enhance bone healing, yet more thorough prospective studies are warranted. Pharmacologic agents that influence bone remodeling are an essential component of osteoporosis management. Because many patients are first diagnosed with osteoporosis when presenting with a fragility fracture, it is critical to understand how osteoporotic medications influence fracture healing. Vitamin D and its analogs are essential for the mineralization of the callus and may also play a role in callus formation and remodeling that enhances biomechanical strength. In animal models, antiresorptive medications, including bisphosphonates, denosumab, calcitonin, estrogen, and raloxifene, do not impede endochondral fracture healing but may delay repair due to impaired remodeling. Although bisphosphonates and denosumab delay callus remodeling, they increase callus volume and result in unaltered biomechanical properties. Calcitonin increases cartilage formation and callus maturation, resulting in improved biomechanical properties. Parathyroid hormone, an anabolic agent, has demonstrated promise in animal models, resulting in accelerated healing with increased callus volume and density, more rapid remodeling to mature bone, and improved biomechanical properties. Clinical data with parathyroid hormone have demonstrated enhanced healing in distal radius and pelvic fractures as well as postoperatively following spine surgery. Strontium ranelate, which may have both antiresorptive and anabolic properties, affects fracture healing differently in normal and osteoporotic bone. While there is no effect in normal bone, in osteoporotic bone, strontium ranelate increases callus bone formation, maturity, and

  13. Demineralized Bone Matrix Add-On for Acceleration of Bone Healing in Atypical Subtrochanteric Femoral Fracture: A Consecutive Case-Control Study

    PubMed Central

    Kulachote, Noratep; Sirisreetreerux, Norachart; Chanplakorn, Pongsthorn; Fuangfa, Praman; Suphachatwong, Chanyut; Wajanavisit, Wiwat

    2016-01-01

    Background. Delayed union and nonunion are common complications in atypical femoral fractures (AFFs) despite having good fracture fixation. Demineralized bone matrix (DBM) is a successfully proven method for enhancing fracture healing of the long bone fracture and nonunion and should be used in AFFs. This study aimed to compare the outcome after subtrochanteric AFFs (ST-AFFs) fixation with and without DBM. Materials and Methods. A prospective study was conducted on 9 ST-AFFs patients using DBM (DBM group) during 2013-2014 and compared with a retrospective consecutive case series of ST-AFFs patients treated without DBM (2010–2012) (NDBM group, 9 patients). All patients were treated with the same standard guideline and followed up until fractures completely united. Postoperative outcomes were then compared. Results. DBM group showed a significant shorter healing time than NDBM group (28.1 ± 14.4 versus 57.9 ± 36.8 weeks, p = 0.04). Delayed union was found in 4 patients (44%) in DBM group compared with 7 patients (78%) in NDBM group (p > 0.05). No statistical difference of nonunion was demonstrated between both groups (DBM = 1 and NDBM = 2, p > 0.05). Neither postoperative infection nor severe local tissue reaction was found. Conclusions. DBM is safe and effective for accelerating the fracture healing in ST-AFFx and possibly reduces nonunion after fracture fixation. Trial registration number is TCTR20151021001. PMID:27022610

  14. Current medical treatment strategies concerning fracture healing

    PubMed Central

    Giannotti, Stefano; Bottai, Vanna; Dell’Osso, Giacomo; Pini, Erica; De Paola, Gaia; Bugelli, Giulia; Guido, Giulio

    2013-01-01

    Summary The morbidity and socioeconomic costs associated with bone healing are considerable. A number of fractures are complicated by impaired healing. This is prevalent in certain risk groups such as elderly, osteoporotics, post-menopausal women, and in people with malnutrition. The biologic process of fracture healing is complex and impacted by multiple factors. Some of them, such as the nutritional and health conditions, are patient-dependent, while others depend on the trauma experienced and stability of the fracture. Fracture healing disorders negatively affect the patient’s quality of life and result in high health-care costs, as a second surgery is required to stabilize the fracture and stimulate bone biology. Future biotechnologies that accelerate fracture healing may be useful tools, which might also prevent the onset of these disorders. We list the characteristics of the drugs used for osteoporosis, but we point out in particular the use of strontium ranelate and teriparatide in our clinical practice in elderly patients, especially females, who reported fractures with risk of nonunion. This medical treatment could impaired fracture healing however, most of the evidence is obtained in animal studies and very few studies have been done in humans. Thus one could hypothesize the possibility of a medical treatment both as a preventive and as support to the synthesis. However, no clinical studies are available so far, and such studies are warranted before any conclusions can be drawn. A positive effect of osteoporosis treatments on bone healing is an interesting possibility and merits further clinical research. PMID:24133528

  15. Fracture healing: mechanisms and interventions

    PubMed Central

    Einhorn, Thomas A.; Gerstenfeld, Louis C.

    2015-01-01

    Fractures are the most common large-organ, traumatic injuries to humans. The repair of bone fractures is a postnatal regenerative process that recapitulates many of the ontological events of embryonic skeletal development. Although fracture repair usually restores the damaged skeletal organ to its pre-injury cellular composition, structure and biomechanical function, about 10% of fractures will not heal normally. This article reviews the developmental progression of fracture healing at the tissue, cellular and molecular levels. Innate and adaptive immune processes are discussed as a component of the injury response, as are environmental factors, such as the extent of injury to the bone and surrounding tissue, fixation and the contribution of vascular tissues. We also present strategies for fracture treatment that have been tested in animal models and in clinical trials or case series. The biophysical and biological basis of the molecular actions of various therapeutic approaches, including recombinant human bone morphogenetic proteins and parathyroid hormone therapy, are also discussed. PMID:25266456

  16. Local Erythropoietin Injection in Tibiofibular Fracture Healing

    PubMed Central

    Bakhshi, Hooman; Kazemian, Gholamhossein; Emami, Mohammad; Nemati, Ali; Karimi Yarandi, Hossein; Safdari, Farshad

    2013-01-01

    Background Erythropoietin (EPO), in addition to its function as an erythropoiesis regulator has a regenerative activity on some nonhematopoietic tissues. Animal studies have suggested a role for erythropoietin in bone healing. Objectives The present study aimed to evaluate the effects of local EPO injection in healing of tibiofibular fractures. Materials and Methods In a prospective double blind study, 60 patients with tibiofibular fracture were divided to equal EPO or placebo groups, randomly. Patients received local injection of either EPO or a placebo to the site of fracture two weeks after surgical fixation. Patients were followed by clinical and radiographic examination to determine the union rate. The period of fracture union and incidence of nonunion were compared between the two groups. Results The demographic data and types of fractures were similar in the both groups. The mean duration of the fracture union was 2.1 weeks shorter in those treated with EPO (P = 0.01). Nonunion was observed in 6 patients of the control group and 2 receiving EPO (P = 0.02). No patient experienced any adverse effect from local EPO injections. Conclusions EPO injection into the site of tibiofibular fractures may possibly accelerate healing. PMID:24350133

  17. [Stress shielding and fracture healing].

    PubMed

    Liu, J G; Xu, X X

    1994-08-01

    The influence of stress shielding after fracture fixation with plate on fracture healing was studied. The results of animal and biomechanical experiments as well as the clinical observations demonstrated that rigidity of the plate was not the only factor causing stress redistribution and stress shielding effects of bone. Either the internal fixation with different implants or external fixation with fixators all might lead to physical and chemical characteristic changes of bone tissue. In the early stage, the disturbance of blood supply and the bone structure remodeling may be the main reasons. Reaction to the implant was another cause in the middle stage. If the affected limb can take weight-bearing normally at late stage, the influences of plate on fracture healing mechanical properties of bone and the osteoporosis cause by stress shielding effects will become much less. The tissue of the affected limb was the most important factor which may cause osteoporosis and refracture. Osteoporosis, bone atrophy and immobilization syndrome of bone and joint can be prevented and treated by taking normal weight-bearing and overcoming infection and implant reaction. PMID:7994658

  18. How do bisphosphonates affect fracture healing?

    PubMed

    Kates, Stephen L; Ackert-Bicknell, Cheryl L

    2016-01-01

    Bisphosphonates (BPs) have been in use for many years for the treatment of osteoporosis, multiple myeloma, Paget's disease, as well as a variety of other diseases in which there is reduced bone mineral density. Given that bisphosphonates inhibit bone resorption, an important stage of fracture healing; this class of compounds has been widely studied in preclinical models regarding their influence on fracture healing. In animal models, bisphosphonate treatment is associated with a larger fracture callus, coincident with a delay in remodeling from primary woven bone to lamellar bone, but there is no delay in formation of the fracture callus. In humans, de novo use of bisphosphonate therapy after fracture does not appear to have a significant effect on fracture healing. Rarely, patients with long term use of Bisphosphonates may develop an atypical fracture and delay in fracture healing has been observed. In summary, bisphosphonates appear safe for use in the setting of acute fracture management in the upper and lower extremity in humans. While much remains unknown about the effects on healing of long-term bisphosphonates, use prior to "typical" fracture, in the special case of atypical fracture, evidence suggests that bisphosphonates negatively influence healing. PMID:26768295

  19. 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.

  20. Local insulin therapy affects fracture healing in a rat model.

    PubMed

    Park, Andrew G; Paglia, David N; Al-Zube, Loay; Hreha, Jeremy; Vaidya, Swaroopa; Breitbart, Eric; Benevenia, Joseph; O'Connor, J Patrick; Lin, Sheldon S

    2013-05-01

    A significant number of lower extremity fractures result in mal-union necessitating effective treatments to restore ambulation. Prior research in diabetic animal fracture models demonstrated improved healing following local insulin application to the fracture site and indicated that local insulin therapy can aid bone regeneration, at least within an insulin-dependent diabetic animal model. This study tested whether local insulin therapy could accelerate femur fracture repair in normal, non-diabetic rats. High (20 units) and low (10 units) doses of insulin were delivered in a calcium sulfate carrier which provided sustained release of the exogenous insulin for 7 days after fracture. Histomorphometry, radiographic scoring, and torsional mechanical testing were used to measure fracture healing. The fracture calluses from rats treated with high-dose insulin had significantly more cartilage than untreated rats after 7 and 14 days of healing. After 4 weeks of healing, femurs from rats treated with low-dose insulin had significantly higher radiographic scores and mechanical strength (p < 0.05), compared to the no treatment control groups. The results of this study suggest that locally delivered insulin is a potential therapeutic agent for treating bone fractures. Further studies are necessary, such as large animal proof of concepts, prior to the clinical use of insulin for bone fracture treatment.

  1. Impaired Fracture Healing after Hemorrhagic Shock

    PubMed Central

    Kobbe, Philipp; Pfeifer, Roman; Campbell, Graeme C.; Tohidnezhad, Mersedeh; Bergmann, Christian; Kadyrov, Mamed; Fischer, Horst; Glüer, Christian C.; Pape, Hans-Christoph; Pufe, Thomas

    2015-01-01

    Impaired fracture healing can occur in severely injured patients with hemorrhagic shock due to decreased soft tissue perfusion after trauma. We investigated the effects of fracture healing in a standardized pressure controlled hemorrhagic shock model in mice, to test the hypothesis that bleeding is relevant in the bone healing response. Male C57/BL6 mice were subjected to a closed femoral shaft fracture stabilized by intramedullary nailing. One group was additionally subjected to pressure controlled hemorrhagic shock (HS, mean arterial pressure (MAP) of 35 mmHg for 90 minutes). Serum cytokines (IL-6, KC, MCP-1, and TNF-α) were analyzed 6 hours after shock. Fracture healing was assessed 21 days after fracture. Hemorrhagic shock is associated with a significant increase in serum inflammatory cytokines in the early phase. Histologic analysis demonstrated a significantly decreased number of osteoclasts, a decrease in bone quality, and more cartilage islands after hemorrhagic shock. μCT analysis showed a trend towards decreased bone tissue mineral density in the HS group. Mechanical testing revealed no difference in tensile failure. Our results suggest a delay in fracture healing after hemorrhagic shock. This may be due to significantly diminished osteoclast recruitment. The exact mechanisms should be studied further, particularly during earlier stages of fracture healing. PMID:26106256

  2. Local transplantation of ex vivo expanded bone marrow-derived CD34-positive cells accelerates fracture healing.

    PubMed

    Kawakami, Yohei; Ii, Masaaki; Alev, Cantas; Kawamoto, Atsuhiko; Matsumoto, Tomoyuki; Kuroda, Ryosuke; Shoji, Taro; Fukui, Tomoaki; Masuda, Haruchika; Akimaru, Hiroshi; Mifune, Yutaka; Kuroda, Tomoya; Horii, Miki; Yokoyama, Ayumi; Kurosaka, Masahiro; Asahara, Takayuki

    2012-01-01

    Transplantation of bone marrow (BM) CD34(+) cells, an endothelial/hematopoietic progenitor-enriched cell population, has shown therapeutic efficiency in the treatment of ischemic diseases enhancing neovascularization. However, the number of CD34(+) cells obtained from bone marrow is not sufficient for routine clinical application. To overcome this issue, we developed a more efficient and clinically applicable CD34(+) cell expansion method. Seven-day ex vivo expansion culture of BM CD34(+) cells with a cocktail of five growth factors containing VEGF, SCF, IL-6, Flt-3 ligand, and TPO resulted in reproducible more than 20-fold increase in cell number. The favorable effect of the local transplantation of culture expanded (cEx)-BM CD34(+) cells on rat unhealing fractures was equivalent or higher than that of nonexpanded (fresh) BM CD34(+) cells exhibiting sufficient therapeutic outcome with frequent vasculogenic/osteogenic differentiation of transplanted cEx-BM CD34(+) cells and fresh BM CD34(+) cells as well as intrinsic enhancement of angiogenesis/osteogenesis at the treated fracture sites. Specifically, cEx-BM CD34(+) cell treatment demonstrated the best blood flow recovery at fracture sites compared with the nonexpanded BM CD34(+) cells. In vitro, cEx-BM CD34(+) cells showed higher colony/tube-forming capacity than nonexpanded BM CD34(+) cells. Both cells demonstrated differentiation potential into osteoblasts. Since fresh BM CD34(+) cells can be easily collected from fracture sites at the time of primary operation and stored for future use, autologous cEx-BM CD34(+) cell transplantation would be not only a simple but also a promising therapeutic strategy for unhealing fractures in the field of orthopedic trauma surgery.

  3. Creep healing of fractures in rock salt

    SciTech Connect

    Costin, L. S.; Wawersik, W. R.

    1980-08-01

    Fracture and healing experiments were performed on specimens of bedded salt from the Salado formation, southeastern New Mexico. Short rod specimens (100 mm in diameter) were loaded to failure in tension. During each test, a crack was initiated along the axis of the specimen. The fracture toughness of the salt was determined from the resulting load-crack opening displacement record. After the test, each specimen was pieced back together, jacketed and placed in a pressure vessel under hydrostatic pressure for several days. The confining pressure (10 to 35 MPa), temperature (22 to 100/sup 0/C) and healing time (4 to 8 days) were varied to determine the effect of each on the healing process. Upon removal from the pressure vessel, each sample was retested and the toughness of the healed fracture was determined. Results show that the salt specimens regained 70 to 80% of their original strength under all conditions except at the lowest temperature and pressure where specimens regained only 20 to 30% of their original strength. It is suspected that the primary mechanism involved is creep of asperities along the fracture surface which forms an interlocking network. Thus, the healing pressure is probably the most significant variable.

  4. Attempts to accelerate wound healing.

    PubMed

    Kasuya, Akira; Tokura, Yoshiki

    2014-12-01

    Wound healing is a well-orchestrated process, where numerous factors are activated or inhibited in a sequence of steps. Immediately after the infliction of damage, the repair of wound stars. The initial step is an inflammatory change with activation of innate immunity, which is followed by proliferation phase, including fibroplasia, angiogenesis and re-epithelialization. Pathological impairment of wound healing process may lead to persistent ulceration as seen in diabetic patients. Various signaling pathways are involved in wound healing. TGFβ/Smad pathway is a representative and well known to participate in fibroplasia, however, its comprehensive effect on wound healing is controversial. Experimental and clinical remedies have been being tried to promote wound healing. Advancement of cell engineering allows us to use stem cells and living skin equivalents.

  5. Inhibition of Midkine Augments Osteoporotic Fracture Healing

    PubMed Central

    Haffner-Luntzer, Melanie; Kemmler, Julia; Heidler, Verena; Prystaz, Katja; Schinke, Thorsten; Amling, Michael; Kovtun, Anna; Rapp, Anna E.; Ignatius, Anita; Liedert, Astrid

    2016-01-01

    The heparin-binding growth and differentiation factor midkine (Mdk) is proposed to negatively regulate osteoblast activity and bone formation in the adult skeleton. As Mdk-deficient mice were protected from ovariectomy (OVX)-induced bone loss, this factor may also play a role in the pathogenesis of postmenopausal osteoporosis. We have previously demonstrated that Mdk negatively influences bone regeneration during fracture healing. Here, we investigated whether the inhibition of Mdk using an Mdk-antibody (Mdk-Ab) improves compromised bone healing in osteoporotic OVX-mice. Using a standardized femur osteotomy model, we demonstrated that Mdk serum levels were significantly enhanced after fracture in both non-OVX and OVX-mice, however, the increase was considerably greater in osteoporotic mice. Systemic treatment with the Mdk-Ab significantly improved bone healing in osteoporotic mice by increasing bone formation in the fracture callus. On the molecular level, we demonstrated that the OVX-induced reduction of the osteoanabolic beta-catenin signaling in the bony callus was abolished by Mdk-Ab treatment. Furthermore, the injection of the Mdk-Ab increased trabecular bone mass in the skeleton of the osteoporotic mice. These results implicate that antagonizing Mdk may be useful for the therapy of osteoporosis and osteoporotic fracture-healing complications. PMID:27410432

  6. Effect of methotrexate on fracture healing.

    PubMed

    Satoh, Koichiro; Mark, Hans; Zachrisson, Peter; Rydevik, Björn; Byröd, Gunnar; Kikuchi, Shin-Ichi; Konno, Shin-Ichi; Sekiguchi, Miho

    2011-01-01

    Low doses of methotrexate (MTX) are safe and effective for treating adult and juvenile rheumatoid arthritis. However, because this powerful anti-inflammatory drug might negatively influence the healing of wounds and fractures, MTX administration is often stopped during surgical procedures. The present study assesses the effects of low- and high-dose MTX on early inflammatory processes and bone healing in an experimental model of fracture. Thirty male Sprague-Dawley rats were assigned to low- and high-dose MTX and control groups. A femur was cut using a reciprocating saw and a 2-mm fracture gap was made using a fixator. One or four weeks thereafter, macrophages were immunostained and new bone formation was histomorphometrically measured. Significantly less new bone was formed in the high-dose MTX, than in the control group (p< 0.01), whereas bone formation did not significantly differ between the low-dose MTX and control groups. These results suggested that a low dose of MTX does not affect the early process of endochondral bone formation during fracture healing, whereas a high dose might delay the progress of new periosteal bone formation. Although more macrophages were found in the groups treated with MTX, their impact on surrounding inflammatory processes remains unclear. PMID:21701078

  7. Fracture healing in the elderly: A review.

    PubMed

    Foulke, Bradley A; Kendal, Adrian R; Murray, David W; Pandit, Hemant

    2016-10-01

    Older patients are commonly at a higher risk of experiencing a bone fracture. Complications during fracture healing, including delayed union and non-union, can arise as a result of a multitude of patient and treatment factors. This review describes those factors which contribute to a greater risk of delayed union and non-union with particular reference to the elderly population and discusses therapies that may enhance the fracture healing process in the hope of reducing the incidence of delayed union and non-union. Increasing age does seem to increase the risk of delayed union or non-union. In addition, smoking and the treatment of post-fracture pain with non-steroidal anti-inflammatory drugs (NSAIDs) put the patient at the greatest risk, while ultrasound therapy appears to be a non-invasive, effective treatment option to reduce the risk of delayed union or non-union. The use of growth factors and of stem cells and the role of surgery are also discussed. PMID:27621238

  8. Indium-111 leukocyte scanning and fracture healing

    SciTech Connect

    Mead, L.P.; Scott, A.C.; Bondurant, F.J.; Browner, B.D. )

    1990-01-01

    This study was undertaken to determine the specificity of indium-111 leukocyte scans for osteomyelitis when fractures are present. Midshaft tibial osteotomies were performed in 14 New Zealand white rabbits, seven of which were infected postoperatively with Staphylococcus aureus per Norden's protocol. All 14 rabbits were scanned following injection with 75 microCi of indium 111 at 72 h after osteotomy and at weekly intervals for 4 weeks. Before the rabbits were killed, the fracture sites were cultured to document the presence or absence of infection. The results of all infected osteotomy sites were positive, whereas no positive scans were found in the noninfected osteotomies. We concluded from this study that uncomplicated fracture healing does not result in a positive indium-111 leukocyte scan.

  9. Electrical stimulation to accelerate wound healing

    PubMed Central

    Thakral, Gaurav; LaFontaine, Javier; Najafi, Bijan; Talal, Talal K.; Kim, Paul; Lavery, Lawrence A.

    2013-01-01

    Background There are several applications of electrical stimulation described in medical literature to accelerate wound healing and improve cutaneous perfusion. This is a simple technique that could be incorporated as an adjunctive therapy in plastic surgery. The objective of this review was to evaluate the results of randomized clinical trials that use electrical stimulation for wound healing. Method We identified 21 randomized clinical trials that used electrical stimulation for wound healing. We did not include five studies with treatment groups with less than eight subjects. Results Electrical stimulation was associated with faster wound area reduction or a higher proportion of wounds that healed in 14 out of 16 wound randomized clinical trials. The type of electrical stimulation, waveform, and duration of therapy vary in the literature. Conclusion Electrical stimulation has been shown to accelerate wound healing and increase cutaneous perfusion in human studies. Electrical stimulation is an adjunctive therapy that is underutilized in plastic surgery and could improve flap and graft survival, accelerate postoperative recovery, and decrease necrosis following foot reconstruction. PMID:24049559

  10. Acceleration Of Wound Healing Ny Photodynamic Therapy

    DOEpatents

    Hasan, Tayyaba; Hamblin, Michael R.; Trauner, Kenneth

    2000-08-22

    Disclosed is a method for accelerating wound healing in a mammal. The method includes identifying an unhealed wound site or partially-healed wound site in a mammal; administering a photosensitizer to the mammal; waiting for a time period wherein the photosensitizer reaches an effective tissue concentration at the wound site; and photoactivating the photosensitizer at the wound site. The dose of photodynamic therapy is selected to stimulate the production of one or more growth factor by cells at the wound site, without causing tissue destruction.

  11. Tibia Fracture Healing Prediction Using First-Order Mathematical Model.

    PubMed

    Sridevi, M; Prakasam, P; Kumaravel, S; Sarma, P Madhava

    2015-01-01

    The prediction of healing period of a tibia fracture in humans across limb using first-order mathematical model is demonstrated. At present, fracture healing is diagnosed using X-rays. Recent studies have demonstrated electric stimulation as a diagnostic tool in fracture healing. A DC electric voltage of 0.7 V was applied across the fracture and stabilized with Teflon coated carbon rings and the data was recorded at different time intervals until the fracture heals. The experimental data fitted a first-order plus dead time zero model (FOPDTZ) that coincided with the mathematical model of electrical simulated tibia fracture limb. Fracture healing diagnosis was proposed using model parameter process gain. Current stabilization in terms of process gain parameter becoming constant indicates that the healing of fracture is a new finding in the work. An error analysis was performed and it was observed that the measured data correlated to the FOPDTZ model with an error of less than 2 percent. Prediction of fracture healing period was done by one of the identified model parameters, namely, process gain. Moreover, mathematically, it is justified that once the fracture is completely united there is no capacitance present across the fracture site, which is a novelty of the work. PMID:26495032

  12. 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.

  13. Acceleration of cutaneous wound healing by brassinosteroids.

    PubMed

    Esposito, Debora; Rathinasabapathy, Thirumurugan; Schmidt, Barbara; Shakarjian, Michael P; Komarnytsky, Slavko; Raskin, Ilya

    2013-01-01

    Brassinosteroids are plant growth hormones involved in cell growth, division, and differentiation. Their effects in animals are largely unknown, although recent studies showed that the anabolic properties of brassinosteroids are possibly mediated through the phosphoinositide 3-kinase/protein kinase B signaling pathway. Here, we examined biological activity of homobrassinolide (HB) and its synthetic analogues in in vitro proliferation and migration assays in murine fibroblast and primary keratinocyte cell culture. HB stimulated fibroblast proliferation and migration and weakly induced keratinocyte proliferation in vitro. The effects of topical HB administration on progression of wound closure were further tested in the mouse model of cutaneous wound healing. C57BL/6J mice were given a full-thickness dermal wound, and the rate of wound closure was assessed daily for 10 days, with adenosine receptor agonist CGS-21680 as a positive control. Topical application of brassinosteroid significantly reduced wound size and accelerated wound healing in treated animals. mRNA levels of transforming growth factor beta and intercellular adhesion molecule 1 were significantly lower, while tumor necrosis factor alpha was nearly suppressed in the wounds from treated mice. Our data suggest that topical application of brassinosteroids accelerates wound healing by positively modulating inflammatory and reepithelialization phases of the wound repair process, in part by enhancing Akt signaling in the skin at the edges of the wound and enhancing migration of fibroblasts in the wounded area. Targeting this signaling pathway with brassinosteroids may represent a promising approach to the therapy of delayed wound healing.

  14. Nrf2 deficiency impairs fracture healing in mice.

    PubMed

    Lippross, Sebastian; Beckmann, Rainer; Streubesand, Nadine; Ayub, Ferda; Tohidnezhad, Mersedeh; Campbell, Graeme; Kan, Yuet Wai; Horst, Fischer; Sönmez, Tolga Taha; Varoga, Deike; Lichte, Philipp; Jahr, Holger; Pufe, Thomas; Wruck, Christoph Jan

    2014-10-01

    Oxidative stress plays an important role in wound healing but data relating oxidative stress to fracture healing are scarce. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the major transcription factor that controls the cellular defence essential to combat oxidative stress by regulating the expression of antioxidative enzymes. This study examined the impact of Nrf2 on fracture healing using a standard closed femoral shaft fracture model in wild-type (WT) and Nrf2-knockout (Nrf2-KO)-mice. Healing was evaluated by histology, real-time RT-PCR, µCT and biomechanical measurements. We showed that Nrf2 expression is activated during fracture healing. Bone healing and remodelling were retarded in the Nrf2-KO compared to the WT-mice. Nrf2-KO-mice developed significantly less callus tissue compared to WT-mice. In addition, biomechanical testing demonstrated lower strength against shear stress in the Nrf2-KO-group compared to WT. The expression of vascular endothelial growth factor (VEGF) and osteocalcin is reduced during fracture healing in Nrf2-KO-mice. Taken together, our results demonstrate that Nrf2 deficiency in mice results in impaired fracture healing suggesting that Nrf2 plays an essential role in bone regeneration. Pharmacological activation of Nrf2 may have therapeutic potential for the enhancement of fracture healing.

  15. The effect of aging on fracture healing in the rat.

    PubMed

    Bak, B; Andreassen, T T

    1989-11-01

    The effect of age on the biomechanical properties of healing tibial fractures was studied by comparing the fracture healing in 2-year-old male Wistar rats with the fracture healing in 3-month-old male Wistar rats after 40 and 80 days of healing. There were no significant differences in the mechanical parameters after 40 days of healing, but after 80 days, a considerable delay in the fracture healing process was noted in the old rats compared with the young adult rats when evaluated by maximum load, maximum stress, stiffness, and energy absorption in a three-point bending procedure. In the contralateral, nonfractured bones, the tibiae from the old animals sustained higher loads and had higher stiffness than the bones from the young adult animals, but stress values, elastic modulus, and capacity for energy absorption was much lower in the old animals.

  16. Ultrasound attenuation as a quantitative measure of fracture healing

    NASA Astrophysics Data System (ADS)

    Gheduzzi, Sabina; Humphrey, Victor F.; Dodd, Simon P.; Cunningham, James L.; Miles, Anthony W.

    2004-10-01

    The monitoring of fracture healing still relies upon the judgment of callus formation and on the manual assessment of the stiffness of the fracture. A diagnostic tool capable of quantitatively measuring healing progression of a fracture would allow the fine-tuning of the treatment regime. Ultrasound attenuation measurements were adopted as a possible method of assessing the healing process in human long bones. The method involves exciting ultrasonic waves at 200 kHz in the bone and measuring the reradiation along the bone and across the fracture zone. Seven cadaveric femora were tested in vitro in intact form and after creating a transverse fracture by sawing through the cortex. The effects of five different fracture types were investigated. A partial fracture, corresponding to a 50% cut through the cortex, a closed fracture, and fractures of widths varying between 1, 2, and 4 mm were investigated. The introduction of a fracture was found to produce a dramatic effect on the amplitude of the signal. Ultrasound attenuation was found to be sensitive to the presence of a fracture, even when the fracture was well reduced. It would therefore appear feasible to adopt attenuation across a fracture as a quantitative measurement of fracture healing.

  17. Special Review: Accelerating fracture repair in humans: a reading of old experiments and recent clinical trials

    PubMed Central

    Aspenberg, Per

    2013-01-01

    Based on their mode of action and preclinical data, one would expect bisphosphonates to improve the healing of fractures in cancellous bone, and bone morphogenetic proteins (BMPs) to reduce the risk of non-union in severe shaft fractures. Parathyreoid hormone (PTH) can be expected to accelerate fracture healing in general. The clinical data in support of this is meager. Stimulation of cancellous bone healing and strength by bisphosphonates has been inadvertently shown in the context of implant fixation, but not convincingly in fractures per se. The clinical BMP literature is confusing, and the chance of ever demonstrating reduced numbers of non-union are small, due to power issues. Still, acceleration of ‘normal' healing may be possible, but largely remains to show. For PTH, the two available clinical trials both show accelerated healing, but none of them is flawless, and there is a need for better studies. PMID:24404375

  18. Chitosan-alginate membranes accelerate wound healing.

    PubMed

    Caetano, Guilherme Ferreira; Frade, Marco Andrey Cipriani; Andrade, Thiago Antônio Moretti; Leite, Marcel Nani; Bueno, Cecilia Zorzi; Moraes, Ângela Maria; Ribeiro-Paes, João Tadeu

    2015-07-01

    The purpose of this study was to evaluate the efficacy of chitosan-alginate membrane to accelerate wound healing in experimental cutaneous wounds. Two wounds were performed in Wistar rats by punching (1.5 cm diameter), treated with membranes moistened with saline solution (CAM group) or with saline only (SL group). After 2, 7, 14, and 21 days of surgery, five rats of each group were euthanized and reepithelialization was evaluated. The wounds/scars were harvested for histological, flow cytometry, neutrophil infiltrate, and hydroxyproline analysis. CAM group presented higher inflammatory cells recruitment as compared to SL group on 2(nd) day. On the 7(th) day, CAM group showed higher CD11b(+) level and lower of neutrophils than SL group. The CAM group presented higher CD4(+) cells influx than SL group on 2(nd) day, but it decreased during the follow up and became lower on 14(th) and 21(st) days. Higher fibroplasia was noticed on days 7 and 14 as well as higher collagenesis on 21(st) in the CAM group in comparison to SL group. CAM group showed faster reepithelialization on 7(th) day than SL group, although similar in other days. In conclusion, chitosan-alginate membrane modulated the inflammatory phase, stimulated fibroplasia and collagenesis, accelerating wound healing process in rats.

  19. In silico design of treatment strategies in wound healing and bone fracture healing.

    PubMed

    Geris, L; Schugart, R; Van Oosterwyck, H

    2010-06-13

    Wound and bone fracture healing are natural repair processes initiated by trauma. Over the last decade, many mathematical models have been established to investigate the healing processes in silico, in addition to ongoing experimental work. In recent days, the focus of the mathematical models has shifted from simulation of the healing process towards simulation of the impaired healing process and the in silico design of treatment strategies. This review describes the most important causes of failure of the wound and bone fracture healing processes and the experimental models and methods used to investigate and treat these impaired healing cases. Furthermore, the mathematical models that are described address these impaired healing cases and investigate various therapeutic scenarios in silico. Examples are provided to illustrate the potential of these in silico experiments. Finally, limitations of the models and the need for and ability of these models to capture patient specificity and variability are discussed.

  20. Comparison of fracture healing among different inbred mouse strains.

    PubMed

    Manigrasso, Michaele B; O'Connor, J Patrick

    2008-06-01

    Quantitative trait locus analysis can be used to identify genes critically involved in biological processes. No such analysis has been applied to identifying genes that control bone fracture healing. To determine the feasibility of such an approach, healing of femur fractures was measured between C57BL/6, DBA/2, and C3H inbred strains of mice. Healing was assessed by radiography and histology and measured by histomorphometry and biomechanical testing. In all strains, radiographic bridging of the fracture was apparent after 3 weeks of healing. Histology showed that healing occurred through endochondral ossification in all strains. Histomorphometric measurements found more bone in the C57BL/6 fracture calluses 7 and 10 days after fracture. In contrast, more cartilage was present after 7 days in the C3H callus, which rapidly declined to levels less than those of C57BL/6 or DBA/2 mice by 14 days after fracture. An endochondral ossification index was calculated by multiplying the callus percent cartilage and bone areas as a measure of endochondral ossification. At 7 and 10 days after fracture, this value was higher in C57BL/6 mice. Using torsional mechanical testing, normalized structural and material properties of the C57BL/6 healing femurs were higher than values from the DBA/2 or C3H mice 4 weeks after fracture. The data indicate that fracture healing proceeds more rapidly in C57BL/6 mice and demonstrate that genetic variability significantly contributes to the process of bone regeneration. Large enough differences exist between C57BL/6 and DBA/2 or C3H mice to permit a quantitative trait locus analysis to identify genes controlling bone regeneration.

  1. Increased callus mass and enhanced strength during fracture healing in mice lacking the sclerostin gene.

    PubMed

    Li, Chaoyang; Ominsky, Michael S; Tan, Hong-Lin; Barrero, Mauricio; Niu, Qing-Tian; Asuncion, Franklin J; Lee, Edward; Liu, Min; Simonet, William S; Paszty, Chris; Ke, Hua Zhu

    2011-12-01

    Humans with inherited sclerostin deficiency have high bone mass. Targeted deletion of the sclerostin gene in mice (SOST-KO) causes increases in bone formation, bone mass and bone strength. Inhibition of sclerostin by a monoclonal antibody increases bone formation and enhances fracture healing in rodent and primate models. In this study, we describe the temporal progression of femoral fracture healing in SOST-KO mice compared with wild type (WT) control mice to further characterize the role of sclerostin in fracture healing. Sixty-seven male 9-10 week-old SOST-KO (N=37) and WT (N=30) mice underwent a closed femoral fracture. Weekly radiography was used to monitor the progress of healing. Histologic sections were used to characterize callus composition, evaluate callus bridging, and quantify lamellar bone formation on days 14 and 28. Densitometry and biomechanical testing were utilized to characterize bone mass and strength at the fractured and contralateral femurs on day 45. A significant improvement in time to radiographic healing (no discernible fracture line) was observed in SOST-KO mice, which corresponded to an increase in histologic bony bridging at 14 days (38% versus 0% in WT). Both genotypes appeared to be nearly fully bridged at 28 days post-fracture. The increased bridging at 14 days was associated with 97% greater bone area and 40% lower cartilage area in the callus of SOST-KO mice as compared to WT mice. Bone formation-related endpoints were higher in SOST-KO mice at both 14 and 28 days. At 45 days post-fracture, peak load and bone mass were significantly greater in the fractured femurs of SOST-KO mice as compared to WT mice. In conclusion, fractures in mice lacking sclerostin showed accelerated bridging, greater callus maturation, and increased bone formation and strength in the callus.

  2. Teriparatide Improves Fracture Healing and Early Functional Recovery in Treatment of Osteoporotic Intertrochanteric Fractures

    PubMed Central

    Huang, Tsan-Wen; Chuang, Po-Yao; Lin, Shih-Jie; Lee, Chien-Yin; Huang, Kuo-Chin; Shih, Hsin-Nung; Lee, Mel S.; Hsu, Robert Wen-Wei; Shen, Wun-Jer

    2016-01-01

    Abstract Osteoporotic intertrochanteric fractures result in serious health problems and decrease health-related quality of life (HRQoL). Faster time-to-union is important for early return to daily activities and reduction of complications. Teriparatide has been shown to accelerate fracture healing, but the literature is sparse on this topic. The aim of this study is to assess whether teriparatide accelerates fracture healing. Between 2008 and 2014, patients with osteoporotic intertrochanteric fractures who underwent surgical interventions were enrolled in this retrospective cohort study. Group 1 included patients who were not on any osteoporosis medication prior to fracture and who postoperatively received only calcium and vitamin D; patients in Group 2 were not on any osteoporosis medication prior to fracture, and received teriparatide and calcium and vitamin D postoperatively. Patients in Group 3 were those who were on alendronate prior to fracture and postfracture received teriparatide as well as calcium and vitamin D. Demographics, time-to-union, HRQoL (short-form health survey [SF]-12 physical component summary [PCS] and SF-12 mental component summary [MCS]), morbidities, mortalities, and radiographic and functional outcomes between groups were compared. A total of 189 patients were enrolled in this study. There were 83 patients in Group 1, 47 patients in Group 2, and 59 patients in Group 3. A significantly shorter time-to-union was found in the teriparatide-treated groups (mean, 13.6, 12.3, and 10.6 weeks, respectively [P = 0.002]). With regard to SF-12 PCS, the scores were significantly better in teriparatide-treated groups at 3 months (mean, 19, 28, and 29, respectively [P = 0.002]) and 6 months (mean, 28, 37, and 38, respectively [P = 0.008]). Similar inter-group differences were noted when comparing the pain scores, the ability to get around the house, the ability to get out of the house, and the ability to go shopping at 3 and 6 months

  3. Pentoxifylline and electromagnetic field improved bone fracture healing in rats

    PubMed Central

    Atalay, Yusuf; Gunes, Nedim; Guner, Mehmet Dervis; Akpolat, Veysi; Celik, Mustafa Salih; Guner, Rezzan

    2015-01-01

    Background The aim of this study was to evaluate the effects of a phosphodiesterase inhibitor pentoxifylline (PTX), electromagnetic fields (EMFs), and a mixture of both materials on bone fracture healing in a rat model. Materials and methods Eighty male Wistar rats were randomly divided into four groups: Group A, femur fracture model with no treatment; Group B, femur fracture model treated with PTX 50 mg/kg/day intraperitoneal injection; Group C, femur fracture model treated with EMF 1.5±0.2 Mt/50 Hz/6 hours/day; and Group D, femur fracture model treated with PTX 50 mg/kg/day intraperitoneal injection and EMF 1.5±0.2 Mt/50 Hz/6 hours/day. Results Bone fracture healing was significantly better in Group B and Group C compared to Group A (P<0.05), but Group D did not show better bone fracture healing than Group A (P>0.05). Conclusion It can be concluded that both a specific EMF and PTX had a positive effect on bone fracture healing but when used in combination, may not be beneficial. PMID:26388687

  4. In vivo measurement of bending stiffness in fracture healing

    PubMed Central

    Hente, Reiner; Cordey, Jacques; Perren, Stephan M

    2003-01-01

    Background Measurement of the bending stiffness a healing fracture represents a valid variable in the assessment of fracture healing. However, currently available methods typically have high measurement errors, even for mild pin loosening. Furthermore, these methods cannot provide actual values of bending stiffness, which precludes comparisons among individual fractures. Thus, even today, little information is available with regards to the fracture healing pattern with respect to actual values of bending stiffness. Our goals were, therefore: to develop a measurement device that would allow accurate and sensitive measurement of bending stiffness, even in the presence of mild pin loosening; to describe the course of healing in individual fractures; and help to evaluate whether the individual pattern of bending stiffness can be predicted at an early stage of healing. Methods A new measurement device has been developed to precisely measure the bending stiffness of the healing fracture by simulating four-point-bending. The system was calibrated on aluminum models and intact tibiae. The influence of pin loosening on measurement error was evaluated. The system was tested at weekly intervals in an animal experiment to determine the actual bending stiffness of the fracture. Transverse fractures were created in the right tibia of twelve sheep, and then stabilized with an external fixator. At ten weeks, bending stiffness of the tibiae were determined in a four-point-bending test device to validate the in-vivo-measurement data. Results In-vivo bending stiffness can be measured accurately and sensitive, even in the early phase of callus healing. Up to a bending stiffness of 10 Nm/degree, measurement error was below 3.4% for one pin loose, and below 29.3% for four pins loose, respectively. Measurement of stiffness data over time revealed a significant logarithmic increase between the third and seventh weeks, whereby the logarithmic rate of change among sheep was similar, but

  5. Are OPG and RANKL involved in human fracture healing?

    PubMed

    Köttstorfer, Julia; Thomas, Anita; Gregori, Markus; Kecht, Mathias; Kaiser, Georg; Eipeldauer, Stefan; Sarahrudi, Kambiz

    2014-12-01

    Human fracture healing is a complex interaction of several cytokines that regulate osteoblast and osteoclast activity. By monitoring OPG (osteoprotegerin) and sRANKL we aimed to possibly predict normal or impaired fracture healing. In 64 patients with a fracture of a long bone serum level of sRANKL and OPG were evaluated with respect to bony union (n=57) or pseudarthrosis (n=7). Measurements were carried out at admission and at 1, 2, 4, 6, 8, 12, 24, and 48 weeks after the injury. Patients' serum levels were compared to 33 healthy controls. Fracture hematoma contained significantly higher sRANKL and OPG concentrations compared to patients serum (p=0.005, p=0.028). OPG level in fracture hematoma was higher compared to the unions serum level (p=0.028). sRANKL was decreased in unions during the observation period. In non-unions sRANKL and OPG levels showed a variable course, with no statistical significance. This is the first study to document the course of OPG and sRANKL in normal and delayed human fracture healing emphasizing its local and systemic involvement. We provide evidence of strongly enhanced OPG levels in patients with a long bone fracture compared to healthy controls. Further, levels of free sRANKL were decreased during regular fracture repair.

  6. Systemic treatment with telmisartan improves femur fracture healing in mice.

    PubMed

    Zhao, Xiong; Wang, Jia-xing; Feng, Ya-fei; Wu, Zi-xiang; Zhang, Yang; Shi, Lei; Tan, Quan-chang; Yan, Ya-bo; Lei, Wei

    2014-01-01

    Recent clinical studies indicated that angiotensin receptor blockers (ARBs) would decrease the risk of bone fractures in the elderly populations. There is little known about the role of the ARBs in the process of fracture healing. The purpose of the present study was to verify the hypothesis that systemic treatment with telmisartan has the ability to promote fracture healing. In this study, femur fractures were produced in 96 mature male BALB/c mice. Animals were treated with the ARBs telmisartan or vehicle. Fracture healing was analysed after 2, 5 and 10 weeks postoperatively using X-ray, biomechanical testing, histomorphometry, immunohistochemistry and micro-computed tomography (micro-CT). Radiological analysis showed the diameter of the callus in the telmisartan treated animals was significantly increased when compared with that of vehicle treated controls after two weeks of fracture healing. The radiologically observed promotion of callus formation was confirmed by histomorphometric analyses, which revealed a significantly increased amount of bone formation when compared with vehicle-treated controls. Biomechanical testing further showed a significantly greater peak torque at failure, and a higher torsional stiffness in telmisartan-treated animals compared with controls. There was an increased fraction of PCNA-positive cells and VEGF-positive cells in telmisartan-treated group compared with vehicle-treated controls. From the three-dimensional reconstruction of the bony callus, telmisartan-treated group significantly increased the values of BV/TV by 21.7% and CsAr by 26.0% compared to the vehicle-treated controls at 5 weeks post-fracture. In summary, we demonstrate in the current study that telmisartan could promote fracture healing in a mice model via increasing mechanical strength and improving microstructure. The most mechanism is probably by an increase of cell proliferation and neovascularization associated with a decreased VEGF expression in hypertrophic

  7. Systemic Treatment with Telmisartan Improves Femur Fracture Healing in Mice

    PubMed Central

    Wu, Zi-xiang; Zhang, Yang; Shi, Lei; Tan, Quan-chang; Yan, Ya-bo; Lei, Wei

    2014-01-01

    Recent clinical studies indicated that angiotensin receptor blockers (ARBs) would decrease the risk of bone fractures in the elderly populations. There is little known about the role of the ARBs in the process of fracture healing. The purpose of the present study was to verify the hypothesis that systemic treatment with telmisartan has the ability to promote fracture healing. In this study, femur fractures were produced in 96 mature male BALB/c mice. Animals were treated with the ARBs telmisartan or vehicle. Fracture healing was analysed after 2, 5 and 10 weeks postoperatively using X-ray, biomechanical testing, histomorphometry, immunohistochemistry and micro-computed tomography (micro-CT). Radiological analysis showed the diameter of the callus in the telmisartan treated animals was significantly increased when compared with that of vehicle treated controls after two weeks of fracture healing. The radiologically observed promotion of callus formation was confirmed by histomorphometric analyses, which revealed a significantly increased amount of bone formation when compared with vehicle-treated controls. Biomechanical testing further showed a significantly greater peak torque at failure, and a higher torsional stiffness in telmisartan-treated animals compared with controls. There was an increased fraction of PCNA-positive cells and VEGF-positive cells in telmisartan-treated group compared with vehicle-treated controls. From the three-dimensional reconstruction of the bony callus, telmisartan-treated group significantly increased the values of BV/TV by 21.7% and CsAr by 26.0% compared to the vehicle-treated controls at 5 weeks post-fracture. In summary, we demonstrate in the current study that telmisartan could promote fracture healing in a mice model via increasing mechanical strength and improving microstructure. The most mechanism is probably by an increase of cell proliferation and neovascularization associated with a decreased VEGF expression in hypertrophic

  8. Radiation-induced alterations of fracture healing biomechanics

    SciTech Connect

    Pelker, R.R.; Friedlaender, G.E.; Panjabi, M.M.; Kapp, D.; Doganis, A.

    1984-01-01

    The effects of irradiation on the normal temporal progression of the physical properties of healing fractures were studied in a rat model. Fractures were surgically produced in the femur, stabilized with an intramedullary pin, and irradiated. One group of rats was exposed to 2,500 rads in divided doses over 2 weeks, beginning 3 days after fracture, and compared to a control group with fractures which were not irradiated. Animals were sacrificed at periodic intervals and the bones were tested to failure in torsion. The torque, stiffness, and energy increased and the angle decreased for the nonirradiated specimens in the expected fashion. This progression was deleteriously altered in the irradiated femurs.

  9. Fracture healing in protease-activated receptor-2 deficient mice.

    PubMed

    O'Neill, Kevin R; Stutz, Christopher M; Mignemi, Nicholas A; Cole, Heather; Murry, Matthew R; Nyman, Jeffry S; Hamm, Heidi; Schoenecker, Jonathan G

    2012-08-01

    Protease-activated receptor-2 (PAR-2) provides an important link between extracellular proteases and the cellular initiation of inflammatory responses. The effect of PAR-2 on fracture healing is unknown. This study investigates the in vivo effect of PAR-2 deletion on fracture healing by assessing differences between wild-type (PAR-2(+/+)) and knock-out (PAR-2(-/-)) mice. Unilateral mid-shaft femur fractures were created in 34 PAR-2(+/+) and 28 PAR-2(-/-) mice after intramedullary fixation. Histologic assessments were made at 1, 2, and 4 weeks post-fracture (wpf), and radiographic (plain radiographs, micro-computed tomography (µCT)) and biomechanical (torsion testing) assessments were made at 7 and 10 wpf. Both the fractured and un-fractured contralateral femur specimens were evaluated. Polar moment of inertia (pMOI), tissue mineral density (TMD), bone volume fraction (BV/TV) were determined from µCT images, and callus diameter was determined from plain radiographs. Statistically significant differences in callus morphology as assessed by µCT were found between PAR-2(-/-) and PAR-2(+/+) mice at both 7 and 10 wpf. However, no significant histologic, plain radiographic, or biomechanical differences were found between the genotypes. The loss of PAR-2 was found to alter callus morphology as assessed by µCT but was not found to otherwise effect fracture healing in young mice.

  10. Role of mathematical modeling in bone fracture healing

    PubMed Central

    Pivonka, Peter; Dunstan, Colin R

    2012-01-01

    Bone fracture healing is a complex physiological process commonly described by a four-phase model consisting of an inflammatory phase, two repair phases with soft callus formation followed by hard callus formation, and a remodeling phase, or more recently by an anabolic/catabolic model. Data from humans and animal models have demonstrated crucial environmental conditions for optimal fracture healing, including the mechanical environment, blood supply and availability of mesenchymal stem cells. Fracture healing spans multiple length and time scales, making it difficult to know precisely which factors and/or phases to manipulate in order to obtain optimal fracture-repair outcomes. Deformations resulting from physiological loading or fracture fixation at the organ scale are sensed at the cellular scale by cells inside the fracture callus. These deformations together with autocrine and paracrine signals determine cellular differentiation, proliferation and migration. The local repair activities lead to new bone formation and stabilization of the fracture. Although experimental data are available at different spatial and temporal scales, it is not clear how these data can be linked to provide a holistic view of fracture healing. Mathematical modeling is a powerful tool to quantify conceptual models and to establish the missing links between experimental data obtained at different scales. The objective of this review is to introduce mathematical modeling to readers who are not familiar with this methodology and to demonstrate that once validated, such models can be used for hypothesis testing and to assist in clinical treatment as will be shown for the example of atrophic nonunions. PMID:24228159

  11. Biomechanical Characteristics of Osteoporotic Fracture Healing in Ovariectomized Rats: A Systematic Review.

    PubMed

    Chen, Lin; Yang, Long; Yao, Min; Cui, Xue-Jun; Xue, Chun-Chun; Wang, Yong-Jun; Shu, Bing

    2016-01-01

    Biomechanical tests are widely used in animal studies on osteoporotic fracture healing. However, the biomechanical recovery process is still unknown, leading to difficulty in choosing time points for biomechanical tests and in correctly assessing osteoporotic fracture healing. To determine the biomechanical recovery process during osteoporotic fracture healing, studies on osteoporotic femur fracture healing with biomechanical tests in ovariectomized rat (OVX) models were collected from PUBMED, EMBASE, and Chinese databases. Quadratic curves of fracture healing time and maximum load were fitted with data from the analyzed studies. In the fitted curve for normal fractures, the predicted maximum load was 145.56 N, and the fracture healing time was 88.0 d. In the fitted curve for osteoporotic fractures, the predicted maximum load was 122.30 N, and the fracture healing time was 95.2 d. The maximum load of fractured femurs in OVX rats was also lower than that in sham rats at day 84 post-fracture (D84 PF). The fracture healing time was prolonged and maximum load at D84 PF decreased in OVX rats with closed fractures. The maximum load of Wister rats was higher than that of Sprague-Dawley (SD) rats, but the fracture healing time of SD and Wister rats was similar. Osteoporotic fracture healing was delayed in rats that were < = 12 weeks old when ovariectomized, and at D84 PF, the maximum load of rats < = 12 weeks old at ovariectomy was lower than that of rats >12 weeks old at ovariectomy. There was no significant difference in maximum load at D84 PF between rats with an osteoporosis modeling time <12 weeks and > = 12 weeks. In conclusion, fracture healing was delayed and biomechanical property decreased by osteoporosis. Time points around D95.2 PF should be considered for biomechanical tests of osteoporotic femur fracture healing in OVX rat models. Osteoporotic fracture healing in OVX rats was affected by the fracture type but not by the strain of the rat. PMID:27055104

  12. Biomechanical Characteristics of Osteoporotic Fracture Healing in Ovariectomized Rats: A Systematic Review.

    PubMed

    Chen, Lin; Yang, Long; Yao, Min; Cui, Xue-Jun; Xue, Chun-Chun; Wang, Yong-Jun; Shu, Bing

    2016-01-01

    Biomechanical tests are widely used in animal studies on osteoporotic fracture healing. However, the biomechanical recovery process is still unknown, leading to difficulty in choosing time points for biomechanical tests and in correctly assessing osteoporotic fracture healing. To determine the biomechanical recovery process during osteoporotic fracture healing, studies on osteoporotic femur fracture healing with biomechanical tests in ovariectomized rat (OVX) models were collected from PUBMED, EMBASE, and Chinese databases. Quadratic curves of fracture healing time and maximum load were fitted with data from the analyzed studies. In the fitted curve for normal fractures, the predicted maximum load was 145.56 N, and the fracture healing time was 88.0 d. In the fitted curve for osteoporotic fractures, the predicted maximum load was 122.30 N, and the fracture healing time was 95.2 d. The maximum load of fractured femurs in OVX rats was also lower than that in sham rats at day 84 post-fracture (D84 PF). The fracture healing time was prolonged and maximum load at D84 PF decreased in OVX rats with closed fractures. The maximum load of Wister rats was higher than that of Sprague-Dawley (SD) rats, but the fracture healing time of SD and Wister rats was similar. Osteoporotic fracture healing was delayed in rats that were < = 12 weeks old when ovariectomized, and at D84 PF, the maximum load of rats < = 12 weeks old at ovariectomy was lower than that of rats >12 weeks old at ovariectomy. There was no significant difference in maximum load at D84 PF between rats with an osteoporosis modeling time <12 weeks and > = 12 weeks. In conclusion, fracture healing was delayed and biomechanical property decreased by osteoporosis. Time points around D95.2 PF should be considered for biomechanical tests of osteoporotic femur fracture healing in OVX rat models. Osteoporotic fracture healing in OVX rats was affected by the fracture type but not by the strain of the rat.

  13. Biomechanical Characteristics of Osteoporotic Fracture Healing in Ovariectomized Rats: A Systematic Review

    PubMed Central

    Chen, Lin; Yang, Long; Yao, Min; Cui, Xue-Jun; Xue, Chun-Chun; Wang, Yong-Jun; Shu, Bing

    2016-01-01

    Biomechanical tests are widely used in animal studies on osteoporotic fracture healing. However, the biomechanical recovery process is still unknown, leading to difficulty in choosing time points for biomechanical tests and in correctly assessing osteoporotic fracture healing. To determine the biomechanical recovery process during osteoporotic fracture healing, studies on osteoporotic femur fracture healing with biomechanical tests in ovariectomized rat (OVX) models were collected from PUBMED, EMBASE, and Chinese databases. Quadratic curves of fracture healing time and maximum load were fitted with data from the analyzed studies. In the fitted curve for normal fractures, the predicted maximum load was 145.56 N, and the fracture healing time was 88.0 d. In the fitted curve for osteoporotic fractures, the predicted maximum load was 122.30 N, and the fracture healing time was 95.2 d. The maximum load of fractured femurs in OVX rats was also lower than that in sham rats at day 84 post-fracture (D84 PF). The fracture healing time was prolonged and maximum load at D84 PF decreased in OVX rats with closed fractures. The maximum load of Wister rats was higher than that of Sprague-Dawley (SD) rats, but the fracture healing time of SD and Wister rats was similar. Osteoporotic fracture healing was delayed in rats that were < = 12 weeks old when ovariectomized, and at D84 PF, the maximum load of rats < = 12 weeks old at ovariectomy was lower than that of rats >12 weeks old at ovariectomy. There was no significant difference in maximum load at D84 PF between rats with an osteoporosis modeling time <12 weeks and > = 12 weeks. In conclusion, fracture healing was delayed and biomechanical property decreased by osteoporosis. Time points around D95.2 PF should be considered for biomechanical tests of osteoporotic femur fracture healing in OVX rat models. Osteoporotic fracture healing in OVX rats was affected by the fracture type but not by the strain of the rat. PMID:27055104

  14. Exogenous Parathyroid Hormone-Related Peptide Promotes Fracture Healing in Lepr(-/-) Mice.

    PubMed

    Liu, Anlong; Li, Yishan; Wang, Yinhe; Liu, Li; Shi, Hongfei; Qiu, Yong

    2015-12-01

    Diabetic osteoporosis continues to surge worldwide, increasing the risk of fracture. We have previously demonstrated that haploinsufficiency of endogenous parathyroid hormone-related peptide (PTHrP) impairs fracture healing. However, whether an exogenous supply of PTHrP can repair bone damage and accelerate fracture healing remains unclear. This study aimed to assess the efficacy and safety of PTHrP in healing fractures. Standardized mid-diaphyseal femur fractures were generated in 12-week-old wild-type and leptin receptor null Lepr(-/-) mice. After administration of PTHrP for 2 weeks, callus tissue properties were analyzed by radiography, micro-computed tomography, histology, histochemistry, immunohistochemistry, and molecular biology techniques. At 2 weeks post-fracture, cartilaginous callus areas were reduced, while total callus and bony callus areas were increased in PTHrP-treated Lepr(-/-) animals and control wild-type mice, compared with vehicle-treated Lepr(-/-) mice. The following parameters were enhanced both in Lepr(-/-) mice after treatment with PTHrP and vehicle-treated wild-type animals, compared with vehicle-treated Lepr(-/-) mice: osteoblast numbers; tissue alkaline phosphatase (ALP) and Type I collagen immunopositive areas; mRNA levels of ALP, Type I collagen, osteoprotegerin, and receptor activator for nuclear factor-κ B ligand; protein levels of Runt-related transcription factor 2 and insulin-like growth factor-1; and the number and surface of osteoclasts. In conclusion, exogenous PTHrP by subcutaneous injection promotes fracture repair in Lepr(-/-) mice by increasing callus formation and accelerating cell transformation: upregulated osteoblastic gene and protein expression, increased endochondral bone formation, osteoblastic bone formation, and osteoclastic bone resorption. However, complete repair was not obtained in PTHrP-treated Lepr(-/-) mice as in control wild-type animals. PMID:26314884

  15. The effect of immunonutrition (glutamine, alanine) on fracture healing

    PubMed Central

    Küçükalp, Abdullah; Durak, Kemal; Bayyurt, Sarp; Sönmez, Gürsel; Bilgen, Muhammed S.

    2014-01-01

    Background There have been various studies related to fracture healing. Glutamine is an amino acid with an important role in many cell and organ functions. This study aimed to make a clinical, radiological, and histopathological evaluation of the effects of glutamine on fracture healing. Methods Twenty rabbits were randomly allocated into two groups of control and immunonutrition. A fracture of the fibula was made to the right hind leg. All rabbits received standard food and water. From post-operative first day for 30 days, the study group received an additional 2 ml/kg/day 20% L-alanine L-glutamine solution via a gastric catheter, and the control group received 2 ml/kg/day isotonic via gastric catheter. At the end of 30 days, the rabbits were sacrificed and the fractures were examined clinically, radiologically, and histopathologically in respect to the degree of union. Results Radiological evaluation of the control group determined a mean score of 2.5 according to the orthopaedists and 2.65 according to the radiologists. In the clinical evaluation, the mean score was 1.875 for the control group and 2.0 for the study group. Histopathological evaluation determined a mean score of 8.5 for the control group and 9.0 for the study group. Conclusion One month after orally administered glutamine–alanine, positive effects were observed on fracture healing radiologically, clinically, and histopathologically, although no statistically significant difference was determined.

  16. Fracture and Healing of Rock Salt Related to Salt Caverns

    SciTech Connect

    Chan, K.S.; Fossum, A.F.; Munson, D.E.

    1999-03-01

    In recent years, serious investigations of potential extension of the useful life of older caverns or of the use of abandoned caverns for waste disposal have been of interest to the technical community. All of the potential applications depend upon understanding the reamer in which older caverns and sealing systems can fail. Such an understanding will require a more detailed knowledge of the fracture of salt than has been necessary to date. Fortunately, the knowledge of the fracture and healing of salt has made significant advances in the last decade, and is in a position to yield meaningful insights to older cavern behavior. In particular, micromechanical mechanisms of fracture and the concept of a fracture mechanism map have been essential guides, as has the utilization of continuum damage mechanics. The Multimechanism Deformation Coupled Fracture (MDCF) model, which is summarized extensively in this work was developed specifically to treat both the creep and fracture of salt, and was later extended to incorporate the fracture healing process known to occur in rock salt. Fracture in salt is based on the formation and evolution of microfractures, which may take the form of wing tip cracks, either in the body or the boundary of the grain. This type of crack deforms under shear to produce a strain, and furthermore, the opening of the wing cracks produce volume strain or dilatancy. In the presence of a confining pressure, microcrack formation may be suppressed, as is often the case for triaxial compression tests or natural underground stress situations. However, if the confining pressure is insufficient to suppress fracture, then the fractures will evolve with time to give the characteristic tertiary creep response. Two first order kinetics processes, closure of cracks and healing of cracks, control the healing process. Significantly, volume strain produced by microfractures may lead to changes in the permeability of the salt, which can become a major concern in

  17. Biglycan modulates angiogenesis and bone formation during fracture healing.

    PubMed

    Berendsen, Agnes D; Pinnow, Emily L; Maeda, Azusa; Brown, Aaron C; McCartney-Francis, Nancy; Kram, Vardit; Owens, Rick T; Robey, Pamela G; Holmbeck, Kenn; de Castro, Luis F; Kilts, Tina M; Young, Marian F

    2014-04-01

    Matrix proteoglycans such as biglycan (Bgn) dominate skeletal tissue and yet its exact role in regulating bone function is still unclear. In this paper we describe the potential role of (Bgn) in the fracture healing process. We hypothesized that Bgn could regulate fracture healing because of previous work showing that it can affect normal bone formation. To test this hypothesis, we created fractures in femurs of 6-week-old male wild type (WT or Bgn+/0) and Bgn-deficient (Bgn-KO or Bgn-/0) mice using a custom-made standardized fracture device, and analyzed the process of healing over time. The formation of a callus around the fracture site was observed at both 7 and 14 days post-fracture in WT and Bgn-deficient mice and immunohistochemistry revealed that Bgn was highly expressed in the fracture callus of WT mice, localizing within woven bone and cartilage. Micro-computed tomography (μCT) analysis of the region surrounding the fracture line showed that the Bgn-deficient mice had a smaller callus than WT mice. Histology of the same region also showed the presence of less cartilage and woven bone in the Bgn-deficient mice compared to WT mice. Picrosirius red staining of the callus visualized under polarized light showed that there was less fibrillar collagen in the Bgn-deficient mice, a finding confirmed by immunohistochemistry using antibodies to type I collagen. Interestingly, real time RT-PCR of the callus at 7 days post-fracture showed a significant decrease in relative vascular endothelial growth factor A (VEGF) gene expression by Bgn-deficient mice as compared to WT. Moreover, VEGF was shown to bind directly to Bgn through a solid-phase binding assay. The inability of Bgn to directly enhance VEGF-induced signaling suggests that Bgn has a unique role in regulating vessel formation, potentially related to VEGF storage or stabilization in the matrix. Taken together, these results suggest that Bgn has a regulatory role in the process of bone formation during

  18. Excess dietary methionine does not affect fracture healing in mice

    PubMed Central

    Holstein, Joerg H.; Schmalenbach, Julia; Herrmann, Markus; Ölkü, Ilona; Garcia, Patric; Histing, Tina; Herrmann, Wolfgang; Menger, Michael D.; Pohlemann, Tim; Claes, Lutz

    2012-01-01

    Summary Background An elevated serum concentration of homocysteine (hyperhomocysteinemia) has been shown to disturb fracture healing. As the essential amino acid, methionine, is a precursor of homocysteine, we aimed to investigate whether excess methionine intake affects bone repair. Material/Methods We analyzed bone repair in 2 groups of mice. One group was fed a methionine-rich diet (n=13), and the second group received an equicaloric control diet without methionine supplementation (n=12). Using a closed femoral fracture model, bone repair was analyzed by histomorphometry and biomechanical testing at 4 weeks after fracture. Blood was sampled to measure serum concentrations of homocysteine, the bone formation marker osteocalcin, and the bone resorption marker collagen I C-terminal crosslaps Results Serum concentrations of homocysteine were significantly higher in the methionine group than in the control group, while serum markers of bone turnover did not differ significantly between the 2 groups. Histomorphometry revealed no significant differences in size and tissue composition of the callus between animals fed the methionine-enriched diet and those receiving the control diet. Accordingly, animals of the 2 groups showed a comparable bending stiffness of the healing bones. Conclusions We conclude that excess methionine intake causes hyperhomocysteinemia, but does not affect fracture healing in mice. PMID:23197225

  19. Generation of self-healing and transverse accelerating optical vortices

    NASA Astrophysics Data System (ADS)

    Wei, Bing-Yan; Chen, Peng; Ge, Shi-Jun; Duan, Wei; Hu, Wei; Lu, Yan-Qing

    2016-09-01

    Self-healing and transverse accelerating optical vortices are generated via modulating Gaussian beams through subsequent liquid crystal q-plate and polarization Airy mask. We analyze the propagation dynamics of these vortex Airy beams, and find that they possess the features of both optical vortices and Airy beams. Topological charges and characteristics of nondiffraction, self-healing, and transverse acceleration are experimentally verified. In addition, vortex Airy beams with both topological charge and radial index are demonstrated and mode switch among Gaussian, vortex, vector, Airy beams and their combinations can be acquired easily. Our design provides a flexible and highly efficient way to generate unique optical vortices with self-healing and transverse acceleration properties, and facilitates prospective applications in optics and photonics.

  20. The effects of local platelet rich plasma delivery on diabetic fracture healing.

    PubMed

    Gandhi, Ankur; Doumas, Christopher; Dumas, Christopher; O'Connor, J Patrick; Parsons, J Russell; Lin, Sheldon S

    2006-04-01

    Several studies have documented that diabetes impairs bone healing clinically and experimentally. The percutaneous delivery of platelet rich plasma (PRP) was used in the diabetic BB Wistar femur fracture model to investigate the use of PRP as a concentrated source of critical early growth factors on bone healing. PRP delivery at the fracture site normalized the early (cellular proliferation and chondrogenesis) parameters while improving the late (mechanical strength) parameters of diabetic fracture healing. These results suggest a role for PRP in mediating diabetic fracture healing and potentially other high risk fractures.

  1. Simvastatin Prodrug Micelles Target Fracture and Improve Healing

    PubMed Central

    Dusad, Anand; Yuan, Hongjiang; Ren, Ke; Li, Fei; Fehringer, Edward V.; Purdue, P. Edward; Goldring, Steven R.; Daluiski, Aaron; Wang, Dong

    2014-01-01

    Simvastatin (SIM), a widely used anti-lipidaemic drug, has been identified as a bone anabolic agent. Its poor water solubility and the lack of distribution to the skeleton, however, have limited its application in the treatment of bone metabolic diseases. In this study, an amphiphilic macromolecular prodrug of SIM was designed and synthesized to overcome these limitations. The polyethylene glycol (PEG)-based prodrug can spontaneously self-assemble to form micelles. The use of SIM trimer as the prodrug’s hydrophobic segment allows easy encapsulation of additional free SIM. The in vitro studies showed that SIM/SIM-mPEG micelles were internalized by MC3T3 cells via lysosomal trafficking and consistently induced expression of both BMP2 and DKK1 mRNA, suggesting that the prodrug micelle retains the biological functions of SIM. After systemic administration, optical imaging suggests that the micelles would passively target to bone fracture sites associated with hematoma and inflammation. Furthermore, flow cytometry study revealed that SIM/SIM-mPEG micelles had preferred cellular uptake by inflammatory and resident cells within the fracture callus tissue. The treatment study using a mouse osteotomy model validated the micelles’ therapeutic efficacy in promoting bone fracture healing as demonstrated by micro-CT and histological analyses. Collectively, these data suggest that the macromolecular prodrug-based micelle formulation of SIM may have great potential for clinical management of impaired fracture healing. PMID:25542644

  2. Traumatic subchondral fracture of the femoral head in a healed trochanteric fracture

    PubMed Central

    Lee, Sang Yang; Niikura, Takahiro; Iwakura, Takashi; Kurosaka, Masahiro

    2014-01-01

    An 82-year-old woman sustained a trochanteric fracture of the left femur after a fall. Fracture fixation was performed using proximal femoral nail antirotation (PFNA) II, and she was able to walk with a T-cane after 3 months. Eleven months following the operation, the patient presented with left hip pain after a fall. Radiographs showed a subchondral collapse of the femoral head located above the blade tip. The authors removed the PFNA-II and subsequently performed cemented bipolar hemiarthroplasty. Histological evaluation of the femoral head showed osteoporosis with no evidence of osteonecrosis. Repair tissue, granulation tissue and callus formation were seen at the collapsed subchondral area. Based on these findings, a traumatic subchondral fracture of the femoral head in a healed trochanteric fracture was diagnosed. A traumatic subchondral fracture of the femoral head may need to be considered as a possible diagnosis after internal fixation of the trochanteric fracture. PMID:25015169

  3. A short peptide from frog skin accelerates diabetic wound healing.

    PubMed

    Liu, Han; Duan, Zilei; Tang, Jing; Lv, Qiumin; Rong, Mingqiang; Lai, Ren

    2014-10-01

    Delayed wound healing will result in the development of chronic wounds in some diseases, such as diabetes. Amphibian skins possess excellent wound-healing ability and represent a resource for prospective wound-healing promoting compounds. A potential wound-healing promoting peptide (CW49; amino acid sequence APFRMGICTTN) was identified from the frog skin of Odorrana grahami. It promotes wound healing in a murine model with a full-thickness dermal wound in both normal and diabetic animals. In addition to its strong angiogenic ability with respect to the upregulation of some angiogenic proteins, CW49 also showed a significant anti-inflammatory effect in diabetic wounds, which was very important for healing chronic wounds. CW49 had little effect on re-epithelialization, resulting in no significant effect on wound closure rate compared to a vehicle control. Altogether, this indicated that CW49 might accelerate diabetic wound healing by promoting angiogenesis and preventing any excessive inflammatory response. Considering its favorable traits as a small peptide that significantly promotes angiogenesis, CW49 might be an excellent candidate or template for the development of a drug for use in the treatment of diabetic wounds.

  4. Effects of Boric Acid on Fracture Healing: An Experimental Study.

    PubMed

    Gölge, Umut Hatay; Kaymaz, Burak; Arpaci, Rabia; Kömürcü, Erkam; Göksel, Ferdi; Güven, Mustafa; Güzel, Yunus; Cevizci, Sibel

    2015-10-01

    Boric acid (BA) has positive effects on bone tissue. In this study, the effects of BA on fracture healing were evaluated in an animal model. Standard closed femoral shaft fractures were created in 40 male Sprague-Dawley rats under general anesthesia. The rats were allocated into five groups (n = 8 each): group 1, control with no BA; groups 2 and 3, oral BA at doses of 4 and 8 mg/kg/day, respectively; group 4, local BA (8 mg/kg); and group 5, both oral and local BA (8 mg/kg/day orally and 8 mg/kg locally). After closed fracture creation, the fracture line was opened with a mini-incision, and BA was locally administered to the fracture area in groups 4 and 5. In groups 2, 3, and 5, BA was administered by gastric gavage daily until sacrifice. The rats were evaluated by clinical, radiological, and histological examinations. The control group (group 1) significantly differed from the local BA-exposed groups (groups 4 and 5) in the clinical evaluation. Front-rear and lateral radiographs revealed significant differences between the local BA-exposed groups and the control and other groups (p < 0.05). Clinical and radiological evaluations demonstrated adequate agreement between observers. The average histological scores significantly differed across groups (p = 0.007) and were significantly higher in groups 4 and 5 which were the local BA (8 mg/kg) and both oral and local BA (8 mg/kg/day orally and 8 mg/kg locally), respectively, compared to the controls. This study suggests that BA may be useful in fracture healing. Further research is required to demonstrate the most effective local dosage and possible use of BA-coated implants. PMID:25846213

  5. Effects of Boric Acid on Fracture Healing: An Experimental Study.

    PubMed

    Gölge, Umut Hatay; Kaymaz, Burak; Arpaci, Rabia; Kömürcü, Erkam; Göksel, Ferdi; Güven, Mustafa; Güzel, Yunus; Cevizci, Sibel

    2015-10-01

    Boric acid (BA) has positive effects on bone tissue. In this study, the effects of BA on fracture healing were evaluated in an animal model. Standard closed femoral shaft fractures were created in 40 male Sprague-Dawley rats under general anesthesia. The rats were allocated into five groups (n = 8 each): group 1, control with no BA; groups 2 and 3, oral BA at doses of 4 and 8 mg/kg/day, respectively; group 4, local BA (8 mg/kg); and group 5, both oral and local BA (8 mg/kg/day orally and 8 mg/kg locally). After closed fracture creation, the fracture line was opened with a mini-incision, and BA was locally administered to the fracture area in groups 4 and 5. In groups 2, 3, and 5, BA was administered by gastric gavage daily until sacrifice. The rats were evaluated by clinical, radiological, and histological examinations. The control group (group 1) significantly differed from the local BA-exposed groups (groups 4 and 5) in the clinical evaluation. Front-rear and lateral radiographs revealed significant differences between the local BA-exposed groups and the control and other groups (p < 0.05). Clinical and radiological evaluations demonstrated adequate agreement between observers. The average histological scores significantly differed across groups (p = 0.007) and were significantly higher in groups 4 and 5 which were the local BA (8 mg/kg) and both oral and local BA (8 mg/kg/day orally and 8 mg/kg locally), respectively, compared to the controls. This study suggests that BA may be useful in fracture healing. Further research is required to demonstrate the most effective local dosage and possible use of BA-coated implants.

  6. Biotherapeutics in orthopaedic medicine: accelerating the healing process?

    PubMed

    Puleo, David

    2003-01-01

    Musculoskeletal injuries have a significant human and financial impact on society. In particular, fractures that lead to delayed union or even nonunion represent a serious clinical challenge for which few treatment options are available. The multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life. Biotechnological advances have made possible a host of potential treatments for enhancing and accelerating the repair of bone. By stimulating the body's own healing mechanisms, clinical outcomes may be improved while also containing procedural costs. Biotherapeutics may take the form of proteins, genes or cells that can be used to treat the injury. Protein biotherapeutics have received the greatest attention. Using recombinant DNA techniques, growth factors that play important roles in bone development and repair are being produced. By delivering exogenous growth factors to the site of injury in an appropriate manner, bone formation can be stimulated. Although individual proteins have been the primary focus of investigation, combinations of biomolecules can have additive, and perhaps synergistic, effects. Alternatively, genes coding for osteotropic growth factors can be delivered to the site of injury. Expression of the gene effectively results in localised delivery of the growth factor. Delivery of cells having osteogenic potential can also result in bone formation. Furthermore, it may be possible to obtain additional benefits by combining biotherapeutic approaches, such as by introducing cells genetically modified to overexpress therapeutic proteins of interest. Although biotherapeutics have great potential for stimulating bone repair, only a limited number of treatments have been approved by governmental regulatory agencies for clinical use. Bone morphogenetic activity was initially described in 1965, but not until 2001 and 2002 did two protein biotherapeutics, utilising bone morphogenetic proteins 2 and 7, receive

  7. Laboratory investigation of crushed salt consolidation and fracture healing

    SciTech Connect

    Not Available

    1987-01-01

    A laboratory test program was conducted to investigate the consolidation behavior of crushed salt and fracture healing in natural and artificial salt. Crushed salt is proposed for use as backfill in a nuclear waste repository in salt. Artificial block salt is proposed for use in sealing a repository. Four consolidation tests were conducted in a hydrostatic pressure vessel at a maximum pressure of 2500 psi (17.2 MPa) and at room temperature. Three 1-month tests were conducted on salt obtained from the Waste Isolation Pilot Plant and one 2-month test was conducted on salt from Avery Island. Permeability was obtained using argon and either a steady-state or transient method. Initial porosities ranged from 0.26 to 0.36 and initial permeabilities from 2000 to 50,000 md. Final porosities and permeabilities ranged from 0.05 to 0.19 and from <10/sup -5/ md to 110 md, respectively. The lowest final porosity (0.05) and permeability (<10/sup -5/ md) were obtained in a 1-month test in which 2.3% moisture was added to the salt at the beginning of the test. The consolidation rate was much more rapid than in any of the dry salt tests. The fracture healing program included 20 permeability tests conducted on fractured and unfractured samples. The tests were conducted in a Hoek cell at hydrostatic pressures up to 3000 psi (20.6 MPa) with durations up to 8 days. For the natural rock salt tested, permeability was strongly dependent on confining pressure and time. The effect of confining pressure was much weaker in the artificial salt. In most cases the combined effects of time and pressure were to reduce the permeability of fractured samples to the same order of magnitude (or less) as the permeability measured prior to fracturing.

  8. TP508 accelerates fracture repair by promoting cell growth over cell death

    SciTech Connect

    Li Xinmin; Wang Hali; Touma, Edward; Qi Yuchen; Rousseau, Emma; Quigg, Richard J.; Ryaby, James T.

    2007-12-07

    TP508 is a synthetic 23-amino acid peptide representing a receptor-binding domain of human thrombin. We have previously shown that a single injection of TP508 accelerates fracture healing in a rat femoral fracture model. To understand how TP508 acts at the protein level during fracture healing, we compared the translational profiles between saline-control and fractured femur at six time points after TP508 treatment using the second generation of BD Clontech{sup TM} Antibody Microarray. Here, we demonstrate that TP508 accelerates fracture healing by modulating expression levels of proteins primarily involved in the functional categories of cell cycle, cellular growth and proliferation, and cell death. The majority of those proteins are physically interrelated and functionally overlapped. The action of those proteins is highlighted by a central theme of promoting cell growth via balance of cell survival over cell death signals. This appears to occur through the stimulation of several bone healing pathways including cell cycle-G1/S checkpoint regulation, apoptosis, JAK/STAT, NF-{kappa}B, PDGF, PI3K/AKT, PTEN, and ERK/MAPK.

  9. Non-invasive low-intensity pulsed ultrasound accelerates bone healing in the rabbit.

    PubMed

    Pilla, A A; Mont, M A; Nasser, P R; Khan, S A; Figueiredo, M; Kaufman, J J; Siffert, R S

    1990-01-01

    The effect of ultrasound (US) on the rate of fibula osteotomy healing in 139 mature New Zealand white rabbits was assessed in this study. Bilateral midshaft fibular osteotomies were made using a 1-mm Gigli saw. US was noninvasively applied to one limb for 20 minutes daily, while the contralateral limb served as a control. A 2.5-cm PZT transducer was applied to both limbs, with the treated limb receiving a 200-microseconds burst of 1.5-MHz sine waves repeated at 1.0 kHz. The incident intensity was approximately 30 mW/cm2. Animals were killed at intervals between 14 and 28 days. Maximum strength increases (significant to p less than or equal to 0.01) ranged from 40 to 85% from postoperative day 14 to 23. On day 28, no significant difference in ultimate strength was noted. From day 17 through day 28, all US-treated fractures were as strong as intact bones (p less than or equal to 0.005). On the other hand, the ultimate strength of the control osteotomies attained intact values only by day 28. These results indicate that biomechanical healing is accelerated by a factor of nearly 1.7. This occurs with an overall acceleration of the healing curve in this fresh fracture model. If noninvasive low-intensity pulsed sine wave ultrasound can significantly accelerate bone repair in clinical application with an in-home treatment of 20 minutes daily, then US may be a useful adjunct for fracture care with a concomitant impact on patient morbidity.

  10. Osteoblast and osteocyte-specific loss of Connexin43 results in delayed bone formation and healing during murine fracture healing.

    PubMed

    Loiselle, Alayna E; Paul, Emmanuel M; Lewis, Gregory S; Donahue, Henry J

    2013-01-01

    Connexin43 (Cx43) plays an important role in osteoblastic differentiation in vitro, and bone formation in vivo. Mice with osteoblast/osteocyte-specific loss of Cx43 display decreased gap junctional intercellular communication (GJIC), bone density, and cortical thickness. To determine the role of Cx43 in fracture healing, a closed femur fracture was induced in Osteocalcin-Cre+; Cx43(flox/flox) (Cx43cKO) and Cre-; Cx43(flox/flox) (WT) mice. We tested the hypothesis that loss of Cx43 results in decreased bone formation and impaired healing following fracture. Here, we show that osteoblast and osteocyte-specific deletion of Cx43 results in decreased bone formation, bone remodeling, and mechanical properties during fracture healing. Cx43cKO mice display decreased bone volume, total volume, and fewer TRAP+ osteoclasts. Furthermore, loss of Cx43 in mature osteoblasts and osteocytes results in a significant decrease in torsional rigidity between 21 and 35 days post-fracture, compared to WT mice. These studies identify a novel role for the gap junction protein Cx43 during fracture healing, suggesting that loss of Cx43 can result in both decreased bone formation and bone resorption. Therefore, enhancing Cx43 expression or GJIC may provide a novel means to enhance bone formation during fracture healing.

  11. Biodistribution of Fracture-Targeted GSK3β Inhibitor-Loaded Micelles for Improved Fracture Healing.

    PubMed

    Low, Stewart A; Galliford, Chris V; Yang, Jiyuan; Low, Philip S; Kopeček, Jindřich

    2015-10-12

    Bone fractures constitute a major cause of morbidity and mortality especially in the elderly. Complications associated with osteoporosis drugs and the age of the patient slow bone turnover and render such fractures difficult to heal. Increasing the speed of fracture repair by administration of a fracture-targeted bone anabolic agent could find considerable application. Aspartic acid oligopeptides are negatively charged molecules at physiological pH that adsorb to hydroxyapatite, the mineral portion of bone. This general adsorption is the strongest where bone turnover is highest or where hydroxyapatite is freshly exposed. Importantly, both of these conditions are prominent at fracture sites. GSK3β inhibitors are potent anabolic agents that can promote tissue repair when concentrated in a damaged tissue. Unfortunately, they can also cause significant toxicity when administered systemically and are furthermore difficult to deliver due to their strong hydrophobicity. In this paper, we solve both problems by conjugating the hydrophobic GSK3β inhibitor to a hydrophilic aspartic acid octapeptide using a hydrolyzable bond, thereby generating a bone fracture-targeted water-soluble form of the drug. The resulting amphiphile is shown to assemble into micelles, extending its circulation time while maintaining its fracture-targeting abilities. For measurement of pharmacokinetics, an 125I was introduced at the location of the bromine in the GSK3β inhibitor to minimize any structural differences. Biodistribution studies demonstrate a greater than 4-fold increase in fracture accumulation over healthy bone. PMID:26331790

  12. Biodistribution of fracture-targeted GSK3β inhibitor-loaded micelles for improved fracture healing

    PubMed Central

    Low, Stewart A.; Galliford, Chris V.; Yang, Jiyuan; Low, Philip S.; Kopeček, Jindřich

    2016-01-01

    Bone fractures constitute a major cause of morbidity and mortality especially in the elderly. Complications associated with osteoporosis drugs and the age of the patient slow bone turnover and render such fractures difficult to heal. Increasing the speed of fracture repair by administration of a fracture-targeted bone anabolic agent could find considerable application. Aspartic acid oligopeptides are negatively charged molecules at physiological pH that adsorb to hydroxyapatite, the mineral portion of bone. This general adsorption is the strongest where bone turnover is highest or where hydroxyapatite is freshly exposed. Importantly, both of these conditions are prominent at fracture sites. GSK3β inhibitors are potent anabolic agents that can promote tissue repair when concentrated in a damaged tissue. Unfortunately, they can also cause significant toxicity when administered systemically and are furthermore difficult to deliver due to their strong hydrophobicity. In this paper, we solve both problems by conjugating the hydrophobic GSK3β inhibitor to a hydrophilic aspartic acid octapeptide using a hydrolyzable bond, thereby generating a bone fracture-targeted water-soluble form of the drug. The resulting amphiphile is shown to assemble into micelles, extending its circulation time while maintaining its fracture-targeting abilities. For measurement of pharmacokinetics, an 125I was introduced at the location of the bromine in the GSK3β inhibitor to minimize any structural differences. Biodistribution studies demonstrate a greater than 4-fold increase in fracture accumulation over healthy bone. PMID:26331790

  13. Systemic treatment with vanadium absorbed by Coprinus comatus promotes femoral fracture healing in streptozotocin-diabetic rats.

    PubMed

    Wang, Guangbin; Wang, Jiashi; Fu, Yonghui; Bai, Lunhao; He, Ming; Li, Bin; Fu, Qin

    2013-03-01

    The purpose of this study was to analyze the impact of vanadium absorbed by Coprinus comatus (VACC) on fracture healing in streptozotocin-diabetic rats. Forty-five male Wistar rats used were divided into three groups: normal rats (control), diabetic rats, and diabetic rats treated with VACC. A standardized fracture-healing model with a stable plate fixation was established for the rat femoral fracture. After a 4-week stable fixation, callus quality was assessed by microcomputerized tomography and histological and biomechanical examinations. In addition, bone samples were obtained to evaluate the content of mineral substances in bones. Compared with the diabetic group, vanadium treatment significantly increased bone mineral content and biomechanical strength and improved microstructural properties of the callus. The ultimate load was increased by 29.1 % (P<0.05), and the total bone volume of callus enhanced by 11.2 % (P<0.05) at 4 weeks post fracture. Vanadium also promoted callus bone formation, which caused a 35.5 % increase in the total area of callus. However, VACC did not accelerate the fracture repair process in histological analysis. In conclusion, the current study suggests that systemic treatment with vanadium could promote fracture healing in streptozotocin-diabetic rats.

  14. Mice Lacking Pten in Osteoblasts Have Improved Intramembranous and Late Endochondral Fracture Healing

    PubMed Central

    Burgers, Travis A.; Hoffmann, Martin F.; Collins, Caitlyn J.; Zahatnansky, Juraj; Alvarado, Martin A.; Morris, Michael R.; Sietsema, Debra L.; Mason, James J.; Jones, Clifford B.; Ploeg, Heidi L.; Williams, Bart O.

    2013-01-01

    The failure of an osseous fracture to heal (development of a non-union) is a common and debilitating clinical problem. Mice lacking the tumor suppressor Pten in osteoblasts have dramatic and progressive increases in bone volume and density throughout life. Since fracture healing is a recapitulation of bone development, we investigated the process of fracture healing in mice lacking Pten in osteoblasts (Ocn-cretg/+;Ptenflox/flox). Mid-diaphyseal femoral fractures induced in wild-type and Ocn-cretg/+;Ptenflox/flox mice were studied via micro-computed tomography (µCT) scans, biomechanical testing, histological and histomorphometric analysis, and protein expression analysis. Ocn-cretg/+;Ptenflox/flox mice had significantly stiffer and stronger intact bones relative to controls in all cohorts. They also had significantly stiffer healing bones at day 28 post-fracture (PF) and significantly stronger healing bones at days 14, 21, and 28 PF. At day 7 PF, the proximal and distal ends of the Pten mutant calluses were more ossified. By day 28 PF, Pten mutants had larger and more mineralized calluses. Pten mutants had improved intramembranous bone formation during healing originating from the periosteum. They also had improved endochondral bone formation later in the healing process, after mature osteoblasts are present in the callus. Our results indicate that the inhibition of Pten can improve fracture healing and that the local or short-term use of commercially available Pten-inhibiting agents may have clinical application for enhancing fracture healing. PMID:23675511

  15. Substance P enhances EPC mobilization for accelerated wound healing.

    PubMed

    Um, Jihyun; Jung, Nunggum; Chin, Sukbum; Cho, Younggil; Choi, Sanghyuk; Park, Ki-Sook

    2016-03-01

    Wound healing is essential for the survival and tissue homeostasis of unicellular and multicellular organisms. The current study demonstrated that the neuropeptide substance P (SP) accelerated the wound healing process, particularly in the skin. Subcutaneous treatment of SP accelerated wound closing, increased the population of α-smooth muscle actin positive myofibroblasts, and increased extracellular matrix deposition at the wound site. Moreover, SP treatment enhances angiogenesis without a local increase in the expression levels of vascular endothelial growth factor and stromal cell-derived factor-1. Importantly, SP treatment increased both the population of circulating endothelial progenitor cells in the peripheral blood and in CD31 positive cells in Matrigel plugs. The tube forming potential of endothelial cells was also enhanced by SP treatment. The results suggested that the subcutaneous injection of SP accelerated the wound healing in the skin via better reconstitution of blood vessels, which possibly followed an increase in the systemic mobilization of endothelial progenitor cells and a more effective assembly of endothelial cells into tubes. PMID:26749197

  16. Stimulation of fracture healing with Electromagnetic Fields of Extremely Low Frequency (EMF of ELF)

    SciTech Connect

    Wahlstroem, O.

    1984-06-01

    This randomized, controlled study was performed to evaluate how electromagnetic fields affect the accumulation of /sup 99m/Technetium - methylendiphosphonate (Tc-MDP) in fresh fractures. Thirty women with Colles' fractures, aged 50-70 years, participated in this study--some in a control group and some in a treated group. After reduction, all patients were immobilized for four weeks. After randomization, 15 patients were treated by electromagnetic fields of extremely low frequency (EMF of ELF), which were generated by a coil and a battery-powered portable current generator during the time of immobilization. The frequency of the alternating magnetic field was 1-1000 Hz; the magnitude was 4 gauss (RMS (root-mean-square) value). The scintigrams were performed one, two, four, and eight weeks after the injury. The activity ratio in the fracture area was significantly higher at the examination of one and two weeks in the treated group than it was in the control group. The clinical relevance of the results is not known, but one interpretation of the data is that the stimulation with EMF of ELF improves (accelerates) the early phase of fracture healing. The data warrant further investigation of fresh fracture treatment with this method.

  17. 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.

  18. HoxD3 accelerates wound healing in diabetic mice

    SciTech Connect

    Hansen, Scott L.; Myers, Connie A.; Charboneau, Aubri; Young, David M.; and Boudreau, Nancy

    2003-12-01

    Poorly healing diabetic wounds are characterized by diminished collagen production and impaired angiogenesis. HoxD3, a homeobox transcription factor that promotes angiogenesis and collagen synthesis, is up-regulated during normal wound repair whereas its expression is diminished in poorly healing wounds of the genetically diabetic (db/db) mouse. To determine whether restoring expression of HoxD3 would accelerate diabetic wound healing, we devised a novel method of gene transfer, which incorporates HoxD3 plasmid DNA into a methylcellulose film that is placed on wounds created on db/db mice. The HoxD3 transgene was expressed in endothelial cells, fibroblasts, and keratinocytes of the wounds for up to 10 days. More importantly, a single application of HoxD3 to db/db mice resulted in a statistically significant acceleration of wound closure compared to control-treated wounds. Furthermore, we also observed that the HoxD3-mediated improvement in diabetic wound repair was accompanied by increases in mRNA expression of the HoxD3 target genes, Col1A1 and beta 3-integrin leading to enhanced angiogenesis and collagen deposition in the wounds. Although HoxD3-treated wounds also show improved re-epithelialization as compared to control db/db wounds, this effect was not due to direct stimulation of keratinocyte migration by HoxD3. Finally, we show that despite the dramatic increase in collagen synthesis and deposition in HoxD3-treated wounds, these wounds showed normal remodeling and we found no evidence of abnormal wound healing. These results indicate that HoxD3 may provide a means to directly improve collagen deposition, angiogenesis and closure in poorly healing diabetic wounds.

  19. Modeling of an initial stage of bone fracture healing

    NASA Astrophysics Data System (ADS)

    Lu, Yanfei; Lekszycki, Tomasz

    2015-09-01

    In case of the secondary bone fracture healing, four characteristic steps are often distinguished. The first stage, hematoma and clot formation, which is an object of our study, is important because it prepares the environment for the following stages. In this work, a new mathematical model describing basic effects present short after the injury is proposed. The main idea is based on the assumption that blood leaking from the ruptured blood vessels propagates into a poroelastic saturated tissue close to the fracture and mixes with the interstitial liquid present in pores. After certain time period from the first contact with surrounding tissue, the solidification of blood in the fluid mixture starts. This results in clot formation. By assuming the time necessary to initiate solidification and critical saturation of blood in the mixture, the shape and the structure of blood clot could be determined. In numerical example, proposed mathematical formulas were used to study the size of the gap between fractured parts and its effect in blood clot formation.

  20. Healing of fractures with freeze-dried cortical bone plates. Comparison with compression plating.

    PubMed

    Malinin, T; Latta, L L; Wagner, J L; Brown, M D

    1984-11-01

    The healing of fractures of the radius with internal fixation by stainless-steel compression plates was compared with fractures fixed with freeze-dried bone-plate allografts. Fractures fixed with metallic plates gained slightly less than half the biomechanical strength of the contralateral control bone and healed without noticeable external callus formation. Bone-plated fractures regained three-fourths of the biomechanical strength of controls and healed by forming an external callus. Bone-plate allografts were eventually incorporated in the host bone. Allograft plates were vascularized and remodeled into cancellous bone in the process of incorporation in the host bones.

  1. Implantable microelectromechanical sensors for diagnostic monitoring and post-surgical prediction of bone fracture healing.

    PubMed

    McGilvray, Kirk C; Unal, Emre; Troyer, Kevin L; Santoni, Brandon G; Palmer, Ross H; Easley, Jeremiah T; Demir, Hilmi Volkan; Puttlitz, Christian M

    2015-10-01

    The relationship between modern clinical diagnostic data, such as from radiographs or computed tomography, and the temporal biomechanical integrity of bone fracture healing has not been well-established. A diagnostic tool that could quantitatively describe the biomechanical stability of the fracture site in order to predict the course of healing would represent a paradigm shift in the way fracture healing is evaluated. This paper describes the development and evaluation of a wireless, biocompatible, implantable, microelectromechanical system (bioMEMS) sensor, and its implementation in a large animal (ovine) model, that utilized both normal and delayed healing variants. The in vivo data indicated that the bioMEMS sensor was capable of detecting statistically significant differences (p-value <0.04) between the two fracture healing groups as early as 21 days post-fracture. In addition, post-sacrifice micro-computed tomography, and histology data demonstrated that the two model variants represented significantly different fracture healing outcomes, providing explicit supporting evidence that the sensor has the ability to predict differential healing cascades. These data verify that the bioMEMS sensor can be used as a diagnostic tool for detecting the in vivo course of fracture healing in the acute post-treatment period.

  2. Implantable microelectromechanical sensors for diagnostic monitoring and post-surgical prediction of bone fracture healing.

    PubMed

    McGilvray, Kirk C; Unal, Emre; Troyer, Kevin L; Santoni, Brandon G; Palmer, Ross H; Easley, Jeremiah T; Demir, Hilmi Volkan; Puttlitz, Christian M

    2015-10-01

    The relationship between modern clinical diagnostic data, such as from radiographs or computed tomography, and the temporal biomechanical integrity of bone fracture healing has not been well-established. A diagnostic tool that could quantitatively describe the biomechanical stability of the fracture site in order to predict the course of healing would represent a paradigm shift in the way fracture healing is evaluated. This paper describes the development and evaluation of a wireless, biocompatible, implantable, microelectromechanical system (bioMEMS) sensor, and its implementation in a large animal (ovine) model, that utilized both normal and delayed healing variants. The in vivo data indicated that the bioMEMS sensor was capable of detecting statistically significant differences (p-value <0.04) between the two fracture healing groups as early as 21 days post-fracture. In addition, post-sacrifice micro-computed tomography, and histology data demonstrated that the two model variants represented significantly different fracture healing outcomes, providing explicit supporting evidence that the sensor has the ability to predict differential healing cascades. These data verify that the bioMEMS sensor can be used as a diagnostic tool for detecting the in vivo course of fracture healing in the acute post-treatment period. PMID:26174472

  3. A PTH-responsive circadian clock operates in ex vivo mouse femur fracture healing site

    PubMed Central

    Kunimoto, Tatsuya; Okubo, Naoki; Minami, Yoichi; Fujiwara, Hiroyoshi; Hosokawa, Toshihiro; Asada, Maki; Oda, Ryo; Kubo, Toshikazu; Yagita, Kazuhiro

    2016-01-01

    The circadian clock contains clock genes including Bmal1 and Period2, and it maintains an interval rhythm of approximately 24 hours (the circadian rhythm) in various organs including growth plate and articular cartilage. As endochondral ossification is involved not only in growth plate but also in fracture healing, we investigated the circadian clock functions in fracture sites undergoing healing. Our fracture models using external fixation involved femurs of Period2::Luciferase knock-in mice which enables the monitoring of endogenous circadian clock state via bioluminescence. Organ culture was performed by collecting femurs, and fracture sites were observed using bioluminescence imaging systems. Clear bioluminescence rhythms of 24-hour intervals were revealed in fracture healing sites. When parathyroid hormone (PTH) was administered to fractured femurs in organ culture, peak time of Period2::Luciferase activity in fracture sites and growth plates changed, indicating that PTH-responsive circadian clock functions in the mouse femur fracture healing site. While PTH is widely used in treating osteoporosis, many studies have reported that it contributes to improvement of fracture healing. Future studies of the role of this local clock in wound healing may reveal a novel function of the circadian timing mechanism in skeletal cells. PMID:26926165

  4. Mice with a heterozygous Lrp6 deletion have impaired fracture healing

    PubMed Central

    Burgers, Travis A; Vivanco, Juan F; Zahatnansky, Juraj; Moren, Andrew J Vander; Mason, James J; Williams, Bart O

    2016-01-01

    Bone fracture non-unions, the failure of a fracture to heal, occur in 10%–20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6 +/−) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6 +/− mice and wild-type controls (Lrp6 +/+). Fractures were analyzed using micro-computed tomography (μCT) scans, biomechanical testing, and histological analysis. Lrp6 +/− mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing. PMID:27635281

  5. Mice with a heterozygous Lrp6 deletion have impaired fracture healing

    PubMed Central

    Burgers, Travis A; Vivanco, Juan F; Zahatnansky, Juraj; Moren, Andrew J Vander; Mason, James J; Williams, Bart O

    2016-01-01

    Bone fracture non-unions, the failure of a fracture to heal, occur in 10%–20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6 +/−) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6 +/− mice and wild-type controls (Lrp6 +/+). Fractures were analyzed using micro-computed tomography (μCT) scans, biomechanical testing, and histological analysis. Lrp6 +/− mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.

  6. Mice with a heterozygous Lrp6 deletion have impaired fracture healing.

    PubMed

    Burgers, Travis A; Vivanco, Juan F; Zahatnansky, Juraj; Moren, Andrew J Vander; Mason, James J; Williams, Bart O

    2016-01-01

    Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 (Lrp6 (+/-)) and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6 (+/-) mice and wild-type controls (Lrp6 (+/+)). Fractures were analyzed using micro-computed tomography (μCT) scans, biomechanical testing, and histological analysis. Lrp6 (+/-) mice had significantly decreased stiffness and strength at 28 days post fracture (PF) and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. Our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing. PMID:27635281

  7. Potential of oncostatin M to accelerate diabetic wound healing.

    PubMed

    Shin, Soo Hye; Han, Seung-Kyu; Jeong, Seong-Ho; Kim, Woo-Kyung

    2014-08-01

    Oncostatin M (OSM) is a multifunctional cytokine found in a variety of pathologic conditions, which leads to excessive collagen deposition. Current studies demonstrate that OSM is also a mitogen for fibroblasts and has an anti-inflammatory action. It was therefore hypothesised that OSM may play an important role in healing of chronic wounds that usually involve decreased fibroblast function and persist in the inflammatory stage for a long time. In a previous in vitro study, the authors showed that OSM increased wound healing activities of diabetic dermal fibroblasts. However, wound healing in vivo is a complex process involving multiple factors. Thus, the purpose of this study was to evaluate the effect of OSM on diabetic wound healing in vivo. Five diabetic mice were used in this study. Four full-thickness round wounds were created on the back of each mouse (total 20 wounds). OSM was applied on the two left-side wounds (n = 10) and phosphate-buffered saline was applied on the two right-side wounds (n = 10). After 10 days, unhealed wound areas of the OSM and control groups were compared using the stereoimage optical topometer system. Also, epithelialisation, wound contraction and reduction in wound volume in each group were compared. The OSM-treated group showed superior results in all of the tested parameters. In particular, the unhealed wound area and the reduction in wound volume demonstrated statistically significant differences (P < 0·05). The results of this study indicate that topical application of OSM may have the potential to accelerate healing of diabetic wounds.

  8. Analgesic effects of p38 kinase inhibitor treatment on bone fracture healing.

    PubMed

    Cottrell, Jessica A; Meyenhofer, Markus; Medicherla, Satyanarayana; Higgins, Linda; O'Connor, J Patrick

    2009-03-01

    Traditional and COX-2 selective non-steroidal anti-inflammatory drug (NSAID) treatment inhibits fracture healing in animal models. This indicates that either the inflammatory phase following a bone fracture is necessary for efficient or sufficient bone regeneration to heal the fracture or COX-2 may have a specific function during bone regeneration unrelated to inflammation. These observations also indicate that NSAID use during fracture healing may be contra-indicated. Thus, identification of different analgesics for fracture pain or other orthopaedic surgical procedures would be of significant clinical benefit. Inhibitors of p38 kinase also have significant analgesic properties. However, p38 kinase is a critical regulator of inflammation. To assess the potential use of p38 kinase inhibition as a therapeutic strategy to manage fracture pain, the analgesic properties of SCIO-469, a p38alpha kinase inhibitor, were assessed in a rat fracture model and compared to other common analgesics. In addition, the effects of SCIO-469 treatment on ultimate fracture healing outcomes were measured by radiography and torsional mechanical testing. The data indicate that SCIO-469 was an effective analgesic. No adverse events related to fracture healing were observed in rats treated with SCIO-469. Immunohistochemistry showed that p38 kinase is activated primarily in the first days following a fracture. These observations suggest that p38alpha kinase inhibition may be an effective therapeutic strategy to manage orthopaedic-related pain. These observations also indicate that COX-2 has a specific function during bone regeneration other than promoting inflammation.

  9. Simulated microgravity alters the expression of key genes involved in fracture healing

    NASA Astrophysics Data System (ADS)

    McCabe, N. Patrick; Androjna, Caroline; Hill, Esther; Globus, Ruth K.; Midura, Ronald J.

    2013-11-01

    Fracture healing in animal models has been shown to be altered in both ground based analogs of spaceflight and in those exposed to actual spaceflight. The molecular mechanisms behind altered fracture healing as a result of chronic exposure to microgravity remain to be elucidated. This study investigates temporal gene expression of multiple factors involved in secondary fracture healing, specifically those integral to the development of a soft tissue callus and the transition to that of hard tissue. Skeletally mature female rats were subjected to a 4 week period of simulated microgravity and then underwent a closed femoral fracture procedure. Thereafter, they were reintroduced to the microgravity and allowed to heal for a 1 or 2 week period. A synchronous group of weight bearing rats was used as a normal fracture healing control. Utilizing Real-Time quantitative PCR on mRNA from fracture callus tissue, we found significant reductions in the levels of transcripts associated with angiogenesis, chondrogenesis, and osteogenesis. These data suggest an altered fracture healing process in a simulated microgravity environment, and these alterations begin early in the healing process. These findings may provide mechanistic insight towards developing countermeasure protocols to mitigate these adaptations.

  10. Fracture healing with alendronate treatment in the Brtl/+ mouse model of osteogenesis imperfecta.

    PubMed

    Meganck, J A; Begun, D L; McElderry, J D; Swick, A; Kozloff, K M; Goldstein, S A; Morris, M D; Marini, J C; Caird, M S

    2013-09-01

    Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by increased skeletal fragility. Patients are often treated with bisphosphonates to attempt to reduce fracture risk. However, bisphosphonates reside in the skeleton for many years and long-term administration may impact bone material quality. Acutely, there is concern about risk of non-union of fractures that occur near the time of bisphosphonate administration. This study investigated the effect of alendronate, a potent aminobisphosphonate, on fracture healing. Using the Brtl/+ murine model of type IV OI, tibial fractures were generated in 8-week-old mice that were untreated, treated with alendronate before fracture, or treated before and after fracture. After 2, 3, or 5 weeks of healing, tibiae were assessed using microcomputed tomography (μCT), torsion testing, quantitative histomorphometry, and Raman microspectroscopy. There were no morphologic, biomechanical or histomorphometric differences in callus between untreated mice and mice that received alendronate before fracture. Alendronate treatment before fracture did not cause a significant increase in cartilage retention in fracture callus. Both Brtl/+ and WT mice that received alendronate before and after fracture had increases in the callus volume, bone volume fraction and torque at failure after 5 weeks of healing. Raman microspectroscopy results did not show any effects of alendronate in wild-type mice, but calluses from Brtl/+ mice treated with alendronate during healing had a decreased mineral-to-matrix ratio, decreased crystallinity and an increased carbonate-to-phosphate ratio. Treatment with alendronate altered the dynamics of healing by preventing callus volume decreases later in the healing process. Fracture healing in Brtl/+ untreated animals was not significantly different from animals in which alendronate was halted at the time of fracture.

  11. A constitutive model for representing coupled creep, fracture, and healing in rock salt

    SciTech Connect

    Chan, K.S.; Bodner, S.R.; Munson, D.E.; Fossum, A.F.

    1996-03-01

    The development of a constitutive model for representing inelastic flow due to coupled creep, damage, and healing in rock salt is present in this paper. This model, referred to as Multimechanism Deformation Coupled Fracture model, has been formulated by considering individual mechanisms that include dislocation creep, shear damage, tensile damage, and damage healing. Applications of the model to representing the inelastic flow and fracture behavior of WIPP salt subjected to creep, quasi-static loading, and damage healing conditions are illustrated with comparisons of model calculations against experimental creep curves, stress-strain curves, strain recovery curves, time-to-rupture data, and fracture mechanism maps.

  12. Hyaluronidase Modulates Inflammatory Response and Accelerates the Cutaneous Wound Healing

    PubMed Central

    Fronza, Marcio; Caetano, Guilherme F.; Leite, Marcel N.; Bitencourt, Claudia S.; Paula-Silva, Francisco W. G.; Andrade, Thiago A. M.; Frade, Marco A. C.; Merfort, Irmgard; Faccioli, Lúcia H.

    2014-01-01

    Hyaluronidases are enzymes that degrade hyaluronan an important constituent of the extracellular matrix. They have been used as a spreading agent, improving the absorption of drugs and facilitating the subcutaneous infusion of fluids. Here, we investigated the influence of bovine testes hyaluronidase (HYAL) during cutaneous wound healing in in vitro and in vivo assays. We demonstrated in the wound scratch assay that HYAL increased the migration and proliferation of fibroblasts in vitro at low concentration, e.g. 0.1 U HYAL enhanced the cell number by 20%. HYAL presented faster and higher reepithelialization in in vivo full-thickness excisional wounds generated on adult Wistar rats back skin already in the early phase at 2nd day post operatory compared to vehicle-control group. Wound closured area observed in the 16 U and 32 U HYAL treated rats reached 38% and 46% compared to 19% in the controls, respectively. Histological and biochemical analyses supported the clinical observations and showed that HYAL treated wounds exhibited increased granulation tissue, diminished edema formation and regulated the inflammatory response by modulating the release of pro and anti-inflammatory cytokines, growth factor and eicosanoids mediators. Moreover, HYAL increased gene expression of peroxisome proliferator-activated receptors (PPAR) γ and PPAR β/δ, the collagen content in the early stages of healing processes as well as angiogenesis. Altogether these data revealed that HYAL accelerates wound healing processes and might be beneficial for treating wound disorders. PMID:25393024

  13. 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.

  14. BDNF and its TrkB receptor in human fracture healing.

    PubMed

    Kilian, Olaf; Hartmann, Sonja; Dongowski, Nicole; Karnati, Srikanth; Baumgart-Vogt, Eveline; Härtel, Frauke V; Noll, Thomas; Schnettler, Reinhard; Lips, Katrin Susanne

    2014-09-01

    Fracture healing is a physiological process of repair which proceeds in stages, each characterized by a different predominant tissue in the fracture gap. Matrix reorganization is regulated by cytokines and growth factors. Neurotrophins and their receptors might be of importance to osteoblasts and endothelial cells during fracture healing. The aim of this study was to examine the presence of brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) during human fracture healing. BDNF and TrkB were investigated in samples from human fracture gaps and cultured cells using RT-PCR, Western blot, and immunohistochemistry. Endothelial cells and osteoblastic cell lines demonstrated a cytoplasmic staining pattern of BDNF and TrkB in vitro. At the mRNA level, BDNF and TrkB were expressed in the initial and osteoid formation phase of human fracture healing. In the granulation tissue of fracture gap, both proteins--BDNF and TrkB--are concentrated in endothelial and osteoblastic cells at the margins of woven bone suggesting their involvement in the formation of new vessels. There was no evidence of BDNF or TrkB during fracture healing in chondrocytes of human enchondral tissue. Furthermore, BDNF is absent in mature bone. Taken together, BDNF and TrkB are involved in vessel formation and osteogenic processes during human fracture healing. The detection of BDNF and its TrkB receptor during various stages of the bone formation process in human fracture gap tissue were shown for the first time. The current study reveals that both proteins are up-regulated in human osteoblasts and endothelial cells in fracture healing. PMID:24984919

  15. Mobilised bone marrow-derived cells accelerate wound healing.

    PubMed

    Wang, Yu; Sun, Yu; Yang, Xiao-Yan; Ji, Shi-Zhao; Han, Shu; Xia, Zhao-Fan

    2013-08-01

    Massive skin defects caused by severe burn and trauma are a clinical challenge to surgeons. Timely and effective wound closure is often hindered by the lack of skin donor site. Bone marrow-derived cells (BMDCs) have been shown to 'differentiate' into multiple tissue cells. In this study we focused on the direct manipulation of endogenous BMDCs, avoiding the immunocompatibility issues and complicated cell isolation, purification, identification and amplification procedures in vitro on wound repair. We found that mobilisation of the BMDCs into the circulation significantly increased the amount of BMDCs at the injury site which in turn accelerated healing of large open wound. We used a chimeric green fluorescent protein (GFP) mouse model to track BMDCs and to investigate their role in full-thickness skin excisional wounds. We have shown that bone marrow mobilisation by granulocyte colony stimulating factor (G-CSF) exerted multiple beneficial effects on skin repair, both by increasing the engraftment of BMDCs into the skin to differentiate into multiple skin cell types and by upregulating essential cytokine mRNAs critical to wound repair. The potential trophic effects of G-CSF on bone marrow stem cells to accelerate wound healing could have a significant clinical impact.

  16. Teriparatide for the rapid resolution of delayed healing of atypical fractures associated with long-term bisphosphonate use

    PubMed Central

    Mastaglia, Silvina R.; Aguilar, Gabriel; Oliveri, Beatriz

    2016-01-01

    Bisphosphonates (BPs) are the most widely used drugs to treat osteoporosis. However, recent reports associated to long-term BPs use with atypical low-impact fractures and prodromal pain. It is estimated that 26% of the cases of atypical fractures associated with the long-term use of BPs show delayed healing or nonunion. Teriparatide [PTH1-34] (TPTD) is an anabolic drug shown to be effective in stimulating bone formation. The aim was to describe the course of a right diaphyseal femoral fracture sustained by a patient on long-term BPs treatment. A 57-year-old postmenopausal Caucasian female presented with delayed healing of a right femoral diaphyseal fracture 10 months after the fracture, despite having received orthopedic treatment. The fracture was preceded by progressive, severe, and bilateral thigh pain. Her medical history included osteopenia that was treated with alendronate over 7 years. On presentation at our clinic, the patient ambulated with the aid of a walking cane. The diagnosis was an atypical right femoral fracture associated with long-term alendronate use. The levels of the following parameters were measured: mineral metabolism laboratory: intact parathormone, 40 ng/mL (reference values (rv): 10–65 ng/mL); 25-hydroxyvitamin D, 40 ng/mL (rv: >30 ng/mL); serum Crosslaps, 318 ng/mL (rv: 80–590 ng/mL); and bone-specific alkaline phosphatase, 76UI/L (rv: 31–95UI/L)]. Magnetic resonance imaging of the left femur was performed, which revealed a diaphyseal stress fracture. She was prescribed 20 μg/day of subcutaneous (s.c.) TPTD (PTH1-34, Forteo; Eli Lilly Co., Indianapolis, IN, United States). A computed tomography scan performed 3 months later showed that the fracture had healed; the patient was able to resume her usual activities. Twenty micrograms per day of s.c. TPD accelerated the healing of the atypical fracture associated with long-term alendronate therapy, allowing a fast recovery of ambulation and quality of life. PMID:27708978

  17. Sensitivities of biomechanical assessment methods for fracture healing of long bones.

    PubMed

    Chen, G; Wu, F Y; Zhang, J Q; Zhong, G Q; Liu, F

    2015-07-01

    There is a controversy as to whether the biomechanical methods are feasible to assess fracture healing of long bones. This paper investigated the sensitivities of two biomechanical methods, torsion and bending, for assessing fracture healing of long bones; both a simplified beam model and finite element model of an artificial femur were employed. The results demonstrated that, in the initial healing stage, the whole-bone stiffness of the fractured bone is extremely sensitive to the variation of the callus stiffness at the fracture site; when the shear (or Young's) modulus of the callus reaches 15% that of the intact bone, the whole-bone stiffness rises up to 90% that of the intact bone. After that, the whole-bone torsional (or bending) stiffness increases slowly; it becomes less sensitive to the variation of the callus stiffness. These results imply that the whole-bone stiffness is of limited reliability to assess the healing quality particular at late stages of the healing process. The simplified model in this paper provided a theoretical framework to explain why the whole-bone stiffness is insensitive to the healing process of fractured long bones in the late stage of healing. The conclusions obtained from the simplified model were verified with the finite element simulations of the artificial femur. PMID:25983068

  18. Sensitivities of biomechanical assessment methods for fracture healing of long bones.

    PubMed

    Chen, G; Wu, F Y; Zhang, J Q; Zhong, G Q; Liu, F

    2015-07-01

    There is a controversy as to whether the biomechanical methods are feasible to assess fracture healing of long bones. This paper investigated the sensitivities of two biomechanical methods, torsion and bending, for assessing fracture healing of long bones; both a simplified beam model and finite element model of an artificial femur were employed. The results demonstrated that, in the initial healing stage, the whole-bone stiffness of the fractured bone is extremely sensitive to the variation of the callus stiffness at the fracture site; when the shear (or Young's) modulus of the callus reaches 15% that of the intact bone, the whole-bone stiffness rises up to 90% that of the intact bone. After that, the whole-bone torsional (or bending) stiffness increases slowly; it becomes less sensitive to the variation of the callus stiffness. These results imply that the whole-bone stiffness is of limited reliability to assess the healing quality particular at late stages of the healing process. The simplified model in this paper provided a theoretical framework to explain why the whole-bone stiffness is insensitive to the healing process of fractured long bones in the late stage of healing. The conclusions obtained from the simplified model were verified with the finite element simulations of the artificial femur.

  19. The Changed Route of Anterior Tibial Artery due to Healed Fracture

    PubMed Central

    Gökkuş, Kemal; Sagtas, Ergin; Comert, Nuri; Unal, Mehmet Bekir; Baloglu, Murat

    2016-01-01

    We would like to highlight unusual sequelae of healed distal third diaphyseal tibia fracture that was treated conservatively 36 years ago, in which we incidentally detected peripheral CT angiography. The anterior tibial artery was enveloped three-quarterly by the healing callus of the bone (distal tibia). PMID:27019760

  20. Impairment of wound healing after operative treatment of mandibular fractures, and the influence of dexamethasone.

    PubMed

    Snäll, Johanna; Kormi, Eeva; Lindqvist, Christian; Suominen, Anna Liisa; Mesimäki, Karri; Törnwall, Jyrki; Thorén, Hanna

    2013-12-01

    Our aim was to clarify the incidence of impaired wound healing after open reduction and ostheosynthesis of mandibular fractures, and to find out whether the use of dexamethasone during the operation increased the risk. Patients were drawn from a larger group of healthy adult dentate patients who had participated in a single-blind, randomised study, the aim of which was to clarify the benefits of operative dexamethasone after treatment of facial fractures. The present analysis comprised 41 patients who had had open reduction and fixation of mandibular fractures with titanium miniplates and monocortical screws through one or 2 intraoral approaches. The outcome variable was impaired healing of the wound. The primary predictive variable was the perioperative use of dexamethasone; other potential predictive variables were age, sex, smoking habit, type of fracture, delay in treatment, and duration of operation. Wound healing was impaired in 13/41 patients (32%) (13/53 of all fractures). The incidence among patients who were given dexamethasone and those who were not did not differ significantly. Only age over 25 was significantly associated with delayed healing (p=0.02). The use of dexamethasone 30 mg perioperatively did not significantly increase the risk of impaired wound healing in healthy patients with clinically uninfected mandibular fractures fixed with titanium miniplates through an intraoral approach. Older age is a significant predictor of impaired healing, which emphasises the importance of thorough anti-infective care in these patients during and after the operation.

  1. Role of medicinal plants and natural products on osteoporotic fracture healing.

    PubMed

    Abd Jalil, Mohd Azri; Shuid, Ahmad Nazrun; Muhammad, Norliza

    2012-01-01

    Popularly known as "the silent disease" since early symptoms are usually absent, osteoporosis causes progressive bone loss, which renders the bones susceptible to fractures. Bone fracture healing is a complex process consisting of four overlapping phases-hematoma formation, inflammation, repair, and remodeling. The traditional use of natural products in bone fractures means that phytochemicals can be developed as potential therapy for reducing fracture healing period. Located closely near the equator, Malaysia has one of the world's largest rainforests, which are homes to exotic herbs and medicinal plants. Eurycoma longifolia (Tongkat Ali), Labisia pumila (Kacip Fatimah), and Piper sarmentosum (Kaduk) are some examples of the popular ethnic herbs, which have been used in the Malay traditional medicine. This paper focuses on the use of natural products for treating fracture as a result of osteoporosis and expediting its healing. PMID:22973405

  2. Role of Medicinal Plants and Natural Products on Osteoporotic Fracture Healing

    PubMed Central

    Abd Jalil, Mohd Azri; Shuid, Ahmad Nazrun; Muhammad, Norliza

    2012-01-01

    Popularly known as “the silent disease” since early symptoms are usually absent, osteoporosis causes progressive bone loss, which renders the bones susceptible to fractures. Bone fracture healing is a complex process consisting of four overlapping phases—hematoma formation, inflammation, repair, and remodeling. The traditional use of natural products in bone fractures means that phytochemicals can be developed as potential therapy for reducing fracture healing period. Located closely near the equator, Malaysia has one of the world's largest rainforests, which are homes to exotic herbs and medicinal plants. Eurycoma longifolia (Tongkat Ali), Labisia pumila (Kacip Fatimah), and Piper sarmentosum (Kaduk) are some examples of the popular ethnic herbs, which have been used in the Malay traditional medicine. This paper focuses on the use of natural products for treating fracture as a result of osteoporosis and expediting its healing. PMID:22973405

  3. Intact fibula improves fracture healing in a rat tibia osteotomy model.

    PubMed

    Shefelbine, Sandra J; Augat, Peter; Claes, Lutz; Beck, Alexander

    2005-03-01

    Rat tibia fractures are often used in fracture healing studies. Usually the fracture is stabilized with an intramedullary pin, which provides bending stiffness, but little torsional stiffness. The objective of this research was to determine the in vitro torsional rigidity of an osteotomized tibia with and without the fibula, and to determine if this difference influences the healing process in vivo. In vitro eleven rat tibias received an osteotomy, were stabilized with an intramedullary pin, and were tested in internal rotation to determine the torsional rigidity. The fibula was then manually broken and the torsional rigidity measured again. In vivo 18 rats received a tibial osteotomy, eight of which had an additional fractured fibula. After three weeks, the rats were sacrificed and the tibias were analyzed. Bone density in the fracture callus was measured with qCT. Bending rigidity and maximum breaking moment were determined in three-point bending. In vitro testing demonstrated that the torsional rigidity with an intact fibula was nearly two times higher than when the fibula was fractured. Though the torsional rigidity was still small in comparison with an intact bone, it resulted in a significantly different healing process in vivo. Rats with intact fibulas had significantly higher bone mineral density, bending rigidity, and maximum breaking moment compared to rats with a fractured fibula. These results indicate that torsional stability considerably affects the healing process. In a fracture model, it is critical to characterize the mechanical environment of the fracture.

  4. Effects of prefracture irradiation on the biomechanical parameters of fracture healing.

    PubMed

    Widmann, R F; Pelker, R R; Friedlaender, G E; Panjabi, M M; Peschel, R E

    1993-05-01

    This study examined the effects on the biomechanical parameters of fracture healing of a single dose of 900 rad (the approximate single-dose equivalent of 2,500 rad in 10 divided doses), given 1 day prior to closed fracture of the femur. The femurs were recovered at 2, 3, 4, 8, and 16 weeks after fracture and were mounted and tested to failure in torsion; the results were compared with those in nonirradiated controls from a previously published study. Prefracture irradiation delayed the progressive increase in biomechanical parameters of fracture healing. The delay was statistically significant up to 8 weeks after fracture. At 4 weeks, the normalized torque was 44% that of intact bone in the treated group compared with 75% for the control group. Sixteen weeks after fracture, the biomechanical and histological parameters of fracture healing of the irradiated femurs were no different from those of the nonirradiated controls. Within the treated group, the irradiated fractures remained significantly weaker than their contralateral intact bone at all time intervals, with a torque of only 79% that of intact bone at 16 weeks. Thus, femoral fractures in rats healed (or regained substantial strength) following palliative doses of radiation delivered 1 day prior to injury, but the repair process was delayed compared with that of nonirradiated controls.

  5. Do bisphosphonates inhibit direct fracture healing?: A laboratory investigation using an animal model.

    PubMed

    Savaridas, T; Wallace, R J; Salter, D M; Simpson, A H R W

    2013-09-01

    Fracture repair occurs by two broad mechanisms: direct healing, and indirect healing with callus formation. The effects of bisphosphonates on fracture repair have been assessed only in models of indirect fracture healing. A rodent model of rigid compression plate fixation of a standardised tibial osteotomy was used. Ten skeletally mature Sprague-Dawley rats received daily subcutaneous injections of 1 µg/kg ibandronate (IBAN) and ten control rats received saline (control). Three weeks later a tibial osteotomy was rigidly fixed with compression plating. Six weeks later the animals were killed. Fracture repair was assessed with mechanical testing, radiographs and histology. The mean stress at failure in a four-point bending test was significantly lower in the IBAN group compared with controls (8.69 Nmm(-2) (sd 7.63) vs 24.65 Nmm(-2) (sd 6.15); p = 0.017). On contact radiographs of the extricated tibiae the mean bone density assessment at the osteotomy site was lower in the IBAN group than in controls (3.7 mmAl (sd 0.75) vs 4.6 mmAl (sd 0.57); p = 0.01). In addition, histological analysis revealed progression to fracture union in the controls but impaired fracture healing in the IBAN group, with predominantly cartilage-like and undifferentiated mesenchymal tissue (p = 0.007). Bisphosphonate treatment in a therapeutic dose, as used for risk reduction in fragility fractures, had an inhibitory effect on direct fracture healing. We propose that bisphosphonate therapy not be commenced until after the fracture has united if the fracture has been rigidly fixed and is undergoing direct osteonal healing. PMID:23997143

  6. Diazoxide accelerates wound healing by improving EPC function.

    PubMed

    Li, Zhang-Peng; Xin, Ru-Juan; Yang, Hong; Jiang, Guo-Jun; Deng, Ya-Ping; Li, Dong-Jie; Shen, Fu-Ming

    2016-01-01

    Endothelial cell dysfunction is the primary cause of microvascular complications in diabetes. Diazoxide enables beta cells to rest by reversibly suppressing glucose-induced insulin secretion by opening ATP-sensitive K+ channels in the beta cells. This study investigated the role of diazoxide in wound healing in mice with streptozotocin (STZ)-induced diabetes and explored the possible mechanisms of its effect. Compared to the controls, mice with STZ-induced diabetes exhibited significantly impaired wound healing. Diazoxide treatment (30 mg/kg/d, intragastrically) for 28 days accelerated wound closure and stimulated angiogenesis in the diabetic mice. Circulating endothelial progenitor cells (EPCs) increased significantly in the diazoxide-treated diabetic mice. The adhesion, migration, and tube formation abilities of bone marrow (BM)-EPCs were impaired by diabetes, and these impairments were improved by diazoxide treatment. The expression of both p53 and TSP-1 increased in diabetic mice compared to that in the controls, and these increases were inhibited significantly by diazoxide treatment. In vitro, diazoxide treatment improved the impaired BM-EPC function and diminished the increased expression of p53 and TSP-1 in cultured BM-EPCs caused by high glucose levels. We conclude that diazoxide improved BM-EPC function in mice with STZ-induced diabetes, possibly via a p53- and TSP-1-dependent pathway. PMID:27100489

  7. The effects of alpha-tocopherol supplementation on fracture healing in a postmenopausal osteoporotic rat model

    PubMed Central

    Mohamad, Sharlina; Shuid, Ahmad Nazrun; Mohamed, Norazlina; Fadzilah, Fazalina Mohd; Mokhtar, Sabarul Afian; Abdullah, Shahrum; Othman, Faizah; Suhaimi, Farihah; Muhammad, Norliza; Soelaiman, Ima Nirwana

    2012-01-01

    OBJECTIVE: Osteoporosis increases the risk of bone fractures and may impair fracture healing. The aim of this study was to investigate whether alpha-tocopherol can improve the late-phase fracture healing of osteoporotic bones in ovariectomized rats. METHOD: In total, 24 female Sprague-Dawley rats were divided into three groups. The first group was sham-operated, and the other two groups were ovariectomized. After two months, the right femora of the rats were fractured under anesthesia and internally repaired with K-wires. The sham-operated and ovariectomized control rat groups were administered olive oil (a vehicle), whereas 60 mg/kg of alpha-tocopherol was administered via oral gavage to the alpha-tocopherol group for six days per week over the course of 8 weeks. The rats were sacrificed, and the femora were dissected out. Computed tomography scans and X-rays were performed to assess fracture healing and callus staging, followed by the assessment of callus strengths through the biomechanical testing of the bones. RESULTS: Significantly higher callus volume and callus staging were observed in the ovariectomized control group compared with the sham-operated and alpha-tocopherol groups. The ovariectomized control group also had significantly lower fracture healing scores than the sham-operated group. There were no differences between the alpha-tocopherol and sham-operated groups with respect to the above parameters. The healed femora of the ovariectomized control group demonstrated significantly lower load and strain parameters than the healed femora of the sham-operated group. Alpha-tocopherol supplementation was not able to restore these biomechanical properties. CONCLUSION: Alpha-tocopherol supplementation appeared to promote bone fracture healing in osteoporotic rats but failed to restore the strength of the fractured bone. PMID:23018307

  8. Osteogenic growth peptide accelerates bone healing during distraction osteogenesis in rabbit tibia.

    PubMed

    Zhao, Z-Y; Shao, L; Zhao, H-M; Zhong, Z-H; Liu, J-Y; Hao, C-G

    2011-01-01

    Distraction osteogenesis is a valuable treatment method that allows limb lengthening or reconstruction of large bone defects. However, its major disadvantage is the long period required for the consolidation of a distraction callus. Osteogenic growth peptide (OGP) stimulates endochondral bone formation in fracture callus, but its capacity to promote regenerate ossification during distraction osteogenesis has not been evaluated. This study investigated whether intravenously administered OGP accelerated bone healing during distraction osteogenesis in 36 male New Zealand White rabbits, randomized into two groups. The treatment group received OGP (200 ng/kg body weight) in phosphate-buffered saline (PBS), intravenously, each day; the control group received PBS alone. A 15-mm lengthening of the right lower leg was performed using the method of Ilizarov. Evidence from biomechanical, histological and radiographic evaluations demonstrated that systemic OGP treatment promoted optimal new bone formation during distraction osteogenesis in this rabbit model.

  9. Effect of Teriparatide on Healing of Atypical Femoral Fractures: A Systemic Review

    PubMed Central

    Lee, Seong-Hyun

    2015-01-01

    Background Bisphosphonates (BPs) are the most commonly used anti-osteoporotic drugs, which have been proven to reduce the risk of osteoporotic fractures. However, use of BPs, particularly for long periods of time, is associated with an increased risk of atypical femoral fracture (AFF). Healing of BP-associated AFF is usually delayed because of suppressed bone turnover. Teriparatide (TPTD), a recombinant form of parathyroid hormone (PTH), enhances bone healing in patients with delayed healing or non-union. Methods In this study, we summarized and performed a systemic review of the published literature on treatment of AFF using TPTD. Results Although there is a lack of level 1 studies on the evidence of TPTD in promoting bone union in AFFs, this systemic review of the available literature revealed that TPTD works positively in AFFs, and we put together the evidence that TPTD is a viable treatment option for enhancing fracture healing in AFFs. Conclusions While anecdotal evidence of beneficial effects of TPTD on fracture healing offer limited guidance for clinical decision making, a better understanding of the role of TPTD in fracture healing may be elucidated with future prospective trials. PMID:26713309

  10. Effects of foot posture on fifth metatarsal fracture healing: a finite element study.

    PubMed

    Brilakis, Emmanuel; Kaselouris, Evaggelos; Xypnitos, Frank; Provatidis, Christopher G; Efstathopoulos, Nicolas

    2012-01-01

    The goal of this study was to evaluate the effects of maintaining different foot postures during healing of proximal fifth metatarsal fractures for each of 3 common fracture types. A 3-dimensional (3D) finite element model of a human foot was developed and 3 loading situations were evaluated, including the following: (1) normal weightbearing, (2) standing with the affected foot in dorsiflexion at the ankle, and (3) standing with the affected foot in eversion. Three different stages of the fracture-healing process were studied, including: stage 1, wherein the material interposed between the fractured edges was the initial connective tissue; stage 2, wherein connective tissue had been replaced by soft callus; and stage 3, wherein soft callus was replaced by mature bone. Thus, 30 3D finite element models were analyzed that took into account fracture type, foot posture, and healing stage. Different foot postures did not statistically significantly affect the peak-developed strains on the fracture site. When the fractured foot was everted or dorsiflexed, it developed a slightly higher strain within the fracture than when it was in the normal weightbearing position. In Jones fractures, eversion of the foot caused further torsional strain and we believe that this position should be avoided during foot immobilization during the treatment of fifth metatarsal base fractures. Tuberosity avulsion fractures and Jones fractures seem to be biomechanically stable fractures, as compared with shaft fractures. Our understanding of the literature and experience indicate that current clinical observations and standard therapeutic options are in accordance with the results that we observed in this investigation, with the exception of Jones fractures.

  11. The Effect of Teriparatide on Fracture Healing of Osteoporotic Patients: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Lou, Shenghan; Lv, Houchen; Wang, Guoqi; Zhang, Licheng; Li, Ming; Li, Zhirui; Zhang, Lihai

    2016-01-01

    Purpose. This meta-analysis is to assess the effectiveness of teriparatide in fracture healing and clinical function improvement of the osteoporotic patients. Methods. We searched PubMed, Embase, Web of Science, and the Cochrane databases for randomized and quasi-randomized controlled trials comparing teriparatide to placebo, no treatment, or comparator interventions in the osteoporotic patients. Results. Five studies with 251 patients were included. Patients treated with teriparatide therapy had a significant shorter radiological fracture healing time compared with those in the control group (mean difference [MD] −4.54 days, 95% confidence interval [CI] −8.80 to −0.28). Stratified analysis showed that lower limb group had significant shorter healing time (MD −6.24 days, 95% CI −7.20 to −5.29), but upper limb group did not (MD −1 days, 95% CI −2.02 to 0.2). Patients treated with teriparatide therapy showed better functional outcome than those in the control group (standardized mean difference [SMD] −1.02, 95% CI −1.81 to −0.22). Patients with therapy duration over 4 weeks would have better functional outcome (SMD −1.68, 95% CI −2.07 to −1.29). Conclusions. Teriparatide is effective in accelerating fracture healing and improving functional outcome of osteoporotic women. However, more clinical studies are warranted in order to determine whether the results are applicable to males and the clinical indications for teriparatide after osteoporotic fractures. PMID:27429980

  12. The Pathobiology of Diabetes Mellitus in Bone Metabolism, Fracture Healing, and Complications.

    PubMed

    Forslund, Johan M; Archdeacon, Michael T

    2015-10-01

    Complications and inferior outcomes of fractures in the setting of diabetes mellitus (DM) are well documented. The incidence of DM is increasing rapidly, particularly in an aging and obese population. Thus, the combination of DM and fracture is becoming a serious health problem worldwide. As many fractures are relatively uncomplicated in the healthy patient population, a concerted effort to improve outcomes of fractures in patients with DM is warranted. In this article, we review relevant studies and examine the pathobiological mechanisms influencing fracture outcomes, including complications related to bone and soft-tissue healing, and infection. PMID:26447406

  13. Analyzing the cellular contribution of bone marrow to fracture healing using bone marrow transplantation in mice

    SciTech Connect

    Colnot, C. . E-mail: colnotc@orthosurg.ucsf.edu; Huang, S.; Helms, J.

    2006-11-24

    The bone marrow is believed to play important roles during fracture healing such as providing progenitor cells for inflammation, matrix remodeling, and cartilage and bone formation. Given the complex nature of bone repair, it remains difficult to distinguish the contributions of various cell types. Here we describe a mouse model based on bone marrow transplantation and genetic labeling to track cells originating from bone marrow during fracture healing. Following lethal irradiation and engraftment of bone marrow expressing the LacZ transgene constitutively, wild type mice underwent tibial fracture. Donor bone marrow-derived cells, which originated from the hematopoietic compartment, did not participate in the chondrogenic and osteogenic lineages during fracture healing. Instead, the donor bone marrow contributed to inflammatory and bone resorbing cells. This model can be exploited in the future to investigate the role of inflammation and matrix remodeling during bone repair, independent from osteogenesis and chondrogenesis.

  14. Inhibition of angiotensin-converting enzyme stimulates fracture healing and periosteal callus formation – role of a local renin-angiotensin system

    PubMed Central

    Garcia, P; Schwenzer, S; Slotta, JE; Scheuer, C; Tami, AE; Holstein, JH; Histing, T; Burkhardt, M; Pohlemann, T; Menger, MD

    2010-01-01

    Background and purpose: The renin-angiotensin system (RAS) regulates blood pressure and electrolyte homeostasis. In addition, ‘local’ tissue-specific RAS have been identified, regulating regeneration, cell growth, apoptosis, inflammation and angiogenesis. Although components of the RAS are expressed in osteoblasts and osteoclasts, a local RAS in bone has not yet been described and there is no information on whether the RAS is involved in fracture healing. Therefore, we studied the expression and function of the key RAS component, angiotensin-converting enzyme (ACE), during fracture healing. Experimental approach: In a murine femur fracture model, animals were treated with the ACE inhibitor perindopril or vehicle only. Fracture healing was analysed after 2, 5 and 10 weeks using X-ray, micro-CT, histomorphometry, immunohistochemistry, Western blotting and biomechanical testing. Key results: ACE was expressed in osteoblasts and hypertrophic chondrocytes in the periosteal callus during fracture healing, accompanied by expression of the angiotensin type-1 and type-2 receptors. Perindopril treatment reduced blood pressure and bone mineral density in unfractured femora. However, it improved periosteal callus formation, bone bridging of the fracture gap and torsional stiffness. ACE inhibition did not affect cell proliferation, but reduced apoptotic cell death. After 10 week treatment, a smaller callus diameter and bone volume after perindopril treatment indicated an advanced stage of bone remodelling. Conclusions: Our study provides evidence for a local RAS in bone that influenced the process of fracture healing. We show for the first time that inhibition of ACE is capable of accelerating bone healing and remodelling. PMID:20233225

  15. Effect of Pentoxifylline Administration on an Experimental Rat Model of Femur Fracture Healing With Intramedullary Fixation

    PubMed Central

    Vashghani Farahani, Mohammad Mahdi; Masteri Farahani, Reza; Mostafavinia, Ataroalsadat; Abbasian, Mohammad Reza; Pouriran, Ramin; Noruzian, Mohammad; Ghoreishi, Seyed Kamran; Aryan, Arefe; Bayat, Mohammad

    2015-01-01

    Background: Globally, musculoskeletal injuries comprise a major public health problem that contributes to a large burden of disability and suffering. Pentoxifylline (PTX) has been originally used as a hemorheologic drug to treat intermittent claudication. Previous test tube and in vivo studies reported the beneficial effects of PTX on bony tissue. Objectives: This study aims to evaluate the effects of different dosages of PTX on biomechanical properties that occur during the late phase of the fracture healing process following a complete femoral osteotomy in a rat model. We applied intramedullary pin fixation as the treatment of choice. Materials and Methods: This experimental study was conducted at the Shahid Beheshti University of Medical Sciences, Tehran, Iran. We used the simple random technique to divide 35 female rats into five groups. Group 1 received intraperitoneal (i.p.) PTX (50 mg/kg, once daily) injections, starting 15 days before surgery, and group 2, group 3, and group 4 received 50 mg/kg, 100 mg/kg, and 200 mg/kg i.p. PTX injections, respectively, once daily after surgery. All animals across groups received treatment for six weeks (until sacrificed). Complete surgical transverse osteotomy was performed in the right femur of all rats. At six weeks after surgery, the femurs were subjected to a three-point bending test. Results: Daily administration of 50 mg/kg PTX (groups 1 and 2) decreased the high stress load in repairing osteotomized femurs when compared with the control group. The highest dose of PTX (200 mg/kg) significantly increased the high stress load when compared with the control group (P = 0.030), group 1 (P = 0.023), group 2 (P = 0.008), and group 3 (P = 0.010), per the LSD findings. Conclusions: Treatment with 200 mg/kg PTX accelerated fracture healing when compared with the control group. PMID:26756019

  16. 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

  17. Accelerated healing of cardiovascular textiles promoted by an RGD peptide.

    PubMed

    Tweden, K S; Harasaki, H; Jones, M; Blevitt, J M; Craig, W S; Pierschbacher, M; Helmus, M N

    1995-07-01

    Polytetrafluoroethylene (PTFE) and polyethylene terephthalate (Dacron polyester) fabrics are used extensively in cardiovascular devices, e.g. heart valve sewing cuffs and vascular prostheses. While devices containing these fabrics are generally successful, it is recognized that fabrics cause complications prior to tissue ingrowth due to their thrombogenic nature. A surface active synthetic peptide, called PepTite Coating (PepTite), which was modeled after the cell attachment domain of human fibronectin has been marketed as a biocompatible coating. This peptide stimulates cell attachment through the arginine-glycine-aspartic acid (RGD) sequence. Modification of medical implants with PepTite has been shown to promote ingrowth of surrounding cells into the material leading to better tissue integration, reduced inflammation and reduced fibrotic encapsulation. In this study, polyester and PTFE textiles were modified with PepTite. The effectiveness of this coating in enhancing wound healing was investigated in a simple vascular and cardiac valve model. Our results indicate that the RGD-containing peptide, PepTite, promoted the formation of an endothelial-like cell layer on both polyester and PTFE vascular patches in the dog model. PepTite was also found to promote the formation of a significantly thinner neointima (pannus) on polyester as compared to that on its uncoated control. These results were corroborated in the cardiac valve model in which a greater amount of thin pannus and less thrombus were seen on coated polyester sewing cuffs than on control uncoated cuffs. This research shows the promising tissue response to RGD coated textiles and the potential role of this peptide in material passivation via accelerated healing.

  18. Mesenchymal Stem Cells with Increased Stromal Cell-Derived Factor 1 Expression Enhanced Fracture Healing

    PubMed Central

    Ho, Chih-Yuan; Hua, Jia; Coathup, Melanie; Kalia, Priya; Blunn, Gordon

    2015-01-01

    Treatment of critical size bone defects pose a challenge in orthopedics. Stem cell therapy together with cytokines has the potential to improve bone repair as they cause the migration and homing of stem cells to the defect site. However, the engraftment, participation, and recruitment of other cells within the regenerating tissue are important. To enhance stem cell involvement, this study investigated overexpression of stem cells with stromal cell-derived factor 1 (SDF-1) using an adenovirus. We hypothesized that these engineered cells would effectively increase the migration of native cells to the site of fracture, enhancing bone repair. Before implantation, we showed that SDF-1 secreted by transfected cells increased the migration of nontransfected cells. In a rat defect bone model, bone marrow mesenchymal stem cells overexpressing SDF-1 showed significantly (p=0.003) more new bone formation within the gap and less bone mineral loss at the area adjacent to the defect site during the early bone healing stage. In conclusion, SDF-1 was shown to play an important role in accelerating fracture repair and contributing to bone repair in rat models, by recruiting more host stem cells to the defect site and encouraging osteogenic differentiation and production of bone. PMID:25251779

  19. Aryl Hydrocarbon Receptor-Mediated Impairment of Chondrogenesis and Fracture Healing by Cigarette Smoke and Benzo(α)pyrene

    PubMed Central

    Kung, Ming H.; Yukata, Kiminori; O’Keefe, Regis J.; Zuscik, Michael J.

    2012-01-01

    The clinical literature strongly suggests that bone healing in cigarette smokers is impaired. Since cigarette smoke (CS) contains numerous polycyclic aromatic hydrocarbons (PAHs), and since dioxins impair bone formation in vivo via the Aryl Hydrocarbon Receptor (AHR), we investigated the impact of PAH/AHR signaling on chondrogenesis and on healing in a mouse tibial fracture model. We established that CS activates AHR signaling in fractures by up-regulating the AHR target gene cytochrome p4501A1 (Cyp1A1). For in vitro studies, we employed the mouse limb bud micromass chondrogenesis model. After confirming that chondrocytes express AHR during differentiation, we treated cells with a prototypical PAH found in CS, benzo(α)pyrene (BaP), or cigarette smoke extract (CSE). Both BaP and CSE both strongly inhibited chondrogenesis in mesenchymal cells generated from E11 limb buds, with BaP also accelerating chondrocyte hypertrophy in cultures generated from E12 limb buds. Detection of DNA adducts in the BaP-treated cultures suggests that the distinct phenotypic effects of BaP may be due to the formation of reactive metabolites. Blockade of AHR signaling with the AHR antagonist MNF reverses the effects of BaP, but not CSE, suggesting that CSE inhibition of chondrogenesis is AHR-independent. Correlating with these results, tibial fracture calluses from BaP-treated mice were smaller and contained less mineralized tissue than vehicle controls. Overall, BaP is identified as a potent inhibitor of chondrogenesis in vitro with correlated effects on fracture healing similar to those of CS itself, suggesting a basis for PAHs as key compounds in the influence of CS on fracture repair. PMID:21567390

  20. What is the role of bosentan in healing of femur fractures in a rat model?

    PubMed

    Aydin, Ali; Halici, Zekai; Akpinar, Erol; Aksakal, A Murat; Saritemur, Murat; Yayla, Muhammed; Kunak, C Semih; Cadirci, Elif; Atmaca, H Tarik; Karcioglu, S Sena

    2015-09-01

    The purpose of this study was to examine the effects bosentan (which is a strong vasoconstrictor) on bone fracture pathophysiology, and investigate the roles of the nonselective endothelin 1 receptor blocker bosentan on the bone fractures formed in rats through radiographic, histopathologic, and immunohistochemical methods. The rats were divided into three groups (six rats in each group): a femoral fracture control group, a femoral fracture plus bosentan at 50 mg/kg group, and a femoral fracture plus bosentan at 100 mg/kg group. The femoral fracture model was established by transversely cutting the femur at the midsection. After manual reduction, the fractured femur was fixed with intramedullary Kirschner wires. The radiographic healing scores of the bosentan 100 and 50 mg/kg groups were significantly better that those of the fracture control group. The fracture callus percent of new bone in the bosentan 100 mg/kg group was significantly greater than that in the control group. Also, semiquantitative analysis showed higher positive vascular endothelial growth factor and osteocalcin staining and lower positive endothelin receptor type A staining in the treatment groups than in the control group. Bosentan treatment also decreased tissue endothelin 1 expression relative to that in the fracture control group. As a result of our study, the protective effect of bosentan was shown in experimental femoral fracture healing in rats by radiographic, histopathologic, and molecular analyses.

  1. Fourier Transform Infrared Spectroscopic Imaging of Fracture Healing in the Normal Mouse

    PubMed Central

    Gollwitzer, Hans; Yang, Xu; Spevak, Lyudmila; Lukashova, Lyudmila; Nocon, Allina; Fields, Kara; Pleshko, Nancy; Courtland, Hayden William; Bostrom, Mathias P.; Boskey, Adele L.

    2015-01-01

    Fourier transform infrared spectroscopic imaging (FTIRI) was used to study bone healing with spatial analysis of various callus tissues in wild type mice. Femoral fractures were produced in 28 male C57BL mice by osteotomy. Animals were sacrificed at 1, 2, 4, and 8 weeks to obtain callus tissue at well-defined healing stages. Following microcomputerized tomography, bone samples were cut in consecutive sections for FTIRI and histology, allowing for spatial correlation of both imaging methods in different callus areas (early calcified cartilage, woven bone, areas of intramembranous and endochondral bone formation). Based on FTIRI, mineral/matrix ratio increased significantly during the first 4 weeks of fracture healing in all callus areas and correlated with bone mineral density measured by micro-CT. Carbonate/phosphate ratio was elevated in newly formed calcified tissue and at week 2 attained values comparable to cortical bone. Collagen maturity and mineral crystallinity increased during weeks 1–8 in most tissues while acid phosphate substitution decreased. Temporal and callus area dependent changes were detected throughout the healing period. These data assert the usefulness of FTIRI for evaluation of fracture healing in the mouse and its potential to evaluate pathologic fracture healing and the effects of therapeutic interventions. PMID:26034749

  2. Correlations of radiographic analysis of healing fractures with strength: a statistical analysis of experimental osteotomies.

    PubMed

    Panjabi, M M; Walter, S D; Karuda, M; White, A A; Lawson, J P

    1985-01-01

    The assessment of fracture healing strength using routine roentgenograms is difficult and controversial. There are few experimental data that correlate radiographic appearance with the actual quantitative strength of healing fractures. However, this method is widely used in clinical practice. A study is presented in which transversely osteotomized rabbit tibiae were allowed to heal for 3 to 8 weeks. A pair of orthogonal roentgenograms was taken of each bone and the bones were tested for strength in a dynamic torsion testing machine. Statistical analyses were done to study the correlations between the roentgenographic and strength parameters. Cortical continuity was found to be the best single predictor of strength of a healing fracture (correlation coefficient r = 0.80). The least important predictor was the callus area (r = 0.17). Fracture displacement, callus thickness, and callus diameter had negative correlations. From these experimental findings in an animal model, we conclude that even under laboratory conditions the information gained from plain radiographs is not sufficient to accurately predict the strength of a healing fracture.

  3. Backstroke technique: an effective way to improve the healing of tibia fracture.

    PubMed

    Lee, Qi; Zeng, Bing-Fang; Luo, Cong-Feng; Wang, Jin-Wu; Lu, Nan-Ji

    2006-10-01

    To assess the method and results of applying a backstroke technique, we treated 43 patients with tibial shaft fracture using unreamed tibial nails (UTN). Of these patients, 27 suffered a closed fracture and 16 an open fracture. After the operation, the effect of treatment was evaluated: 42 of 43 cases were followed up from four to 18 months, averaging 13.6 months. The four-month and 12-month healing rates of open fracture were 54.6 and 80.9%, respectively, the former of which is significantly higher than the average rate of the AO/ASIF multicentre study. Our results indicate that applying a backstroke technique in treating tibial shaft fracture with UTN can improve the healing rate and reduce complications. PMID:16628441

  4. Influence of age on mechanical properties of healing fractures and intact bones in rats.

    PubMed

    Ekeland, A; Engesoeter, L B; Langeland, N

    1982-08-01

    Mechanical properties of fractured and intact femora have been studied in young and adult, male rats. A standardized, closed, mid-diaphyseal fracture was produced in the left femur, the right femur serving as control. The fracture was left to heal without immobilization. At various intervals, both fractured and intact femora were loaded in torsion until failure. The fractured femora regained the mechanical properties of the contralateral, intact bones after about 4 weeks in young and after about 12 weeks in adult rats. For intact bones, both the ultimate torsional moment (strength) and the torsional stiffness increased with age of the animals, whereas the ultimate torsional angle remained unchanged. For bone as a material, however, the ultimate torsional stress (strength) and the modulus of rigidity (stiffness) increased with age only in young rats, being almost constant in the adult animals. The various biomechanical parameters of the healing fractures did not reach those of the contralateral, intact bones simultaneously. The torsional moment required to twist a healing femoral fracture 20 degrees (0.35 radians), a deformation close to what an intact femur can resist, proved to be a functional and simple measure of the degree of fracture repair in rats.

  5. Novel Perfused Compression Bioreactor System as an in vitro Model to Investigate Fracture Healing

    PubMed Central

    Hoffmann, Waldemar; Feliciano, Sandra; Martin, Ivan; de Wild, Michael; Wendt, David

    2015-01-01

    Secondary bone fracture healing is a physiological process that leads to functional tissue regeneration via endochondral bone formation. In vivo studies have demonstrated that early mobilization and the application of mechanical loads enhances the process of fracture healing. However, the influence of specific mechanical stimuli and particular effects during specific phases of fracture healing remain to be elucidated. In this work, we have developed and provided proof-of-concept of an in vitro human organotypic model of physiological loading of a cartilage callus, based on a novel perfused compression bioreactor (PCB) system. We then used the fracture callus model to investigate the regulatory role of dynamic mechanical loading. Our findings provide a proof-of-principle that dynamic mechanical loading applied by the PCB can enhance the maturation process of mesenchymal stromal cells toward late hypertrophic chondrocytes and the mineralization of the deposited extracellular matrix. The PCB provides a promising tool to study fracture healing and for the in vitro assessment of alternative fracture treatments based on engineered tissue grafts or pharmaceutical compounds, allowing for the reduction of animal experiments. PMID:25699254

  6. HIF-1α change in serum and callus during fracture healing in ovariectomized mice

    PubMed Central

    Li, Wenliang; Wang, Kejie; Liu, Zhiwei; Ding, Wenge

    2015-01-01

    The purpose was to detect the effects of ovariectomy (OVX) on femoral fracture healing through different angiogenesis and HIF-1α expression in mice. Thirty-six young female C57 mice were randomized into two groups: OVX and age-matched intact control (CON). The femoral fracture was generated at 3 weeks after OVX or CON. At 2 or 4 weeks after fracture, the femoral fracture area was evaluated healing status by bone mineral density (BMD), callus formation and mineralization and neovascularization in callus, biomechanical analysis, and HIF-1α tests. OVX mice showed lower BMD as compared with CON mice. Callus geometric microstructural parameters of the femora in OVX mice were significantly lower than CON mice. OVX induced significant changes of biomechanical parameters in the femoral fracture healing area. The callus forming, callus neovascularization and HIF-1α tests in OVX mice were significantly lower than in CON mice. HIF-1α results have the positive proportion with osteoporotic fracture healing. PMID:25755698

  7. Clinician's ability to evaluate the strength of healing fractures from plain radiographs

    SciTech Connect

    Panjabi, M.M.; Lindsey, R.W.; Walter, S.D.; White, A.A. 3d.

    1989-01-01

    The present study was designed to analyze the usefulness of plain radiographs in evaluating bone healing. Rabbit tibiae were osteotomized, externally fixed, and allowed to heal for 3-8 weeks. Bones were harvested, x-rayed, and tested to failure in a dynamic torsion tester. AP and lateral radiographs of 10 rabbit tibia pairs and 10 individual rabbit tibiae were selected randomly for use in a questionnaire, given to 93 physicians who routinely assess fracture healing to evaluate clinicians' ability to assess bone strength. The results indicated that clinicians can differentiate the relative strength of bones by comparing two sets of radiographs. However, the strength determination from a single set of radiographs of a fracture is unreliable, the tendency being to evaluate the fracture to be weaker than it actually is.

  8. The clinician's ability to evaluate the strength of healing fractures from plain radiographs.

    PubMed

    Panjabi, M M; Lindsey, R W; Walter, S D; White, A A

    1989-01-01

    The present study was designed to analyze the usefulness of plain radiographs in evaluating bone healing. Rabbit tibiae were osteotomized, externally fixed, and allowed to heal for 3-8 weeks. Bones were harvested, x-rayed, and tested to failure in a dynamic torsion tester. AP and lateral radiographs of 10 rabbit tibia pairs and 10 individual rabbit tibiae were selected randomly for use in a questionnaire, given to 93 physicians who routinely assess fracture healing to evaluate clinicians' ability to assess bone strength. The results indicated that clinicians can differentiate the relative strength of bones by comparing two sets of radiographs. However, the strength determination from a single set of radiographs of a fracture is unreliable, the tendency being to evaluate the fracture to be weaker than it actually is.

  9. Periosteal PTHrP Regulates Cortical Bone Remodeling During Fracture Healing.

    PubMed

    Wang, Meina; Nasiri, Ali R; Broadus, Arthur E; Tommasini, Steven M

    2015-12-01

    Parathyroid hormone-related protein (PTHrP) is widely expressed in the fibrous outer layer of the periosteum (PO), and the PTH/PTHrP type I receptor (PTHR1) is expressed in the inner PO cambial layer. The cambial layer gives rise to the PO osteoblasts (OBs) and osteoclasts (OCs) that model/remodel the cortical bone surface during development as well as during fracture healing. PTHrP has been implicated in the regulation of PO modeling during development, but nothing is known as regards a role of PTHrP in this location during fracture healing. We propose that PTHrP in the fibrous layer of the PO may be a key regulatory factor in remodeling bone formation during fracture repair. We first assessed whether PTHrP expression in the fibrous PO is associated with PO osteoblast induction in the subjacent cambial PO using a tibial fracture model in PTHrP-lacZ mice. Our results revealed that both PTHrP expression and osteoblast induction in PO were induced 3 days post-fracture. We then investigated a potential functional role of PO PTHrP during fracture repair by performing tibial fracture surgery in 10-week-old CD1 control and PTHrP conditional knockout (PTHrP cKO) mice that lack PO PTHrP. We found that callus size and formation as well as woven bone mineralization in PTHrP cKO mice were impaired compared to that in CD1 mice. Concordant with these findings, functional enzyme staining revealed impaired OB formation and OC activity in the cKO mice. We conclude that deleting PO PTHrP impairs cartilaginous callus formation, maturation and ossification as well as remodeling during fracture healing. These data are the initial genetic evidence suggesting that PO PTHrP may induce osteoblastic activity and regulate fracture healing on the cortical bone surface. PMID:26164475

  10. Anti-IL-20 monoclonal antibody promotes bone fracture healing through regulating IL-20-mediated osteoblastogenesis

    PubMed Central

    Hsu, Yu-Hsiang; Chiu, Yi-Shu; Chen, Wei-Yu; Huang, Kuo-Yuan; Jou, I-Ming; Wu, Po-Tin; Wu, Chih-Hsing; Chang, Ming-Shi

    2016-01-01

    Bone loss and skeletal fragility in bone fracture are caused by an imbalance in bone remodeling. The current challenge in bone fracture healing is to promote osteoblastogenesis and bone formation. We aimed to explore the role of IL-20 in osteoblastogenesis, osteoblast differentiation and bone fracture. Serum IL-20 was significantly correlated with serum sclerostin in patients with bone fracture. In a mouse model, anti-IL-20 monoclonal antibody (mAb) 7E increased bone formation during fracture healing. In vitro, IL-20 inhibited osteoblastogenesis by upregulating sclerostin, and downregulating osterix (OSX), RUNX2, and osteoprotegerin (OPG). IL-20R1 deficiency attenuated IL-20-mediated inhibition of osteoblast differentiation and maturation and reduced the healing time after a bone fracture. We conclude that IL-20 affects bone formation and downregulates osteoblastogenesis by modulating sclerostin, OSX, RUNX2, and OPG on osteoblasts. Our results demonstrated that IL-20 is involved in osteoregulation and anti-IL-20 mAb is a potential therapeutic for treating bone fracture or metabolic bone diseases. PMID:27075747

  11. Haploinsufficiency of endogenous parathyroid hormone-related peptide impairs bone fracture healing.

    PubMed

    Wang, Yin-He; Qiu, Yong; Han, Xiao-Dong; Xiong, Jin; Chen, Yi-Xin; Shi, Hong-Fei; Karaplis, Andrew

    2013-11-01

    Previous studies have demonstrated that endogenous parathyroid hormone-related peptide (PTHrP) plays a central role in the physiological regulation of bone formation. However, it is unclear whether endogenous PTHrP plays an important function in enhancing bone fracture healing. To determine whether endogenous PTHrP haploinsufficiency impaired bone fracture healing, closed mid-diaphyseal femur fractures were created in 8-week-old wild-type and Pthrp(+/-) mice. Callus tissue properties were analysed 1, 2 and 4 weeks after fracture by radiography, histology, histochemistry, immunohistochemistry and molecular biology. The size of the calluses was reduced 2 weeks after fracture, and the fracture repairs were poor 4 weeks after fractures, in Pthrp(+/-) compared with wild-type mice. Cartilaginous callus areas were reduced 1 week after fracture, but were increased 2 weeks after fracture in Pthrp(+/-) mice. There was a reduction in the number of ostoblasts, alkaline phosphatase (ALP)-positive areas, Type I collagen immunopositive areas, mRNA levels of ALP, Runt-related transcription factor 2 (Runx2) and Type I collagen, Runx2 and insulin-like growth factor-1 protein levels, the number of osteoclasts and the surface in callus tissues in Pthrp(+/-) compared with wild-type mice. These results demonstrate that endogenous PTHrP haploinsufficiency impairs the fracture repair process by reducing cartilaginous and bony callus formation, with downregulation of osteoblastic gene and protein expression and a reduction in endochondral bone formation, osteoblastic bone formation and osteoclastic bone resorption. Together, the results indicate that endogenous PTHrP plays an important role in fracture healing.

  12. The initial phase of fracture healing is specifically sensitive to mechanical conditions.

    PubMed

    Klein, Petra; Schell, Hanna; Streitparth, Florian; Heller, Markus; Kassi, Jean-Pierre; Kandziora, Frank; Bragulla, Hermann; Haas, Norbert P; Duda, Georg N

    2003-07-01

    Interfragmentary movements affect the quality and quantity of callus formation. The mounting plane of monolateral external fixators may give direction to those movements. Therefore, the aim of this study was to determine the influence of the fixator mounting plane on the process of fracture healing. Identically configured fixators were mounted either medially or anteromedially on the tibiae of sheep. Interfragmentary movements and ground reaction forces were evaluated in vivo during a nine week period. Histomorphological and biomechanical parameters described the bone healing processes. Changing only the mounting plane led to a modification of interfragmentary movements in the initial healing phase. The difference in interfragmentary movements between the groups was only significant during the first post-operative period. However, these initial differences in mechanical conditions influenced callus tissue formation significantly. The group with the anteromedially mounted fixator, initially showing significantly more interfragmentary movements, ended up with a significantly smaller callus diameter and a significantly higher callus stiffness as a result of advanced fracture healing. This demonstrates that the initial phase of healing is sensitive to mechanical conditions and influences the course of healing. Therefore, initial mechanical stability of an osteosynthesis should be considered an important factor in clinical fracture treatment.

  13. Amifostine Preserves Osteocyte Number and Osteoid Formation in Fracture Healing Following Radiotherapy

    PubMed Central

    Donneys, Alexis; Tchanque-Fossuo, Catherine N.; Blough, Jordan T.; Nelson, Noah S.; Deshpande, Sagar S.; Buchman, Steven R.

    2013-01-01

    Purpose Radiation is known to diminish osteocyte count and function leading to bone weakening. A treatment strategy to mitigate these consequences could have immense therapeutic ramifications. We have previously demonstrated significantly diminished osteocyte count and mineralization capacity in a rat model of fracture healing after radiotherapy. We hypothesize that amifostine (AMF) will preserve osteocyte number and function in this model. Materials and Methods Thirty-six rats were divided into three groups: fracture, radiated fracture, and radiated fracture with AMF. Radiated groups underwent human equivalent radiotherapy to the mandible prior to fixator placement and mandibular osteotomy. The AMF group received a subcutaneous injection prior to each dose of radiotherapy. After 40 days, mandibles were harvested for histologic processing. Quantification of osteocyte count (Oc), empty lacunae (EL) and osteoid ratio (OV/TV) was performed and the results were compared using ANOVA (p<0.05). Results Radiated fractures demonstrated significantly diminished Oc, increased EL and diminished capacity to produce new osteoid at the fracture site as measured with OV/TV when compared to non-radiated fractures. In mandibles treated with amifostine, these metrics were not statistically different than control, indicating a preservation of osteocyte number and function. Conclusions Our results support the hypothesis that amifostine preserves osteocyte number and function, thereby preventing the pernicious effects of radiotherapy on the cellular environment of fracture healing. Based on these findings, we encourage future investigation of this promising therapy for use in the prevention of pathologic fractures and osteoradionecrosis. PMID:24342580

  14. Ginsenoside Rg1 promotes osteogenic differentiation of rBMSCs and healing of rat tibial fractures through regulation of GR-dependent BMP-2/SMAD signaling

    PubMed Central

    Gu, Yanqing; Zhou, Jinchun; Wang, Qin; Fan, Weimin; Yin, Guoyong

    2016-01-01

    Fracture healing is closely related to the number and activity of bone marrow mesenchymal stem cells (BMSCs) near the fracture site. The present study was to investigate the effect of Rg1 on osteogenic differentiation of cultured BMSCs and related mechanisms and on the fracture healing in a fracture model. In vitro experiments showed that Rg1 promoted the proliferation and osteogenic differentiation of BMSCs. Western blot analyses demonstrated that Rg1 promoted osteogenic differentiation of BMSCs through the glucocorticoid receptor (GR)-dependent BMP-2/Smad signaling pathway. In vivo, X-ray examination showed that callus growth in rats treated with Rg1 was substantially faster than that in control rats after fracture. The results of H&E and Safranin-O/Fast Green staining revealed that, compared with controls, rats in the Rg1 treatment group had a significantly higher proportion of trabecular bone but a much lower proportion of fibers and cartilage components inside the callus. Micro-CT suggested that bone mineral density (BMD), percent bone volume (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th) were significantly increased in the treatment group, whereas trabecular separation (Tb.Sp) was significantly reduced. Thus, Rg1 promotes osteogenic differentiation by activating the GR/BMP-2 signaling pathway, enhances bone calcification, and ultimately accelerates the fracture healing in rats. PMID:27141994

  15. Parameters for Lithium Treatment Are Critical in Its Enhancement of Fracture-Healing in Rodents

    PubMed Central

    Bernick, Joshua; Wang, Yufa; Sigal, Ian A.; Alman, Benjamin A.; Whyne, Cari M.; Nam, Diane

    2014-01-01

    Background: Lithium, a treatment for bipolar disorder, is not clinically indicated for use in fracture management but has been reported to positively influence bone biology. It is hypothesized that lithium dosing for beneficial effects on bone health may be much lower than the dosing required for psychotropic benefits in patients with bipolar disorder. A preclinical study with a rodent fracture model was utilized to best define the lowest effective dose, best timing of treatment onset, and optimal treatment duration for the use of lithium as a new treatment in fracture care. Methods: A design-of-experiments approach was used to assess the parameters of dose, timing of treatment onset, and treatment duration. Closed femoral shaft fractures were generated and analyzed with use of destructive torsional mechanical testing and microcomputed tomography-based image analysis. Eleven different outcome measures were quantified, with maximum yield torque as the primary study outcome, to assess the quality of long-bone fracture-healing. Results: Fracture-healing was maximized with a lithium treatment combination of a low dose (twenty milligrams per kilogram of body weight per day), later onset of lithium treatment (seven days after fracture), and longer treatment duration (two weeks), with maximum yield torque displaying a 46% increase compared with nontreated and sham-treated controls (481.1 ± 104.0 N-mm compared with 329.9 ± 135.8 N-mm; p = 0.04). Design-of-experiments analysis determined the timing of treatment onset to be the most influential parameter for improving fracture-healing, with femora treated at a later onset (seven days after fracture) showing a significant (21%) increase in maximum yield torque compared with those treated at an earlier onset (three days after fracture) (p = 0.01). Conclusions: A later onset of lithium administration significantly improved femoral fracture-healing. Trends indicated that a lower dose and longer treatment duration also had a

  16. Influence of mechanical rock properties and fracture healing rate on crustal fluid flow dynamics

    NASA Astrophysics Data System (ADS)

    Sachau, Till; Bons, Paul; Gomez-Rivas, Enrique; Koehn, Daniel; de Riese, Tamara

    2016-04-01

    Fluid flow in the Earth's crust is very slow over extended periods of time, during which it occurs within the connected pore space of rocks. If the fluid production rate exceeds a certain threshold, matrix permeability alone is insufficient to drain the fluid volume and fluid pressure builds up, thereby reducing the effective stress supported by the rock matrix. Hydraulic fractures form once the effective pressure exceeds the tensile strength of the rock matrix and act subsequently as highly effective fluid conduits. Once local fluid pressure is sufficiently low again, flow ceases and fractures begin to heal. Since fluid flow is controlled by the alternation of fracture permeability and matrix permeability, the flow rate in the system is strongly discontinuous and occurs in intermittent pulses. Resulting hydraulic fracture networks are largely self-organized: opening and subsequent healing of hydraulic fractures depends on the local fluid pressure and on the time-span between fluid pulses. We simulate this process with a computer model and describe the resulting dynamics statistically. Special interest is given to a) the spatially and temporally discontinuous formation and closure of fractures and fracture networks and b) the total flow rate over time. The computer model consists of a crustal-scale dual-porosity setup. Control parameters are the pressure- and time-dependent fracture healing rate, and the strength and the permeability of the intact rock. Statistical analysis involves determination of the multifractal properties and of the power spectral density of the temporal development of the total drainage rate and hydraulic fractures. References Bons, P. D. (2001). The formation of large quartz veins by rapid ascent of fluids in mobile hydrofractures. Tectonophysics, 336, 1-17. Miller, S. a., & Nur, A. (2000). Permeability as a toggle switch in fluid-controlled crustal processes. Earth and Planetary Science Letters, 183(1-2), 133-146. Sachau, T., Bons, P. D

  17. Knockout of Angiotensin AT2 receptors accelerates healing but impairs quality

    PubMed Central

    Faghih, Mahya; Hosseini, Sayed M.; Smith, Barbara; Ansari, Amir Mehdi.; Lay, Frank; Ahmed, Ali Karim; Inagami, Tedashi; Marti, Guy P.; Harmon, John W.; Walston, Jeremy D.; Abadir, Peter M.

    2015-01-01

    Wounds are among the most common, painful, debilitating and costly conditions in older adults. Disruption of the angiotensin type 1 receptors (AT1R), has been associated with impaired wound healing, suggesting a critical role for AT1R in this repair process. Biological functions of angiotensin type 2 receptors (AT2R) are less studied. We investigated effects of genetically disrupting AT2R on rate and quality of wound healing. Our results suggest that AT2R effects on rate of wound closure depends on the phase of wound healing. We observed delayed healing during early phase of wound healing (inflammation). An accelerated healing rate was seen during later stages (proliferation and remodeling). By day 12, fifty percent of AT2R−/− mice had complete wound closure as compared to none in either C57/BL6 or AT1R−/− mice. There was a significant increase in AT1R, TGFβ1 and TGFβ2 expression during the proliferative and remodeling phases in AT2R−/− mice. Despite the accelerated closure rate, AT2R−/− mice had more fragile healed skin. Our results suggest that in the absence of AT2R, wound healing rate is accelerated, but yielded worse skin quality. Elucidating the contribution of both of the angiotensin receptors may help fine tune future intervention aimed at wound repair in older individuals. PMID:26727887

  18. Inhibition of indoleamine 2,3-dioxygenase activity accelerates skin wound healing.

    PubMed

    Ito, Hiroyasu; Ando, Tatsuya; Ogiso, Hideyuki; Arioka, Yuko; Saito, Kuniaki; Seishima, Mitsuru

    2015-06-01

    Skin wound healing is a complex process involving several stages that include inflammation, proliferation, and remodeling. In the inflammatory phase, pro-inflammatory cytokines and chemokines are induced at the wound site and, they contribute to the development of wound healing. These cytokines also induce indoleamine 2,3-dioxygenase (IDO1) activity; this is the rate-limiting and first enzyme in the l-tryptophan (TRP)-l-kynurenine (KYN) pathway. This study examined the effect of IDO1 on the process of skin wound healing. The expression of the Ido1 mRNA was enhanced after creating a wound in wild-type (WT) mice. TRP concentration was simultaneously reduced at the wound site. The rate of wound healing in IDO1 knockout (IDO-KO) mice was significantly higher than that in WT mice. 1-Methyl-dl-tryptophan (1-MT), a potent inhibitor of IDO1, increased the rate of wound healing in WT mice. The administration of TRP accelerated wound healing in vivo and in an in vitro experimental model, whereas the rate of wound healing was not affected by the administration of KYN. The present study identifies the role of IDO1 in skin wound healing, and indicates that the local administration of 1-MT or TRP may provide an effective strategy for accelerating wound healing.

  19. [Bone fracture and the healing mechanisms. Fragility fracture and bone quality].

    PubMed

    Mawatari, Taro; Iwamoto, Yukihide

    2009-05-01

    Fracture occurs in bone having less than normal elastic resistance without any violence. Numerous terms have been used to classify various types of fractures from low trauma events; "fragility fracture", "stress fracture", "insufficiency fracture", "fatigue fracture", "pathologic fracture", etc. The definitions of these terms and clinical characteristics of these fractures are discussed. Also state-of-the-art bone quality assessments; Finite element analysis of clinical CT scans, assessments of the Microdamage, and the Cross-links of Collagen are introduced in this review.

  20. Relationship between microstructure, material distribution, and mechanical properties of sheep tibia during fracture healing process.

    PubMed

    Gao, Jiazi; Gong, He; Huang, Xing; Fang, Juan; Zhu, Dong; Fan, Yubo

    2013-01-01

    The aim of this study was to investigate the relationship between microstructural parameters, material distribution, and mechanical properties of sheep tibia at the apparent and tissue levels during the fracture healing process. Eighteen sheep underwent tibial osteotomy and were sacrificed at 4, 8, and 12 weeks. Radiographs and micro-computed tomography (micro-CT) scanning were taken for microstructural assessment, material distribution evaluation, and micro-finite element analysis. A displacement of 5% compressive strain on the longitudinal direction was applied to the micro-finite element model, and apparent and tissue-level mechanical properties were calculated. Principle component analysis and linear regression were used to establish the relationship between principle components (PCs) and mechanical parameters. Visible bony callus formation was observed throughout the healing process from radiographic assessment. Apparent mechanical property increased at 8 weeks, but tissue-level mechanical property did not increase significantly until 12 weeks. Three PCs were extracted from microstructural parameters and material distribution, which accounted for 87.592% of the total variation. The regression results showed a significant relationship between PCs and mechanical parameters (R>0.8, P<0.05). Results of this study show that microstructure and material distribution based on micro-CT imaging could efficiently predict bone strength and reflect the bone remodeling process during fracture healing, which provides a basis for exploring the fracture healing mechanism and may be used as an approach for fractured bone strength assessment.

  1. Impaired Fracture Healing Caused by Deficiency of the Immunoreceptor Adaptor Protein DAP12.

    PubMed

    Kamimura, Masayuki; Mori, Yu; Sugahara-Tobinai, Akiko; Takai, Toshiyuki; Itoi, Eiji

    2015-01-01

    Osteoclasts play an important role in bone metabolism, but their exact role in fracture healing remains unclear. DAP12 is an immunoadaptor protein with associated immunoreceptors on myeloid lineage cells, including osteoclasts. Its deficiency causes osteopetrosis due to suppression of osteoclast development and activation. In this report, we assessed the impact of DAP12 on the fracture healing process using C57BL/6 (B6) and DAP12-/- mice. Healing was evaluated using radiography, micro-CT, histology, immunohistochemistry and real-time RT-PCR. Radiography showed lower callus volume and lower callus radiolucency in DAP12-/- mice during later stages. Micro-CT images and quantitative structural analysis indicated that DAP12-/- mice developed calluses of dense trabecular structures and experienced deteriorated cortical shell formation on the surface. Histologically, DAP12-/- mice showed less cartilaginous resorption and woven bone formation. In addition, prominent cortical shell formation was much less in DAP12-/- mice. Immunohistochemistry revealed lower invasion of F4/80 positive monocytes and macrophages into the fracture hematoma in DAP12-/- mice. The expression levels of Col1a1, Col2a1 and Col10a1 in DAP12-/- mice increased and subsequently became higher than those in B6 mice. There was a decrease in the gene expression of Tnf during the early stages in DAP12-/- mice. Our results indicate that DAP12 deficiency impairs fracture healing, suggesting a significant role of DAP12 in the initial inflammatory response, bone remodeling and regeneration. PMID:26030755

  2. Micro-computed tomography assessment of the progression of fracture healing in mice.

    PubMed

    O'Neill, Kevin R; Stutz, Christopher M; Mignemi, Nicholas A; Burns, Michael C; Murry, Matthew R; Nyman, Jeffry S; Schoenecker, Jonathan G

    2012-06-01

    The mouse fracture model is ideal for research into the pathways of healing because of the availability of genetic and transgenic mice and the ability to create cell-specific genetic mutations. While biomechanical tests and histology are available to assess callus integrity and tissue differentiation, respectively, micro-computed tomography (μCT) analysis has increasingly been utilized in fracture studies because it is non-destructive and provides descriptions of the structural and compositional properties of the callus. However, the dynamic changes of μCT properties that occur during healing are not well defined. Thus, the purpose of this study was to determine which μCT properties change with the progression of fracture repair and converge to values similar to unfractured bone in the mouse femur fracture model. A unilateral femur fracture was performed in C57BL/6 mice and intramedullary fixation performed. Fractured and un-fractured contralateral specimens were harvested from groups of mice between 2 and 12 weeks post-fracture. Parameters describing callus based on μCT were obtained, including polar moment of inertia (J), bending moment of inertia (I), total volume (TV), tissue mineral density (TMD), total bone volume fraction (BV/TV), and volumetric bone mineral density (vBMD). For comparison, plain radiographs were used to measure the callus diameter (D) and area (A); and biomechanical properties were evaluated using either three-point bending or torsion. The μCT parameters J, I, TV, and TMD converged toward their respective values of the un-fractured femurs over time, although significant differences existed between the two sides at every time point evaluated (p<0.05). Radiograph measurement D changed with repair progression in similar manner to TV. In contrast, BV/TV and BMD increased and decreased over time with statistical differences between callus and un-fractured bone occurring sporadically. Similarly, none of the biomechanical properties were found

  3. 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. PMID:25452136

  4. Chondrocyte BMP2 signaling plays an essential role in bone fracture healing

    PubMed Central

    Mi, Meng; Jin, Hongting; Wang, Baoli; Yukata, Kiminori; Sheu, Tzong-jen; Ke, Qiao Han; Tong, Peijian; Im, Hee-Jeong; Xiao, Guozhi; Chen, Di

    2012-01-01

    The specific role of endogenous Bmp2 gene in chondrocytes and in osteoblasts in fracture healing was investigated by generation and analysis of chondrocyte- and osteoblast-specific Bmp2 conditional knockout (cKO) mice. The unilateral open transverse tibial fractures were created in these Bmp2 cKO mice. Bone fracture callus samples were collected and analyzed by X-ray, micro-CT, histology analyses, biomechanical testing and gene expression assays. The results demonstrated that the lack of Bmp2 expression in chondrocytes leads to a prolonged cartilage callus formation and a delayed osteogenesis initiation and progression into mineralization phase with lower biomechanical properties. In contrast, when the Bmp2 gene was deleted in osteoblasts, the mice showed no significant difference in the fracture healing process compared to control mice. These findings suggest that endogenous BMP2 expression in chondrocytes may play an essential role in cartilage callus maturation at an early stage of fracture healing. Our studies may provide important information for clinical application of BMP2. PMID:23107765

  5. Inhibition of beta-catenin signaling by Pb leads to incomplete fracture healing.

    PubMed

    Beier, Eric E; Sheu, Tzong-Jen; Buckley, Taylor; Yukata, Kiminori; O'Keefe, Regis; Zuscik, Michael J; Puzas, J Edward

    2014-11-01

    There is strong evidence in the clinical literature to suggest that elevated lead (Pb) exposure impairs fracture healing. Since Pb has been demonstrated to inhibit bone formation, and Wnt signaling is an important anabolic pathway in chondrocyte maturation and endochondral ossification, we investigated the impact of Wnt therapy on Pb-exposed mice undergoing bone repair in a mouse tibial fracture model. We established that tibial fracture calluses from Pb-treated mice were smaller and contained less mineralized tissue than vehicle controls. This resulted in the persistence of immature cartilage in the callus and decreased β-catenin levels. Reduction of β-catenin protein was concurrent with systemic elevation of LRP5/6 antagonists DKK1 and sclerostin in Pb-exposed mice throughout fracture healing. β-catenin stimulation by the GSK3 inhibitor BIO reversed these molecular changes and restored the amount of mineralized callus. Overall, Pb is identified as a potent inhibitor of endochondral ossification in vivo with correlated effects on bone healing with noted deficits in β-catenin signaling, suggesting the Wnt/β-catenin as a pivotal pathway in the influence of Pb on fracture repair. PMID:25044211

  6. 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.

  7. Dipyrone has no effects on bone healing of tibial fractures in rats

    PubMed Central

    Gali, Julio Cesar; Sansanovicz, Dennis; Ventin, Fernando Carvalho; Paes, Rodrigo Henrique; Quevedo, Francisco Carlos; Caetano, Edie Benedito

    2014-01-01

    OBJECTIVE: To evaluate the effect of dipyrone on healing of tibial fractures in rats. METHODS: Fourty-two Wistar rats were used, with mean body weight of 280g. After being anesthetized, they were submitted to closed fracture of the tibia and fibula of the right posterior paw through manual force. The rats were randomly divided into three groups: the control group that received a daily intraperitoneal injection of saline solution; group D-40, that received saline injection containing 40mg/Kg dipyrone; and group D-80, that received saline injection containing 80mg/Kg dipyrone. After 28 days the rats were sacrificed and received a new label code that was known by only one researcher. The fractured limbs were then amputated and X-rayed. The tibias were disarticulated and subjected to mechanical, radiological and histological evaluation. For statistical analysis the Kruskal-Wallis test was used at a significance level of 5%. RESULTS: There wasn't any type of dipyrone effect on healing of rats tibial fractures in relation to the control group. CONCLUSION: Dipyrone may be used safely for pain control in the treatment of fractures, without any interference on bone healing. Level of Evidence II, Controlled Laboratory Study. PMID:25246852

  8. Bone turnover markers for early detection of fracture healing disturbances: A review of the scientific literature.

    PubMed

    Sousa, Cristina P; Dias, Isabel R; Lopez-Peña, Mónica; Camassa, José A; Lourenço, Paulo J; Judas, Fernando M; Gomes, Manuela E; Reis, Rui L

    2015-01-01

    Imaging techniques are the standard method for assessment of fracture healing processes. However, these methods are perhaps not entirely reliable for early detection of complications, the most frequent of these being delayed union and non-union. A prompt diagnosis of such disorders could prevent prolonged patient distress and disability. Efforts should be directed towards the development of new technologies for improving accuracy in diagnosing complications following bone fractures. The variation in the levels of bone turnover markers (BTMs) have been assessed with regard to there ability to predict impaired fracture healing at an early stage, nevertheless the conclusions of some studies are not consensual. In this article the authors have revised the potential of BTMs as early predictors of prognosis in adult patients presenting traumatic bone fractures but who did not suffer from osteopenia or postmenopausal osteoporosis. The available information from the different studies performed in this field was systematized in order to highlight the most promising BTMs for the assessment of fracture healing outcome. PMID:25993365

  9. Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing.

    PubMed

    Gerstenfeld, Louis C; Sacks, Daniel J; Pelis, Megan; Mason, Zachary D; Graves, Dana T; Barrero, Mauricio; Ominsky, Michael S; Kostenuik, Paul J; Morgan, Elise F; Einhorn, Thomas A

    2009-02-01

    The role of osteoclast-mediated resorption during fracture healing was assessed. The impact of two osteoclast inhibitors with different mechanisms of action, alendronate (ALN) and denosumab (DMAB), were examined during fracture healing. Male human RANKL knock-in mice that express a chimeric (human/murine) form of RANKL received unilateral transverse femur fractures. Mice were treated biweekly with ALN 0.1 mg/kg, DMAB 10 mg/kg, or PBS (control) 0.1 ml until death at 21 and 42 days after fracture. Treatment efficacy assessed by serum levels of TRACP 5b showed almost a complete elimination of TRACP 5b levels in the DMAB-treated animals but only approximately 25% reduction of serum levels in the ALN-treated mice. Mechanical testing showed that fractured femurs from both ALN and DMAB groups had significantly increased mechanical properties at day 42 compared with controls. muCT analysis showed that callus tissues from DMAB-treated mice had significantly greater percent bone volume and BMD than did both control and ALN-treated tissues at both 21 and 42 days, whereas ALN-treated bones only had greater percent bone volume and BMC than control at 42 days. Qualitative histological analysis showed that the 21-and 42-day ALN and DMAB groups had greater amounts of unresorbed cartilage or mineralized cartilage matrix compared with the controls, whereas unresorbed cartilage could still be seen in the DMAB groups at 42 days after fracture. Although ALN and DMAB delayed the removal of cartilage and the remodeling of the fracture callus, this did not diminish the mechanical integrity of the healing fractures in mice receiving these treatments. In contrast, strength and stiffness were enhanced in these treatment groups compared with control bones.

  10. Micro-computed tomography assessment of fracture healing: relationships among callus structure, composition, and mechanical function.

    PubMed

    Morgan, Elise F; Mason, Zachary D; Chien, Karen B; Pfeiffer, Anthony J; Barnes, George L; Einhorn, Thomas A; Gerstenfeld, Louis C

    2009-02-01

    Non-invasive characterization of fracture callus structure and composition may facilitate development of surrogate measures of the regain of mechanical function. As such, quantitative computed tomography- (CT-) based analyses of fracture calluses could enable more reliable clinical assessments of bone healing. Although previous studies have used CT to quantify and predict fracture healing, it is unclear which of the many CT-derived metrics of callus structure and composition are the most predictive of callus mechanical properties. The goal of this study was to identify the changes in fracture callus structure and composition that occur over time and that are most closely related to the regain of mechanical function. Micro-computed tomography (microCT) imaging and torsion testing were performed on murine fracture calluses (n=188) at multiple post-fracture timepoints and under different experimental conditions that alter fracture healing. Total callus volume (TV), mineralized callus volume (BV), callus mineralized volume fraction (BV/TV), bone mineral content (BMC), tissue mineral density (TMD), standard deviation of mineral density (sigma(TMD)), effective polar moment of inertia (J(eff)), torsional strength, and torsional rigidity were quantified. Multivariate statistical analyses, including multivariate analysis of variance, principal components analysis, and stepwise regression were used to identify differences in callus structure and composition among experimental groups and to determine which of the microCT outcome measures were the strongest predictors of mechanical properties. Although calluses varied greatly in the absolute and relative amounts of mineralized tissue (BV, BMC, and BV/TV), differences among timepoints were most strongly associated with changes in tissue mineral density. Torsional strength and rigidity were dependent on mineral density as well as the amount of mineralized tissue: TMD, BV, and sigma(TMD) explained 62% of the variation in

  11. Corroboration of mechanoregulatory algorithms for tissue differentiation during fracture healing: Comparison with in vivo results.

    PubMed

    Isaksson, Hanna; van Donkelaar, Corrinus C; Huiskes, Rik; Ito, Keita

    2006-05-01

    Several mechanoregulation algorithms proposed to control tissue differentiation during bone healing have been shown to accurately predict temporal and spatial tissue distributions during normal fracture healing. As these algorithms are different in nature and biophysical parameters, it raises the question of which reflects the actual mechanobiological processes the best. The aim of this study was to resolve this issue by corroborating the mechanoregulatory algorithms with more extensive in vivo bone healing data from animal experiments. A poroelastic three-dimensional finite element model of an ovine tibia with a 2.4 mm gap and external callus was used to simulate the course of tissue differentiation during fracture healing in an adaptive model. The mechanical conditions applied were similar to those used experimentally, with axial compression or torsional rotation as two distinct cases. Histological data at 4 and 8 weeks, and weekly radiographs, were used for comparison. By applying new mechanical conditions, torsional rotation, the predictions of the algorithms were distinguished successfully. In torsion, the algorithms regulated by strain and hydrostatic pressure failed to predict healing and bone formation as seen in experimental data. The algorithm regulated by deviatoric strain and fluid velocity predicted bridging and healing in torsion, as observed in vivo. The predictions of the algorithm regulated by deviatoric strain alone did not agree with in vivo data. None of the algorithms predicted patterns of healing entirely similar to those observed experimentally for both loading modes. However, patterns predicted by the algorithm based on deviatoric strain and fluid velocity was closest to experimental results. It was the only algorithm able to predict healing with torsional loading as seen in vivo.

  12. Acceleration of diabetic wound healing using a novel protease–anti-protease combination therapy

    PubMed Central

    Gao, Ming; Nguyen, Trung T.; Suckow, Mark A.; Wolter, William R.; Gooyit, Major; Mobashery, Shahriar; Chang, Mayland

    2015-01-01

    Nonhealing chronic wounds are major complications of diabetes resulting in >70,000 annual lower-limb amputations in the United States alone. The reasons the diabetic wound is recalcitrant to healing are not fully understood, and there are limited therapeutic agents that could accelerate or facilitate its repair. We previously identified two active forms of matrix metalloproteinases (MMPs), MMP-8 and MMP-9, in the wounds of db/db mice. We argued that the former might play a role in the body’s response to wound healing and that the latter is the pathological consequence of the disease with detrimental effects. Here we demonstrate that the use of compound ND-336, a novel highly selective inhibitor of gelatinases (MMP-2 and MMP-9) and MMP-14, accelerates diabetic wound healing by lowering inflammation and by enhancing angiogenesis and re-epithelialization of the wound, thereby reversing the pathological condition. The detrimental role of MMP-9 in the pathology of diabetic wounds was confirmed further by the study of diabetic MMP-9–knockout mice, which exhibited wounds more prone to healing. Furthermore, topical administration of active recombinant MMP-8 also accelerated diabetic wound healing as a consequence of complete re-epithelialization, diminished inflammation, and enhanced angiogenesis. The combined topical application of ND-336 (a small molecule) and the active recombinant MMP-8 (an enzyme) enhanced healing even more, in a strategy that holds considerable promise in healing of diabetic wounds. PMID:26598687

  13. Acceleration of diabetic wound healing using a novel protease-anti-protease combination therapy.

    PubMed

    Gao, Ming; Nguyen, Trung T; Suckow, Mark A; Wolter, William R; Gooyit, Major; Mobashery, Shahriar; Chang, Mayland

    2015-12-01

    Nonhealing chronic wounds are major complications of diabetes resulting in >70,000 annual lower-limb amputations in the United States alone. The reasons the diabetic wound is recalcitrant to healing are not fully understood, and there are limited therapeutic agents that could accelerate or facilitate its repair. We previously identified two active forms of matrix metalloproteinases (MMPs), MMP-8 and MMP-9, in the wounds of db/db mice. We argued that the former might play a role in the body's response to wound healing and that the latter is the pathological consequence of the disease with detrimental effects. Here we demonstrate that the use of compound ND-336, a novel highly selective inhibitor of gelatinases (MMP-2 and MMP-9) and MMP-14, accelerates diabetic wound healing by lowering inflammation and by enhancing angiogenesis and re-epithelialization of the wound, thereby reversing the pathological condition. The detrimental role of MMP-9 in the pathology of diabetic wounds was confirmed further by the study of diabetic MMP-9-knockout mice, which exhibited wounds more prone to healing. Furthermore, topical administration of active recombinant MMP-8 also accelerated diabetic wound healing as a consequence of complete re-epithelialization, diminished inflammation, and enhanced angiogenesis. The combined topical application of ND-336 (a small molecule) and the active recombinant MMP-8 (an enzyme) enhanced healing even more, in a strategy that holds considerable promise in healing of diabetic wounds.

  14. Self-healing of cement fractures under dynamic flow of CO2-rich brine

    NASA Astrophysics Data System (ADS)

    Cao, Peilin; Karpyn, Zuleima T.; Li, Li

    2015-06-01

    Fractures and defects in wellbore cement can lead to increased possibilities of CO2 leakage from abandoned wells during geological carbon sequestration. To investigate the physicochemical response of defective wellbore cement to CO2-rich brine, we carried out a reactive flow-through experiment using an artificially fractured cement sample at a length of 224.8 mm. A brine solution with dissolved CO2 at a pH of approximately 3.9 was injected through the sample at a constant rate of 0.0083 cm3/s. Surface optical profilometry analysis and 3-D X-ray microtomography imaging confirmed fracture closure and self-healing behavior consistent with the measured permeability decrease. Visual inspection of the reacted fracture surface showed the development of reactive patterns mapping the flow velocity field inside the fracture, as well as restricted flow toward the sample outlet. The postexperiment permeability of the core sample was measured at half of its initial permeability. A reactive transport model was developed with parameters derived from the experiment to further examine property evolution of fractured cement under dynamic flow of CO2-rich brine. Sensitivity analysis showed that residence time and the size of initial fracture aperture are the key factors controlling the tendency to self-healing or fracture opening behavior and therefore determine the long-term integrity of the wellbore cement. Longer residence time and small apertures promote mineral precipitation, fracture closure, and therefore flow restriction. This work also suggests a narrow threshold separating the fracture opening and self-sealing behavior.

  15. Bioinformatics and Microarray Analysis of miRNAs in Aged Female Mice Model Implied New Molecular Mechanisms for Impaired Fracture Healing

    PubMed Central

    He, Bing; Zhang, Zong-Kang; Liu, Jin; He, Yi-Xin; Tang, Tao; Li, Jie; Guo, Bao-Sheng; Lu, Ai-Ping; Zhang, Bao-Ting; Zhang, Ge

    2016-01-01

    Impaired fracture healing in aged females is still a challenge in clinics. MicroRNAs (miRNAs) play important roles in fracture healing. This study aims to identify the miRNAs that potentially contribute to the impaired fracture healing in aged females. Transverse femoral shaft fractures were created in adult and aged female mice. At post-fracture 0-, 2- and 4-week, the fracture sites were scanned by micro computed tomography to confirm that the fracture healing was impaired in aged female mice and the fracture calluses were collected for miRNA microarray analysis. A total of 53 significantly differentially expressed miRNAs and 5438 miRNA-target gene interactions involved in bone fracture healing were identified. A novel scoring system was designed to analyze the miRNA contribution to impaired fracture healing (RCIFH). Using this method, 11 novel miRNAs were identified to impair fracture healing at 2- or 4-week post-fracture. Thereafter, function analysis of target genes was performed for miRNAs with high RCIFH values. The results showed that high RCIFH miRNAs in aged female mice might impair fracture healing not only by down-regulating angiogenesis-, chondrogenesis-, and osteogenesis-related pathways, but also by up-regulating osteoclastogenesis-related pathway, which implied the essential roles of these high RCIFH miRNAs in impaired fracture healing in aged females, and might promote the discovery of novel therapeutic strategies. PMID:27527150

  16. Selective and non-selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna.

    PubMed

    Kidd, Lisa J; Cowling, Nick R; Wu, Andy C; Kelly, Wendy L; Forwood, Mark R

    2013-02-01

    Anti-inflammatory drugs are widely used to manage pain associated with stress fractures (SFxs), but little is known about their effects on healing of those injuries. We hypothesized that selective and non-selective anti-inflammatory treatments would retard the healing of SFx in the rat ulna. SFxs were created by cyclic loading of the ulna in Wistar rats. Ulnae were harvested 2, 4 or 6 weeks following loading. Rats were treated with non-selective NSAID, ibuprofen (30 mg/kg/day); selective COX-2 inhibition, [5,5-dimethyl-3-3 (3 fluorophenyl)-4-(4 methylsulfonal) phenyl-2 (5H)-furanone] (DFU) (2.0 mg/kg/day); or the novel c5a anatagonist PMX53 (10 mg/kg/day, 4 and 6 weeks only); with appropriate vehicle as control. Quantitative histomorphometric measurements of SFx healing were undertaken. Treatment with the selective COX-2 inhibitor, DFU, reduced the area of resorption along the fracture line at 2 weeks, without affecting bone formation at later stages. Treatment with the non-selective, NSAID, ibuprofen decreased both bone resorption and bone formation so that there was significantly reduced length and area of remodeling and lamellar bone formation within the remodeling unit at 6 weeks after fracture. The C5a receptor antagonist PMX53 had no effect on SFx healing at 4 or 6 weeks after loading, suggesting that PMX53 would not delay SFx healing. Both selective COX-2 inhibitors and non-selective NSAIDs have the potential to compromise SFx healing, and should be used with caution when SFx is diagnosed or suspected. PMID:22847634

  17. Determining the Role of Sost and Sostdc1 During Fracture Healing

    SciTech Connect

    Yee, Cristal Sook Ngei

    2016-01-01

    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 can 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.

  18. Experimental study of high-energy fractures delayed operation in promote bone healing

    PubMed Central

    Pan, Zhi-Jun; Li, Zhong; Li, Jing

    2015-01-01

    To investigate role of delayed operation to stimulate growth of strong external callus in high-energy fractures, and explore a new way for bone healing. Twenty adult dogs were employed, and randomly divided into four groups, including group A-D. The dogs underwent osteotomy by wire saw in middle of femur, electric coagulation damaged surrounding periosteum, forming a 1 cm defect. Group A were internal fixed 14 days after osteotomy (higher-energy fractures delayed operation), Group B and C were internal fixed immediately (no delayed operation), Group D were internal fixed 14 days after osteotomy (delayed operation, but resected granulations around extremities). The results showed that groups of early fixed have no external callus growth and almost no growth in internal callus, these conditions leads to atrophy nonunion. On contrary, the porosis was strong and callus union was steady in group A and D, which have a delayed operation. In conclusion, early surgical fixation of high-energy fracture restrains external callus growth, easily lead to poor callus healing phenomenon of low-quality. Delayed surgical fixation can begin to repair soft tissues injury, stimulate external callus growth and improve fracture healing, so a small incision open reduction produce more robust growth effect than closed reduction. PMID:26379852

  19. Shock wave therapy as a treatment of nonunions, avascular necrosis, and delayed healing of stress fractures.

    PubMed

    Furia, John P; Rompe, Jan D; Cacchio, Angelo; Maffulli, Nicola

    2010-12-01

    Shock wave therapy (SWT) stimulates angiogenesis and osteogenesis. SWT is commonly used to treat soft tissue musculoskeletal conditions such as fasciopathies and tendinopathies. Recent basic science and clinical data suggest that SWT can also be used to treat disorders of bone. Nonunions, avascular necrosis, and delayed healing of stress fractures have all been successfully treated with SWT. Success rates with SWT are equal to those with standard surgical treatment, but SWT has the advantage of decreased morbidity. The procedure is safe, well tolerated, yields few complications, and, typically, can be performed on an outpatient basis. SWT is a viable noninvasive alternative to stimulate healing of bone.

  20. Exposure to 100% Oxygen Abolishes the Impairment of Fracture Healing after Thoracic Trauma

    PubMed Central

    Kemmler, Julia; Bindl, Ronny; McCook, Oscar; Wagner, Florian; Gröger, Michael; Wagner, Katja; Scheuerle, Angelika; Radermacher, Peter; Ignatius, Anita

    2015-01-01

    In polytrauma patients a thoracic trauma is one of the most critical injuries and an important trigger of post-traumatic inflammation. About 50% of patients with thoracic trauma are additionally affected by bone fractures. The risk for fracture malunion is considerably increased in such patients, the pathomechanisms being poorly understood. Thoracic trauma causes regional alveolar hypoxia and, subsequently, hypoxemia, which in turn triggers local and systemic inflammation. Therefore, we aimed to unravel the role of oxygen in impaired bone regeneration after thoracic trauma. We hypothesized that short-term breathing of 100% oxygen in the early post-traumatic phase ameliorates inflammation and improves bone regeneration. Mice underwent a femur osteotomy alone or combined with blunt chest trauma 100% oxygen was administered immediately after trauma for two separate 3 hour intervals. Arterial blood gas tensions, microcirculatory perfusion and oxygenation were assessed at 3, 9 and 24 hours after injury. Inflammatory cytokines and markers of oxidative/nitrosative stress were measured in plasma, lung and fracture hematoma. Bone healing was assessed on day 7, 14 and 21. Thoracic trauma induced pulmonary and systemic inflammation and impaired bone healing. Short-term exposure to 100% oxygen in the acute post-traumatic phase significantly attenuated systemic and local inflammatory responses and improved fracture healing without provoking toxic side effects, suggesting that hyperoxia could induce anti-inflammatory and pro-regenerative effects after severe injury. These results suggest that breathing of 100% oxygen in the acute post-traumatic phase might reduce the risk of poorly healing fractures in severely injured patients. PMID:26147725

  1. Amifostine Protects Vascularity and Improves Unions in a Model of Irradiated Mandibular Fracture Healing

    PubMed Central

    Sarhaddi, Deniz; Tchanque-Fossuo, Catherine N.; Poushanchi, Behdod; Donneys, Alexis; Deshpande, Sagar S.; Weiss, Daniela M.; Buchman, Steven R.

    2013-01-01

    Background Pathologic fractures after irradiation (XRT) can be a devastating problem for cancer patients as XRT has a pernicious effect on bone healing in a large part due to impairment of vascularity. Our aim is to ascertain whether Amifostine (AMF), a radio-protective drug, will preserve the vascularity of the irradiated mandible, thereby improving bony healing and unions after exposure to a human equivalent dose of radiation (HEDR) in our murine model of mandibular fracture repair. Methods Rats were randomized into: Fx (n=9), XRT/Fx (n=5) and AMF/XRT/Fx (n=7). XRT/Fx and AMF/XRT/Fx underwent HEDR directed at the left hemimandible. AMF/XRT/Fx received AMF concomitantly with HEDR. All animals underwent unilateral left-mandibular osteotomy with external fixation set to a 2.1mm fracture gap. Fracture healing was allowed for 40 days prior to perfusion with Microfil. Vascular radiomorphometrics were quantified with micro-computed tomography. Results We observed a 100% rate of bony union in the non-irradiated Fx compared to 25% in XRT/Fx. Union rate in AMF/XRT/Fx more than doubled to 57%. We also saw substantial increase in Vessel Number (123%,p<0.05) and a corresponding decrease in Vessel Separation (55.5%,p<0.05) in AMF/XRT/Fx versus XRT/Fx and no differences between Fx and AMF/XRT/Fx. Conclusions We report that AMF prophylaxis maintains vascularity at levels seen in non-irradiated Fx specimens, correlating with a significant increase in bony unions after HEDR. Our results set the stage for exploration of this targeted therapy alone, and in combination with other treatments, to mitigate the harmful effects of XRT on fracture repair and bone healing in the clinical setting. PMID:24281582

  2. Formylpeptide receptors mediate rapid neutrophil mobilization to accelerate wound healing.

    PubMed

    Liu, Mingyong; Chen, Keqiang; Yoshimura, Teizo; Liu, Ying; Gong, Wanghua; Le, Yingying; Gao, Ji-Liang; Zhao, Jianhua; Wang, Ji Ming; Wang, Aimin

    2014-01-01

    Wound healing is a multi-phased pathophysiological process requiring chemoattractant receptor-dependent accumulation of myeloid cells in the lesion. Two G protein-coupled formylpeptide receptors Fpr1 and Fpr2 mediate rapid neutrophil infiltration in the liver of Listeria-infected mice by sensing pathogen-derived chemotactic ligands. These receptors also recognize host-derived chemotactic peptides in inflammation and injury. Here we report the capacity of Fprs to promote the healing of sterile skin wound in mice by initiating neutrophil infiltration. We found that in normal miceneutrophils rapidly infiltrated the dermis in the wound before the production of neutrophil-specific chemokines by the injured tissue. In contrast, rapid neutrophil infiltration was markedly reduced with delayed wound closure in mice deficient in both Fprs. In addition, we detected Fpr ligand activity that chemoattracted neutrophils into the wound tissue. Our study thus demonstrates that Fprs are critical for normal healing of the sterile skin wound by mediating the first wave of neutrophil infiltration.

  3. Experimental Timescales of Fracture-Healing Rheological Behavior of Thermoreversible Gels

    NASA Astrophysics Data System (ADS)

    Thornell, Travis L.; Subramaniam, Krithika; Erk, Kendra A.

    Acrylic thermoreversible physical gels were used as a model soft material system to investigate fracture-healing behavior by shear rheometry. By using shear start-up experiments, gels at various concentrations and temperatures were measured to determine shear stress responses, and fracture was indicated by a decrease in shear stress (confirmed with rheophysical flow visualization experiments). Fractured gels were allowed to recover in the rheometer for set periods of time and were tested again using the same shear start-up procedure to evaluate the recovery kinetics of network strength. Relationships between the network recovery and the normalized ratio of the resting times and characteristic relaxation times of the gels were determined. It was found that resting times for fully healed networks needed to be 2 or 3 orders of magnitude greater than the relaxation times. The extent of fracture was also investigated. Gels that were deformed to smaller total strain magnitudes were suspected to have incomplete (or partial) fracture as results showed various responses for given resting times.

  4. Assessment of the healing process in distal radius fractures by high resolution peripheral quantitative computed tomography.

    PubMed

    de Jong, Joost J A; Willems, Paul C; Arts, Jacobus J; Bours, Sandrine G P; Brink, Peter R G; van Geel, Tineke A C M; Poeze, Martijn; Geusens, Piet P; van Rietbergen, Bert; van den Bergh, Joop P W

    2014-07-01

    In clinical practice, fracture healing is evaluated by clinical judgment in combination with conventional radiography. Due to limited resolution, radiographs don't provide detailed information regarding the bone micro-architecture and bone strength. Recently, assessment of in vivo bone density, architectural and mechanical properties at the microscale became possible using high resolution peripheral quantitative computed tomography (HR-pQCT) in combination with micro finite element analysis (μFEA). So far, such techniques have been used mainly to study intact bone. The aim of this study was to explore whether these techniques can also be used to assess changes in bone density, micro-architecture and bone stiffness during fracture healing. Therefore, the fracture region in eighteen women, aged 50 years or older with a stable distal radius fracture, was scanned using HR-pQCT at 1-2 (baseline), 3-4, 6-8 and 12weeks post-fracture. At 1-2 and 12 weeks post-fracture the distal radius at the contra-lateral side was also scanned as control. Standard bone density, micro-architectural and geometric parameters were calculated and bone stiffness in compression, torsion and bending was assessed using μFEA. A linear mixed effect model with time post-fracture as fixed effect was used to detect significant (p-value ≤0.05) changes from baseline. Wrist pain and function were scored using the patient-rated wrist evaluation (PRWE) questionnaire. Correlations between the bone parameters and the PRWE score were calculated by Spearman's correlation coefficient. At the fracture site, total and trabecular bone density increased by 11% and 20%, respectively, at 6-8 weeks, whereas cortical density was decreased by 4%. Trabecular thickness increased by 23-31% at 6-8 and 12 weeks and the intertrabecular area became blurred, indicating intertrabecular bone formation. Compared to baseline, calculated bone stiffness in compression, torsion and bending was increased by 31% after 12 weeks. A

  5. 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. PMID:26840708

  6. Analysis of fracture healing in osteopenic bone caused by disuse: experimental study

    PubMed Central

    Paiva, A.G.; Yanagihara, G.R.; Macedo, A.P.; Ramos, J.; Issa, J.P.M.; Shimano, A.C.

    2016-01-01

    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. PMID:26840708

  7. 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.

  8. Constructing the toolbox: Patient-specific genetic factors of altered fracture healing

    PubMed Central

    Drissi, Hicham; Paglia, David N.; Alaee, Farhang; Yoshida, Ryu

    2014-01-01

    The multifaceted sequence of events that follow fracture repair can be further complicated when considering risk factors for impaired union, present in a large and growing percentage of the population. Risk factors such as diabetes, substance abuse, and poor nutrition affect both the young and old alike, and have been shown to dramatically impair the body’s natural healing processes. To this end, biotherapeudic interventions such as ultrasound, electrical simulation, growth factor treatment (BMP-2, BMP-7, PDGF-BB, FGF-2) have been evaluated in preclinical models and in some cases are used widely for patients with established non-union or risk/indication or impaired healing (ie. ultrasound, BMP-2, etc.). Despite the promise of these interventions, they have been shown to be reliant on patient compliance and can produce adverse side-effects such as heterotopic ossification. Gene and cell therapy approaches have attempted to apply controlled regimens of these factors and have produced promising results. However, there are safety and efficacy concerns that may limit the translation of these approaches. In addition, none of the above mentioned approaches consider genetic variation between individual patients. Several clinical and preclinical studies have demonstrated a genetic component to fracture repair and that SNPs and genetic background variation play major roles in the determination of healing outcomes. Despite this, there is a need for preclinical data to dissect the mechanism underlying the influence of specific gene loci on the processes of fracture healing, which will be paramount in the future of patient-centered interventions for fracture repair. PMID:25558470

  9. Impaired Fracture Healing Caused by Deficiency of the Immunoreceptor Adaptor Protein DAP12

    PubMed Central

    Kamimura, Masayuki; Mori, Yu; Sugahara-Tobinai, Akiko; Takai, Toshiyuki; Itoi, Eiji

    2015-01-01

    Osteoclasts play an important role in bone metabolism, but their exact role in fracture healing remains unclear. DAP12 is an immunoadaptor protein with associated immunoreceptors on myeloid lineage cells, including osteoclasts. Its deficiency causes osteopetrosis due to suppression of osteoclast development and activation. In this report, we assessed the impact of DAP12 on the fracture healing process using C57BL/6 (B6) and DAP12–/– mice. Healing was evaluated using radiography, micro-CT, histology, immunohistochemistry and real-time RT-PCR. Radiography showed lower callus volume and lower callus radiolucency in DAP12–/– mice during later stages. Micro-CT images and quantitative structural analysis indicated that DAP12–/– mice developed calluses of dense trabecular structures and experienced deteriorated cortical shell formation on the surface. Histologically, DAP12–/– mice showed less cartilaginous resorption and woven bone formation. In addition, prominent cortical shell formation was much less in DAP12–/– mice. Immunohistochemistry revealed lower invasion of F4/80 positive monocytes and macrophages into the fracture hematoma in DAP12–/– mice. The expression levels of Col1a1, Col2a1 and Col10a1 in DAP12–/– mice increased and subsequently became higher than those in B6 mice. There was a decrease in the gene expression of Tnf during the early stages in DAP12–/– mice. Our results indicate that DAP12 deficiency impairs fracture healing, suggesting a significant role of DAP12 in the initial inflammatory response, bone remodeling and regeneration. PMID:26030755

  10. Locally applied simvastatin improves fracture healing at late period in osteoporotic rat

    NASA Astrophysics Data System (ADS)

    Tian, Faming; Zhang, Liu; Kang, Yuchuan; Zhang, Junshan; Ao, Jiao; Yang, Fang

    effect of simvastatin locally applied from a bioactive polymer coating of implants on osteoporotic fracture healing at late period. Methods:Femur fracture model was established on normal or osteotoporotic mature female SD rats, intramedullary stabilization was achieved with uncoated titanium Kirschnerwires in normal rats(group A),with polymer-only coated vs. polymer plus simvastatin coated titanium Kirschner wires in osteoporotic rats(group B and C, respectively).Femurs were harvested after 12 weeks, and underwent radiographic and histologic analysis, as well as immunohistochemical evaluation for BMP-2 expression. Results:Radiographic results demonstrated progressed callus in the simvastatin-treated groups compared to the uncoated group.The histologic analysis revealed a significantly processed callus with irregular-shaped newly formed bone trabeculae in simvastatin-treated group. Immunohistochemical evaluation showed markedly higher expression levels of B:MP-2 in simvastatin-treated group.Conclusions: The present study revealed a improved fracture healing under local application of simvastatin in osteoporotic rat,which might partially from upregulation of the B:MP-2 expression at fractured site.

  11. Sodium humate accelerates cutaneous wound healing by activating TGF-β/Smads signaling pathway in rats

    PubMed Central

    Ji, Yuanyuan; Zhang, Aijun; Chen, Xiaobin; Che, Xiaoxia; Zhou, Kai; Wang, Zhidong

    2016-01-01

    Sodium humate (HA-Na) has been topically used as a wound healing and anti-inflammatory agent in folk medicine. In the present study, HA-Na was investigated for cutaneous wound healing in Sprague–Dawley rats. HA-Na solution (1.0%, w/v) was topically administered to rats undergoing excision wound models. Healing was assessed with a recombinant bovine basic fibroblast growth factor for external use as positive control. Wound healing rates were calculated on Day 3, 6, 9, 14 and 21 after injury, and tissues were also harvested after the same intervals for histological analysis. In addition, tissue hydroxyproline levels were measured. Furthermore, mRNA levels and protein expressions of transforming growth factor-β1, 2, 3 (TGF-β1, 2, 3) were determined by RT-PCR and western blot. Protein expression levels of Smad-2, -3, -4 and -7 were also detected by western blot. Our study demonstrates that HA-Na has the capacity to promote wound healing in rats via accelerated wound contraction and increased hydroxyproline content. More importantly, these wound healing effects of HA-Na might be mediated through the TGF-β/Smad signaling pathway. HA-Na may be an effective agent for enhanced wound healing. PMID:27006897

  12. Fracture Healing Is Delayed in Immunodeficient NOD/scid‑IL2Rγcnull Mice

    PubMed Central

    Recknagel, Stefan; Erbacher, Annika; Müller, Ingo; Schrezenmeier, Hubert; Ehrnthaller, Christian; Gebhard, Florian; Ignatius, Anita

    2016-01-01

    Following bone fracture, the repair process starts with an inflammatory reaction at the fracture site. Fracture healing is disturbed when the initial inflammation is increased or prolonged, whereby, a balanced inflammatory response is anticipated to be crucial for fracture healing, because it may induce down-stream responses leading to tissue repair. However, the impact of the immune response on fracture healing remains poorly understood. Here, we investigated bone healing in NOD/scid-IL2Rγcnull mice, which exhibit severe defects in innate and adaptive immunity, by biomechanical testing, histomorphometry and micro-computed tomography. We demonstrated that NOD/scid-IL2Rγcnull mice exhibited normal skeletal anatomy and a mild bone phenotype with a slightly reduced bone mass in the trabecular compartment in comparison to immunocompetent Balb/c mice. Fracture healing was impaired in immunodeficient NOD/scid-IL2Rγcnull mice. Callus bone content was unaffected during the early healing stage, whereas it was significantly reduced during the later healing period. Concomitantly, the amount of cartilage was significantly increased, indicating delayed endochondral ossification, most likely due to the decreased osteoclast activity observed in cells isolated from NOD/scid-IL2Rγcnull mice. Our results suggest that—under aseptic, uncomplicated conditions—the immediate immune response after fracture is non-essential for the initiation of bone formation. However, an intact immune system in general is important for successful bone healing, because endochondral ossification is delayed in immunodeficient NOD/scid-IL2Rγcnull mice. PMID:26849055

  13. Accelerated healing of excisional skin wounds by PL 14736 in alloxan-hyperglycemic rats.

    PubMed

    Seveljević-Jaran, D; Cuzić, S; Dominis-Kramarić, M; Glojnarić, I; Ivetić, V; Radosević, S; Parnham, M J

    2006-01-01

    PL 14736 is a synthetic peptide, originally isolated from human gastric juice, that has anti-inflammatory and tissue-protective actions in experimental models of gastrointestinal inflammation. To investigate its possible benefit in poorly healing skin wounds, the effects of the topical application of PL 14736 in a gel formulation have been studied on full-thickness excisional wounds in rats, either healthy or made hyperglycemic by alloxan (175 mg/kg s.c.) 5 days previously. The effects of becaplermin gel (platelet-derived growth factor, PDGF-BB, Regranex, a standard therapy for diabetic foot ulcers, were investigated for comparison. Healing was evaluated for up to 7 days after wounding, using digital planimetry analysis, macroscopic scoring and histology. While healing was too rapid in healthy rats to observe enhancement by either treatment, in the hyperglycemic rats which exhibited delayed healing, PL 14736 (10-1,000 microg/wound) produced a dose-dependent acceleration of wound healing (determined by macroscopic scoring) equivalent at the highest doses to that observed with becaplermin. The beneficial effect on healing was associated with increased deposition of organized granulation tissue by day 7 for both PL 14736 and becaplermin, as determined histologically. PL 14736 tended to have a greater effect than becaplermin on the formation of granulation tissue containing mature collagen. Wound contraction, as measured by planimetry, was not significantly affected. In conclusion, topical PL 14736 produces a dose-dependent acceleration of deficient skin wound healing in hyperglycemic rats by facilitating granulation tissue formation, similar to the response seen with topical becaplermin, the standard therapy for diabetic skin wounds. PL 14736 may represent an alternative therapy for delayed wound healing, such as that seen with diabetic foot ulcers, without the proliferative concerns or immunogenicity associated with growth factors. PMID:16785777

  14. 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.

  15. Fracture and healing in magmas: a dual role on permeability evolution

    NASA Astrophysics Data System (ADS)

    Lamur, Anthony; Lavallée, Yan; Wall, Richard; Ashworth, James; Kendrick, Jackie; Wadsworth, Fabian

    2016-04-01

    The development of a permeable network in silicic volcanic conduits controls outgassing and plays a major role on the subsequent eruptive behaviour. Efficient outgassing, at higher permeabilities, is achieved through the coalescence of pores and fractures. Whilst the relationship between permeability and increasing connected porosity is now relatively well constrained, the effects of fractures have, on the other hand, rarely been investigated. Here, we present the results of an experimental study focusing on the impacts of tensile fracturing and healing on permeability. Permeability measurements have been performed on over 60 disk-shaped samples (26 mm diameter, 13 mm thickness) with connected porosities ranging from 2 to 45%. Our results for unfractured samples display the same porosity-permeability trend as previous studies and permeabilities span from 10-15 at low porosities to over 5x10-12 m2 at higher porosities. These samples were then broken via Brazilian tests and the resultant permeability of the rocks were then measured across the fracture zone. Whilst high porosity samples reached permeabilities of about 5x10-10 m2 (2 orders of magnitude higher than intact samples), low porosity samples, on the other hand, reached permeabilities around 5x10-12 m2 (more than 3 orders of magnitude above intact samples). Our results show that fracturing favours the development of a permeable network that adheres to a different permeability-porosity relationship than previously presented, and that this effect is emphasized in magmas with low connected porosities. The effect of fracture healing by diffusion on permeability has been investigated through a series of experiments on borosilicate standard glass (NIST 717a). These experiments were conducted at 560oC (viscosity of 1010.33 Pa.s) on pairs of columns pressed and held in contact at constant load for times varying between 0.5s and 15000 s before being pulled apart at a strain rate of 10-3s-1. Using Maxwell's theory of

  16. Fracture healing after reamed and unreamed intramedullary nailing in sheep tibia.

    PubMed

    Högel, F; Schlegel, U; Südkamp, N; Müller, C

    2011-07-01

    Intramedullary nailing is a well-established method for stabilisation of long-bone shaft fractures. It is still a controversy as to whether the procedure should be done by an unreamed or reamed technique. In the present animal study, 24 sheep were treated with intramedullary nailing. Midshaft fractures (Arbeitsgemeinschaft für Osteosynthese (AO) type 42-A2/3) were created. Eight sheep were treated with an unreamed nailing technique (UN), a further eight sheep underwent tibia nailing by the reamed technique using the conventional AO reaming system (RC) and in a further eight sheep, reamed nailing was performed using an experimental reaming system (RE). Intra-operatively, the intramedullary pressure was measured and, during a healing time of 10 weeks, the growth of callus formation was labelled with fluorescence markers after 4 and 6 weeks. After 10 weeks, the animals were euthanised and the quality of fracture healing was determined by recording stiffness in torsion, antero-posterior and mediolateral bending and the load at yield. In addition, the callus formation at the fracture zone was evaluated by fluorescence microscopy and macroradiographs. The results showed a decrease of intramedullary pressure when reamed nailing was performed with the RE (72.5 mmHg) system compared with the conventional AO reaming system (227 mmHg). Mechanical testing did not reveal any significant differences either for torsional or bending stiffness or for load at yield for any of the three procedures. Histological evaluation showed a similar callus formation for the UN group and the RE group. Callus formation in the UN (65 mm(2)) and RE (63 mm(2)) groups showed a higher increase during the first 6 weeks than those treated with the conventional AO reaming system (27 mm(2)). This means that, especially during the first weeks of fracture healing, damage to the bone by the reaming process can be reduced by reaming with a reaming device with lowered cutting flutes and smaller drive

  17. Mechanics and mechano-biology of fracture healing in normal and osteoporotic bone.

    PubMed

    Augat, Peter; Simon, Ulrich; Liedert, Astrid; Claes, Lutz

    2005-03-01

    Fracture repair, which aims at regaining the functional competence of a bone, is a complex and multifactorial process. For the success of fracture repair biology and mechanics are of immense importance. The biological and mechanical environments must be compatible with the processes of cell and tissue proliferation and differentiation. The biological environment is characterized by the vascular supply and by many biochemical components, the biochemical milieu. A good vascular supply is a prerequisite for the initiation of the fracture repair process. The biochemical milieu involves complex interactions among local and systemic regulatory factors such as growth factors or cytokines. The mechanical environment is determined by the local stress and strain within the fracture. However, the local stress and strain is not accessible, and the mechanical environment, therefore, is described by global mechanical factors, e.g., gap size or interfragmentary movement. The relationship between local stress and strain and the global mechanical factors can be obtained by numerical models (Finite Element Model). Moreover, there is considerable interaction between biological factors and mechanical factors, creating a biomechanical environment for the fracture healing process. The biomechanical environment is characterized by osteoblasts and osteocytes that sense the mechanical signal and express biological markers, which effect the repair process. This review will focus on the effects of biomechanical factors on fracture repair as well as the effects of age and osteoporosis.

  18. Alginate-hyaluronan composite hydrogels accelerate wound healing process.

    PubMed

    Catanzano, O; D'Esposito, V; Acierno, S; Ambrosio, M R; De Caro, C; Avagliano, C; Russo, P; Russo, R; Miro, A; Ungaro, F; Calignano, A; Formisano, P; Quaglia, F

    2015-10-20

    In this paper we propose polysaccharide hydrogels combining alginate (ALG) and hyaluronan (HA) as biofunctional platform for dermal wound repair. Hydrogels produced by internal gelation were homogeneous and easy to handle. Rheological evaluation of gelation kinetics of ALG/HA mixtures at different ratios allowed understanding the HA effect on ALG cross-linking process. Disk-shaped hydrogels, at different ALG/HA ratio, were characterized for morphology, homogeneity and mechanical properties. Results suggest that, although the presence of HA does significantly slow down gelation kinetics, the concentration of cross-links reached at the end of gelation is scarcely affected. The in vitro activity of ALG/HA dressings was tested on adipose derived multipotent adult stem cells (Ad-MSC) and an immortalized keratinocyte cell line (HaCaT). Hydrogels did not interfere with cell viability in both cells lines, but significantly promoted gap closure in a scratch assay at early (1 day) and late (5 days) stages as compared to hydrogels made of ALG alone (p<0.01 and 0.001 for Ad-MSC and HaCaT, respectively). In vivo wound healing studies, conducted on a rat model of excised wound indicated that after 5 days ALG/HA hydrogels significantly promoted wound closure as compared to ALG ones (p<0.001). Overall results demonstrate that the integration of HA in a physically cross-linked ALG hydrogel can be a versatile strategy to promote wound healing that can be easily translated in a clinical setting.

  19. Validation of a standardised gait score to predict the healing of tibial fractures.

    PubMed

    Macri, F; Marques, L F; Backer, R C; Santos, M J; Belangero, W D

    2012-04-01

    There is no absolute method of evaluating healing of a fracture of the tibial shaft. In this study we sought to validate a new clinical method based on the systematic observation of gait, first by assessing the degree of agreement between three independent observers regarding the gait score for a given patient, and secondly by determining how such a score might predict healing of a fracture. We used a method of evaluating gait to assess 33 patients (29 men and four women, with a mean age of 29 years (15 to 62)) who had sustained an isolated fracture of the tibial shaft and had been treated with a locked intramedullary nail. There were 15 closed and 18 open fractures (three Gustilo and Anderson grade I, seven grade II, seven grade IIIA and one grade IIIB). Assessment was carried out three and six months post-operatively using videos taken with a digital camera. Gait was graded on a scale ranging from 1 (extreme difficulty) to 4 (normal gait). Bivariate analysis included analysis of variance to determine whether the gait score statistically correlated with previously validated and standardised scores of clinical status and radiological evidence of union. An association was found between the pattern of gait and all the other variables. Improvement in gait was associated with the absence of pain on weight-bearing, reduced tenderness over the fracture, a higher Radiographic Union Scale in Tibial Fractures score, and improved functional status, measured using the Brazilian version of the Short Musculoskeletal Function Assessment questionnaire (all p < 0.001). Although further study is needed, the analysis of gait in this way may prove to be a useful clinical tool. PMID:22434473

  20. The contributions of dietary protein and mineral to the healing of experimental fractures. A biomechanical study.

    PubMed

    Einhorn, T A; Bonnarens, F; Burstein, A H

    1986-12-01

    We examined the contributions of dietary protein and mineral to fracture-healing by assessing the mechanical properties of fracture callus in rats that were fed a diet that was deficient in or enriched by these nutrients. In order to isolate the effects of diet on fracture-healing, we developed a method for producing a standard closed femoral fracture with minimum-soft-tissue injury. Three groups of animals were studied. Group I was a control group, in which the rats did not undergo an operation. The rats in Group II underwent intramedullary pinning of the right femur, but no fracture was created. The rats in Group III underwent pinning identical to that used for Group II, after which a closed, transverse femoral fracture was produced. Immediately after surgery, the animals in each group were subdivided into five diet-treatment subgroups. Subgroup A received a regular diet; Subgroup B received a protein-free diet; and Subgroup C received a mineral-free diet that was lacking in calcium, phosphorus, and vitamin D. Subgroup D received a protein-supplemented diet that was composed of three times the calculated requirement of protein, and Subgroup E received a mineral-supplemented diet that was composed of three times the calculated requirements of calcium and phosphorus as well as a therapeutic dose of vitamin D, equivalent to that used in the treatment of osteomalacia. At the end of five weeks, the animals were killed and the right femur of each one was subjected to torsion-testing to failure.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Experimental study of effect of stress-relaxation bone plate on fracture healing.

    PubMed

    Zhang, Xianlong; Zhang, Wei; Dai, Kerong

    2000-11-15

    OBJECTIVE: To study the change of the stress shi elding rate of stress-relaxation plate in vivo and its influence on fracture he aling. METHODS: The diaphyses of bilateral tibias in 70 New Zealand ra bbits were osteotomized and fixed with stress-relaxation plates (SRP, the SRP g roup) and rigid plates (RP, the RP group), respectively. The fracture healing pr ocess in these 2 groups was investigated by radiography, light and polarized l ight microscopy and biomechanical test at 2 to 48 weeks postoperatively. RESULTS: Early after fixation the stress shielding rate was abo ut 70% in both groups. While in the SRP group the stress shielding rate decrease d gradually as time passed, which was significantly lower than that of the RP gr oup (P<0.05) by the end of the 8th postoperative week, and stabilized at the level of about 27% at 36-48 weeks after fixation. Abund ant external callus associated with the formation of cartilaginous callus could be observed in the SRP group at 2-4 weeks postoperatively. The transformation o f the callus into the lamellar bone began at 8-12 weeks, the collagen gradually arranged in order, and the mechanical nature of the united bone was gradually s trengthened, too. In the RP group, the external callus was scarce at the early s tage of fracture healing, and the callus remodeling at the late stage of fractur e healing was dominated by bone absorption. The ultimate bending strength (UBS) was only 57.95% of that of the normal by 48 weeks. CONCLUSIONS: The decrease of the stress shielding rate of SRP i n vivo was well interrelated with the time of fixation. The application of SRP c ould promote the callus formation and bone reconstruction thus to favor the reco very of the mechanical strength of the united bone. PMID:11874675

  2. Carcinogenic Parasite Secretes Growth Factor That Accelerates Wound Healing and Potentially Promotes Neoplasia.

    PubMed

    Smout, Michael J; Sotillo, Javier; Laha, Thewarach; Papatpremsiri, Atiroch; Rinaldi, Gabriel; Pimenta, Rafael N; Chan, Lai Yue; Johnson, Michael S; Turnbull, Lynne; Whitchurch, Cynthia B; Giacomin, Paul R; Moran, Corey S; Golledge, Jonathan; Daly, Norelle; Sripa, Banchob; Mulvenna, Jason P; Brindley, Paul J; Loukas, Alex

    2015-10-01

    Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). Injury from feeding activities of this parasite within the human biliary tree causes extensive lesions, wounds that undergo protracted cycles of healing, and re-injury over years of chronic infection. We show that O. viverrini secreted proteins accelerated wound resolution in human cholangiocytes, an outcome that was compromised following silencing of expression of the fluke-derived gene encoding the granulin-like growth factor, Ov-GRN-1. Recombinant Ov-GRN-1 induced angiogenesis and accelerated mouse wound healing. Ov-GRN-1 was internalized by human cholangiocytes and induced gene and protein expression changes associated with wound healing and cancer pathways. Given the notable but seemingly paradoxical properties of liver fluke granulin in promoting not only wound healing but also a carcinogenic microenvironment, Ov-GRN-1 likely holds marked potential as a therapeutic wound-healing agent and as a vaccine against an infection-induced cancer of major public health significance in the developing world. PMID:26485648

  3. Carcinogenic Parasite Secretes Growth Factor That Accelerates Wound Healing and Potentially Promotes Neoplasia

    PubMed Central

    Smout, Michael J.; Sotillo, Javier; Laha, Thewarach; Papatpremsiri, Atiroch; Rinaldi, Gabriel; Pimenta, Rafael N.; Chan, Lai Yue; Johnson, Michael S.; Turnbull, Lynne; Whitchurch, Cynthia B.; Giacomin, Paul R.; Moran, Corey S.; Golledge, Jonathan; Daly, Norelle; Sripa, Banchob; Mulvenna, Jason P.

    2015-01-01

    Abstract Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). Injury from feeding activities of this parasite within the human biliary tree causes extensive lesions, wounds that undergo protracted cycles of healing, and re-injury over years of chronic infection. We show that O. viverrini secreted proteins accelerated wound resolution in human cholangiocytes, an outcome that was compromised following silencing of expression of the fluke-derived gene encoding the granulin-like growth factor, Ov-GRN-1. Recombinant Ov-GRN-1 induced angiogenesis and accelerated mouse wound healing. Ov-GRN-1 was internalized by human cholangiocytes and induced gene and protein expression changes associated with wound healing and cancer pathways. Given the notable but seemingly paradoxical properties of liver fluke granulin in promoting not only wound healing but also a carcinogenic microenvironment, Ov-GRN-1 likely holds marked potential as a therapeutic wound-healing agent and as a vaccine against an infection-induced cancer of major public health significance in the developing world. PMID:26485648

  4. Extracorporeal shockwave therapy (ESWT) ameliorates healing of tibial fracture non-union unresponsive to conventional therapy.

    PubMed

    Haffner, Nicolas; Antonic, Vlado; Smolen, Daniel; Slezak, Paul; Schaden, Wolfgang; Mittermayr, Rainer; Stojadinovic, Alexander

    2016-07-01

    Tibial non-unions are common cause of demanding revision surgeries and are associated with a significant impact on patients' quality of life and health care costs. Extracorporeal shockwave therapy (ESWT) has been shown to improve osseous healing in vitro and in vivo. The main objective of present study was to evaluate the efficacy of ESWT in healing of tibial non-unions unresponsive to previous surgical and non-surgical measures. A retrospective multivariant analysis of a prospective open, single-centre, clinical trial of tibia non-union was conducted. 56 patients with 58 eligible fractures who met the FDA criteria were included. All patients received 3000-4000 impulses of electrohydraulic shockwaves at an energy flux density of 0.4mJ/mm(2) (-6dB). On average patients underwent 1.9 times (±1.3SD) surgical interventions prior to ESWT displaying the rather negatively selected cohort and its limited therapy responsiveness. In 88.5% of patients receiving ESWT complete bone healing was observed after six months irrespective of underlying pathology. The multivariant analysis showed that time of application is important for therapy success. Patients achieving healing received ESWT earlier: mean number of days between last surgical intervention and ESWT (healed - 355.1 days±167.4SD vs. not healed - 836.7 days±383.0SD; p<0.0001). ESWT proved to be a safe, effective and non-invasive treatment modality in tibial non-unions recalcitrant to standard therapies. The procedure is well tolerated, time-saving, lacking side effects, with potential to significantly decrease health care costs. Thus, in our view, ESWT should be considered the treatment of first choice in established tibial non-unions.

  5. Extracorporeal shockwave therapy (ESWT) ameliorates healing of tibial fracture non-union unresponsive to conventional therapy.

    PubMed

    Haffner, Nicolas; Antonic, Vlado; Smolen, Daniel; Slezak, Paul; Schaden, Wolfgang; Mittermayr, Rainer; Stojadinovic, Alexander

    2016-07-01

    Tibial non-unions are common cause of demanding revision surgeries and are associated with a significant impact on patients' quality of life and health care costs. Extracorporeal shockwave therapy (ESWT) has been shown to improve osseous healing in vitro and in vivo. The main objective of present study was to evaluate the efficacy of ESWT in healing of tibial non-unions unresponsive to previous surgical and non-surgical measures. A retrospective multivariant analysis of a prospective open, single-centre, clinical trial of tibia non-union was conducted. 56 patients with 58 eligible fractures who met the FDA criteria were included. All patients received 3000-4000 impulses of electrohydraulic shockwaves at an energy flux density of 0.4mJ/mm(2) (-6dB). On average patients underwent 1.9 times (±1.3SD) surgical interventions prior to ESWT displaying the rather negatively selected cohort and its limited therapy responsiveness. In 88.5% of patients receiving ESWT complete bone healing was observed after six months irrespective of underlying pathology. The multivariant analysis showed that time of application is important for therapy success. Patients achieving healing received ESWT earlier: mean number of days between last surgical intervention and ESWT (healed - 355.1 days±167.4SD vs. not healed - 836.7 days±383.0SD; p<0.0001). ESWT proved to be a safe, effective and non-invasive treatment modality in tibial non-unions recalcitrant to standard therapies. The procedure is well tolerated, time-saving, lacking side effects, with potential to significantly decrease health care costs. Thus, in our view, ESWT should be considered the treatment of first choice in established tibial non-unions. PMID:27158008

  6. Combination of low level light therapy and nitrosyl-cobinamide accelerates wound healing.

    PubMed

    Spitler, Ryan; Ho, Hsiang; Norpetlian, Frederique; Kong, Xiangduo; Jiang, Jingjing; Yokomori, Kyoko; Andersen, Bogi; Boss, Gerry R; Berns, Michael W

    2015-05-01

    Low level light therapy (LLLT) has numerous therapeutic benefits, including improving wound healing, but the precise mechanisms involved are not well established; in particular, the underlying role of cytochrome C oxidase (C-ox) as the primary photoacceptor and the associated biochemical mechanisms still require further investigation. We previously showed the nitric oxide (NO) donating drug nitrosyl-cobinamide (NO-Cbi) enhances wound healing through a cGMP/cGMP-dependent protein kinase/ERK1/2 mechanism. Here, we show that the combination of LLLT and NO-Cbi markedly improves wound healing compared to either treatment alone. LLLT-enhanced wound healing proceeded through an electron transport chain-C-ox-dependent mechanism with a reduction of reactive oxygen species and increased adenosine triphosphate production. C-ox was validated as the primary photoacceptor by three observations: increased oxygen consumption, reduced wound healing in the presence of sodium azide, and disassociation of cyanide, a known C-ox ligand, following LLLT. We conclude that LLLT and NO-Cbi accelerate wound healing through two independent mechanisms, the electron transport chain-C-ox pathway and cGMP signaling, respectively, with both resulting in ERK1/2 activation. PMID:25562608

  7. Combination of low level light therapy and nitrosyl-cobinamide accelerates wound healing

    PubMed Central

    Spitler, Ryan; Ho, Hsiang; Norpetlian, Frederique; Kong, Xiangduo; Jiang, Jingjing; Yokomori, Kyoko; Andersen, Bogi; Boss, Gerry R.; Berns, Michael W.

    2015-01-01

    Abstract. Low level light therapy (LLLT) has numerous therapeutic benefits, including improving wound healing, but the precise mechanisms involved are not well established; in particular, the underlying role of cytochrome C oxidase (C-ox) as the primary photoacceptor and the associated biochemical mechanisms still require further investigation. We previously showed the nitric oxide (NO) donating drug nitrosyl-cobinamide (NO-Cbi) enhances wound healing through a cGMP/cGMP-dependent protein kinase/ERK1/2 mechanism. Here, we show that the combination of LLLT and NO-Cbi markedly improves wound healing compared to either treatment alone. LLLT-enhanced wound healing proceeded through an electron transport chain-C-ox-dependent mechanism with a reduction of reactive oxygen species and increased adenosine triphosphate production. C-ox was validated as the primary photoacceptor by three observations: increased oxygen consumption, reduced wound healing in the presence of sodium azide, and disassociation of cyanide, a known C-ox ligand, following LLLT. We conclude that LLLT and NO-Cbi accelerate wound healing through two independent mechanisms, the electron transport chain-C-ox pathway and cGMP signaling, respectively, with both resulting in ERK1/2 activation. PMID:25562608

  8. Epidermal stem cells (ESCs) accelerate diabetic wound healing via the Notch signalling pathway

    PubMed Central

    Yang, Rong-Hua; Qi, Shao-Hai; Shu, Bin; Ruan, Shu-Bin; Lin, Ze-Peng; Lin, Yan; Shen, Rui; Zhang, Feng-Gang; Chen, Xiao-Dong; Xie, Ju-Lin

    2016-01-01

    Chronic, non-healing wounds are a major complication of diabetes. Recently, various cell therapies have been reported for promotion of diabetic wound healing. Epidermal stem cells (ESCs) are considered a powerful tool for tissue therapy. However, the effect and the mechanism of the therapeutic properties of ESCs in the diabetic wound healing are unclear. Herein, to determine the ability of ESCs to diabetic wound healing, a dorsal skin defect in a streptozotocin (STZ)-induced diabetes mellitus (DM) mouse model was used. ESCs were isolated from mouse skin. We found that both the mRNA and protein levels of a Notch ligand Jagged1 (Jag1), Notch1 and Notch target gene Hairy Enhancer of Split-1 (Hes1) were significantly increased at the wound margins. In addition, we observed that Jag1 was high expressed in ESCs. Overexpression of Jag1 promotes ESCs migration, whereas knockdown Jag1 resulted in a significant reduction in ESCs migration in vitro. Importantly, Jag1 overexpression improves diabetic wound healing in vivo. These results provide evidence that ESCs accelerate diabetic wound healing via the Notch signalling pathway, and provide a promising potential for activation of the Notch pathway for the treatment of diabetic wound. PMID:27129289

  9. Epidermal stem cells (ESCs) accelerate diabetic wound healing via the Notch signalling pathway.

    PubMed

    Yang, Rong-Hua; Qi, Shao-Hai; Shu, Bin; Ruan, Shu-Bin; Lin, Ze-Peng; Lin, Yan; Shen, Rui; Zhang, Feng-Gang; Chen, Xiao-Dong; Xie, Ju-Lin

    2016-08-01

    Chronic, non-healing wounds are a major complication of diabetes. Recently, various cell therapies have been reported for promotion of diabetic wound healing. Epidermal stem cells (ESCs) are considered a powerful tool for tissue therapy. However, the effect and the mechanism of the therapeutic properties of ESCs in the diabetic wound healing are unclear. Herein, to determine the ability of ESCs to diabetic wound healing, a dorsal skin defect in a streptozotocin (STZ)-induced diabetes mellitus (DM) mouse model was used. ESCs were isolated from mouse skin. We found that both the mRNA and protein levels of a Notch ligand Jagged1 (Jag1), Notch1 and Notch target gene Hairy Enhancer of Split-1 (Hes1) were significantly increased at the wound margins. In addition, we observed that Jag1 was high expressed in ESCs. Overexpression of Jag1 promotes ESCs migration, whereas knockdown Jag1 resulted in a significant reduction in ESCs migration in vitro Importantly, Jag1 overexpression improves diabetic wound healing in vivo These results provide evidence that ESCs accelerate diabetic wound healing via the Notch signalling pathway, and provide a promising potential for activation of the Notch pathway for the treatment of diabetic wound. PMID:27129289

  10. Combination of low level light therapy and nitrosyl-cobinamide accelerates wound healing

    NASA Astrophysics Data System (ADS)

    Spitler, Ryan; Ho, Hsiang; Norpetlian, Frederique; Kong, Xiangduo; Jiang, Jingjing; Yokomori, Kyoko; Andersen, Bogi; Boss, Gerry R.; Berns, Michael W.

    2015-05-01

    Low level light therapy (LLLT) has numerous therapeutic benefits, including improving wound healing, but the precise mechanisms involved are not well established; in particular, the underlying role of cytochrome C oxidase (C-ox) as the primary photoacceptor and the associated biochemical mechanisms still require further investigation. We previously showed the nitric oxide (NO) donating drug nitrosyl-cobinamide (NO-Cbi) enhances wound healing through a cGMP/cGMP-dependent protein kinase/ERK1/2 mechanism. Here, we show that the combination of LLLT and NO-Cbi markedly improves wound healing compared to either treatment alone. LLLT-enhanced wound healing proceeded through an electron transport chain-C-ox-dependent mechanism with a reduction of reactive oxygen species and increased adenosine triphosphate production. C-ox was validated as the primary photoacceptor by three observations: increased oxygen consumption, reduced wound healing in the presence of sodium azide, and disassociation of cyanide, a known C-ox ligand, following LLLT. We conclude that LLLT and NO-Cbi accelerate wound healing through two independent mechanisms, the electron transport chain-C-ox pathway and cGMP signaling, respectively, with both resulting in ERK1/2 activation.

  11. 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

  12. Biodegradable nanocomposite coatings accelerate bone healing: In vivo evaluation

    PubMed Central

    Mehdikhani-Nahrkhalaji, Mehdi; Fathi, Mohammad Hossein; Mortazavi, Vajihesadat; Mousavi, Sayed Behrouz; Akhavan, Ali; Haghighat, Abbas; Hashemi-Beni, Batool; Razavi, Sayed Mohammad; Mashhadiabbas, Fatemeh

    2015-01-01

    Background: The aim of this study was to evaluate the interaction of bioactive and biodegradable poly (lactide-co-glycolide)/bioactive glass/hydroxyapatite (PBGHA) and poly (lactide-co-glycolide)/bioactive glass (PBG) nanocomposite coatings with bone. Materials and Methods: Sol-gel derived 58S bioactive glass nanoparticles, 50/50 wt% poly (lactic acid)/poly (glycolic acid) and hydroxyapatite nanoparticles were used to prepare the coatings. The nanocomposite coatings were characterized by scanning electron microscopy, X-ray diffraction and atomic force microscopy. Mechanical stability of the prepared nanocomposite coatings was studied during intramedullary implantation of coated Kirschner wires (K-wires) into rabbit tibia. Titanium mini-screws coated with nanocomposite coatings and without coating were implanted intramedullary in rabbit tibia. Bone tissue interaction with the prepared nanocomposite coatings was evaluated 30 and 60 days after surgery. The non-parametric paired Friedman and Kruskal-Wallis tests were used to compare the samples. For all tests, the level of significance was P < 0.05. Results: The results showed that nanocomposite coatings remained stable on the K-wires with a minimum of 96% of the original coating mass. Tissue around the coated implants showed no adverse reactions to the coatings. Woven and trabecular bone formation were observed around the coated samples with a minimum inflammatory reaction. PBG nanocomposite coating induced more rapid bone healing than PBGHA nanocomposite coating and titanium without coating (P < 0.05). Conclusion: It was concluded that PBG nanocomposite coating provides an ideal surface for bone formation and it could be used as a candidate for coating dental and orthopedic implants. PMID:25709681

  13. A biomechanical comparison of the effects of constant and cyclic compression on fracture healing in rabbit long bones.

    PubMed

    Panjabi, M M; White, A A; Wolf, J W

    1979-12-01

    In a biomechanical study, the strength of healing experimental fractures in rabbit tibias was compared for two different healing environments. During the healing period large constant compression was applied to one leg, while the other leg was subjected to cyclic compression forces. Rabbits were sacrificed at 3, 4, 5, 6, and 8 weeks after the operation. The healing bones were tested in a dynamic torsion testing machine. Results indicate that on an average basis the cyclic compression treated bones exhibited higher torque and energy absorption to failure, but lower stiffness as compared with the constant compression treated bones, during the 30 to 50 days' healing period. These differences were statistically significant. Additionally, it was estimated that a 27 per cent saving in healing time may be realized for a bone treated with cyclic as compared with constant compression.

  14. Disruption of glucocorticoid signaling in chondrocytes delays metaphyseal fracture healing but does not affect normal cartilage and bone development

    PubMed Central

    Tu, Jinwen; Henneicke, Holger; Zhang, Yaqing; Stoner, Shihani; Cheng, Tegan L.; Schindeler, Aaron; Chen, Di; Tuckermann, Jan; Cooper, Mark S.; Seibel, Markus J.; Zhou, Hong

    2014-01-01

    States of glucocorticoid excess are associated with defects in chondrocyte function. Most prominently there is a reduction in linear growth but delayed healing of fractures that require endochondral ossification to also occur. In contrast, little is known about the role of endogenous glucocorticoids in chondrocyte function. As glucocorticoids exert their cellular actions through the glucocorticoid receptor (GR), we aimed to elucidate the role of endogenous glucocorticoids in chondrocyte function in vivo through characterization of tamoxifen-inducible chondrocyte-specific GR knockout (chGRKO) mice in which the GR was deleted at various post-natal ages. Knee joint architecture, cartilage structure, growth plates, intervertebral discs, long bone length and bone micro-architecture were similar in chGRKO and control mice at all ages. Analysis of fracture healing in chGRKO and control mice demonstrated that in metaphyseal fractures, chGRKO mice formed a larger cartilaginous callus at 1 and 2 week post-surgery, as well as a smaller amount of well-mineralized bony callus at the fracture site 4 week post-surgery, when compared to control mice. In contrast, chondrocyte-specific GR knockout did not affect diaphyseal fracture healing. We conclude that endogenous GC signaling in chondrocytes plays an important role during metaphyseal fracture healing but is not essential for normal long bone growth. PMID:25193158

  15. Older Age Does Not Affect Healing Time and Functional Outcomes After Fracture Nonunion Surgery

    PubMed Central

    Taormina, David P.; Shulman, Brandon S.; Karia, Raj; Spitzer, Allison B.; Konda, Sanjit R.

    2014-01-01

    Introduction: Elderly patients are at risk of fracture nonunion, given the potential setting of osteopenia, poorer fracture biology, and comorbid medical conditions. Risk factors predicting fracture nonunion may compromise the success of fracture nonunion surgery. The purpose of this study was to investigate the effect of patient age on clinical and functional outcome following long bone fracture nonunion surgery. Materials and Methods: A retrospective analysis of prospectively collected data identified 288 patients (aged 18-91) who were indicated for long bone nonunion surgery. Two-hundred and seventy-two patients satisfied study inclusion criteria and analyses were performed comparing elderly patients aged ≥65 years (n = 48) with patients <65 years (n = 224) for postoperative wound complications, Short Musculoskeletal Functional Assessment (SMFA) functional status, healing, and surgical revision. Regression analyses were performed to look for associations between age, smoking status, and history of previous nonunion surgery with healing and functional outcome. Twelve-month follow-up was obtained on 91.5% (249 of 272) of patients. Results: Despite demographic differences in the aged population, including a predominance of medical comorbidities (P < .01) and osteopenia (P = .02), there was no statistical differences in the healing rate of elderly patients (95.8% vs 95.1%, P = .6) or time to union (6.2 ± 4.1 months vs. 7.2 ± 6.6, P = .3). Rates of postoperative wound complications and surgical revision did not statistically differ. Elderly patients reported similar levels of function up to 12 months after surgery. Regression analyses failed to show any significant association between age and final union or time to union. There was a strong positive association between smoking and history of previous nonunion surgery with time to union. Age was associated (positively) with 12-month SMFA activity score. Conclusions: Smoking and failure of previous surgical

  16. An external fixation method and device to study fracture healing in rats.

    PubMed

    Mark, Hans; Bergholm, Jan; Nilsson, Anders; Rydevik, Björn; Strömberg, Lennart

    2003-08-01

    We wished to establish a reproducible model for fracture fixation to be used in fracture healing research and therefore developed an external fixation construct and surgical procedure adapted to Sprague-Dawley rats. We evaluated the mechanical properties of the construct in brass rods and rat bone, in an Instron test machine with axial and transverse loading, and the in vivo performance. We found that the mechanical properties of the construct in brass rods were predictable and could be repeated in rat femora. In all tests, the axial load was about 10 times the transverse for the same degree of deformation. The stiffness among fixators was uniform. 1 mm pins caused about 50% less stiffness than 1.2 mm pins in axial loading of rat bone (p < 0.001) and brass rods (p < 0.001) as well as in transverse loading of brass rods (p < 0.001). Loosening of 1 or 2 screws that lock the pins to the fixator reduced stiffness by about 50% in axial loading of rat bone (p = 0.009) and brass rods (p = 0.05). A change in the distance between the bone surface and the fixator was linearly related to the stiffness in axial loading of rat bone (p < 0.001) and brass rods (p < 0.001) and in transverse loading of brass rods (p < 0.001). If the bone ends touched each other, the axial stiffness of the construct increased almost 10 times (265 N/mm), as compared to a fracture gap size of 2 mm (31 N/mm). In vivo experiments had a complication rate of less than 10% when we used 1.2 mm pins, 6 mm offset and rats weighing 350-450 g. Our method and device for experimental external fixation of rat femora are reliable and the findings are reproducible. These can be used in bone repair and fracture healing research. PMID:14521302

  17. Diabetes reduces mesenchymal stem cells in fracture healing through a TNFα-mediated mechanism

    PubMed Central

    Tian, Chen; Alblowi, Jazia; Kayal, Rayyan A.; Einhorn, Thomas A.; Gerstenfeld, Louis C.; Pignolo, Robert J.; Graves, Dana T.

    2015-01-01

    Aims/hypothesis Diabetes interferes with bone formation and impairs fracture healing, an important complication in humans and animal models. The aim of this study was to examine the impact of diabetes on mesenchymal stem cells (MSCs) during fracture repair. Methods Fracture of the long bones was induced in a streptozotocin-induced type 1 diabetic mouse model with or without insulin or a specific TNFα inhibitor, pegsunercept. MSCs were detected with cluster designation-271 (also known as p75 neurotrophin receptor) or stem cell antigen-1 (Sca-1) antibodies in areas of new endochondral bone formation in the calluses. MSC apoptosis was measured by TUNEL assay and proliferation was measured by Ki67 antibody. In vitro apoptosis and proliferation were examined in C3H10T1/2 and human-bone-marrow-derived MSCs following transfection with FOXO1 small interfering (si)RNA. Results Diabetes significantly increased TNFα levels and reduced MSC numbers in new bone area. MSC numbers were restored to normal levels with insulin or pegsunercept treatment. Inhibition of TNFα significantly reduced MSC loss by increasing MSC proliferation and decreasing MSC apoptosis in diabetic animals, but had no effect on MSCs in normoglycaemic animals. In vitro experiments established that TNFα alone was sufficient to induce apoptosis and inhibit proliferation of MSCs. Furthermore, silencing forkhead box protein O1 (FOXO1) prevented TNFα-induced MSC apoptosis and reduced proliferation by regulating apoptotic and cell cycle genes. Conclusions/interpretation Diabetes-enhanced TNFα significantly reduced MSC numbers in new bone areas during fracture healing. Mechanistically, diabetes-enhanced TNFα reduced MSC proliferation and increased MSC apoptosis. Reducing the activity of TNFα in vivo may help to preserve endogenous MSCs and maximise regenerative potential in diabetic patients. PMID:25563724

  18. Healing.

    PubMed

    Ventres, William B

    2016-01-01

    My personal ethos of healing is an expression of the belief that I can and do act to heal patients while I attend to the traditional goals of medicine. The 7 supporting principles that inform my ethos are dignity, authenticity, integrity, transparency, solidarity, generosity, and resiliency. I invite others, including medical students, residents, and practicing physicians, to reflect and discover their own ethos of healing and the principles that guide their professional growth. A short digital documentary accompanies this essay for use as a reflective prompt to encourage personal and professional development. PMID:26755787

  19. [Fracture healing after intramedullary nailing of simple tibial shaft fractures. A clinical comparison of reamed and unreamed procedures].

    PubMed

    Ruchholtz, S; Nast-Kolb, D; Betz, A; Schweiberer, L

    1995-07-01

    From January 1990 to June 1993, 56 patients with simple tibial shaft fractures were treated in the Surgical Department of the University/Municipal Hospital in Munich by primary intramedullary nailing, and 44 of these patients were followed up. The results in 17 who underwent unreamed intramedullary nailing (UTN) were compared with those in 27 in whom reamed procedures (RTN) were applied. There was no difference between the two groups in age, fracture type and localization. Soft tissue trauma prevailed, with 35% I degrees open fractures in the UTN group (RTN group, 3%). UTN patients were operated on an average of 45 h after trauma, and RTN patients, 5 days after trauma. Both groups showed about the same proportion of good and very good results (criteria of Johner and Wruhs), with 83% in the UTN group and 84% in the RTN group. The rate of complications was the same in both groups (11%), and we did not find any kind of infection. Two complications requiring revisions (nonunion, perforation of the nail) after UTN stress the importance of two-dimensional barring in the main fragments (especially when close to the metaphysis) and of reduced weight-bearing for 6 weeks after the operation. The slightly greater intramedullar instability after UTN did not cause a higher rate of nonunions or of fracture healing in a wrong position than RTN. The X-ray findings showed beginning osseous reunion after 13 weeks in the UTN group. This corresponds to earlier painless full weight-bearing after an average of 9.7 weeks, as against 12 weeks in the RTN group.

  20. Systemic Inhibition of Canonical Notch Signaling Results in Sustained Callus Inflammation and Alters Multiple Phases of Fracture Healing

    PubMed Central

    Dishowitz, Michael I.; Mutyaba, Patricia L.; Takacs, Joel D.; Barr, Andrew M.; Engiles, Julie B.; Ahn, Jaimo; Hankenson, Kurt D.

    2013-01-01

    The Notch signaling pathway is an important regulator of embryological bone development, and many aspects of development are recapitulated during bone repair. We have previously reported that Notch signaling components are upregulated during bone fracture healing. However, the significance of the Notch pathway in bone regeneration has not been described. Therefore, the objective of this study was to determine the importance of Notch signaling in regulating bone fracture healing by using a temporally controlled inducible transgenic mouse model (Mx1-Cre;dnMAMLf/-) to impair RBPjκ-mediated canonical Notch signaling. The Mx1 promoter was synthetically activated resulting in temporally regulated systemic dnMAML expression just prior to creation of bilateral tibial fractures. This allowed for mice to undergo unaltered embryological and post-natal skeletal development. Results showed that systemic Notch inhibition prolonged expression of inflammatory cytokines and neutrophil cell inflammation, and reduced the proportion of cartilage formation within the callus at 10 days-post-fracture (dpf) Notch inhibition did not affect early bone formation at 10dpf, but significantly altered bone maturation and remodeling at 20dpf. Increased bone volume fraction in dnMAML fractures, which was due to a moderate decrease in callus size with no change in bone mass, coincided with increased trabecular thickness but decreased connectivity density, indicating that patterning of bone was altered. Notch inhibition decreased total osteogenic cell density, which was comprised of more osteocytes rather than osteoblasts. dnMAML also decreased osteoclast density, suggesting that osteoclast activity may also be important for altered fracture healing. It is likely that systemic Notch inhibition had both direct effects within cell types as well as indirect effects initiated by temporally upstream events in the fracture healing cascade. Surprisingly, Notch inhibition did not alter cell proliferation

  1. Acceleration of skin wound healing with tragacanth (Astragalus) preparation: an experimental pilot study in rats.

    PubMed

    Fayazzadeh, Ehsan; Rahimpour, Sina; Ahmadi, Seyed Mohsen; Farzampour, Shahrokh; Sotoudeh Anvari, Maryam; Boroumand, Mohammad Ali; Ahmadi, Seyed Hossein

    2014-01-01

    Gum tragacanth is a natural complex mixture of polysaccharides and alkaline minerals extracted from species of Astragalus plant, which is found widely in arid regions of the Middle East. In a pilot experimental study we examined the effects of its topical application on wound healing in ten albino adult male rats. Two similar parasagittal elliptical full-thickness wounds (control vs. test samples) were created on the dorsum of each animal. Test group samples were fully covered by a thin layer of gum tragacanth daily. The extent of wound healing was evaluated by planimetric analysis on multiple occasions during the 10-day study period. On the 7th day of the study, the percent of wound closure was significantly higher in gum tragacanth-treated specimens compared to the control samples (87%±2% vs. 70%±4%, P<0.001). The majority of wounds in the test group were completely closed by the 10th day of the study. The difference in wound healing index measured by histological examination on day 10 of the study was also statistically meaningful between the two groups (0.624±0.097 vs. 0.255±0.063, P<0.05). The results of this study clearly showed the useful effects of topical application of gum tragacanth in acceleration of skin wound contraction and healing. More studies are encouraged to identify the implicating agents and precisely understand the mechanism by which they exert their wound healing effects.

  2. Reduced FOXO1 Expression Accelerates Skin Wound Healing and Attenuates Scarring

    PubMed Central

    Mori, Ryoichi; Tanaka, Katsuya; de Kerckhove, Maiko; Okamoto, Momoko; Kashiyama, Kazuya; Tanaka, Katsumi; Kim, Sangeun; Kawata, Takuya; Komatsu, Toshimitsu; Park, Seongjoon; Ikematsu, Kazuya; Hirano, Akiyoshi; Martin, Paul; Shimokawa, Isao

    2015-01-01

    The forkhead box O (FOXO) family has been extensively investigated in aging and metabolism, but its role in tissue-repair processes remains largely unknown. Herein, we clarify the molecular aspect of the FOXO family in skin wound healing. We demonstrated that Foxo1 and Foxo3a were both up-regulated during murine skin wound healing. Partial knockout of Foxo1 in Foxo1+/− mice throughout the body led to accelerated skin wound healing with enhanced keratinocyte migration, reduced granulation tissue formation, and decreased collagen density, accompanied by an attenuated inflammatory response, but we observed no wound phenotype in Foxo3a−/− mice. Fibroblast growth factor 2, adiponectin, and notch1 genes were significantly increased at wound sites in Foxo1+/− mice, along with markedly altered extracellular signal–regulated kinase 1/2 and AKT phosphorylation. Similarly, transient knockdown of Foxo1 at the wound site by local delivery of antisense oligodeoxynucleotides enhanced skin wound healing. The link between FOXO1 and scarring extends to patients, in particular keloid scars, where we see FOXO1 expression markedly increased in fibroblasts and inflammatory cells within the otherwise normal dermis. This occurs in the immediate vicinity of the keloid by comparison to the center of the mature keloid, indicating that FOXO1 is associated with the overgrowth of this fibrotic response into adjacent normal skin. Overall, our data indicate that molecular targeting of FOXO1 may improve the quality of healing and reduce pathological scarring. PMID:25010393

  3. Is there a relationship between fracture healing and mean platelet volume?

    PubMed Central

    Serbest, Sancar; Tiftikci, Ugur; Tosun, Haci Bayram; Gumustas, Seyit Ali; Uludag, Abuzer

    2016-01-01

    Objectives Platelet volume has been defined to be a marker that shows thrombocyte activation and function and it is measured as mean platelet volume (MPV). MPV shows the mean volume of circulating thrombocytes and it is one of the routine parameters in complete blood count. Increased thrombocyte volume is associated with thrombocyte activation. Patients and methods This study included 76 patients who were operated on due to fractures of long tubular bones. Patients who had union without any additional interventions were defined as group I, and patients who needed additional interventions due to nonunion or inadequate union were defined as group II. The control group included healthy volunteers who did not have a fracture. Hematologic test values of the patients that were obtained at admission to emergency ward were recorded. Results The groups were not statistically different in terms of age, sex, and the affected extremity. There were significant differences between group I and group II in terms of mean erythrocyte sedimentation rate, C-reactive protein, and MPV values (P<0.001), but there were no significant differences between group I and the control group. There was also no statistically significant difference among groups in terms of hematologic and biochemical variables. Conclusion In our study, fractures in patients who had lower MPV values than controls during the inflammation process healed without any problem, but fractures in patients with high MPV values more frequently needed additional surgical interventions. PMID:27471388

  4. Success of long bone fracture healing in ancient Egypt: a paleoepidemiological study of the Giza Necropolis skeletons.

    PubMed

    Erfan Zaki, Moushira

    2013-01-01

    Complications may provide information regarding the management of fractures in ancient populations. The aim of this study was to determine the rates of long-bone fractures and the proportion of misalignments as indicators of failed treatment or no treatment at all in skeletons from the Giza Necropolis dating to the Old Kingdom period (2700-2190 BC). We visually examined for fractures 2287 long bones of 204 adult skeletons (112 male and 92 female) and took x-rays of fractured bones in standard AP and ML views, so that we can analyse misalignments. Fractures were found in 45 of the 2287 examined long bones (1.97 %). Most of the fractures healed with good alignment, most likely as a result of successful treatment, and only three fractures showed misalignment.

  5. EXOGEN ultrasound bone healing system for long bone fractures with non-union or delayed healing: a NICE medical technology guidance.

    PubMed

    Higgins, Ailish; Glover, Matthew; Yang, Yaling; Bayliss, Susan; Meads, Catherine; Lord, Joanne

    2014-10-01

    A routine part of the process for developing National Institute for Health and Care Excellence (NICE) medical technologies guidance is a submission of clinical and economic evidence by the technology manufacturer. The Birmingham and Brunel Consortium External Assessment Centre (EAC; a consortium of the University of Birmingham and Brunel University) independently appraised the submission on the EXOGEN bone healing system for long bone fractures with non-union or delayed healing. This article is an overview of the original evidence submitted, the EAC's findings, and the final NICE guidance issued.

  6. Expression of Sulf1 and Sulf2 in cartilage, bone and endochondral fracture healing.

    PubMed

    Zaman, G; Staines, K A; Farquharson, C; Newton, P T; Dudhia, J; Chenu, C; Pitsillides, A A; Dhoot, G K

    2016-01-01

    SULF1/SULF2 enzymes regulate cell signalling that impacts the growth and differentiation of many tissues. To determine their possible role in cartilage and bone growth or repair, their expression was examined during development and bone fracture healing using RT-PCR and immunochemical analyses. Examination of epiphyseal growth plates revealed differential, inverse patterns of SULF1 and SULF2 expressions, with the former enriched in quiescent and the latter in hypertrophic chondrocyte zones. Markedly higher levels of both SULFs, however, were expressed in osteoblasts actively forming bone when compared with proliferating pre-osteoblasts in the periosteum or the entombed osteocytes which express the lowest levels. The increased expression of Sulf1 and Sulf2 in differentiating osteoblasts was further confirmed by RT-PCR analysis of mRNA levels in rat calvarial osteoblast cultures. SULF1 and SULF2 were expressed in most foetal articular chondrocytes but down-regulated in a larger subset of cells in the post-natal articular cartilage. Unlike adult articular chondrocytes, SULF1/SULF2 expression varied markedly in post-natal hypertrophic chondrocytes in the growth plate, with very high SULF2 expression compared with SULF1 apparent during neonatal growth in both primary and secondary centres of ossification. Similarly, hypertrophic chondrocytes expressed greatly higher levels of SULF2 but not SULF1 during bone fracture healing. SULF2 expression unlike SULF1 also spread to the calcifying matrix around the hypertrophic chondrocytes indicating its possible ligand inhibiting role through HSPG desulphation. Higher levels of SULF2 in both developing and healing bone closely correlated with parallel increases in hedgehog signalling analysed by ptc1 receptor expression. PMID:26464246

  7. The axolotl limb: a model for bone development, regeneration and fracture healing.

    PubMed

    Hutchison, Cara; Pilote, Mireille; Roy, Stéphane

    2007-01-01

    Among vertebrates, urodele amphibians (e.g., axolotls) have the unique ability to perfectly regenerate complex body parts after amputation. The limb has been the most widely studied due to the presence of three defined axes and its ease of manipulation. Hence, the limb has been chosen as a model to study the process of skeletogenesis during axolotl development, regeneration and to analyze this animal's ability to heal bone fractures. Extensive studies have allowed researchers to gain some knowledge of the mechanisms controlling growth and pattern formation in regenerating and developing limbs, offering an insight into how vertebrates are able to regenerate tissues. In this study, we report the cloning and characterization of two axolotl genes; Cbfa-1, a transcription factor that controls the remodeling of cartilage into bone and PTHrP, known for its involvement in the differentiation and maturation of chondrocytes. Whole-mount in situ hybridization and immunohistochemistry results show that Cbfa-1, PTHrP and type II collagen are expressed during limb development and regeneration. These genes are expressed during specific stages of limb development and regeneration which are consistent with the appearance of skeletal elements. The expression pattern for Cbfa-1 in late limb development was similar to the expression pattern found in the late stages of limb regeneration (i.e. re-development phase) and it did not overlap with the expression of type II collagen. It has been reported that the molecular mechanisms involved in the re-development phase of limb regeneration are a recapitulation of those used in developing limbs; therefore the detection of Cbfa-1 expression during regeneration supports this assertion. Conversely, PTHrP expression pattern was different during limb development and regeneration, by its intensity and by the localization of the signal. Finally, despite its unsurpassed abilities to regenerate, we tested whether the axolotl was able to regenerate non

  8. Fracture-induced mechanophore activation and solvent healing in poly(methyl methacrylate)

    NASA Astrophysics Data System (ADS)

    Celestine, Asha-Dee N.

    of the crack tip. Control specimens in which the mechanophore is absent or tethered in positions in which no mechanochemical activation is expected are also tested and exhibit no change in color or fluorescence intensity with crack propagation. The relationship between fracture-induced mechanophore activation in rubber toughened SP-PMMA and the strain and stress ahead of the propagating crack is also studied. SP activation is again detected and quantified by in situ fluorescence imaging. Digital Image Correlation (DIC) is used to measure the strain ahead of the crack tip. The corresponding stress is generated through the use of the Hutchinson-Rice-Rosengren (HRR) singularity field equations. Mechanophore activation ahead of the crack tip is shown to follow a power law distribution that is closely aligned with strain. The potential of SP as a damage sensor is explored further by incorporating the spiropyran into the core of rubber nanoparticles. SP-linked rubber nanoparticles are synthesized using a seeded emulsion polymerization process and incorporated into cross-linked PMMA at a concentration of 5 wt%. Cylindrical specimens are torsion tested and the activation of the SP within the nanoparticles is monitored via full field fluorescence imaging. SP activation within the core is shown to increase with shear strain. Autonomous damage repair in PMMA is also investigated. The first demonstration of fully autonomous self-healing in PMMA is achieved through the use of solvent microcapsules. Solvent microcapsules with a PMMA-anisole liquid core are prepared and embedded within a linear PMMA matrix. Specimens of the microcapsule-loaded material are then fabricated for Double Cleavage Drilled Compression (DCDC) fracture testing. The DCDC specimens, containing increasing concentrations of solvent microcapsules, are tested and then allowed to heal for a fixed period of time before a second DCDC test. The healing efficiency of each material system is evaluated based on the

  9. Effect of leptin combined with CoCl2 on healing in Sprague Dawley Rat fracture model

    PubMed Central

    Liu, Pengcheng; Liu, Junfeng; Xia, Kuo; Chen, Liyang; Wu, Xing

    2016-01-01

    To evaluate the effect of leptin combined with CoCl2 on rat femur fracture healing. 48 male Sprague Dawley rats were randomly divided into two main groups. Then standardized femur fractures were created to all rats. Control group rats were treated with 0.5 mL physiological saline, and experimental group rats were treated with 5 μg/Kg.d leptin and 15 mg/Kg.d CoCl2 along with 0.5 mL physiological saline for 42 days intraperitoneally. Each main group was divided into three subgroups for each evaluation at second, fourth and sixth weeks, each subgroup included eight rats. The radiological evaluation showed that the fracture healing progress of experimental group was superior to control group from second week. At fourth week, experimental group had better fracture healing progress than control group significantly. Results of biomechanics show the ultimate load (N) and deflection ultimate load (mm) of experimental group was significantly increased than that in control group from fourth week. The present result demonstrated that leptin combined with CoCl2 significantly increased the mRNA expression levels of HIF1A, Vegfa, Runx2, Bmp2, Bglap and Alpl. It suggested that leptin combined with CoCl2 have a positive effect on rat femur fracture healing by activating the HIF1A pathway. PMID:27468656

  10. Neuromuscular electrical stimulation enhances fracture healing: results of an animal model.

    PubMed

    Park, Sang-Hyun; Silva, Mauricio

    2004-03-01

    Neuromuscular electrical stimulation (NMES) could simulate physiological muscle functions known to be associated with the normal bone healing process. The object of the present study was to evaluate the effect of NMES on fracture healing, using an animal model. Thirty rabbits received unilateral, transverse, mid-tibial, 3-mm gapped osteotomies that were stabilized with double-bar external fixators. The femoral vein was ligated to induce venous stasis. From the fourth post-operative day, the study group was treated with 1 h daily of NMES for four weeks, while the control group was treated without NMES. For NMES, two surface electrodes were used: one above the patellar tendon and another around the lateral thigh. Callus area and mineral content at the osteotomy gap were measured, biweekly, using computerized tomographic examinations. Biomechanical properties of healing were evaluated with a torsion test, eight weeks after the index operation. Osteotomies treated with NMES exhibited 31% (p=0.01) higher mineral content and 27% (p=0.009) larger callus area than control osteotomies at eight weeks. The maximum torque, torsional stiffness, angular displacement at maximum torque, and energy required to failure of specimens in the study group were 62% (p=0.006), 29% (p=0.03), 34.6% (p=0.008), and 124% (p<0.0001) higher, respectively, than those in the control group at eight weeks. The results of the present study demonstrated that the use of NMES can enhance callus development and mineralization, with the consequent improvement in biomechanical properties of the healing bone.

  11. Skin wound healing is accelerated and scarless in the absence of commensal microbiota.

    PubMed

    Canesso, Maria C C; Vieira, Angélica T; Castro, Tiago B R; Schirmer, Brígida G A; Cisalpino, Daniel; Martins, Flaviano S; Rachid, Milene A; Nicoli, Jacques R; Teixeira, Mauro M; Barcelos, Lucíola S

    2014-11-15

    The commensal microbiota has a high impact on health and disease by modulating the development and homeostasis of host immune system. Immune cells are involved in virtually every aspect of the wound repair process; however, the impact of commensal microbiota on skin wound healing is largely unknown. In this study, we evaluated the influence of commensal microbiota on tissue repair of excisional skin wounds by using germ-free (GF) Swiss mice. We observed that macroscopic wound closure rate is accelerated in the absence of commensal microbiota. Accordantly, histologically assessed wound epithelization was accelerated in GF in comparison with conventional (CV) Swiss mice. The wounds of GF mice presented a significant decrease in neutrophil accumulation and an increase in mast cell and macrophage infiltration into wounds. Interestingly, alternatively activated healing macrophage-related genes were highly expressed in the wound tissue of GF mice. Moreover, levels of the anti-inflammatory cytokine IL-10, the angiogenic growth factor VEGF and angiogenesis were higher in the wound tissue of those mice. Conversely, scarring and levels of the profibrogenic factor TGF-β1 were greatly reduced in GF mice wounded skin when compared with CV mice. Of note, conventionalization of GF mice with CV microbiota restored wound closure rate, neutrophil and macrophage accumulation, cytokine production, and scarring to the same extent as CV mice. Overall, our findings suggest that, in the absence of any contact with microbiota, skin wound healing is accelerated and scarless, partially because of reduced accumulation of neutrophils, increased accumulation of alternatively activated healing macrophages, and better angiogenesis at wound sites.

  12. Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing.

    PubMed

    Kazmers, Nikolas H; McKenzie, Jennifer A; Shen, Tony S; Long, Fanxin; Silva, Matthew J

    2015-12-01

    Hedgehog (Hh) signaling is critical in developmental osteogenesis, and recent studies suggest it may also play a role in regulating osteogenic gene expression in the post-natal setting. However, there is a void of studies directly assessing the effect of Hh inhibition on post-natal osteogenesis. This study utilized a cyclic loading-induced ulnar stress fracture model to evaluate the hypothesis that Hh signaling contributes to osteogenesis and angiogenesis during stress fracture healing. Immediately prior to loading, adult rats were given GDC-0449 (Vismodegib - a selective Hh pathway inhibitor; 50mg/kg orally twice daily), or vehicle. Hh signaling was upregulated in response to stress fracture at 3 days (Ptch1, Gli1 expression), and was markedly inhibited by GDC-0449 at 1 day and 3 days in the loaded and non-loaded ulnae. GDC-0449 did not affect Hh ligand expression (Shh, Ihh, Dhh) at 1 day, but decreased Shh expression by 37% at 3 days. GDC-0449 decreased woven bone volume (-37%) and mineral density (-17%) at 7 days. Dynamic histomorphometry revealed that the 7 day callus was composed predominantly of woven bone in both groups. The observed reduction in woven bone occurred concomitantly with decreased expression of Alpl and Ibsp, but was not associated with differences in early cellular proliferation (as determined by callus PCNA staining at 3 days), osteoblastic differentiation (Osx expression at 1 day and 3 days), chondrogenic gene expression (Acan, Sox9, and Col2α1 expression at 1 day and 3 days), or bone resorption metrics (callus TRAP staining at 3 days, Rankl and Opg expression at 1 day and 3 days). To evaluate angiogenesis, vWF immunohistochemistry showed that GDC-0449 reduced fracture callus blood vessel density by 55% at 3 days, which was associated with increased Hif1α gene expression (+30%). Dynamic histomorphometric analysis demonstrated that GDC-0449 also inhibited lamellar bone formation. Lamellar bone analysis of the loaded limb (directly adjacent

  13. Role of Simvastatin on fracture healing and osteoporosis: a systematic review on in vivo investigations.

    PubMed

    Moshiri, Ali; Sharifi, Ali Mohammad; Oryan, Ahmad

    2016-07-01

    Simvastatin is a lipid lowering drug whose beneficial role on bone metabolism was discovered in 1999. Several in vivo studies evaluated its role on osteoporosis and fracture healing, however, controversial results are seen in the literature. For this reason, Simvastatin has not been the focus of any clinical trials as yet. This systematic review clears the mechanisms of action of Simvastatin on bone metabolism and focuses on in vivo investigations that have evaluated its role on osteoporosis and fracture repair to find out (i) whether Simvastatin is effective on treatment of osteoporosis and fracture repair, and (ii) which of the many available protocols may have the ability to be translated in the clinical setting. Simvastatin induces osteoinduction by increasing osteoblast activity and differentiation and inhibiting their apoptosis. It also reduces osteoclastogenesis by decreasing both the number and activity of osteoclasts and their differentiation. Controversial results between the in vivo studies are mostly due to the differences in the route of administration, dose, dosage and carrier type. Local delivery of Simvastatin through controlled drug delivery systems with much lower doses and dosages than the systemic route seems to be the most valuable option in fracture healing. However, systemic delivery of Simvastatin with much higher doses and dosages than the clinical ones seems to be effective in managing osteoporosis. Simvastatin, in a particular range of doses and dosages, may be beneficial in managing osteoporosis and fracture injuries. This review showed that Simvastatin is effective in the treatment of osteoporosis and fracture healing.

  14. Application of coenzyme Q10 for accelerating soft tissue wound healing after tooth extraction in rats.

    PubMed

    Yoneda, Toshiki; Tomofuji, Takaaki; Kawabata, Yuya; Ekuni, Daisuke; Azuma, Tetsuji; Kataoka, Kota; Kunitomo, Muneyoshi; Morita, Manabu

    2014-12-10

    Accelerating wound healing after tooth extraction is beneficial in dental treatment. Application of antioxidants, such as reduced coenzyme Q10 (rCoQ10), may promote wound healing after tooth extraction. In this study, we examined the effects of topical application of rCoQ10 on wound healing after tooth extraction in rats. After maxillary first molars were extracted, male Fischer 344 rats (8 weeks old) (n = 27) received topical application of ointment containing 5% rCoQ10 (experimental group) or control ointment (control group) to the sockets for 3 or 8 days (n = 6-7/group). At 3 days after extraction, the experimental group showed higher collagen density and lower numbers of polymorphonuclear leukocytes in the upper part of socket, as compared to the control group (p < 0.05). Gene expression of interleukin-1β, tumor necrosis factor-α and nuclear factor-κB were also lower in the experimental group than in the control group (p < 0.05). At 8 days after tooth extraction, there were no significant differences in collagen density, number of polymorphonuclear leukocytes and bone fill between the groups. Our results suggest that topical application of rCoQ10 promotes wound healing in the soft tissue of the alveolar socket, but that rCoQ10 has a limited effect on bone remodeling in rats.

  15. Potential Activity of 3-(2-Chlorophenyl)-1-phenyl-propenonein Accelerating Wound Healing in Rats

    PubMed Central

    Dhiyaaldeen, Summaya M.; Alshawsh, Mohammed A.; Salama, Suzy M.; Alwajeeh, Nahla S. I.

    2014-01-01

    Wound healing involves inflammation followed by granular tissue development and scar formation. In this study, synthetic chalcone 3-(2-Chlorophenyl)-1-phenyl-propenone (CPPP) was investigated for a potential role in enhancing wound healing and closure. Twenty-four male rats were divided randomly into 4 groups: carboxymethyl cellulose (CMC) (0.2 mL), Intrasite gel, and CPPP (25 or 50 mg/mL). Gross morphology, wounds treatment with the CPPP, and Intrasite gel accelerate the rate of wound healing compared to CMC group. Ten days after surgery, the animals were sacrificed. Histological assessment revealed that the wounds treated with CPPP showed that wound closure site contained little amount of scar and the granulation tissue contained more collagen and less inflammatory cells than wound treated with CMC. This finding was confirmed with Masson's trichrome staining. The antioxidant defence enzymes catalase (CAT) and superoxide dismutase (SOD) were significantly increased in the wound homogenates treated with CPPP (P < 0.05) compared to CMC treated group. However, in the CPPP treatment group, lipid peroxidation (MDA) was significantly decreased (P < 0.05), suggesting that the CPPP also has an important role in protection against lipid peroxidation-induced skin injury after ten days of treatment with CPPP, which is similar to the values of cytokines TGF-β and TNF-α in tissue homogenate. Finally the administration of CPPP at a dosage of 25 and 50 mg/kg was suitable for the stimulation of wound healing. PMID:24587992

  16. In Vivo Hypobaric Hypoxia Performed During the Remodeling Process Accelerates Bone Healing in Mice

    PubMed Central

    Durand, Marjorie; Collombet, Jean-Marc; Frasca, Sophie; Begot, Laurent; Lataillade, Jean-Jacques; Le Bousse-Kerdilès, Marie-Caroline

    2014-01-01

    We investigated the effects of respiratory hypobaric hypoxia on femoral bone-defect repair in mice because hypoxia is believed to influence both mesenchymal stromal cell (MSC) and hematopoietic stem cell mobilization, a process involved in the bone-healing mechanism. To mimic conditions of non-weight-bearing limb immobilization in patients suffering from bone trauma, our hypoxic mouse model was further subjected to hind-limb unloading. A hole was drilled in the right femur of adult male C57/BL6J mice. Four days after surgery, mice were subjected to hind-limb unloading for 1 week. Seven days after surgery, mice were either housed for 4 days in a hypobaric room (FiO2 at 10%) or kept under normoxic conditions. Unsuspended control mice were housed in either hypobaric or normoxic conditions. Animals were sacrificed on postsurgery day 11 to allow for collection of both contralateral and lesioned femurs, blood, and spleen. As assessed by microtomography, delayed hypoxia enhanced bone-healing efficiency by increasing the closing of the cortical defect and the newly synthesized bone volume in the cavity by +55% and +35%, respectively. Proteome analysis and histomorphometric data suggested that bone-repair improvement likely results from the acceleration of the natural bone-healing process rather than from extended mobilization of MSC-derived osteoprogenitors. Hind-limb unloading had hardly any effect beyond delayed hypoxia-enhanced bone-healing efficiency. PMID:24944208

  17. Blumea balsamifera Oil for the Acceleration of Healing of Burn Injuries.

    PubMed

    Fan, Zuo-Wang; Pang, Yu-Xin; Wang, Kai; Yu, Fu-Lai; Wang, Dan; Yang, Quan; Ma, Qing-Song; Li, Xiao-Ting; Zou, Jin; Zhang, Wen-Qing; Wu, Li-Fen

    2015-01-01

    Blumea balsamifera oil (BBO) is a main extract obtained from Blumea balsamifera (L.) DC (Ainaxiang) leaves, which are widely used as a traditional medicine by the Miao and Li Nations to promote skin trauma or burn injury healing. This study was initiated to investigate the healing efficacy in deep second-degree burn model in rats. The rats were treated by BBO for 21 consecutive days. The rate of healing, scabs dropped time and re-epithelialization time were observed every three days for 21 days after burn injury. The samples were collected from different treated rats by sacrificing the animals on the 1st, 2nd, 5th, 9th, 14th, and 21st day post-burn creation. Then, the water content of burn tissue was measured. Plasma interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) levels were evaluated, and the tissue expressions of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-β) were determined along with skin histopathology. The results showed that the water content of tissue was significantly reduced, the scabs dropped time shortened, and healing accelerated after treatment with BBO in the burn injury rats. Furthermore, the expressions of growth factors were significantly increased in the tissue; however, the levels of inflammatory factors on plasma decreased. This study confirms the efficacy of BBO consumption on burn injuries. PMID:26393555

  18. Blumea balsamifera Oil for the Acceleration of Healing of Burn Injuries.

    PubMed

    Fan, Zuo-Wang; Pang, Yu-Xin; Wang, Kai; Yu, Fu-Lai; Wang, Dan; Yang, Quan; Ma, Qing-Song; Li, Xiao-Ting; Zou, Jin; Zhang, Wen-Qing; Wu, Li-Fen

    2015-09-17

    Blumea balsamifera oil (BBO) is a main extract obtained from Blumea balsamifera (L.) DC (Ainaxiang) leaves, which are widely used as a traditional medicine by the Miao and Li Nations to promote skin trauma or burn injury healing. This study was initiated to investigate the healing efficacy in deep second-degree burn model in rats. The rats were treated by BBO for 21 consecutive days. The rate of healing, scabs dropped time and re-epithelialization time were observed every three days for 21 days after burn injury. The samples were collected from different treated rats by sacrificing the animals on the 1st, 2nd, 5th, 9th, 14th, and 21st day post-burn creation. Then, the water content of burn tissue was measured. Plasma interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) levels were evaluated, and the tissue expressions of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-β) were determined along with skin histopathology. The results showed that the water content of tissue was significantly reduced, the scabs dropped time shortened, and healing accelerated after treatment with BBO in the burn injury rats. Furthermore, the expressions of growth factors were significantly increased in the tissue; however, the levels of inflammatory factors on plasma decreased. This study confirms the efficacy of BBO consumption on burn injuries.

  19. Fracture healing in mice lacking Pten in osteoblasts: a micro-computed tomography image-based analysis of the mechanical properties of the femur.

    PubMed

    Collins, Caitlyn J; Vivanco, Juan F; Sokn, Scott A; Williams, Bart O; Burgers, Travis A; Ploeg, Heidi-Lynn

    2015-01-21

    In the United States, approximately eight million osseous fractures are reported annually, of which 5-10% fail to create a bony union. Osteoblast-specific deletion of the gene Pten in mice has been found to stimulate bone growth and accelerate fracture healing. Healing rates at four weeks increased in femurs from Pten osteoblast conditional knock-out mice (Pten-CKO) compared to wild-type mice (WT) of the same genetic strain as measured by an increase in mechanical stiffness and failure load in four-point bending tests. Preceding mechanical testing, each femur was imaged using a Skyscan 1172 micro-computed tomography (μCT) scanner (Skyscan, Kontich, Belgium). The present study used µCT image-based analysis to test the hypothesis that the increased femoral fracture force and stiffness in Pten-CKO were due to greater section properties with the same effective material properties as that of the WT. The second moment of area and section modulus were computed in ImageJ 1.46 (National Institutes of Health) and used to predict the effective flexural modulus and the stress at failure for fourteen pairs of intact and callus WT and twelve pairs of intact and callus Pten-CKO femurs. For callus and intact femurs, the failure stress and tissue mineral density of the Pten-CKO and WT were not different; however, the section properties of the Pten-CKO were more than twice as large 28 days post-fracture. It was therefore concluded, when the gene Pten was conditionally knocked-out in osteoblasts, the resulting increased bending stiffness and force to fracture were due to increased section properties.

  20. Fracture Healing in Mice Lacking Pten in Osteoblasts: A Micro-Computed Tomography Image-Based Analysis of the Mechanical Properties of the Femur

    PubMed Central

    Collins, Caitlyn J.; Vivanco, Juan; Sokn, Scott; Williams, Bart O.; Burgers, Travis A.; Ploeg, Heidi-Lynn

    2014-01-01

    In the United States, approximately 8 million osseous fractures are reported annually, of which 5-10% fail to create a bony union. Osteoblast-specific deletion of the gene Pten in mice has been found to stimulate bone growth and accelerate fracture healing. Healing rates at four weeks increased in femurs from Pten osteoblast conditional knock-out mice (Pten-CKO) compared to wild-type mice (WT) of the same genetic strain as measured by an increase in mechanical stiffness and failure load in four-point bending tests. Preceding mechanical testing, each femur was imaged using a Skyscan 1172 micro-computed tomography (μCT) scanner (Skyscan, Kontich, Belgium). The present study used μCT image-based analysis to test the hypothesis that the increased femoral fracture force and stiffness in Pten-CKO were due to greater section properties with the same effective material properties as that of the WT. The second moment of area and section modulus were computed in ImageJ 1.46 (National Institutes of Health) and used to predict the effective flexural modulus and the stress at failure for fourteen pairs of intact and callus WT and twelve pairs of intact and callus Pten-CKO femurs. For callus and intact femurs, the failure stress and tissue mineral density of the Pten-CKO and WT were not different; however, the section properties of the Pten-CKO were more than twice as large 28 days post-fracture. It was therefore concluded, when the gene Pten was conditionally knocked-out in osteoblasts, the resulting increased bending stiffness and force to fracture were due to increased section properties. PMID:25498366

  1. Strains caused by daily loading might be responsible for delayed healing of an incomplete atypical femoral fracture.

    PubMed

    Gustafsson, Anna; Schilcher, Jörg; Grassi, Lorenzo; Aspenberg, Per; Isaksson, Hanna

    2016-07-01

    Atypical femoral fractures are insufficiency fractures in the lateral femoral diaphysis or subtrochanteric region that mainly affect older patients on bisphosphonate therapy. Delayed healing is often seen in patients with incomplete fractures (cracks), and histology of bone biopsies shows mainly necrotic material inside the crack. We hypothesized that the magnitude of the strains produced in the soft tissue inside the crack during normal walk exceeds the limit for new bone formation, and thereby inhibit healing. A patient specific finite element model was developed, based on clinical CT images and high resolution μCT images of a biopsy from the crack site. Strain distributions in the femur and inside the crack were calculated for load cases representing normal walk. The models predicted large strains inside the crack, with strain levels above 10% in more than three quarters of the crack volume. According to two different tissue differentiation theories, bone would only form in less than 1-5% of the crack volume. This can explain the impaired healing generally seen in incomplete atypical fractures. Furthermore, the microgeometry of the crack highly influenced the strain distributions. Hence, a realistic microgeometry needs to be considered when modeling the crack. Histology of the biopsy showed signs of remodeling in the bone tissue adjacent to the fracture line, while the crack itself contained mainly necrotic material and signs of healing only in portions that seemed to have been widened by resorption. In conclusion, the poor healing capacity of incomplete atypical femoral fractures can be explained by biomechanical factors, and daily low impact activities are enough to cause strain magnitudes that prohibit bone formation. PMID:27113528

  2. Nitric oxide-mediated vasodilation increases blood flow during the early stages of stress fracture healing.

    PubMed

    Tomlinson, Ryan E; Shoghi, Kooresh I; Silva, Matthew J

    2014-02-15

    Despite the strong connection between angiogenesis and osteogenesis in skeletal repair conditions such as fracture and distraction osteogenesis, little is known about the vascular requirements for bone formation after repetitive mechanical loading. Here, established protocols of damaging (stress fracture) and nondamaging (physiological) forelimb loading in the adult rat were used to stimulate either woven or lamellar bone formation, respectively. Positron emission tomography was used to evaluate blood flow and fluoride kinetics at the site of bone formation. In the group that received damaging mechanical loading leading to woven bone formation (WBF), (15)O water (blood) flow rate was significantly increased on day 0 and remained elevated 14 days after loading, whereas (18)F fluoride uptake peaked 7 days after loading. In the group that received nondamaging mechanical loading leading to lamellar bone formation (LBF), (15)O water and (18)F fluoride flow rates in loaded limbs were not significantly different from nonloaded limbs at any time point. The early increase in blood flow rate after WBF loading was associated with local vasodilation. In addition, Nos2 expression in mast cells was increased in WBF-, but not LBF-, loaded limbs. The nitric oxide (NO) synthase inhibitor N(ω)-nitro-l-arginine methyl ester was used to suppress NO generation, resulting in significant decreases in early blood flow rate and bone formation after WBF loading. These results demonstrate that NO-mediated vasodilation is a key feature of the normal response to stress fracture and precedes woven bone formation. Therefore, patients with impaired vascular function may heal stress fractures more slowly than expected. PMID:24356518

  3. Young coconut juice can accelerate the healing process of cutaneous wounds

    PubMed Central

    2012-01-01

    Background Estrogen has been reported to accelerate cutaneous wound healing. This research studies the effect of young coconut juice (YCJ), presumably containing estrogen-like substances, on cutaneous wound healing in ovairectomized rats. Methods Four groups of female rats (6 in each group) were included in this study. These included sham-operated, ovariectomized (ovx), ovx receiving estradiol benzoate (EB) injections intraperitoneally, and ovx receiving YCJ orally. Two equidistant 1-cm full-thickness skin incisional wounds were made two weeks after ovariectomy. The rats were sacrificed at the end of the third and the fourth week of the study, and their serum estradiol (E2) level was measured by chemiluminescent immunoassay. The skin was excised and examined in histological sections stained with H&E, and immunostained using anti-estrogen receptor (ER-α an ER-β) antibodies. Results Wound healing was accelerated in ovx rats receiving YCJ, as compared to controls. This was associated with significantly higher density of immunostaining for ER-α an ER-β in keratinocytes, fibroblasts, white blood cells, fat cells, sebaceous gland, skeletal muscles, and hair shafts and follicles. This was also associated with thicker epidermis and dermis, but with thinner hypodermis. In addition, the number and size of immunoreactive hair follicles for both ER-α and ER-β were the highest in the ovx+YCJ group, as compared to the ovx+EB group. Conclusions This study demonstrates that YCJ has estrogen-like characteristics, which in turn seem to have beneficial effects on cutaneous wound healing. PMID:23234369

  4. Serpina3n accelerates tissue repair in a diabetic mouse model of delayed wound healing.

    PubMed

    Hsu, I; Parkinson, L G; Shen, Y; Toro, A; Brown, T; Zhao, H; Bleackley, R C; Granville, D J

    2014-10-09

    Chronic, non-healing wounds are a major complication of diabetes and are characterized by chronic inflammation and excessive protease activity. Although once thought to function primarily as a pro-apoptotic serine protease, granzyme B (GzmB) can also accumulate in the extracellular matrix (ECM) during chronic inflammation and cleave ECM proteins that are essential for proper wound healing, including fibronectin. We hypothesized that GzmB contributes to the pathogenesis of impaired diabetic wound healing through excessive ECM degradation. In the present study, the murine serine protease inhibitor, serpina3n (SA3N), was administered to excisional wounds created on the dorsum of genetically induced type-II diabetic mice. Wound closure was monitored and skin wound samples were collected for analyses. Wound closure, including both re-epithelialization and contraction, were significantly increased in SA3N-treated wounds. Histological and immunohistochemical analyses of SA3N-treated wounds revealed a more mature, proliferative granulation tissue phenotype as indicated by increased cell proliferation, vascularization, fibroblast maturation and differentiation, and collagen deposition. Skin homogenates from SA3N-treated wounds also exhibited greater levels of full-length intact fibronectin compared with that of vehicle wounds. In addition, GzmB-induced detachment of mouse embryonic fibroblasts correlated with a rounded and clustered phenotype that was prevented by SA3N. In summary, topical administration of SA3N accelerated wound healing. Our findings suggest that GzmB contributes to the pathogenesis of diabetic wound healing through the proteolytic cleavage of fibronectin that is essential for normal wound closure, and that SA3N promotes granulation tissue maturation and collagen deposition.

  5. Accelerated reepithelialization by triterpenes: proof of concept in the healing of surgical skin lesions.

    PubMed

    Metelmann, Hans-Robert; Brandner, Johanna M; Schumann, Hauke; Bross, Felix; Fimmers, Rolf; Böttger, Kerstin; Scheffler, Armin; Podmelle, Fred

    2015-01-01

    The acceleration of wound healing is a major surgical concern. A triterpene extract from birch bark (Betulae cortex) experimentally enhances keratinocyte differentiation in vitro and accelerates wound healing ex vivo. We conducted an open, blind-evaluated, controlled, prospective, randomized (1:1) phase II clinical trial in patients requiring split-thickness skin graft transplantation at two university hospitals in Germany. Donor sites on the upper legs were covered with a moist silicone-coated dressing. Oleogel-S10 ointment containing 10% birch bark extract was randomly applied to the distal or proximal half of the wound, with the other half serving as an intraindividual control, for 14 days after the skin graft surgery. The primary efficacy variable was faster reepithelialization as determined from macrophotographs by independent, blinded experts. Twenty-four patients were randomized and completed the trial. After the 14-day test period, the planned interim analysis revealed a highly significant (p < 0.0001) superiority of Oleogel-S10 in the primary efficacy variable and the trial was terminated early due to ethical concerns. The treatment side was also better reepithelialized and more similar to normal skin after 3 months. In conclusion, Oleogel-S10 significantly accelerated reepithelialization at split-thickness skin graft donor sites. Treatment with Oleogel-S10 was safe and well tolerated.

  6. Fractures

    PubMed Central

    Hall, Michael C.

    1963-01-01

    Recent studies on the epidemiology and repair of fractures are reviewed. The type and severity of the fracture bears a relation to the age, sex and occupation of the patient. Bone tissue after fracture shows a process of inflammation and repair common to all members of the connective tissue family, but it repairs with specific tissue. Cartilage forms when the oxygen supply is outgrown. After a fracture, the vascular bed enlarges. The major blood supply to healing tissue is from medullary vessels and destruction of them will cause necrosis of the inner two-thirds of the cortex. Callus rapidly mineralizes, but full mineralization is achieved slowly; increased mineral metabolism lasts several years after fracture. PMID:13952119

  7. Coacervate delivery of HB-EGF accelerates healing of type 2 diabetic wounds.

    PubMed

    Johnson, Noah R; Wang, Yadong

    2015-01-01

    Chronic wounds such as diabetic ulcers pose a significant challenge as a number of underlying deficiencies prevent natural healing. In pursuit of a regenerative wound therapy, we developed a heparin-based coacervate delivery system that provides controlled release of heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) within the wound bed. In this study, we used a polygenic type 2 diabetic mouse model to evaluate the capacity of HB-EGF coacervate to overcome the deficiencies of diabetic wound healing. In full-thickness excisional wounds on NONcNZO10 diabetic mice, HB-EGF coacervate enhanced the proliferation and migration of epidermal keratinocytes, leading to accelerated epithelialization. Furthermore, increased collagen deposition within the wound bed led to faster wound contraction and greater wound vascularization. Additionally, in vitro assays demonstrated that HB-EGF released from the coacervate successfully increased migration of diabetic human keratinocytes. The multifunctional role of HB-EGF in the healing process and its enhanced efficacy when delivered by the coacervate make it a promising therapy for diabetic wounds.

  8. Traditional Japanese Formula Kigikenchuto Accelerates Healing of Pressure-Loading Skin Ulcer in Rats

    PubMed Central

    Kimura, Mari; Shibahara, Naotoshi; Hikiami, Hiroaki; Yoshida, Toshiko; Jo, Michiko; Kaneko, Maria; Nogami, Tatsuya; Fujimoto, Makoto; Goto, Hirozo; Shimada, Yutaka

    2011-01-01

    We evaluated the effect of kigikenchuto (KKT), a traditional Japanese formula, in a modified rat pressure-loading skin ulcer model. Rats were divided into three groups, KKT extract orally administered (250 or 500 mg/kg/day for 35 days) and control. KKT shortened the duration until healing. Immunohistochemically, KKT increased CD-31-positive vessels in early phase and increased α-smooth muscle actin-(α-SMA-) positive fibroblastic cells in early phase and decreased them in late phase of wound healing. By Western blotting, KKT showed the potential to decrease inflammatory cytokines (MCP-1, IL-1β, and TNF-α) in early phase, decrease vascular endothelial growth factor in early phase and increase it in late phase, and modulate the expression of extracellular protein matrix (α-SMA, TGF-β1, bFGF, collagen III, and collagen I). These results suggested the possibility that KKT accelerates pressure ulcer healing through decreases of inflammatory cytokines, increase of angiogenesis, and induction of extracellular matrix remodeling. PMID:21660308

  9. Umbilical Cord Mesenchymal Stem Cells Combined With a Collagenfibrin Double-layered Membrane Accelerates Wound Healing.

    PubMed

    Nan, Wenbin; Liu, Rui; Chen, Hongli; Xu, Zhihao; Chen, Jiannan; Wang, Manman; Yuan, Zhiqing

    2015-05-01

    The aim of this study was to examine the effects of human umbilical cord mesenchymal stem cells (hUCMSCs) in combination with a collagen-fibrin double-layered membrane on wound healing in mice. A collagen-fibrin double-layered membrane was prepared, and the surface properties of the support material were investigated using a scanning electron microscope. Twenty-four mice were prepared for use as full-thickness skin wound models and randomly divided into 3 groups: group A, a control group in which the wounds were bound using a conventional method; group B, a group treated with hUCMSCs combined with a collagen membrane; and group C, a group treated with hUCMSCs combined with a collagen-fibrin double-layered membrane. The postoperative concrescence of the wounds was observed daily to evaluate the effects of the different treatments. Scanning electron microscope observation showed the collagen-fibrin scaffolds exhibited a highly porous and interconnected structure, and wound healing in the double-layered membrane group was better than in groups A or B. Treatment with hUCMSCs combined with a collagen-fibrin double-layered membrane accelerated wound healing.

  10. Yeast-incorporated gallium promotes fracture healing by increasing callus bony area and improving trabecular microstructure on ovariectomized osteopenic rats.

    PubMed

    Pei, Yi; Fu, Qin

    2011-06-01

    The purpose of this study was to analyze the impact of yeast-incorporated gallium on fracture healing in ovariectomized osteopenic rats. Forty Wistar female rats used were divided into three groups: sham-operated rats (SHAM), ovariectomized (OVX) rats, and ovx rats treated with yeast-bound gallium (YG). A standardized fracture-healing model with stable plate fixation was established for rat femoral. After 4-week stable fixation, animals were killed to prepare bones for Micro-CT, biomechanical testing, and histomorphometry. In addition, bone samples were obtained to evaluate the content of mineral substances in bones. Quantitative analysis of the bones from animals in the organic gallium group revealed significantly increased mineral contents compared to bones from OVX and SHAM groups. Micro-CT showed that treatment with yeast-incorporated gallium increased BV/TV and trabecular thickness and decreased trabecular separation in ovx animals. Histomorphometric evaluation demonstrated that YG increased callus area and callus bone formation. Yeast-bound gallium also improved the biomechanical properties of bone healing. In conclusion, this study suggests that yeast-incorporated gallium could promote fracture healing in ovariectomized rats.

  11. Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts.

    PubMed

    Kogan, Natalya M; Melamed, Eitan; Wasserman, Elad; Raphael, Bitya; Breuer, Aviva; Stok, Kathryn S; Sondergaard, Rachel; Escudero, Ana V Villarreal; Baraghithy, Saja; Attar-Namdar, Malka; Friedlander-Barenboim, Silvina; Mathavan, Neashan; Isaksson, Hanna; Mechoulam, Raphael; Müller, Ralph; Bajayo, Alon; Gabet, Yankel; Bab, Itai

    2015-10-01

    Cannabinoid ligands regulate bone mass, but skeletal effects of cannabis (marijuana and hashish) have not been reported. Bone fractures are highly prevalent, involving prolonged immobilization and discomfort. Here we report that the major non-psychoactive cannabis constituent, cannabidiol (CBD), enhances the biomechanical properties of healing rat mid-femoral fractures. The maximal load and work-to-failure, but not the stiffness, of femurs from rats given a mixture of CBD and Δ(9) -tetrahydrocannabinol (THC) for 8 weeks were markedly increased by CBD. This effect is not shared by THC (the psychoactive component of cannabis), but THC potentiates the CBD stimulated work-to-failure at 6 weeks postfracture followed by attenuation of the CBD effect at 8 weeks. Using micro-computed tomography (μCT), the fracture callus size was transiently reduced by either CBD or THC 4 weeks after fracture but reached control level after 6 and 8 weeks. The callus material density was unaffected by CBD and/or THC. By contrast, CBD stimulated mRNA expression of Plod1 in primary osteoblast cultures, encoding an enzyme that catalyzes lysine hydroxylation, which is in turn involved in collagen crosslinking and stabilization. Using Fourier transform infrared (FTIR) spectroscopy we confirmed the increase in collagen crosslink ratio by CBD, which is likely to contribute to the improved biomechanical properties of the fracture callus. Taken together, these data show that CBD leads to improvement in fracture healing and demonstrate the critical mechanical role of collagen crosslinking enzymes.

  12. Pretreatment of photoaged forearm skin with topical tretinoin accelerates healing of full-thickness wounds.

    PubMed

    Popp, C; Kligman, A M; Stoudemayer, T J

    1995-01-01

    Pretreatment of skin with all-trans retinoic acid (tretinoin) has been shown to enhance wound healing. Previous studies have mainly used animal models to demonstrate this effect. We wanted to determine whether pretreatment could promote wound healing in severely photoaged dorsal forearm skin. Four elderly men with severely actinically damaged forearms were treated daily for 16 weeks. One arm was treated with 0.05-0.1% tretinoin cream (Retin A, Ortho), and the other with Purpose cream (Ortho) as a vehicle control. Four-millimetre punch biopsies were taken from both dorsal forearms prior to treatment. After 16 weeks, full-thickness 2-mm punch biopsies were taken from both sides. Serial photographs were taken, and healing of the wounds quantitatively assessed by image analysis. On the 11th day, the wounds were excised using a 4-mm biopsy punch. Biopsies were processed for light microscopy. After 16 weeks, the tretinoin-treated forearms showed moderate erythema and scaling. Polarized light photographs revealed multiple, red, vascularized foci and/or a diffuse network of small vessels. The histological effects were typical for tretinoin, i.e. compaction of the stratum corneum, epidermal acanthosis with correction of atypia, an increase in small vessels, and increased cellularity in the upper dermis. Purpose cream had no effect, either clinically or histologically. On the tretinoin-treated side, the wound areas were 35-37% smaller on days 1 and 4, and 47-50% smaller on days 6, 8, 11, compared with the controls. Clinically and histologically, reepithelialization occurred more rapidly. Thus tretinoin dramatically accelerated wound healing in photodamaged skin.

  13. Cinnamtannin B-1 Promotes Migration of Mesenchymal Stem Cells and Accelerates Wound Healing in Mice.

    PubMed

    Fujita, Kosuke; Kuge, Katsunori; Ozawa, Noriyasu; Sahara, Shunya; Zaiki, Kaori; Nakaoji, Koichi; Hamada, Kazuhiko; Takenaka, Yukiko; Tanahashi, Takao; Tamai, Katsuto; Kaneda, Yasufumi; Maeda, Akito

    2015-01-01

    Substances that enhance the migration of mesenchymal stem cells to damaged sites have the potential to improve the effectiveness of tissue repair. We previously found that ethanol extracts of Mallotus philippinensis bark promoted migration of mesenchymal stem cells and improved wound healing in a mouse model. We also demonstrated that bark extracts contain cinnamtannin B-1, a flavonoid with in vitro migratory activity against mesenchymal stem cells. However, the in vivo effects of cinnamtannin B-1 on the migration of mesenchymal stem cells and underlying mechanism of this action remain unknown. Therefore, we examined the effects of cinnamtannin B-1 on in vivo migration of mesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stem cells pharmacologically and structurally. The mobilization of endogenous mesenchymal stem cells into the blood circulation was enhanced in cinnamtannin B-1-treated mice as shown by flow cytometric analysis of peripheral blood cells. Whole animal imaging analysis using luciferase-expressing mesenchymal stem cells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stem cells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stem cells was pharmacologically susceptible to inhibitors of phosphatidylinositol 3-kinase, phospholipase C, lipoxygenase, and purines. Furthermore, biflavonoids with similar structural features to cinnamtannin B-1 also augmented the migration of mesenchymal stem cells by similar pharmacological mechanisms. These results demonstrate that cinnamtannin B-1 promoted mesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration of mesenchymal stem cells may be mediated by specific signaling pathways, and the flavonoid skeleton may be relevant to its effects on

  14. Cinnamtannin B-1 Promotes Migration of Mesenchymal Stem Cells and Accelerates Wound Healing in Mice.

    PubMed

    Fujita, Kosuke; Kuge, Katsunori; Ozawa, Noriyasu; Sahara, Shunya; Zaiki, Kaori; Nakaoji, Koichi; Hamada, Kazuhiko; Takenaka, Yukiko; Tanahashi, Takao; Tamai, Katsuto; Kaneda, Yasufumi; Maeda, Akito

    2015-01-01

    Substances that enhance the migration of mesenchymal stem cells to damaged sites have the potential to improve the effectiveness of tissue repair. We previously found that ethanol extracts of Mallotus philippinensis bark promoted migration of mesenchymal stem cells and improved wound healing in a mouse model. We also demonstrated that bark extracts contain cinnamtannin B-1, a flavonoid with in vitro migratory activity against mesenchymal stem cells. However, the in vivo effects of cinnamtannin B-1 on the migration of mesenchymal stem cells and underlying mechanism of this action remain unknown. Therefore, we examined the effects of cinnamtannin B-1 on in vivo migration of mesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stem cells pharmacologically and structurally. The mobilization of endogenous mesenchymal stem cells into the blood circulation was enhanced in cinnamtannin B-1-treated mice as shown by flow cytometric analysis of peripheral blood cells. Whole animal imaging analysis using luciferase-expressing mesenchymal stem cells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stem cells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stem cells was pharmacologically susceptible to inhibitors of phosphatidylinositol 3-kinase, phospholipase C, lipoxygenase, and purines. Furthermore, biflavonoids with similar structural features to cinnamtannin B-1 also augmented the migration of mesenchymal stem cells by similar pharmacological mechanisms. These results demonstrate that cinnamtannin B-1 promoted mesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration of mesenchymal stem cells may be mediated by specific signaling pathways, and the flavonoid skeleton may be relevant to its effects on

  15. PDGF-BB does not accelerate healing in diabetic mice with splinted skin wounds.

    PubMed

    Park, Shin Ae; Raghunathan, Vijay Krishna; Shah, Nihar M; Teixeira, Leandro; Motta, Monica J; Covert, Jill; Dubielzig, Richard; Schurr, Michael; Isseroff, Roslyn Rivkah; Abbott, Nicholas L; McAnulty, Jonathan; Murphy, Christopher J

    2014-01-01

    Topical application of platelet-derived growth factor-BB (PDGF-BB) is considered to accelerate tissue repair of impaired chronic wounds. However, the vast literature is plagued with conflicting reports of its efficacy in animal models and this is often influenced by a wide array of experimental variables making it difficult to compare the results across the studies. To mitigate the confounding variables that influence the efficacy of topically applied PDGF-BB, we used a controlled full thickness splinted excisional wound model in db/db mice (type 2 diabetic mouse model) for our investigations. A carefully-defined silicone-splinted wound model, with reduced wound contraction, controlled splint and bandage maintenance, allowing for healing primarily by reepithelialization was employed. Two splinted 8 mm dorsal full thickness wounds were made in db/db mice. Wounds were topically treated once daily with either 3 µg PDGF-BB in 30 µl of 5% PEG-PBS vehicle or an equal volume of vehicle for 10 days. Body weights, wound contraction, wound closure, reepithelialization, collagen content, and wound bed inflammation were evaluated clinically and histopathologically. The bioactivity of PDGF-BB was confirmed by in vitro proliferation assay. PDGF-BB, although bioactive in vitro, failed to accelerate wound healing in vivo in the db/db mice using the splinted wound model. Considering that the predominant mechanism of wound healing in humans is by re-epithelialization, the most appropriate model for evaluating therapeutics is one that uses splints to prevent excessive wound contraction. Here, we report that PDGF-BB does not promote wound closure by re-epithelialization in a murine splinted wound model. Our results highlight that the effects of cytoactive factors reported in vivo ought to be carefully interpreted with critical consideration of the wound model used.

  16. 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.

  17. Ultrasound accelerates healing of normal wounds but not of ischemic ones.

    PubMed

    Altomare, Mariane; Nascimento, Adriana P; Romana-Souza, Bruna; Amadeu, Thaís P; Monte-Alto-Costa, Andréa

    2009-01-01

    To examine the influence of therapeutic ultrasound (US) on repair of standard and ischemic cutaneous lesions, full-thickness excisional wounds were made in rats and treated with a US 3 MHz, 0.5 W/cm(2) pulsed duty cycle. We used five experimental groups: control (received US powered off on the day of surgery, and on the second and fourth day), control US (received US on the day of surgery, and on the second and fourth day), ischemic (received US powered off on the day of surgery, and on the second and fourth day), ischemic US 3X (received US on the day of surgery, and on the second and fourth day) and ischemic US 5X (received US in the day of surgery, first, second, third and fourth day). The control US group showed acceleration in wound contraction 7 days after wounding, an increase in collagen density, and only focal inflammatory areas. Neo-epidermis formation was more advanced in the control US group than in the control one. Wound contraction was delayed in the ischemic group when compared with the control group as well as the ischemic US 3X group, was but slightly accelerated in the ischemic US 5X group when compared with the ischemic group 7 days after wounding. Reepithelialization was delayed in both ischemic US groups when compared with the ischemic group. The number of inflammatory cells was higher in both US ischemic groups. We conclude that US therapy accelerates wound healing in normal wounds and delays wound healing in ischemic wounds.

  18. Bioinformatics analysis of time-series genes profiling to explore key genes affected by age in fracture healing.

    PubMed

    Wang, Wei; Shen, Hao; Xie, Jingjing; Zhou, Qiang; Chen, Yu; Lu, Hua

    2014-06-01

    The present study was aimed to explore possible key genes and bioprocess affected by age during fracture healing. GSE589, GSE592 and GSE1371 were downloaded from gene expression omnibus database. The time-series genes of three age levels rats were firstly identified with hclust function in R. Then functional and pathway enrichment analysis for selected time-series genes were performed. Finally, the VennDiagram package of R language was used to screen overlapping n time-series genes. The expression changes of time-series genes in the rats of three age levels were classified into two types: one was higher expressed at 0 day, decreased at 3 day to 2 week, and increased from 4 to 6 week; the other was the opposite. Functional and pathways enrichment analysis showed that 12 time-series genes of adult and old rats were significantly involved in ECM-receptor interaction pathway. The expression changes of 11 genes were consistent with time axis, 10 genes were up-regulated at 3 days after fracture, and increased slowly in 6 week, while Itga2b was down-regulated. The functions of 106 overlapping genes were all associated with growth and development of bone after fracture. The key genes in ECM-receptor interaction pathway including Spp1, Ibsp, Tnn and Col3a1 have been reported to be related to fracture in literatures. The difference during fracture healing in three age levels rats is mainly related to age. The Spp1, Ibsp, Tnn and Col3a1 are possible potential age-related genes and ECM-receptor interaction pathway is the potential age-related process during fracture healing. PMID:24627361

  19. Strontium ranelate enhances callus strength more than PTH 1-34 in an osteoporotic rat model of fracture healing.

    PubMed

    Habermann, Bjoern; Kafchitsas, Konstantinos; Olender, Gavin; Augat, Peter; Kurth, Andreas

    2010-01-01

    Treatment of an underlying disease is often initiated after the occurrence of an osteoporotic fracture. Our aim was to investigate whether teriparatide (PTH 1-34) and strontium ranelate affect fracture healing in ovariectomized (OVX) rats when provided for the first time after the occurrence of an osteoporotic fracture. We combined the model of an OVX rat with a closed diaphyseal fracture. Sixty Sprague Dawley rats were randomly assigned to four groups. Fracture healing in OVX rats after treatment with pharmacological doses of strontium ranelate and PTH 1-34 was compared with OVX and sham-treated control groups. After 28 days, the femur was excised and scanned by micro computed tomography and the callus evaluated, after which biomechanical torsional testing was performed and torque and toughness until reaching the yield point were analyzed. Only treatment with strontium ranelate led to a significant increase in callus resistance compared to the OVX control rats, whereas both PTH 1-34 and strontium ranelate increased the bone volume/tissue volume ratio of the callus. The PTH 1-34-increased trabecular bone volume within the callus was even higher compared to sham. As for the callus tissue volume, the increase induced by strontium ranelate was significant, contrary to the changes induced by PTH. Callus in strontium ranelate-treated animals is more resistant to torsion compared with OVX control rats. To our knowledge, this is the first report of the enhancement of fracture healing by strontium ranelate. Because both treatments enhance bone and tissue volume within the callus, there may be a qualitative difference between the calluses of PTH 1-34- and strontium ranelate-treated OVX rats. The superior results obtained with strontium ranelate compared to PTH in terms of callus resistance could be the consequence of a better quality of the new bone formed within the callus.

  20. Finite element analysis of a bone healing model: 1-year follow-up after internal fixation surgery for femoral fracture

    PubMed Central

    Jiang-jun, Zhou; Min, Zhao; Ya-bo, Yan; Wei, Lei; Ren-fa, Lv; Zhi-yu, Zhu; Rong-jian, Chen; Wei-tao, Yu; Cheng-fei, Du

    2014-01-01

    Objective: Finite element analysis was used to compare preoperative and postoperative stress distribution of a bone healing model of femur fracture, to identify whether broken ends of fractured bone would break or not after fixation dislodgement one year after intramedullary nailing. Method s: Using fast, personalized imaging, bone healing models of femur fracture were constructed based on data from multi-slice spiral computed tomography using Mimics, Geomagic Studio, and Abaqus software packages. The intramedullary pin was removed by Boolean operations before fixation was dislodged. Loads were applied on each model to simulate a person standing on one leg. The von Mises stress distribution, maximum stress, and its location was observed. Results : According to 10 kinds of display groups based on material assignment, the nodes of maximum and minimum von Mises stress were the same before and after dislodgement, and all nodes of maximum von Mises stress were outside the fracture line. The maximum von Mises stress node was situated at the bottom quarter of the femur. The von Mises stress distribution was identical before and after surgery. Conclusion : Fast, personalized model establishment can simulate fixation dislodgement before operation, and personalized finite element analysis was performed to successfully predict whether nail dislodgement would disrupt femur fracture or not. PMID:24772140

  1. Does Anticoagulant Medication Alter Fracture-Healing? A Morphological and Biomechanical Evaluation of the Possible Effects of Rivaroxaban and Enoxaparin Using a Rat Closed Fracture Model

    PubMed Central

    Prodinger, Peter Michael; Burgkart, Rainer; Kreutzer, Kilian; Liska, Franz; Pilge, Hakan; Schmitt, Andreas; Knödler, Martina; Holzapfel, Boris Michael; Hapfelmeier, Alexander; Tischer, Thomas; Bissinger, Oliver

    2016-01-01

    Low molecular weight heparin (LMWH) is routinely used to prevent thromboembolism in orthopaedic surgery, especially in the treatment of fractures or after joint-replacement. Impairment of fracture-healing due to increased bone-desorption, delayed remodelling and lower calcification caused by direct osteoclast stimulation is a well-known side effect of unfractioned heparin. However, the effect of LMWH is unclear and controversial. Recent studies strongly suggest impairment of bone-healing in-vitro and in animal models, characterized by a significant decrease in volume and quality of new-formed callus. Since October 2008, Rivaroxaban (Xarelto) is available for prophylactic use in elective knee- and hip-arthroplasty. Recently, some evidence has been found indicating an in vitro dose independent reduction of osteoblast function after Rivaroxaban treatment. In this study, the possible influence of Rivaroxaban and Enoxaparin on bone-healing in vivo was studied using a standardized, closed rodent fracture-model. 70 male Wistar-rats were randomized to Rivaroxaban, Enoxaparin or control groups. After pinning the right femur, a closed, transverse fracture was produced. 21 days later, the animals were sacrificed and both femora harvested. Analysis was done by biomechanical testing (three-point bending) and micro CT. Both investigated substances showed histomorphometric alterations of the newly formed callus assessed by micro CT analysis. In detail the bone (callus) volume was enhanced (sign. for Rivaroxaban) and the density reduced. The bone mineral content was enhanced accordingly (sign. for Rivaroxaban). Trabecular thickness was reduced (sign. for Rivaroxaban). Furthermore, both drugs showed significant enlarged bone (callus) surface and degree of anisotropy. In contrast, the biomechanical properties of the treated bones were equal to controls. To summarize, the morphological alterations of the fracture-callus did not result in functionally relevant deficits. PMID:27455072

  2. Does Anticoagulant Medication Alter Fracture-Healing? A Morphological and Biomechanical Evaluation of the Possible Effects of Rivaroxaban and Enoxaparin Using a Rat Closed Fracture Model.

    PubMed

    Prodinger, Peter Michael; Burgkart, Rainer; Kreutzer, Kilian; Liska, Franz; Pilge, Hakan; Schmitt, Andreas; Knödler, Martina; Holzapfel, Boris Michael; Hapfelmeier, Alexander; Tischer, Thomas; Bissinger, Oliver

    2016-01-01

    Low molecular weight heparin (LMWH) is routinely used to prevent thromboembolism in orthopaedic surgery, especially in the treatment of fractures or after joint-replacement. Impairment of fracture-healing due to increased bone-desorption, delayed remodelling and lower calcification caused by direct osteoclast stimulation is a well-known side effect of unfractioned heparin. However, the effect of LMWH is unclear and controversial. Recent studies strongly suggest impairment of bone-healing in-vitro and in animal models, characterized by a significant decrease in volume and quality of new-formed callus. Since October 2008, Rivaroxaban (Xarelto) is available for prophylactic use in elective knee- and hip-arthroplasty. Recently, some evidence has been found indicating an in vitro dose independent reduction of osteoblast function after Rivaroxaban treatment. In this study, the possible influence of Rivaroxaban and Enoxaparin on bone-healing in vivo was studied using a standardized, closed rodent fracture-model. 70 male Wistar-rats were randomized to Rivaroxaban, Enoxaparin or control groups. After pinning the right femur, a closed, transverse fracture was produced. 21 days later, the animals were sacrificed and both femora harvested. Analysis was done by biomechanical testing (three-point bending) and micro CT. Both investigated substances showed histomorphometric alterations of the newly formed callus assessed by micro CT analysis. In detail the bone (callus) volume was enhanced (sign. for Rivaroxaban) and the density reduced. The bone mineral content was enhanced accordingly (sign. for Rivaroxaban). Trabecular thickness was reduced (sign. for Rivaroxaban). Furthermore, both drugs showed significant enlarged bone (callus) surface and degree of anisotropy. In contrast, the biomechanical properties of the treated bones were equal to controls. To summarize, the morphological alterations of the fracture-callus did not result in functionally relevant deficits. PMID:27455072

  3. The Pulse of the Crust: Slow fracture and rapid healing during the seismic cycle (Louis Néel Medal Lecture)

    NASA Astrophysics Data System (ADS)

    Meredith, Philip

    2016-04-01

    Earthquake ruptures and volcanic eruptions are the most dramatic manifestations of the dynamic failure of a critically stressed crust. However, these are actually very rare events in both space and time; and most of the crust spends most of its time in a highly stressed but subcritical state. Under upper crustal conditions most rocks accommodate applied stresses in a brittle manner through cracking, fracturing and faulting. Cracks can grow at all scales from the grain scale to the crustal scale, and under different stress regimes. Under tensile stresses, single, long cracks tend to grow at the expense of shorter ones; while under all-round compressive, multiple microcracks tend to coalesce to form macroscopic fractures or faults. Deformation in the crust also occurs over a wide range of strain rates, from the very slow rates associated with tectonic loading up to the very fast rates occurring during earthquake rupture. It is now well-established that reactions between chemically-active pore fluids and the rock matrix can lead to time-dependent, subcritical crack propagation and failure in rocks. In turn, this can allow them to deform and fail over extended periods of time at stresses well below their short-term strength, and even at constant stress; a process known as brittle creep. Such cracking at constant stress eventually leads to accelerated deformation and critical, dynamic failure. However, in the period between sequential dynamic failure events, fractures can become subject to chemically-enhanced time-dependent strength recovery processes such as healing or the growth of mineral veins. We show that such strengthening can be much faster than previously suggested and can occur over geologically very short time-spans. These observations of ultra-slow cracking and ultra-fast healing have profound implications for the evolution and dynamics of the Earth's crust. To obtain a complete understanding of crustal dynamics we require a detailed knowledge of all these

  4. Acceleration of wound healing by α-gal nanoparticles interacting with the natural anti-Gal antibody.

    PubMed

    Galili, Uri

    2015-01-01

    Application of α-gal nanoparticles to wounds and burns induces accelerated healing by harnessing the natural anti-Gal antibody which constitutes ~1% of human immunoglobulins. α-gal nanoparticles present multiple α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R), the carbohydrate ligand of anti-Gal. Studied α-gal nanoparticles were comprised of glycolipids with α-gal epitopes, phospholipids, and cholesterol. Binding of anti-Gal to α-gal nanoparticles in wounds activates the complement cascade, resulting in formation of chemotactic complement cleavage peptides that induce rapid recruitment of many macrophages. The Fc/Fcγ receptors interaction between anti-Gal coating α-gal nanoparticles and the recruited macrophages activates macrophages to produce cytokines/growth factors that promote wound healing and recruit stem cells. Studies of wound healing by α-gal nanoparticles were feasible in α1,3galactosyltransferase knockout mice and pigs. In contrast to other nonprimate mammals, these mice and pigs lack the α-gal epitope, and thus they are not immunotolerant to it and produce anti-Gal. Treatment of skin wounds and burns with α-gal nanoparticles resulted in 40-60% decrease in healing time in comparison with control wounds treated with saline. This accelerated healing is associated with increased recruitment of macrophages and extensive angiogenesis in wounds, faster regrowth of epidermis, and regeneration of the dermis. The accelerated healing further decreases and may completely eliminate fibrosis and scar formation in wounds. Since healing of internal injuries is mediated by mechanisms similar to those in external wound healing, it is suggested that α-gal nanoparticles treatment may also improve regeneration and restoration of biological function following internal injuries such as surgical incisions, myocardial ischemia following infarction, and nerve injuries.

  5. Stress-Shielding Effect of Nitinol Swan-Like Memory Compressive Connector on Fracture Healing of Upper Limb

    NASA Astrophysics Data System (ADS)

    Fu, Q. G.; Liu, X. W.; Xu, S. G.; Li, M.; Zhang, C. C.

    2009-08-01

    In this article, the stress-shielding effect of a Nitinol swan-like memory compressive connector (SMC) is evaluated. Patients with fracture healing of an upper limb after SMC internal fixation or stainless steel plate fixation were randomly selected and observed comparatively. With the informed consent of the SMC group, minimal cortical bone under the swan-body and swan-neck was harvested; and in the steel plate fixation group, minimal cortical bone under the steel plate and opposite side to the steel plate was also harvested for observation. Main outcome measurements were taken such as osteocyte morphology, Harversian canal histological observation under light microscope; radiographic observation of fracture healing, and computed tomography quantitative scanning of cortical bone. As a conclusion, SMC has a lesser stress-shielding effect to fixed bone than steel plate. Finally, the mechanism of the lesser stress-shielding effect of SMC is discussed.

  6. Cement/caprock fracture healing experiments to assess the integrity of CO2 injection wells

    NASA Astrophysics Data System (ADS)

    Du Frane, W. L.; Mason, H. E.; Walsh, S. D.; Ruddle, D. G.; Carroll, S.

    2012-12-01

    It has been speculated that fractures along wellbore cement/caprock interfaces may provide a path for release of carbon from both long-term sequestration-sites and CO2-based enhanced oil recovery operations. The goal of this study is to evaluate the potential for fracture growth and healing in the wellbore environment, and its impact on wellbore permeability. A series of flow-through experiments was conducted, in which sample cores containing a planar fracture between impermeable caprock (compacted quartz, from 13,927' depth in Kern County) and cement (Portland G cured by ATSM standards) were reacted with brine containing variable amounts of carbonic acid (pCO2 between 0 and 3 MPa). The initial fracture geometry was controlled by grinding the caprock and cement pieces flat, and then bead blasting topography into the cement surfaces. Runs lasted 4-8 days with cores and brine maintained at constant temperature (60 °C). Constant confining pressure (24.8 MPa) was applied to cores, while brine was flowed with constant rates (0.05-0.10 mL/min) and pore pressure (12.4 MPa). Geomechanical and geochemical responses of the fractures were monitored by in situ measurements of differential pressure, and by periodically sampling output brine to analyze compositional changes. In every experiment the total permeability of samples cores decreased substantially. For runs using brine with pCO2 = 3 MPa, sample permeability continually decreased by over a factor of 200. Sample permeability also decreased by a factor of 50 having stabilized after ~3 days in a run using brine without CO2 (pCO2 = 0 MPa). These reductions in permeability appear to be the result of chemically-induced changes to the mechanical properties of the cement surface. Prior to reaction, the cement-caprock samples had high strength and elastic response to changes in stress during loading. After the experiments, the samples were weaker, and showed inelastic response to changes in stress during unloading. All cement

  7. Prediction of the time course of callus stiffness as a function of mechanical parameters in experimental rat fracture healing studies--a numerical study.

    PubMed

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

    2014-01-01

    Numerous experimental fracture healing studies are performed on rats, in which different experimental, mechanical parameters are applied, thereby prohibiting direct comparison between each other. Numerical fracture healing simulation models are able to predict courses of fracture healing and offer support for pre-planning animal experiments and for post-hoc comparison between outcomes of different in vivo studies. The aims of this study are to adapt a pre-existing fracture healing simulation algorithm for sheep and humans to the rat, to corroborate it using the data of numerous different rat experiments, and to provide healing predictions for future rat experiments. First, material properties of different tissue types involved were adjusted by comparing experimentally measured callus stiffness to respective simulated values obtained in three finite element (FE) models. This yielded values for Young's moduli of cortical bone, woven bone, cartilage, and connective tissue of 15,750 MPa, 1,000 MPa, 5 MPa, and 1 MPa, respectively. Next, thresholds in the underlying mechanoregulatory tissue differentiation rules were calibrated by modifying model parameters so that predicted fracture callus stiffness matched experimental data from a study that used rigid and flexible fixators. This resulted in strain thresholds at higher magnitudes than in models for sheep and humans. The resulting numerical model was then used to simulate numerous fracture healing scenarios from literature, showing a considerable mismatch in only 6 of 21 cases. Based on this corroborated model, a fit curve function was derived which predicts the increase of callus stiffness dependent on bodyweight, fixation stiffness, and fracture gap size. By mathematically predicting the time course of the healing process prior to the animal studies, the data presented in this work provides support for planning new fracture healing experiments in rats. Furthermore, it allows one to transfer and compare new in vivo

  8. Mitochondrial signal transduction in accelerated wound and retinal healing by near-infrared light therapy.

    PubMed

    Eells, Janis T; Wong-Riley, Margaret T T; VerHoeve, James; Henry, Michele; Buchman, Ellen V; Kane, Mary P; Gould, Lisa J; Das, Rina; Jett, Marti; Hodgson, Brian D; Margolis, David; Whelan, Harry T

    2004-09-01

    Photobiomodulation by light in the red to near infrared range (630-1000 nm) using low energy lasers or light-emitting diode (LED) arrays has been shown to accelerate wound healing, improve recovery from ischemic injury in the heart and attenuate degeneration in the injured optic nerve. Recent evidence indicates that the therapeutic effects of red to near infrared light result, in part, from intracellular signaling mechanisms triggered by the interaction of NIR light with the mitochondrial photoacceptor molecule cytochrome c oxidase. We have demonstrated that NIR-LED photo-irradiation increases the production of cytochrome oxidase in cultured primary neurons and reverses the reduction of cytochrome oxidase activity produced by metabolic inhibitors. We have also shown that NIR-LED treatment prevents the development of oral mucositis in pediatric bone marrow transplant patients. Photobiomodulation improves wound healing in genetically diabetic mice by upregulating genes important in the promotion of wound healing. More recent studies have provided evidence for the therapeutic benefit of NIR-LED treatment in the survival and functional recovery of the retina and optic nerve in vivo after acute injury by the mitochondrial toxin, formic acid generated in the course of methanol intoxication. Gene discovery studies conducted using microarray technology documented a significant upregulation of gene expression in pathways involved in mitochondrial energy production and antioxidant cellular protection. These findings provide a link between the actions of red to near infrared light on mitochondrial oxidative metabolism in vitro and cell injury in vivo. Based on these findings and the strong evidence that mitochondrial dysfunction is involved in the pathogenesis of numerous diseases processes, we propose that NIR-LED photobiomodulation represents an innovative and non-invasive therapeutic approach for the treatment of tissue injury and disease processes in which mitochondrial

  9. Long-term effects of saw osteotomy versus random fracturing on bone healing and remodeling in a sheep tibia model.

    PubMed

    Dumont, Clemens; Kauer, Fritz; Bohr, Stefan; Schmidtmann, Ulrich; Knopp, Werner; Engelhardt, Thomas; Stürmer, Ewa Klara; Stürmer, Klaus Michael

    2009-05-01

    This article is about the evaluation of possible differences in biomechanical or histomorphological properties of bone healing between saw osteotomy and random fracturing after 6 months. A standardized, 30 degrees oblique monocortical saw osteotomy of sheep tibia was carried out, followed by manual fracture completion of the opposed cortical bone. Fixation was performed by bridge plating (4.5 mm, LCDCP, broad). X-rays were taken immediately after surgery and at the end of the study. Polychrome fluorescent staining was performed according to a standardized protocol in the 2nd, 4th 6th, 10th, 14th, 18th, 22th and 26th week. Ten sheep were comprehensively evaluated. Data for stiffness and histomorphology are reported. The average bending stiffness of the operated bone was higher (1.7 (SD 0.3) with plate (MP) vs. 1.5 without plate) than for the intact bone (1.4 (SD 0.2), though no significant differences in bending stiffness were observed (P>0.05). Fluorescence staining revealed small numbers of blood vessels and less fragment resorption and remodeling in the osteotomy gap. Bone healing after saw osteotomy shows a very close resemblance to 'normal' fracture healing. However, vascular density, fragment resorption, fragment remodeling, and callus remodeling are reduced at the osteotomy.

  10. [Fracture healing of the ethmoid bone--a contribution to rhinologic management of naso-ethmoid injuries].

    PubMed

    Hosemann, W; Gottsauner, A; Leuwer, A; Farmand, M; Wenning, W; Göde, U; Stenglein, C; von Glass, W

    1993-08-01

    Severe maxillofacial trauma accompanied by a dislocated ethmoidal bone fracture was confirmed by CT imaging in 15 adult patients. Routine surgical management included reduction of fractures, miniplate fixation and/or intermaxillary fixation with interosseous wiring. The fractured ethmoidal cell system was left to heal spontaneously. A follow-up examination including endoscopy of the nasal cavity as well as active anterior rhinomanometry and computed tomography was carried out approximately 24 months after surgery. The fractured ethmoidal cell system showed a clear tendency to spontaneously reventilate and drain. However, in 8 of 30 sides a traumatic obstruction of the anterior ethmoid led to secondary frontal sinus mucositis. 12 out of 30 maxillary sinuses ranged from marked mucosal swelling to the development of a traumatic mucocele. Altogether, 9 of the 15 patients suffered from paranasal sinusitis. Routine debridement of every fractured ethmoidal cell system does not appear to be necessary. In case of fractures of the anterior ethmoid with probable obstruction of the nasofrontal duct and/or maxillary sinus ostium, endonasal endoscopic surgery is recommended for minimally invasive reconstruction of the ventilation and drainage of the frontal and maxillary sinus during primary surgical management. Furthermore, patients with severe naso-orbito-ethmoidal fractures should undergo rhinological follow-up examination including CT-imaging approximately 3 months after surgery.

  11. Dynamic locking plates provide symmetric axial dynamization to stimulate fracture healing.

    PubMed

    Tsai, Stanley; Fitzpatrick, Daniel C; Madey, Steven M; Bottlang, Michael

    2015-08-01

    Axial dynamization of an osteosynthesis construct can promote fracture healing. This biomechanical study evaluated a novel dynamic locking plate that derives symmetric axial dynamization by elastic suspension of locking holes within the plate. Standard locked and dynamic plating constructs were tested in a diaphyseal bridge-plating model of the femoral diaphysis to determine the amount and symmetry of interfragmentary motion under axial loading, and to assess construct stiffness under axial loading, torsion, and bending. Subsequently, constructs were loaded until failure to determine construct strength and failure modes. Finally, strength tests were repeated in osteoporotic bone surrogates. One body-weight axial loading of standard locked constructs produced asymmetric interfragmentary motion that was over three times smaller at the near cortex (0.1 ± 0.01 mm) than at the far cortex (0.32 ± 0.02 mm). Compared to standard locked constructs, dynamic plating constructs enhanced motion by 0.32 mm at the near cortex and by 0.33 mm at the far cortex and yielded a 77% lower axial stiffness (p < 0.001). Dynamic plating constructs were at least as strong as standard locked constructs under all test conditions. In conclusion, dynamic locking plates symmetrically enhance interfragmentary motion, deliver controlled axial dynamization, and are at least comparable in strength to standard locked constructs. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1218-1225, 2015.

  12. Obestatin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats.

    PubMed

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Bonior, Joanna; Jaworek, Jolanta; Kuśnierz-Cabala, Beata; Konturek, Peter; Ambroży, Tadeusz; Dembiński, Artur

    2016-01-01

    Obestatin, a 23-amino acid peptide derived from the proghrelin, has been shown to exhibit some protective and therapeutic effects in the gut. The aim of present study was to determine the effect of obestatin administration on the course of acetic acid-induced colitis in rats. Materials and Methods. Studies have been performed on male Wistar rats. Colitis was induced by a rectal enema with 3.5% acetic acid solution. Obestatin was administered intraperitoneally twice a day at a dose of 8 nmol/kg, starting 24 h after the induction of colitis. Seven or 14 days after the induction of colitis, the healing rate of the colon was evaluated. Results. Treatment with obestatin after induction of colitis accelerated the healing of colonic wall damage and this effect was associated with a decrease in the colitis-evoked increase in mucosal activity of myeloperoxidase and content of interleukin-1β. Moreover, obestatin administration significantly reversed the colitis-evoked decrease in mucosal blood flow and DNA synthesis. Conclusion. Administration of exogenous obestatin exhibits therapeutic effects in the course of acetic acid-induced colitis and this effect is related, at least in part, to the obestatin-evoked anti-inflammatory effect, an improvement of local blood flow, and an increase in cell proliferation in colonic mucosa.

  13. Electrospun tilapia collagen nanofibers accelerating wound healing via inducing keratinocytes proliferation and differentiation.

    PubMed

    Zhou, Tian; Wang, Nanping; Xue, Yang; Ding, Tingting; Liu, Xin; Mo, Xiumei; Sun, Jiao

    2016-07-01

    The development of biomaterials with the ability to induce skin wound healing is a great challenge in biomedicine. In this study, tilapia skin collagen sponge and electrospun nanofibers were developed for wound dressing. The collagen sponge was composed of at least two α-peptides. It did not change the number of spleen-derived lymphocytes in BALB/c mice, the ratio of CD4(+)/CD8(+) lymphocytes, and the level of IgG or IgM in Sprague-Dawley rats. The tensile strength and contact angle of collagen nanofibers were 6.72±0.44MPa and 26.71±4.88°, respectively. They also had good thermal stability and swelling property. Furthermore, the nanofibers could significantly promote the proliferation of human keratinocytes (HaCaTs) and stimulate epidermal differentiation through the up-regulated gene expression of involucrin, filaggrin, and type I transglutaminase in HaCaTs. The collagen nanofibers could also facilitate rat skin regeneration. In the present study, electrospun biomimetic tilapia skin collagen nanofibers were succesfully prepared, were proved to have good bioactivity and could accelerate rat wound healing rapidly and effectively. These biological effects might be attributed to the biomimic extracellular matrix structure and the multiple amino acids of the collagen nanofibers. Therefore, the cost-efficient tilapia collagen nanofibers could be used as novel wound dressing, meanwhile effectively avoiding the risk of transmitting animal disease in the future clinical apllication. PMID:27037778

  14. Topical Aloe Vera (Aloe barbadensis Miller) Extract Does Not Accelerate the Oral Wound Healing in Rats.

    PubMed

    Coelho, Fernanda Hack; Salvadori, Gabriela; Rados, Pantelis Varvaki; Magnusson, Alessandra; Danilevicz, Chris Krebs; Meurer, Luise; Martins, Manoela Domingues

    2015-07-01

    The effect of topical application of Aloe Vera (Aloe barbadensis Miller) extract was assessed on the healing of rat oral wounds in an in vivo model using 72 male Wistar rats divided into three groups (n = 24): control, placebo and Aloe Vera (0.5% extract hydroalcoholic). Traumatic ulcers were caused in the dorsum of the tongue using a 3-mm punch tool. The Aloe Vera and placebo group received two daily applications. The animals were sacrificed after 1, 5, 10 and 14 days. Clinical analysis (ulcer area and percentage of repair) and histopathological analysis (degree of re-epithelialization and inflammation) were performed. The comparison of the differences between scores based on group and experimental period, both in quantitative and semi-quantitative analyses, was performed using the Kruskal-Wallis test. The significance level was 5%. On day 1, all groups showed predominantly acute inflammatory infiltrate. On day 5, there was partial epithelialization and chronic inflammatory infiltrate. On the days 10 and 14 total repair of ulcers was observed. There was no significant difference between groups in the repair of mouth ulcers. It is concluded that treatment using Aloe Vera as an herbal formulation did not accelerate oral wound healing in rats.

  15. Effect of nicotine and tobacco administration method on the mechanical properties of healing bone following closed fracture.

    PubMed

    Hastrup, Sidsel Gaarn; Chen, Xinqian; Bechtold, Joan E; Kyle, Richard F; Rahbek, Ole; Keyler, Daniel E; Skoett, Martin; Soeballe, Kjeld

    2010-09-01

    We previously showed different effects of tobacco and nicotine on fracture healing, but due to pump reservoir limits, maximum exposure period was 4 weeks. To allow flexibility in pre- and post-fracture exposure periods, the objective of this study was to compare a new oral administration route for nicotine to the established pump method. Four groups were studied: (1) pump saline, (2) pump saline + oral tobacco, (3) pump saline/nicotine + oral tobacco, and (4) pump saline + oral nicotine/tobacco. Sprague-Dawley rats (n = 84) received a transverse femoral fracture stabilized with an intramedullary pin 1 week after initiating dosing. After 3 weeks, no difference was found in torsional strength or stiffness between oral nicotine/tobacco or pump nicotine + tobacco, while energy absorption with oral nicotine/tobacco was greater than pump nicotine + tobacco (p < 0.05). Compared to saline control, strength for oral nicotine/tobacco was higher than control (p < 0.05), and stiffnesses for pump nicotine + tobacco and oral nicotine/tobacco were higher than control (p < 0.05). No differences in energy were found for either nicotine-tobacco group compared to saline control. Mean serum cotinine (stable nicotine metabolite) was different between pump and oral nicotine at 1 and 4 weeks, but all groups were in the range of 1-2 pack/day smokers. In summary, relevant serum cotinine levels can be reached in rats with oral nicotine, and, in the presence of tobacco, nicotine can influence mechanical aspects of fracture healing, dependent on administration method. Caution should be exercised when comparing results of fracture healing studies using different methods of nicotine administration.

  16. Effect of isolated fractures on accelerated flow in unsaturated porous rock

    USGS Publications Warehouse

    Su, G.W.; Nimmo, J.R.; Dragila, M.I.

    2003-01-01

    Fractures that begin and end in the unsaturated zone, or isolated fractures, have been ignored in previous studies because they were generally assumed to behave as capillary barriers and remain nonconductive. We conducted a series of experiments using Berea sandstone samples to examine the physical mechanisms controlling flow in a rock containing a single isolated fracture. The input fluxes and fracture orientation were varied in these experiments. Visualization experiments using dyed water in a thin vertical slab of rock were conducted to identify flow mechanisms occurring due to the presence of the isolated fracture. Two mechanisms occurred: (1) localized flow through the rock matrix in the vicinity of the isolated fracture and (2) pooling of water at the bottom of the fracture, indicating the occurrence of film flow along the isolated fracture wall. These mechanisms were observed at fracture angles of 20 and 60 degrees from the horizontal, but not at 90 degrees. Pooling along the bottom of the fracture was observed over a wider range of input fluxes for low-angled isolated fractures compared to high-angled ones. Measurements of matrix water pressures in the samples with the 20 and 60 degree fractures also demonstrated that preferential flow occurred through the matrix in the fracture vicinity, where higher pressures occurred in the regions where faster flow was observed in the visualization experiments. The pooling length at the terminus of a 20 degree isolated fracture was measured as a function of input flux. Calculations of the film flow rate along the fracture were made using these measurements and indicated that up to 22% of the flow occurred as film flow. These experiments, apparently the first to consider isolated fractures, demonstrate that such features can accelerate flow through the unsaturated zone and should be considered when developing conceptual models.

  17. 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

    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.

  18. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs.

    PubMed

    Gerstenfeld, Louis C; Thiede, Mark; Seibert, Karen; Mielke, Cindy; Phippard, Deborah; Svagr, Bohus; Cullinane, Dennis; Einhorn, Thomas A

    2003-07-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) specifically inhibit cyclooxygenase (COX) activity and are widely used as anti-arthritics, post-surgical analgesics, and for the relief of acute musculoskeletal pain. Recent studies suggest that non-specific NSAIDs, which inhibit both COX-1 and COX-2 isoforms, delay bone healing. The objectives of this study were 2-fold; first, to measure the relative changes in the normal expression of COX-1 and COX-2 mRNAs over a 42 day period of fracture healing and second, to compare the effects of a commonly used non-specific NSAID, ketorolac, with a COX-2 specific NSAID, Parecoxib (a pro-drug of valdecoxib), on this process. Simple, closed, transverse fractures were generated in femora of male Sprague-Dawley rats weighing approximately 450 g each. Total RNA was prepared from the calluses obtained prior to fracture and at 1, 3, 5, 7, 10, 14, 21, 35 and 42 days post-fracture and levels of COX-1 and COX-2 mRNA were measured using real time PCR. While the relative levels of COX-1 mRNA remained constant over a 21-day period, COX-2 mRNA levels showed peak expression during the first 14 days of healing and returned to basal levels by day 21. Mechanical properties of the calluses were then assessed at 21 and 35 days post-fracture in untreated animals and animals treated with either ketorolac or high or low dose parecoxib. At both 21 and 35 days after fracture, calluses in the group treated with the ketorolac showed a significant reduction in mechanical strength and stiffness when compared with controls (p<0.05). At the 21-day time point, calluses of the parecoxib treated animals showed a lower mean mechanical strength than controls, but the inhibition was not statistically significant. Based on physical analysis of the bones, 3 of 12 (25%) of the ketorolac-treated and 1 of 12 (8%) of the high dose parecoxib-treated animals showed failure to unite their fractures by 21 days, while all fractures in both groups showed union by 35 days

  19. Systemic and Local Administration of Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells Promotes Fracture Healing in Rats.

    PubMed

    Huang, Shuo; Xu, Liangliang; Zhang, Yifeng; Sun, Yuxin; Li, Gang

    2015-01-01

    Mesenchymal stem cells (MSCs) are immune privileged and a cell source for tissue repair. Previous studies showed that there is systemic mobilization of osteoblastic precursors to the fracture site. We hypothesized that both systemic and local administration of allogeneic MSCs may promote fracture healing. Bone marrow-derived MSCs and skin fibroblasts were isolated from GFP Sprague-Dawley rats, cultured, and characterized. Closed transverse femoral fracture with internal fixation was established in 48 adult male Sprague-Dawley rats, which were randomly assigned into four groups receiving PBS injection, MSC systemic injection, fibroblast systemic injection, and MSC fracture site injection; 2 × 10(6) cells were injected at 4 days after fracture. All animals were sacrificed at 5 weeks after fracture; examinations included weekly radiograph, micro-CT, mechanical testing, histology, immunohistochemistry, and double immunofluorescence. The callus size of MSC injection groups was significantly larger among all the groups. Radiographs and 3D reconstruction images showed that the fracture gaps united in the MSC injected groups, while gaps were still seen in the fibroblast and PBS injection groups. The mechanical properties were significantly higher in the MSC injection groups than those in the fibroblast and PBS groups, but no difference was found between the MSC local and systemic injection groups. Immunohistochemistry and double immunofluorescence demonstrated that GFP-positive MSCs were present in the callus in the MSC injection groups at 5 weeks after fracture, and some differentiated into osteoblasts. Quantitative analysis revealed the number of GFP-positive cells in the callus in the MSC systemic injection group was significantly lower than that of the MSC local injection group. The proportion of GFP osteoblasts in GFP-positive cells in the MSC systemic injection group was significantly lower than that of the MSC local injection group. These findings provide critical

  20. Dynamic locking plates provide symmetric axial dynamization to stimulate fracture healing.

    PubMed

    Tsai, Stanley; Fitzpatrick, Daniel C; Madey, Steven M; Bottlang, Michael

    2015-08-01

    Axial dynamization of an osteosynthesis construct can promote fracture healing. This biomechanical study evaluated a novel dynamic locking plate that derives symmetric axial dynamization by elastic suspension of locking holes within the plate. Standard locked and dynamic plating constructs were tested in a diaphyseal bridge-plating model of the femoral diaphysis to determine the amount and symmetry of interfragmentary motion under axial loading, and to assess construct stiffness under axial loading, torsion, and bending. Subsequently, constructs were loaded until failure to determine construct strength and failure modes. Finally, strength tests were repeated in osteoporotic bone surrogates. One body-weight axial loading of standard locked constructs produced asymmetric interfragmentary motion that was over three times smaller at the near cortex (0.1 ± 0.01 mm) than at the far cortex (0.32 ± 0.02 mm). Compared to standard locked constructs, dynamic plating constructs enhanced motion by 0.32 mm at the near cortex and by 0.33 mm at the far cortex and yielded a 77% lower axial stiffness (p < 0.001). Dynamic plating constructs were at least as strong as standard locked constructs under all test conditions. In conclusion, dynamic locking plates symmetrically enhance interfragmentary motion, deliver controlled axial dynamization, and are at least comparable in strength to standard locked constructs. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1218-1225, 2015. PMID:25721801

  1. Chondrocytes Transdifferentiate into Osteoblasts in Endochondral Bone during Development, Postnatal Growth and Fracture Healing in Mice

    PubMed Central

    Zhou, Xin; von der Mark, Klaus; Henry, Stephen; Norton, William; Adams, Henry; de Crombrugghe, Benoit

    2014-01-01

    One of the crucial steps in endochondral bone formation is the replacement of a cartilage matrix produced by chondrocytes with bone trabeculae made by osteoblasts. However, the precise sources of osteoblasts responsible for trabecular bone formation have not been fully defined. To investigate whether cells derived from hypertrophic chondrocytes contribute to the osteoblast pool in trabecular bones, we genetically labeled either hypertrophic chondrocytes by Col10a1-Cre or chondrocytes by tamoxifen-induced Agc1-CreERT2 using EGFP, LacZ or Tomato expression. Both Cre drivers were specifically active in chondrocytic cells and not in perichondrium, in periosteum or in any of the osteoblast lineage cells. These in vivo experiments allowed us to follow the fate of cells labeled in Col10a1-Cre or Agc1-CreERT2 -expressing chondrocytes. After the labeling of chondrocytes, both during prenatal development and after birth, abundant labeled non-chondrocytic cells were present in the primary spongiosa. These cells were distributed throughout trabeculae surfaces and later were present in the endosteum, and embedded within the bone matrix. Co-expression studies using osteoblast markers indicated that a proportion of the non-chondrocytic cells derived from chondrocytes labeled by Col10a1-Cre or by Agc1-CreERT2 were functional osteoblasts. Hence, our results show that both chondrocytes prior to initial ossification and growth plate chondrocytes before or after birth have the capacity to undergo transdifferentiation to become osteoblasts. The osteoblasts derived from Col10a1-expressing hypertrophic chondrocytes represent about sixty percent of all mature osteoblasts in endochondral bones of one month old mice. A similar process of chondrocyte to osteoblast transdifferentiation was involved during bone fracture healing in adult mice. Thus, in addition to cells in the periosteum chondrocytes represent a major source of osteoblasts contributing to endochondral bone formation in vivo

  2. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice.

    PubMed

    Zhou, Xin; von der Mark, Klaus; Henry, Stephen; Norton, William; Adams, Henry; de Crombrugghe, Benoit

    2014-12-01

    One of the crucial steps in endochondral bone formation is the replacement of a cartilage matrix produced by chondrocytes with bone trabeculae made by osteoblasts. However, the precise sources of osteoblasts responsible for trabecular bone formation have not been fully defined. To investigate whether cells derived from hypertrophic chondrocytes contribute to the osteoblast pool in trabecular bones, we genetically labeled either hypertrophic chondrocytes by Col10a1-Cre or chondrocytes by tamoxifen-induced Agc1-CreERT2 using EGFP, LacZ or Tomato expression. Both Cre drivers were specifically active in chondrocytic cells and not in perichondrium, in periosteum or in any of the osteoblast lineage cells. These in vivo experiments allowed us to follow the fate of cells labeled in Col10a1-Cre or Agc1-CreERT2 -expressing chondrocytes. After the labeling of chondrocytes, both during prenatal development and after birth, abundant labeled non-chondrocytic cells were present in the primary spongiosa. These cells were distributed throughout trabeculae surfaces and later were present in the endosteum, and embedded within the bone matrix. Co-expression studies using osteoblast markers indicated that a proportion of the non-chondrocytic cells derived from chondrocytes labeled by Col10a1-Cre or by Agc1-CreERT2 were functional osteoblasts. Hence, our results show that both chondrocytes prior to initial ossification and growth plate chondrocytes before or after birth have the capacity to undergo transdifferentiation to become osteoblasts. The osteoblasts derived from Col10a1-expressing hypertrophic chondrocytes represent about sixty percent of all mature osteoblasts in endochondral bones of one month old mice. A similar process of chondrocyte to osteoblast transdifferentiation was involved during bone fracture healing in adult mice. Thus, in addition to cells in the periosteum chondrocytes represent a major source of osteoblasts contributing to endochondral bone formation in vivo

  3. Quantitative histological evaluation of early fracture healing of cortical bones immobilized by stainless steel and composite plates.

    PubMed

    Akeson, W H; Woo, S L; Coutts, R D; Matthews, J V; Gonsalves, M; Amiel, D

    1975-11-24

    Internal fixation devices of less bending stiffness than conventional plates made of stainless steel or vitallium were compared with conventional plates in a study of fracture healing. The material for this investigation was a fine graphite fiber reinforced methyl methacrylate resin composite with a modulus of elasticity approximately ten times less than that of stainless steel. Osteotomies were performed on canine radii. Internal fixation was accomplished by means of a composite plate on the left side, and a stainless steel plate on the right. Clinical assessment, as well as biomechanical and quantitative histological techniques, were used to compare osteotomy healing of the two sides. At four months, all osteotomies had healed and the bioengineering tests showed radii from the two sides had equivalent strength. However, significantly less cortical porosity was found in the side with the composite plate (6.8 per cent), as compared to that of the stainless steel plated side (14 per cent). These results suggest that a less stiff fixation plate may have some advantage in the treatment of long bone fracture if there is no implant failure, and if union rates are equivalent.

  4. Accelerating skin wound healing by M-CSF through generating SSEA-1 and -3 stem cells in the injured sites

    PubMed Central

    Li, Yunyuan; Jalili, Reza Baradar; Ghahary, Aziz

    2016-01-01

    Wound healing is a complicated process requiring the collaborative efforts of different cell lineages. Our recent studies have found that one subset of hematopoietic cells can be induced to dedifferentiate into multipotent stem cells by means of a proliferating fibroblast releasable factor, M-CSF. Understanding the importance of stem cells on skin wound healing, here we evaluate the biological significance of M-CSF on skin wound healing. In an in vivo mouse skin excisional wound model, we found that SSEA-positive stem cells were present in wounded but not normal skin. After isolating skin cells from either normal or wounded skin by collagenase digestion, and analyzing the SSEA-1 positive cells by flow cytometry, we found a significant increase in the number of SSEA-1 positive cells in wounded skin. Topical application of M-CSF in skin wounds accelerated healing remarkably, while application of M-CSF-neutralizing antibody slowed wound healing. Furthermore, injection of EGFP-labeled hematopoietic cell-derived stem cells generated from M-CSF treated splenocytes resulted in EGFP-labeled cells being enriched in the skin wound site and further differentiated into functional organ-specific cells. Together, these data demonstrated that M-CSF makes a significant contribution to the healing process by inducing hematopoietic cell dedifferentiation into stem cells. PMID:27363517

  5. The Effects of Targeted Deliveries of Lovastatin and Tocotrienol on Ossification-Related Gene Expressions in Fracture Healing in an Osteoporosis Rat Model.

    PubMed

    Ibrahim, Nurul 'Izzah; Mohamed, Norazlina; Soelaiman, Ima Nirwana; Shuid, Ahmad Nazrun

    2015-10-01

    Osteoporotic drugs are used to prevent fragility fractures, but their role in fracture healing still remains unknown. Thus, alternative agents with suitable mode of delivery are needed to promote fracture healing. This study was performed to investigate the effects of direct deliveries of lovastatin and tocotrienol to fracture sites on ossification-related gene expression in fracture healing in a postmenopausal osteoporosis model. Forty-eight Sprague Dawley female rats were divided into six groups. Group I comprised the sham-operated rats, while Groups II-VI were ovariectomized rats. After 8 weeks, the right tibiae of all rats were fractured and stabilized. Group I and Group II were given two single injections of lovastatin and tocotrienol carriers. Group III was given an estrogen preparation at 64.5 µg/kg daily via oral gavages. Group IV was injected with lovastatin particles (750 µg/kg), while Group V was injected with tocotrienol particles (60 mg/kg). Group VI received two single injections of 750 µg/kg lovastatin particles and 60 mg/kg tocotrienol particles. After 4 weeks, the gene expressions were measured. Group VI showed significantly higher gene expressions of osteocalcin, BMP-2, VEGF-α, and RUNX-2 compared to Group II. In conclusion, combined treatment of lovastatin and tocotrienol upregulated the expression of genes related to fracture healing. PMID:26501302

  6. The Effects of Targeted Deliveries of Lovastatin and Tocotrienol on Ossification-Related Gene Expressions in Fracture Healing in an Osteoporosis Rat Model

    PubMed Central

    Ibrahim, Nurul ‘Izzah; Mohamed, Norazlina; Soelaiman, Ima Nirwana; Shuid, Ahmad Nazrun

    2015-01-01

    Osteoporotic drugs are used to prevent fragility fractures, but their role in fracture healing still remains unknown. Thus, alternative agents with suitable mode of delivery are needed to promote fracture healing. This study was performed to investigate the effects of direct deliveries of lovastatin and tocotrienol to fracture sites on ossification-related gene expression in fracture healing in a postmenopausal osteoporosis model. Forty-eight Sprague Dawley female rats were divided into six groups. Group I comprised the sham-operated rats, while Groups II–VI were ovariectomized rats. After 8 weeks, the right tibiae of all rats were fractured and stabilized. Group I and Group II were given two single injections of lovastatin and tocotrienol carriers. Group III was given an estrogen preparation at 64.5 µg/kg daily via oral gavages. Group IV was injected with lovastatin particles (750 µg/kg), while Group V was injected with tocotrienol particles (60 mg/kg). Group VI received two single injections of 750 µg/kg lovastatin particles and 60 mg/kg tocotrienol particles. After 4 weeks, the gene expressions were measured. Group VI showed significantly higher gene expressions of osteocalcin, BMP-2, VEGF-α, and RUNX-2 compared to Group II. In conclusion, combined treatment of lovastatin and tocotrienol upregulated the expression of genes related to fracture healing. PMID:26501302

  7. Combined nitric oxide-releasing poly(vinyl alcohol) film/F127 hydrogel for accelerating wound healing.

    PubMed

    Schanuel, Fernanda Seabra; Raggio Santos, Karen Slis; Monte-Alto-Costa, Andréa; de Oliveira, Marcelo G

    2015-06-01

    Nitric oxide (NO) releasing biomaterials represent a potential strategy for use as active wound dressings capable of accelerating wound healing. Topical NO-releasing poly(vinyl alcohol) (PVA) films and Pluronic F127 hydrogels (F127) have already exhibited effective skin vasodilation and wound healing actions. In this study, we functionalized PVA films with SNO groups via esterification with a mixture of mercaptosucinic acid (MSA) and thiolactic acid (TLA) followed by S-nitrosation of the SH moieties. These films were combined with an underlying layer of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), i.e., PEO-PPO-PEO (Pluronic F127) hydrogel and used for the topical treatment of skin lesions in an animal model. The mixed esterification of PVA with MSA and TLA led to chemically crosslinked PVA-SNO films with a high swelling capacity capable of spontaneously releasing NO. Real time NO-release measurements revealed that the hydrogel layer reduces the initial NO burst from the PVA-SNO films. We demonstrate that the combination of PVA-SNO films with F127 hydrogel accelerates wound contraction, decreases wound gap and cellular density and accelerates the inflammatory phase of the lesion. These results were reflected in an increase in myofibroblastic differentiation and collagen type III expression in the cicatricial tissue. Therefore, PVA-SNO films combined with F127 hydrogel may represent a new approach for active wound dressings capable of accelerating wound healing. PMID:25907598

  8. Nano-porous nitrocellulose liquid bandage modulates cell and cytokine response and accelerates cutaneous wound healing in a mouse model.

    PubMed

    Mu, Xiaofeng; Yu, Hao; Zhang, Caizhen; Chen, Xiufang; Cheng, Zhiyun; Bai, Ruyu; Wu, Xunxun; Yu, Qian; Wu, Chunlin; Diao, Yong

    2016-01-20

    Nitrocellulose liquid bandage (L-Bandage) is extensively used in hard-to-cover cuts and wounds management, owing to its flexibility, softness, transparency, and conformability. However, evidence supporting their mechanisms of action as wound dressing is scanty. This study introduces a novel nano-porous L-Bandage, and provides results from a mouse full-thickness wound model investigating its mechanism of action on wound healing. Different characteristics, such as porosity, mechanical properties and water vapor transmission rate (WVTR) were determined. The L-Bandage formed film had a porous network structure with mean diameter of 18 nm that could effectively prevent the bacterial invasion, and favorable properties of tensile strength, elongation, and WVTR. The L-Bandage treated wound exhibited accelerated healing, with reduced inflammations, enhanced wound re-epithelialization, contraction, granulation tissue formation, and rapid angiogenesis. Our data suggested that L-Bandage could serve as a promising wound dressing, because of its desirable properties for wound healing.

  9. Potent anti-inflammatory agent escin does not affect the healing of tibia fracture and abdominal wound in an animal model

    PubMed Central

    ZHANG, LEIMING; WANG, HONGSHENG; WANG, TIAN; JIANG, NA; YU, PENGFEI; LIU, FEIYAN; CHONG, YATING; FU, FENGHUA

    2012-01-01

    Escin, a potent anti-inflammatory and anti-edematous agent, has been widely used clinically in preventing inflammatory edema after trauma, such as fracture and surgery. The aim of this study was to investigate whether escin has an inhibitory effect on fracture healing, and whether escin has an inhibitory effect on wound healing after surgery. Male New Zealand white rabbits underwent tibial mid-diaphyseal osteotomy, and were administered escin once per day for 10 days. At weeks 2, 4 and 6, bone fracture healing and bone mineral density were measured. The histologic examination of callus, osteocalcin, alkaline phosphatase, calcium and phosphate in the serum were also assayed. In another experiment, the rats underwent midline laparotomy, and received escin once prior to or after the operation. Six days later, the abdominal incision wounds were excised for measuring hydroxyproline levels. The results showed that there were no significant differences in fracture healing between the model and rabbits administered escin, and escin did not affect the hydroxyproline levels in the abdominal incision wounds of the rats. These findings suggest that escin has no inhibitory effect on fracture and wound healing in animal models. PMID:22969961

  10. Ultrashort peptide nanofibrous hydrogels for the acceleration of healing of burn wounds.

    PubMed

    Loo, Yihua; Wong, Yong-Chiat; Cai, Elijah Z; Ang, Chuan-Han; Raju, Ashvin; Lakshmanan, Anupama; Koh, Alvin G; Zhou, Hui J; Lim, Thiam-Chye; Moochhala, Shabbir M; Hauser, Charlotte A E

    2014-06-01

    There is an unmet clinical need for wound dressings to treat partial thickness burns that damage the epidermis and dermis. An ideal dressing needs to prevent infection, maintain skin hydration to facilitate debridement of the necrotic tissue, and provide cues to enhance tissue regeneration. We developed a class of 'smart' peptide hydrogels, which fulfill these criteria. Our ultrashort aliphatic peptides have an innate tendency to self-assemble into helical fibers, forming biomimetic hydrogel scaffolds which are non-immunogenic and non-cytotoxic. These nanofibrous hydrogels accelerated wound closure in a rat model for partial thickness burns. Two peptide hydrogel candidates demonstrate earlier onset and completion of autolytic debridement, compared to Mepitel(®), a silicone-coated polyamide net used as standard-of-care. They also promote epithelial and dermal regeneration in the absence of exogenous growth factors, achieving 86.2% and 92.9% wound closure respectively, after 14 days. In comparison, only 62.8% of the burnt area is healed for wounds dressed with Mepitel(®). Since the rate of wound closure is inversely correlated with hypertrophic scar formation and infection risks, our peptide hydrogel technology fills a niche neglected by current treatment options. The regenerative properties can be further enhanced by incorporation of bioactive moieties such as growth factors and cytokines.

  11. Human fibrocyte-derived exosomes accelerate wound healing in genetically diabetic mice.

    PubMed

    Geiger, Adolf; Walker, Audrey; Nissen, Erwin

    2015-11-13

    Diabetic ulcers represent a substantial societal and healthcare burden worldwide and scarcely respond to current treatment strategies. This study was addressed to evaluate the therapeutic potential of exosomes secreted by human circulating fibrocytes, a population of mesenchymal progenitors involved in normal wound healing via paracrine signaling. The exosomes released from cells sequentially stimulated with platelet-derived growth factor-BB and transforming growth factor-β1, in the presence of fibroblast growth factor 2, did not show potential immunogenicity. These exosomes exhibited in-vitro proangiogenic properties, activated diabetic dermal fibroblasts, induced the migration and proliferation of diabetic keratinocytes, and accelerated wound closure in diabetic mice in vivo. Important components of the exosomal cargo were heat shock protein-90α, total and activated signal transducer and activator of transcription 3, proangiogenic (miR-126, miR-130a, miR-132) and anti-inflammatory (miR124a, miR-125b) microRNAs, and a microRNA regulating collagen deposition (miR-21). This proof-of-concept study demonstrates the feasibility of the use of fibrocytes-derived exosomes for the treatment of diabetic ulcers.

  12. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts.

    PubMed

    Hu, Li; Wang, Juan; Zhou, Xin; Xiong, Zehuan; Zhao, Jiajia; Yu, Ran; Huang, Fang; Zhang, Handong; Chen, Lili

    2016-09-12

    Prolonged healing and scar formation are two major challenges in the treatment of soft tissue trauma. Adipose mesenchymal stem cells (ASCs) play an important role in tissue regeneration, and recent studies have suggested that exosomes secreted by stem cells may contribute to paracrine signaling. In this study, we investigated the roles of ASCs-derived exosomes (ASCs-Exos) in cutaneous wound healing. We found that ASCs-Exos could be taken up and internalized by fibroblasts to stimulate cell migration, proliferation and collagen synthesis in a dose-dependent manner, with increased genes expression of N-cadherin, cyclin-1, PCNA and collagen I, III. In vivo tracing experiments demonstrated that ASCs-Exos can be recruited to soft tissue wound area in a mouse skin incision model and significantly accelerated cutaneous wound healing. Histological analysis showed increased collagen I and III production by systemic administration of exosomes in the early stage of wound healing, while in the late stage, exosomes might inhibit collagen expression to reduce scar formation. Collectively, our findings indicate that ASCs-Exos can facilitate cutaneous wound healing via optimizing the characteristics of fibroblasts. Our results provide a new perspective and therapeutic strategy for the use of ASCs-Exos in soft tissue repair.

  13. Green light emitting diodes accelerate wound healing: characterization of the effect and its molecular basis in vitro and in vivo.

    PubMed

    Fushimi, Tomohiro; Inui, Shigeki; Nakajima, Takeshi; Ogasawara, Masahiro; Hosokawa, Ko; Itami, Satoshi

    2012-01-01

    Because light-emitting diodes (LEDs) are low-coherent, quasimonochromatic, and nonthermal, they are an alternative for low level laser therapy, and have photobiostimulative effects on tissue repair. However, the molecular mechanism(s) are unclear, and potential effects of blue and/or green LEDs on wound healing are still unknown. Here, we investigated the effects of red (638 nm), blue (456 nm), and green (518 nm) LEDs on wound healing. In an in vivo study, wound sizes in the skin of ob/ob mice were significantly decreased on day 7 following exposure to green LEDs, and complete reepithelialization was accelerated by red and green LEDs compared with the control mice. To better understand the molecular mechanism(s) involved, we investigated the effects of LEDs on human fibroblasts in vitro by measuring mRNA and protein levels of cytokines secreted by fibroblasts during the process of wound healing and on the migration of HaCat keratinocytes. The results suggest that some cytokines are significantly increased by exposure to LEDs, especially leptin, IL-8, and VEGF, but only by green LEDs. The migration of HaCat keratinocytes was significantly promoted by red or green LEDs. In conclusion, we demonstrate that green LEDs promote wound healing by inducing migratory and proliferative mediators, which suggests that not only red LEDs but also green LEDs can be a new powerful therapeutic strategy for wound healing.

  14. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts.

    PubMed

    Hu, Li; Wang, Juan; Zhou, Xin; Xiong, Zehuan; Zhao, Jiajia; Yu, Ran; Huang, Fang; Zhang, Handong; Chen, Lili

    2016-01-01

    Prolonged healing and scar formation are two major challenges in the treatment of soft tissue trauma. Adipose mesenchymal stem cells (ASCs) play an important role in tissue regeneration, and recent studies have suggested that exosomes secreted by stem cells may contribute to paracrine signaling. In this study, we investigated the roles of ASCs-derived exosomes (ASCs-Exos) in cutaneous wound healing. We found that ASCs-Exos could be taken up and internalized by fibroblasts to stimulate cell migration, proliferation and collagen synthesis in a dose-dependent manner, with increased genes expression of N-cadherin, cyclin-1, PCNA and collagen I, III. In vivo tracing experiments demonstrated that ASCs-Exos can be recruited to soft tissue wound area in a mouse skin incision model and significantly accelerated cutaneous wound healing. Histological analysis showed increased collagen I and III production by systemic administration of exosomes in the early stage of wound healing, while in the late stage, exosomes might inhibit collagen expression to reduce scar formation. Collectively, our findings indicate that ASCs-Exos can facilitate cutaneous wound healing via optimizing the characteristics of fibroblasts. Our results provide a new perspective and therapeutic strategy for the use of ASCs-Exos in soft tissue repair. PMID:27615560

  15. Expectation-induced placebo responses fail to accelerate wound healing in healthy volunteers: results from a prospective controlled experimental trial.

    PubMed

    Vits, Sabine; Dissemond, Joachim; Schadendorf, Dirk; Kriegler, Lisa; Körber, Andreas; Schedlowski, Manfred; Cesko, Elvir

    2015-12-01

    Placebo responses have been shown to affect the symptomatology of skin diseases. However, expectation-induced placebo effects on wound healing processes have not been investigated yet. We analysed whether subjects' expectation of receiving an active drug accelerates the healing process of experimentally induced wounds. In 22 healthy men (experimental group, n = 11; control group, n = 11) wounds were induced by ablative laser on both thighs. Using a deceptive paradigm, participants in the experimental group were informed that an innovative 'wound gel' was applied on one of the two wounds, whereas a 'non-active gel' was applied on the wound of the other thigh. In fact, both gels were identical hydrogels without any active components. A control group was informed to receive a non-active gel on both wounds. Progress in wound healing was documented via planimetry on days 1, 4 and 7 after wound induction. From day 9 onwards wound inspections were performed daily accompanied by a change of the dressing and a new application of the gel. No significant differences could be observed with regard to duration or process of wound healing, either by intraindividual or by interindividual comparisons. These data document no expectation-induced placebo effect on the healing process of experimentally induced wounds in healthy volunteers. PMID:24373522

  16. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts

    PubMed Central

    Hu, Li; Wang, Juan; Zhou, Xin; Xiong, Zehuan; Zhao, Jiajia; Yu, Ran; Huang, Fang; Zhang, Handong; Chen, Lili

    2016-01-01

    Prolonged healing and scar formation are two major challenges in the treatment of soft tissue trauma. Adipose mesenchymal stem cells (ASCs) play an important role in tissue regeneration, and recent studies have suggested that exosomes secreted by stem cells may contribute to paracrine signaling. In this study, we investigated the roles of ASCs-derived exosomes (ASCs-Exos) in cutaneous wound healing. We found that ASCs-Exos could be taken up and internalized by fibroblasts to stimulate cell migration, proliferation and collagen synthesis in a dose-dependent manner, with increased genes expression of N-cadherin, cyclin-1, PCNA and collagen I, III. In vivo tracing experiments demonstrated that ASCs-Exos can be recruited to soft tissue wound area in a mouse skin incision model and significantly accelerated cutaneous wound healing. Histological analysis showed increased collagen I and III production by systemic administration of exosomes in the early stage of wound healing, while in the late stage, exosomes might inhibit collagen expression to reduce scar formation. Collectively, our findings indicate that ASCs-Exos can facilitate cutaneous wound healing via optimizing the characteristics of fibroblasts. Our results provide a new perspective and therapeutic strategy for the use of ASCs-Exos in soft tissue repair. PMID:27615560

  17. Expectation-induced placebo responses fail to accelerate wound healing in healthy volunteers: results from a prospective controlled experimental trial.

    PubMed

    Vits, Sabine; Dissemond, Joachim; Schadendorf, Dirk; Kriegler, Lisa; Körber, Andreas; Schedlowski, Manfred; Cesko, Elvir

    2015-12-01

    Placebo responses have been shown to affect the symptomatology of skin diseases. However, expectation-induced placebo effects on wound healing processes have not been investigated yet. We analysed whether subjects' expectation of receiving an active drug accelerates the healing process of experimentally induced wounds. In 22 healthy men (experimental group, n = 11; control group, n = 11) wounds were induced by ablative laser on both thighs. Using a deceptive paradigm, participants in the experimental group were informed that an innovative 'wound gel' was applied on one of the two wounds, whereas a 'non-active gel' was applied on the wound of the other thigh. In fact, both gels were identical hydrogels without any active components. A control group was informed to receive a non-active gel on both wounds. Progress in wound healing was documented via planimetry on days 1, 4 and 7 after wound induction. From day 9 onwards wound inspections were performed daily accompanied by a change of the dressing and a new application of the gel. No significant differences could be observed with regard to duration or process of wound healing, either by intraindividual or by interindividual comparisons. These data document no expectation-induced placebo effect on the healing process of experimentally induced wounds in healthy volunteers.

  18. In-vivo imaging of the fracture healing in medaka revealed two types of osteoclasts before and after the callus formation by osteoblasts.

    PubMed

    Takeyama, Kazuhiro; Chatani, Masahiro; Takano, Yoshiro; Kudo, Akira

    2014-10-15

    The fracture healing research, which has been performed in mammalian models not only for clinical application but also for bone metabolism, revealed that generally osteoblasts are induced to enter the fracture site before the induction of osteoclasts for bone remodeling. However, it remains unknown how and where osteoclasts and osteoblasts are induced, because it is difficult to observe osteoclasts and osteoblasts in a living animal. To answer these questions, we developed a new fracture healing model by using medaka. We fractured one side of lepidotrichia in a caudal fin ray without injuring the other soft tissues including blood vessels. Using the transgenic medaka in which osteoclasts and osteoblasts were visualized by GFP and DsRed, respectively, we found that two different types of functional osteoclasts were induced before and after osteoblast callus formation. The early-induced osteoclasts resorbed the bone fragments and the late-induced osteoclasts remodeled the callus. Both types of osteoclasts were induced near the surface on the blood vessels, while osteoblasts migrated from adjacent fin ray. Transmission electron microscopy revealed that no significant ruffled border and clear zone were observed in early-induced osteoclasts, whereas the late-induced osteoclasts had clear zones but did not have the typical ruffled border. In the remodeling of the callus, the expression of cox2 mRNA was up-regulated at the fracture site around vessels, and the inhibition of Cox2 impaired the induction of the late-induced osteoclasts, resulting in abnormal fracture healing. Finally, our developed medaka fracture healing model brings a new insight into the molecular mechanism for controlling cellular behaviors during the fracture healing. PMID:25131195

  19. Instantaneous healing of micro-fractures during coseismic slip: Evidence from microstructure and Ti in quartz geochemistry within an exhumed pseudotachylyte-bearing fault in tonalite

    NASA Astrophysics Data System (ADS)

    Bestmann, Michel; Pennacchioni, Giorgio; Mostefaoui, Smail; Göken, Mathias; de Wall, Helga

    2016-06-01

    Exhumed faults within the tonalitic Adamello pluton (Southern Alps) were seismic at depth as indicated by the presence of pseudotachylytes (solidified friction-induced melts). During cooling of tonalite, early-formed joints were first exploited by localized ductile shear zones associated with deposition of quartz veins (at ~ 500 °C), and later by pseudotachylyte-bearing cataclastic faults (at ~ 250-300 °C ambient temperature). Adjacent to pseudotachylytes, quartz of the host tonalite shows pervasive thin (1-10 μm wide) healed micro-fractures and ultra-fine (1-2 μm grain size) recrystallized aggregates along micro-shear zones. Under cathodoluminescence (CL) the healed micro-fractures have a darker gray shade than the host "magmatic" quartz that reflects a change in Ti concentrations ([Ti]) as indicated by NanoSIMS measurements. [Ti] vary from 35-55 ppm in the CL-lighter host quartz to 10-13 ppm along the CL-darker healed micro-fractures. These [Ti] were inherited by the ultra-fine recrystallized aggregates that overprinted both the magmatic quartz and the healed micro-fractures during the high temperature transient related to frictional seismic slip. Based on Ti-in-quartz thermometry, we infer that micro-fracture healing occurred at higher temperatures than the ambient temperatures of faulting (250-300 °C at 0.2 GPa), for which [Ti] < 1 ppm would be expected. Micro-fracture healing can be ascribed to the stage of seismic slip of faults on the basis of the observation that: (i) they are absent in the host rock surrounding high-T quartz veins un-exploited by faults; and (ii) they locally occur at the tip of pseudotachylyte injection veins filling new fractures developed during the propagation of the earthquake rupture. The relatively high [Ti] of micro-fractures are therefore interpreted to reflect quartz healing by a fluid overheated during the initial stages of frictional seismic slip and escaping from fault surface through the damage zone. This suggests that

  20. The role of the lateral pterygoid muscle in the sagittal fracture of mandibular condyle (SFMC) healing process.

    PubMed

    Liu, Chng-Kui; Liu, Ping; Meng, Fan-Wen; Deng, Bang-Lian; Xue, Yang; Mao, Tian-Qiu; Hu, Kai-Jin

    2012-06-01

    The aim of this study was to examine the role of the lateral peterygoid muscle in the reconstruction of the shape of the condyle during healing of a sagittal fracture of the mandibular condyle. Twenty adult sheep were divided into 2 groups: all had a unilateral operation on the right side when the anterior and posterior attachments of the discs were cut, and an oblique vertical osteotomy was made from the lateral pole of the condyle to the medial side of the condylar neck. Ten sheep had the lateral pterygoid muscle cut, and the other 10 sheep did not. Sheep were killed at 4 weeks (n=2 from each group), 12 weeks (n=4), and 24 weeks (n=4) postoperatively. Computed tomograms (CT) were taken before and after operations. We dissected the joints, and recorded with the naked eye the shape, degree of erosion, and amount of calcification of the temporomandibular joint (TMJ). In the group in which the lateral peterygoid muscle had not been cut the joints showed overgrowth of new bone and more advanced ankylosis. Our results show that the lateral pterygoid muscle plays an important part in reconstructing the shape of the condyle during the healing of a sagittal fracture of the mandibular condyle, and combined with the dislocated and damaged disc is an important factor in the aetiology of traumatic ankylosis of the TMJ.

  1. Capturing the wide variety of impaired fracture healing phenotypes in Neurofibromatosis Type 1 with eight key factors: a computational study.

    PubMed

    Carlier, A; Brems, H; Ashbourn, J M A; Nica, I; Legius, E; Geris, L

    2016-01-01

    Congenital pseudarthrosis of the tibia (CPT) is a rare disease which normally presents itself during early childhood by anterolateral bowing of the tibia and spontaneous tibial fractures. Although the exact etiology of CPT is highly debated, 40-80% of CPT patients are carriers of a mutation in the Neurofibromatosis Type 1 (NF1) gene, which can potentially result in an altered phenotype of the skeletal cells and impaired bone healing. In this study we use a computational model of bone regeneration to examine the effect of the Nf1 mutation on bone fracture healing by altering the parameter values of eight key factors which describe the aberrant cellular behaviour of Nf1 haploinsufficient and Nf1 bi-allelically inactivated cells. We show that the computational model is able to predict the formation of a hamartoma as well as a wide variety of CPT phenotypes through different combinations of altered parameter values. A sensitivity analysis by "Design of Experiments" identified the impaired endochondral ossification process and increased infiltration of fibroblastic cells as key contributors to the degree of severity of CPT. Hence, the computational model results have added credibility to the experimental hypothesis of a genetic cause (i.e. Nf1 mutation) for CPT. PMID:26822862

  2. Capturing the wide variety of impaired fracture healing phenotypes in Neurofibromatosis Type 1 with eight key factors: a computational study

    PubMed Central

    Carlier, A.; Brems, H.; Ashbourn, J. M. A.; Nica, I.; Legius, E.; Geris, L.

    2016-01-01

    Congenital pseudarthrosis of the tibia (CPT) is a rare disease which normally presents itself during early childhood by anterolateral bowing of the tibia and spontaneous tibial fractures. Although the exact etiology of CPT is highly debated, 40–80% of CPT patients are carriers of a mutation in the Neurofibromatosis Type 1 (NF1) gene, which can potentially result in an altered phenotype of the skeletal cells and impaired bone healing. In this study we use a computational model of bone regeneration to examine the effect of the Nf1 mutation on bone fracture healing by altering the parameter values of eight key factors which describe the aberrant cellular behaviour of Nf1 haploinsufficient and Nf1 bi-allelically inactivated cells. We show that the computational model is able to predict the formation of a hamartoma as well as a wide variety of CPT phenotypes through different combinations of altered parameter values. A sensitivity analysis by “Design of Experiments” identified the impaired endochondral ossification process and increased infiltration of fibroblastic cells as key contributors to the degree of severity of CPT. Hence, the computational model results have added credibility to the experimental hypothesis of a genetic cause (i.e. Nf1 mutation) for CPT. PMID:26822862

  3. Influence of internal fixator flexibility on murine fracture healing as characterized by mechanical testing and microCT imaging.

    PubMed

    Steck, Roland; Ueno, Masaki; Gregory, Laura; Rijken, Noortje; Wullschleger, Martin E; Itoman, Moritoshi; Schuetz, Michael A

    2011-08-01

    Mechanically well-defined stabilization systems have only recently become available, providing standardized conditions for studying the role of the mechanical environment on mouse bone fracture healing. The aim of this study was to characterize the time course of strength recovery and callus development of mouse femoral osteotomies stabilized with either low or high flexibility (in bending and torsion) internal fixation plates. Animals were euthanized and femora excised at 14, 21, and 28 days post-osteotomy for microCT analysis and torsional strength testing. While a larger mineralized callus was observed in osteotomies under more flexible conditions at all time points, the earlier bridging of the mineralized callus under less flexible conditions by 1 week resulted in an earlier recovery of torsional strength in mice stabilized with low flexibility fixation. Ultimate torque values for these bones were significantly higher at 14 and 21 days post-osteotomy compared to bones with the more flexible stabilization. Our study confirms the high reproducibility of the results that are achieved with this new implant system, therefore making it ideal for studying the influence of the mechanical environment on murine fracture healing under highly standardized conditions.

  4. The association between healed skeletal fractures indicative of interpersonal violence and alcoholic liver disease in a cadaver cohort from the Western Cape, South Africa.

    PubMed

    Geldenhuys, Elsje-Márie; Burger, Elsie H; Alblas, Amanda; Greyling, Linda M; Kotzé, Sanet H

    2016-05-01

    Interpersonal violence (IPV) and heavy alcohol consumption are major problems in the Western Cape Province of South Africa. Cranio-maxillofacial fractures, particularly nasal and zygomatic bone fractures, as well as isolated radial fractures (Colles fractures) and ulnar shaft fractures (parry fractures), are indicative of IPV, while alcoholic liver disease (ALD) is the consequence of chronic alcohol abuse. We therefore aim to investigate whether a significant association exists between the prevalence of cranio-maxillofacial fractures and parry fractures and ALD in a Western Cape population. Embalmed cadavers (n = 124) used for medical students' anatomy training at the Division of Anatomy and Histology, Faculty of Medicine and Health Sciences, Stellenbosch University were studied. The cadavers were dissected according to departmental protocol. The liver of each cadaver was investigated for macroscopic pathology lesions. Tissue samples were removed, processed to wax, and sectioned and stained with hematoxylin and eosin (H&E). All soft tissue was removed from the skulls, radii, and ulnae, which were then investigated for healed skeletal trauma. The results showed 37/124 (29.8%) cadavers had healed cranio-maxillofacial fractures and 24/124 (19.4%) cadavers had morphologic features of ALD. A total of 12/124 (9.7%) cadavers showed signs of both ALD and healed cranio-maxillofacial trauma. More males were affected than females, and left-sided facial fractures were statistically more common compared to the right side. This study illustrated a significant trend between alcohol abuse and cranio-maxillofacial fractures in individuals from communities with a low socio-economic status (SES) where IPV is a major problem.

  5. CYR61 (CCN1) protein expression during fracture healing in an ovine tibial model and its relation to the mechanical fixation stability.

    PubMed

    Lienau, Jasmin; Schell, Hanna; Epari, Devakara R; Schütze, Norbert; Jakob, Franz; Duda, Georg N; Bail, Hermann J

    2006-02-01

    The formation of new blood vessels is a prerequisite for bone healing. CYR61 (CCN1), an extracellular matrix-associated signaling protein, is a potent stimulator of angiogenesis and mesenchymal stem cell expansion and differentiation. A recent study showed that CYR61 is expressed during fracture healing and suggested that CYR61 plays a significant role in cartilage and bone formation. The hypothesis of the present study was that decreased fixation stability, which leads to a delay in healing, would lead to reduced CYR61 protein expression in fracture callus. The aim of the study was to quantitatively analyze CYR61 protein expression, vascularization, and tissue differentiation in the osteotomy gap and relate to the mechanical fixation stability during the course of healing. A mid-shaft osteotomy of the tibia was performed in two groups of sheep and stabilized with either a rigid or semirigid external fixator, each allowing different amounts of interfragmentary movement. The sheep were sacrificed at 2, 3, 6, and 9 weeks postoperatively. The tibiae were tested biomechanically and histological sections from the callus were analyzed immunohistochemically with regard to CYR61 protein expression and vascularization. Expression of CYR61 protein was upregulated at the early phase of fracture healing (2 weeks), decreasing over the healing time. Decreased fixation stability was associated with a reduced upregulation of the CYR61 protein expression and a reduced vascularization at 2 weeks leading to a slower healing. The maximum cartilage callus fraction in both groups was reached at 3 weeks. However, the semirigid fixator group showed a significantly lower CYR61 immunoreactivity in cartilage than the rigid fixator group at this time point. The fraction of cartilage in the semirigid fixator group was not replaced by bone as quickly as in the rigid fixator group leading to an inferior histological and mechanical callus quality at 6 weeks and therefore to a slower healing. The

  6. Instantaneous healing of micro-fractures during coseismic slip: evidence from microstructure and Ti in quartz geochemistry within an exhumed pseudotachylyte-bearing fault in tonalite

    NASA Astrophysics Data System (ADS)

    Bestmann, Michel; Pennacchioni, Giorgio; Moustefaoui, Smail; Göken, Mathias; de Wall, Helga

    2016-04-01

    This study presents detailed microstructural and trace element (Ti) analysis of quartz deformation microstructures associated with seismic slip in order to constrain the complex deformation history during an earthquake event. Exhumed faults within the tonalitic Adamello pluton (Southern Alps) were seismic at depth as indicated by the presence of pseudotachylytes (solidified friction-induced melts). During cooling of tonalite, early-formed joints were first exploited by localized ductile shear zones associated with deposition of quartz veins (at ~500 °C), and later by pseudotachylyte-bearing cataclastic faults (at ~250-300 °C ambient temperature). Adjacent to pseudotachylytes, quartz of the host tonalite shows pervasive thin (1-10 μm wide) healed micro-fractures and ultra-fine (1-2 μm grain size) recrystallized aggregates along micro-shear zones. Under cathodoluminescence (CL) the healed micro-fractures have darker gray shade than the host "magmatic" quartz that reflects a change in Ti concentrations [Ti] as indicated by NanoSIMS measurements. [Ti] vary from 35-55 ppm of the CL-lighter host quartz to 11-15 ppm along the CL-darker healed micro-fractures. These [Ti] were inherited by overprinting recrystallization aggregates developed during the high temperature transient related to frictional seismic slip. Based on Ti-in-quartz thermometry, micro-fracture healing occurred at higher temperatures than the ambient temperatures of faulting (250-300 °C at 0.2 GPa). Micro-fracture healing can be ascribed to the stage of seismic slip of faulting on the basis of the observation that: (i) they are absent in the host rock surrounding earlier high-T quartz veins un-exploited by faults; (ii) they locally occur at the tip of pseudotachylyte injection veins filling new fractures developed during the propagation of the earthquake rupture tip. The relatively high [Ti] of micro-fractures are interpreted to reflect quartz healing by a fluid overheated during the initial stages of

  7. Acceleration of wound healing in gastric ulcers by local injection of neutralising antibody to transforming growth factor beta 1.

    PubMed Central

    Ernst, H; Konturek, P; Hahn, E G; Brzozowski, T; Konturek, S J

    1996-01-01

    BACKGROUND: Application of neutralising antibodies (NAs) to transforming growth factor beta 1 (TGF beta 1) improves wound healing in experimental glomerulonephritis and dermal incision wounds. TGF beta 1 has been detected in the stomach, but despite the fact that this cytokine plays a central part in wound healing no information is available to determine if modulation of the TGF beta 1 profile influences the healing of gastric ulcers. This study examines gastric ulcer healing in the rat after local injection of NAs to TGF beta 1. METHOD: Chronic gastric ulcers were induced in Wistar rats by the application of 100% acetic acid to the serosal surface of the stomach. Immediately after ulcer induction and on day 2, NAs to TGF beta 1 (50 micrograms), TGF beta 1 (50 ng), saline or control antibodies (IgG; 50 micrograms) were locally injected into the subserosa. Controls received no subserosal injections. Animals were killed on day 5 or 11, the ulcer area was measured planimetrically, sections were embedded in paraffin wax, and stained with trichrome or haematoxylin and eosin. Depth of residual ulcer was assessed on day 11 by a scale of 0-3, the percentage of connective tissue was determined by a semiquantitative matrix score and granulocytes and macrophages in the ulcer bed were also assessed. RESULTS: The application of NAs to TGF beta 1 led to a significant acceleration of gastric ulcer healing on day 11 (0.6 (SD 0.8) v 3.7 (SD 2.6) mm2), a reduction in macrophages (23.7 (SD 22.6) v 38 (26) per 40 x power field) and granulocytes (8.5 (SD 5.6) v 20 (10) per 40 x power field), fewer histological residual ulcers (mean 1 (SD 0.9) v 2 (1.1)), a reduced matrix score, and a regenerative healing pattern. Excessive scarring was seen in the TGF beta 1 treated group. CONCLUSION: Further treatment of gastric ulcers may induce a new treatment modality by local injection of NA to TGF beta 1 in an attempt to accelerate and improve ulcer healing. Images Figure 2 Figure 3 PMID:8991853

  8. Chitosan-based copper nanocomposite accelerates healing in excision wound model in rats.

    PubMed

    Gopal, Anu; Kant, Vinay; Gopalakrishnan, Anu; Tandan, Surendra K; Kumar, Dinesh

    2014-05-15

    Copper possesses efficacy in wound healing which is a complex phenomenon involving various cells, cytokines and growth factors. Copper nanoparticles modulate cells, cytokines and growth factors involved in wound healing in a better way than copper ions. Chitosan has been shown to be beneficial in healing because of its antibacterial, antifungal, biocompatible and biodegradable polymeric nature. In the present study, chitosan-based copper nanocomposite (CCNC) was prepared by mixing chitosan and copper nanoparticles. CCNC was applied topically to evaluate its wound healing potential and to study its effects on some important components of healing process in open excision wound model in adult Wistar rats. Significant increase in wound contraction was observed in the CCNC-treated rats. The up-regulation of vascular endothelial growth factor (VEGF) and transforming growth factor-beta1(TGF-β1) by CCNC-treatment revealed its role in facilitating angiogenesis, fibroblast proliferation and collagen deposition. The tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were significantly decreased and increased, respectively, in CCNC-treated rats. Histological evaluation showed more fibroblast proliferation, collagen deposition and intact re-epithelialization in CCNC-treated rats. Immunohistochemistry of CD31 revealed marked increase in angiogenesis. Thus, we concluded that chitosan-based copper nanocomposite efficiently enhanced cutaneous wound healing by modulation of various cells, cytokines and growth factors during different phases of healing process. PMID:24632085

  9. Cementless Titanium Mesh Fixation of Osteoporotic Burst Fractures of the Lumbar Spine Leads to Bony Healing: Results of an Experimental Sheep Model

    PubMed Central

    Roepenack, Paula; Roesner, Jan; Herlyn, Philipp Karl Ewald; Martin, Heiner; Reichel, Martin; Rotter, Robert; Vollmar, Brigitte; Mittlmeier, Thomas; Gradl, Georg

    2016-01-01

    Introduction. Current treatment strategies for osteoporotic vertebral compression fractures (VCFs) focus on cement-associated solutions. Complications associated with cement application are leakage, embolism, adjacent fractures, and compromise in bony healing. This study comprises a validated VCF model in osteoporotic sheep in order to (1) evaluate a new cementless fracture fixation technique using titanium mesh implants (TMIs) and (2) demonstrate the healing capabilities in osteoporotic VCFs. Methods. Twelve 5-year-old Merino sheep received ovariectomy, corticosteroid injections, and a calcium/phosphorus/vitamin D-deficient diet for osteoporosis induction. Standardized VCFs (type AO A3.1) were created, reduced, and fixed using intravertebral TMIs. Randomly additional autologous spongiosa grafting (G1) or no augmentation was performed (G2, n = 6 each). Two months postoperatively, macroscopic, micro-CT and biomechanical evaluation assessed bony consolidation. Results. Fracture reduction succeeded in all cases without intraoperative complications. Bony consolidation was proven for all cases with increased amounts of callus development for G2 (58.3%). Micro-CT revealed cage integration. Neither group showed improved results with biomechanical testing. Conclusions. Fracture reduction/fixation using TMIs without cement in osteoporotic sheep lumbar VCF resulted in bony fracture healing. Intravertebral application of autologous spongiosa showed no beneficial effects. The technique is now available for clinical use; thus, it offers an opportunity to abandon cement-associated complications. PMID:27019848

  10. Low-magnitude high-frequency vibration enhanced mesenchymal stem cell recruitment in osteoporotic fracture healing through the SDF-1/CXCR4 pathway.

    PubMed

    Wei, F Y; Chow, S K; Leung, K S; Qin, J; Guo, A; Yu, O L; Li, G; Cheung, W H

    2016-01-01

    Low-magnitude high-frequency vibration (LMHFV) has been proven to promote osteoporotic fracture healing. Mechanical stimulation was reported to enhance SDF-1/CXCR4 signalling in mesenchymal stem cells (MSCs). We hypothesised that LMHFV promoted osteoporotic fracture healing by enhancing MSC migration through the SDF-1/CXCR4 pathway. 152 ovariectomised SD-rats received closed femoral fracture in groups of vibration+MSC (VMG) (20 min/d, 5 d/week), vibration+MSC+AMD3100 (VMAG; AMD, a CXCR4 inhibitor) (1 mg/kg/d, intraperitoneal), MSC (MG) (1 × 106 MSC, intracardiac) or control (CG) for a treatment duration of 2, 4 or 8 weeks. MSC migration was evaluated by ex-vivo green fluorescent protein signal in the callus; and fracture healing was examined by weekly radiographs, endpoint computed-tomography and mechanical test. At week-2 and week-4, ex-vivo callus GFP intensity of VMG was significantly higher than other groups (p < 0.05). From week-2 to week-3, both callus width and callus area in VMG were significantly larger; and from week-7 to week-8, smaller than other groups (p < 0.05). At week-8, high-density bone volume fraction, bone volume fraction, bone mineral density and stiffness in VMG were significantly higher than other 3 groups (p < 0.05). This study demonstrated that LMHFV promoted MSC migration and fracture healing in osteoporotic rats. This effect was attenuated by CXCR4 inhibitor, providing strong evidence that SDF-1-mediated MSC migration was one of the important mechanisms through which LMHFV enhanced fracture healing. PMID:27215741

  11. Rescue of Impaired Fracture Healing in COX-2−/− Mice via Activation of Prostaglandin E2 Receptor Subtype 4

    PubMed Central

    Xie, Chao; Liang, Bojian; Xue, Ming; Lin, Angela S.P.; Loiselle, Alayna; Schwarz, Edward M.; Guldberg, Robert E.; O'Keefe, Regis J.; Zhang, Xinping

    2009-01-01

    Although the essential role of cyclooxygenase (COX)-2 in fracture healing is known, the targeted genes and molecular pathways remain unclear. Using prostaglandin E2 receptor (EP)2 and EP4 agonists, we examined the effects of EP receptor activation in compensation for the lack of COX-2 during fracture healing. In a fracture-healing model, COX-2−/− mice showed delayed initiation and impaired endochondral bone repair, accompanied by a severe angiogenesis deficiency. The EP4 agonist markedly improved the impaired healing in COX-2−/− mice, as evidenced by restoration of bony callus formation on day 14, a near complete reversal of bone formation, and an approximately 70% improvement of angiogenesis in the COX-2−/− callus. In comparison, the EP2 agonist only marginally enhanced bone formation in COX-2−/− mice. To determine the differential roles of EP2 and EP4 receptors on COX-2-mediated fracture repair, the effects of selective EP agonists on chondrogenesis were examined in E11.5 long-term limb bud micromass cultures. Only the EP4 agonist significantly increased cartilage nodule formation similar to that observed during prostaglandin E2 treatment. The prostaglandin E2/EP4 agonist also stimulated MMP-9 expression in bone marrow stromal cell cultures. The EP4 agonist further restored the reduction of MMP-9 expression in the COX-2−/− fracture callus. Taken together, our studies demonstrate that EP2 and EP4 have differential functions during endochondral bone repair. Activation of EP4, but not EP2 rescued impaired bone fracture healing in COX-2−/− mice. PMID:19628768

  12. Development of ethyl alcohol-precipitated silk sericin/polyvinyl alcohol scaffolds for accelerated healing of full-thickness wounds.

    PubMed

    Siritienthong, Tippawan; Ratanavaraporn, Juthamas; Aramwit, Pornanong

    2012-12-15

    Silk sericin has been recently reported for its advantageous biological properties to promote wound healing. In this study, we established that the ethyl alcohol (EtOH) could be used to precipitate sericin and form the stable sericin/polyvinyl alcohol (PVA) scaffolds without the crosslinking. The sericin/PVA scaffolds were fabricated via freeze-drying and subsequently precipitating in various concentrations of EtOH. The EtOH-precipitated sericin/PVA scaffolds showed denser structure, higher compressive modulus, but lower water swelling ability than the non-precipitated scaffolds. Sericin could be released from the EtOH-precipitated sericin/PVA scaffolds in a sustained manner. After cultured with L929 mouse fibroblasts, the 70 vol% EtOH-precipitated sericin/PVA scaffolds showed the highest potential to promote cell proliferation. After applied to the full-thickness wounds of rats, the 70 vol% EtOH-precipitated sericin/PVA scaffolds showed significantly higher percentage of wound size reduction and higher extent of type III collagen formation and epithelialization, compared with the control scaffolds without sericin. The accelerated wound healing by the 70 vol% EtOH-precipitated sericin/PVA scaffolds was possibly due to (1) the bioactivity of sericin itself to promote wound healing, (2) the sustained release of precipitated sericin from the scaffolds, and (3) the activation and recruitment of wound healing-macrophages by sericin to the wounds. This finding suggested that the EtOH-precipitated sericin/PVA scaffolds were more effective for the wound healing, comparing with the EtOH-precipitated PVA scaffolds without sericin.

  13. Method for detecting moment connection fracture using high-frequency transients in recorded accelerations

    USGS Publications Warehouse

    Rodgers, J.E.; Elebi, M.

    2011-01-01

    The 1994 Northridge earthquake caused brittle fractures in steel moment frame building connections, despite causing little visible building damage in most cases. Future strong earthquakes are likely to cause similar damage to the many un-retrofitted pre-Northridge buildings in the western US and elsewhere. Without obvious permanent building deformation, costly intrusive inspections are currently the only way to determine if major fracture damage that compromises building safety has occurred. Building instrumentation has the potential to provide engineers and owners with timely information on fracture occurrence. Structural dynamics theory predicts and scale model experiments have demonstrated that sudden, large changes in structure properties caused by moment connection fractures will cause transient dynamic response. A method is proposed for detecting the building-wide level of connection fracture damage, based on observing high-frequency, fracture-induced transient dynamic responses in strong motion accelerograms. High-frequency transients are short (<1 s), sudden-onset waveforms with frequency content above 25 Hz that are visually apparent in recorded accelerations. Strong motion data and damage information from intrusive inspections collected from 24 sparsely instrumented buildings following the 1994 Northridge earthquake are used to evaluate the proposed method. The method's overall success rate for this data set is 67%, but this rate varies significantly with damage level. The method performs reasonably well in detecting significant fracture damage and in identifying cases with no damage, but fails in cases with few fractures. Combining the method with other damage indicators and removing records with excessive noise improves the ability to detect the level of damage. ?? 2010 Elsevier B.V. All rights reserved.

  14. Severe complications in wound healing and fracture treatment in two brothers with congenital insensitivity to pain with anhidrosis.

    PubMed

    Rapp, Marion; Spiegler, Juliane; Härtel, Christoph; Gillessen-Kaesbach, Gabrielle; Kaiser, Martin M

    2013-01-01

    Congenital insensitivity to pain with anhidrosis is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene, which encodes the receptor for nerve growth factor. We report the clinical and radiological pitfalls in the diagnosis and treatment of two brothers, aged 5 and 8 years, with congenital insensitivity to pain with anhidrosis, the older brother having a proven NTRK1 mutation. In the neonatal period, both presented with recurrent episodes of fever of unknown origin, but their clinical problems changed later. In addition to severe mental retardation and self-harming behaviour, the older brother developed recurrent nonbacterial destructive infections of both the calcaneus and later the talus. No immunodeficiency was found. The younger brother had three complex fractures with a long history of healing problems: overwhelming production of callus, osteomyelitis and movement restrictions. He has less mental retardation than his older brother and shows no self-mutilation.

  15. Gait and function as tools for the assessment of fracture repair - the role of movement analysis for the assessment of fracture healing.

    PubMed

    Rosenbaum, Dieter; Macri, Felipe; Lupselo, Fernando Silva; Preis, Osvaldo Cristiano

    2014-06-01

    Assessment of gait and function might be as sensitive tool to monitor the progress of fracture healing. Currently available assessment tools for function use instrumented three dimensional gait analysis or pedobarography. The analysis is focused on gait or movement parameters and seeks to identify abnormalities or asymmetries between legs or arms. The additional inclusion of muscle function by electromyography can further elucidate functional performance and its temporal development. Alternative approaches abstain from directly assessing function in the laboratory but rather determine the amount of activities of daily living or the mere ability to perform defined tasks such as walking, stair climbing or running. Some of these methods have been applied to determine recovery after orthopaedic interventions including fracture repair. The combination of lab-based functional measurements and assessment of physical activities in daily live may offer a valuable level of information about the gait quality and quantity of individual patients which sheds light on functional limitations or rehabilitation of gait and mobility after a disease or injury and the respective conservative, medical or surgical treatment.

  16. Inhibition of Prostaglandin Transporter (PGT) Promotes Perfusion and Vascularization and Accelerates Wound Healing in Non-Diabetic and Diabetic Rats.

    PubMed

    Liu, Zhongbo; Benard, Outhiriaradjou; Syeda, Mahrukh M; Schuster, Victor L; Chi, Yuling

    2015-01-01

    Peripheral ischemia, resulting from diminished arterial flow and defective local vascularization, is one of the main causes of impaired wound healing in diabetes. Vasodilatory prostaglandins (PGs), including PGE2 and PGI2, regulate blood flow in peripheral tissues. PGs also stimulate angiogenesis by inducing vascular endothelial growth factor. However, PG levels are reduced in diabetes mainly due to enhanced degradation. We hypothesized that inhibition of the prostaglandin transporter (PGT) (SLCO2A1), which mediates the degradation of PGs, would increase blood flow and stimulate vascularization, thereby mitigating peripheral ischemia and accelerating wound healing in diabetes. Here we report that inhibiting PGT with intravenously injected PGT inhibitor, T26A, increased blood flow in ischemic hind limbs created in non-diabetic rats and streptozotocin induced diabetic rats. Systemic, or combined with topical, T26A accelerated closure of cutaneous wounds. Immunohistochemical examination revealed that inhibition of PGT enhanced vascularization (marked by larger numbers of vessels formed by CD34+ cells), and accelerated re-epithelialization of cutaneous wounds. In cultured primary human bone marrow CD34+ cells and human epidermal keratinocytes (HEKs) either inhibiting or silencing PGT increased migration in both cell lines. Thus PGT directly regulates mobilization of endothelial progenitor cells (EPCs) and HEKs, which could contribute to PGT-mediated vascularization and re-epithelialization. At the molecular level, systemic inhibition of PGT raised circulating PGE2. Taken together, our data demonstrate that PGT modulates arterial blood flow, mobilization of EPCs and HEKs, and vascularization and epithelialization in wound healing by regulating vasodilatory and pro-angiogenic PGs.

  17. Connecting biology and mechanics in fracture healing: an integrated mathematical modeling framework for the study of nonunions.

    PubMed

    Geris, L; Sloten, J Vander; Van Oosterwyck, H

    2010-12-01

    Both mechanical and biological factors play an important role in normal as well as impaired fracture healing. This study aims to provide a mathematical framework in which both regulatory mechanisms are included. Mechanics and biology are coupled by making certain parameters of a previously established bioregulatory model dependent on local mechanical stimuli. To illustrate the potential added value of such a framework, this coupled model was applied to investigate whether local mechanical stimuli influencing only the angiogenic process can explain normal healing as well as overload-induced nonunion development. Simulation results showed that mechanics acting directly on angiogenesis alone was not able to predict the formation of overload-induced nonunions. However, the direct action of mechanics on both angiogenesis and osteogenesis was able to predict overload-induced nonunion formation, confirming the hypotheses of several experimental studies investigating the interconnection between angiogenesis and osteogenesis. This study shows that mathematical models can assist in testing hypothesis on the nature of the interaction between biology and mechanics.

  18. Delayed healing of a navicular stress fracture, following limited weight-bearing activity

    PubMed Central

    Robinson, Matthew; Fulcher, Mark

    2014-01-01

    This report describes a 21-year-old man, a semiprofessional football (soccer) player, with a navicular stress fracture. It highlights the difficulty in diagnosing the condition and the complications arising from inadequate management. The case discusses the optimal management of these stress fractures and the detrimental role of weight-bearing recovery. The diagnosis of navicular stress fractures is challenging, and a high index of suspicion is required. The available literature indicates that limited weightbearing is not an appropriate treatment for navicular stress injuries. Non-weight-bearing (NWB) cast immobilisation for 6–8 weeks appears to be the gold standard treatment; however, open reduction with internal fixation (ORIF) has similar success rates and an equal return-to-play time but should also be followed by a period of NWB. NWB cast immobilisation for 6 weeks remains a good second option at any time following failed limited weight-bearing activity. PMID:24618870

  19. Assessment of bone healing on tibial fractures treated with wire osteosynthesis associated or not with infrared laser light and biphasic ceramic bone graft (HATCP) and guided bone regeneration (GBR): Raman spectroscopy study

    NASA Astrophysics Data System (ADS)

    Bastos de Carvalho, Fabíola; Aciole, Gilberth Tadeu S.; Aciole, Jouber Mateus S.; Silveira, Landulfo, Jr.; Nunes dos Santos, Jean; Pinheiro, Antônio L. B.

    2011-03-01

    The aim of this study was to evaluate, through Raman spectroscopy, the repair of complete tibial fracture in rabbits fixed with wire osteosynthesis - WO, treated or not with infrared laser light (λ 780nm, 50mW, CW) associated or not to the use of HATCP and GBR. Surgical fractures were created under general anesthesia (Ketamine 0.4ml/Kg IP and Xilazine 0.2ml/Kg IP), on the tibia of 15 rabbits that were divided into 5 groups and maintained on individual cages, at day/night cycle, fed with solid laboratory pelted diet and had water ad libidum. On groups II, III, IV and V the fracture was fixed with WO. Animals of groups III and V were grafted with hydroxyapatite + GBR technique. Animals of groups IV and V were irradiated at every other day during two weeks (16J/cm2, 4 x 4J/cm2). Observation time was that of 30 days. After animal death the specimens were kept in liquid nitrogen for further analysis by Raman spectroscopy. Raman spectroscopy showed significant differences between groups (p<0.001). It is concluded that IR laser light was able to accelerate fracture healing and the association with HATCP and GBR resulted on increased deposition of calcium hydroxyapatite.

  20. Transparent crosslinked ultrashort peptide hydrogel dressing with high shape-fidelity accelerates healing of full-thickness excision wounds.

    PubMed

    Seow, Wei Yang; Salgado, Giorgiana; Lane, E Birgitte; Hauser, Charlotte A E

    2016-09-07

    Wound healing is a major burden of healthcare systems worldwide and hydrogel dressings offer a moist environment conducive to healing. We describe cysteine-containing ultrashort peptides that self-assemble spontaneously into hydrogels. After disulfide crosslinking, the optically-transparent hydrogels became significantly stiffer and exhibited high shape fidelity. The peptide sequence (LIVAGKC or LK6C) was then chosen for evaluation on mice with full-thickness excision wounds. Crosslinked LK6C hydrogels are handled easily with forceps during surgical procedures and offer an improvement over our earlier study of a non-crosslinked peptide hydrogel for burn wounds. LK6C showed low allergenic potential and failed to provoke any sensitivity when administered to guinea pigs in the Magnusson-Kligman maximization test. When applied topically as a dressing, the medium-infused LK6C hydrogel accelerated re-epithelialization compared to controls. The peptide hydrogel is thus safe for topical application and promotes a superior rate and quality of wound healing.

  1. Novel anti-microbial peptide SR-0379 accelerates wound healing via the PI3 kinase/Akt/mTOR pathway.

    PubMed

    Tomioka, Hideki; Nakagami, Hironori; Tenma, Akiko; Saito, Yoshimi; Kaga, Toshihiro; Kanamori, Toshihide; Tamura, Nao; Tomono, Kazunori; Kaneda, Yasufumi; Morishita, Ryuichi

    2014-01-01

    We developed a novel cationic antimicrobial peptide, AG30/5C, which demonstrates angiogenic properties similar to those of LL-37 or PR39. However, improvement of its stability and cost efficacy are required for clinical application. Therefore, we examined the metabolites of AG30/5C, which provided the further optimized compound, SR-0379. SR-0379 enhanced the proliferation of human dermal fibroblast cells (NHDFs) via the PI3 kinase-Akt-mTOR pathway through integrin-mediated interactions. Furthermore SR-0379 promoted the tube formation of human umbilical vein endothelial cells (HUVECs) in co-culture with NHDFs. This compound also displays antimicrobial activities against a number of bacteria, including drug-resistant microbes and fungi. We evaluated the effect of SR-0379 in two different would-healing models in rats, the full-thickness defects under a diabetic condition and an acutely infected wound with full-thickness defects and inoculation with Staphylococcus aureus. Treatment with SR-0379 significantly accelerated wound healing when compared to fibroblast growth factor 2 (FGF2). The beneficial effects of SR-0379 on wound healing can be explained by enhanced angiogenesis, granulation tissue formation, proliferation of endothelial cells and fibroblasts and antimicrobial activity. These results indicate that SR-0379 may have the potential for drug development in wound repair, even under especially critical colonization conditions. PMID:24675668

  2. Transparent crosslinked ultrashort peptide hydrogel dressing with high shape-fidelity accelerates healing of full-thickness excision wounds.

    PubMed

    Seow, Wei Yang; Salgado, Giorgiana; Lane, E Birgitte; Hauser, Charlotte A E

    2016-01-01

    Wound healing is a major burden of healthcare systems worldwide and hydrogel dressings offer a moist environment conducive to healing. We describe cysteine-containing ultrashort peptides that self-assemble spontaneously into hydrogels. After disulfide crosslinking, the optically-transparent hydrogels became significantly stiffer and exhibited high shape fidelity. The peptide sequence (LIVAGKC or LK6C) was then chosen for evaluation on mice with full-thickness excision wounds. Crosslinked LK6C hydrogels are handled easily with forceps during surgical procedures and offer an improvement over our earlier study of a non-crosslinked peptide hydrogel for burn wounds. LK6C showed low allergenic potential and failed to provoke any sensitivity when administered to guinea pigs in the Magnusson-Kligman maximization test. When applied topically as a dressing, the medium-infused LK6C hydrogel accelerated re-epithelialization compared to controls. The peptide hydrogel is thus safe for topical application and promotes a superior rate and quality of wound healing. PMID:27600999

  3. Transparent crosslinked ultrashort peptide hydrogel dressing with high shape-fidelity accelerates healing of full-thickness excision wounds

    PubMed Central

    Seow, Wei Yang; Salgado, Giorgiana; Lane, E. Birgitte; Hauser, Charlotte A. E.

    2016-01-01

    Wound healing is a major burden of healthcare systems worldwide and hydrogel dressings offer a moist environment conducive to healing. We describe cysteine-containing ultrashort peptides that self-assemble spontaneously into hydrogels. After disulfide crosslinking, the optically-transparent hydrogels became significantly stiffer and exhibited high shape fidelity. The peptide sequence (LIVAGKC or LK6C) was then chosen for evaluation on mice with full-thickness excision wounds. Crosslinked LK6C hydrogels are handled easily with forceps during surgical procedures and offer an improvement over our earlier study of a non-crosslinked peptide hydrogel for burn wounds. LK6C showed low allergenic potential and failed to provoke any sensitivity when administered to guinea pigs in the Magnusson-Kligman maximization test. When applied topically as a dressing, the medium-infused LK6C hydrogel accelerated re-epithelialization compared to controls. The peptide hydrogel is thus safe for topical application and promotes a superior rate and quality of wound healing. PMID:27600999

  4. Biofunctionalized electrospun silk mats as a topical bioactive dressing for accelerated wound healing.

    PubMed

    Schneider, A; Wang, X Y; Kaplan, D L; Garlick, J A; Egles, C

    2009-09-01

    Materials able to deliver topically bioactive molecules represent a new generation of biomaterials. In this article, we describe the use of silk mats, made of electrospun nanoscale silk fibers containing epidermal growth factor (EGF), for the promotion of wound healing processes. In our experiments, we demonstrated that EGF is incorporated into the silk mats and slowly released in a time-dependent manner (25% EGF release in 170h). We tested these materials using a new model of wounded human skin-equivalents displaying the same structure as human skin and able to heal using the same molecular and cellular mechanisms found in vivo. This human three-dimensional model allows us to demonstrate that the biofunctionalized silk mats, when placed on the wounds as a dressing, aid the healing by increasing the time of wound closure by the epidermal tongue by 90%. The preservation of the structure of the mats during the healing period as demonstrated by electronic microscopy, the biological action of the dressing, as well as the biocompatibility of the silk demonstrate that this biomaterial is a new and very promising material for medical applications, especially for patients suffering from chronic wounds.

  5. Polysaccharide-rich fraction of Termitomyces eurhizus accelerate healing of indomethacin induced gastric ulcer in mice.

    PubMed

    Chatterjee, Ananya; Khatua, Somanjana; Chatterjee, Sirshendu; Mukherjee, Shatavisa; Mukherjee, Atashi; Paloi, Soumitra; Acharya, Krishnendu; Bandyopadhyay, Sandip K

    2013-11-01

    The current study aims to determine the healing activity of water soluble polysaccharide-rich fraction of a wild mushroom, Termitomyces eurhizus (TEps) against the indomethacin induced gastric ulceration in mice model. Gastric tissue histology, myeloperoxidase (MPO) activity, cyclooxygenases (COX) 1 and 2 expression, prostaglandin E2 (PGE2) synthesis, and modulation of pro/anti inflammatory cytokines expression were studied for this purpose. Histological study shows that TEps (20 mg/kg) effectively healed the gastric ulceration. Based on biochemical results, the healing capacities of TEps could be attributed to reduction of MPO activity and protection of mucosal mucin content. Enhanced synthesis of PGE2 by modulation of COX-1 and COX-2 expression and a prominent shift of cytokines expression from pro (TNF-α, IL-1ß) to anti inflammatory (IL-10) side are also held responsible for ulcer healing. The preliminary study highlights the anti-ulcerogenic property of polysaccharide-rich fraction of Termitomyces eurhizus and opens an alternative cure for NSAID induced gastroduodenal diseases.

  6. The probiotic mixture VSL#3 accelerates gastric ulcer healing by stimulating vascular endothelial growth factor.

    PubMed

    Dharmani, Poonam; De Simone, Claudio; Chadee, Kris

    2013-01-01

    Studies assessing the effect and mechanism of probiotics on diseases of the upper gastrointestinal tract (GI) including gastric ulcers are limited despite extensive work and promising results of this therapeutic option for other GI diseases. In this study, we investigated the mechanisms by which the probiotic mixture VSL#3 (a mixture of eight probiotic bacteria including Lactobacilli, Bifidobacteria and Streptococcus species) heals acetic acid induced gastric ulcer in rats. VSL#3 was administered orally at low (6 × 10(9) bacteria) or high (1.2 × 10(10) bacteria) dosages from day 3 after ulcer induction for 14 consecutive days. VSL#3 treatments significantly enhanced gastric ulcer healing in a dose-dependent manner. To assess the mechanism(s) whereby VSL#3 exerted its protective effects, we quantified the gene expression of several pro-inflammatory cytokines, protein and expression of stomach mucin-Muc5ac, regulatory cytokine-IL-10, COX-2 and various growth factors. Of all the components examined, only expression and protein production of VEGF was increased 332-fold on day 7 in the ulcerated tissues of animals treated with VSL#3. Predictably, animals treated with VEGF neutralizing antibody significantly delayed gastric ulcer healing in VSL#3 treated animals. This is the first report to demonstrate high efficacy of the probiotic mixture VSL#3 in enhancing gastric ulcer healing. Probiotic efficacy was effective at higher concentrations of VSL#3 by specifically increasing the expression and production of angiogenesis promoting growth factors, primarily VEGF. PMID:23484048

  7. Curcuma purpurascens BI. rhizome accelerates rat excisional wound healing: involvement of Hsp70/Bax proteins, antioxidant defense, and angiogenesis activity

    PubMed Central

    Rouhollahi, Elham; Moghadamtousi, Soheil Zorofchian; Hajiaghaalipour, Fatemeh; Zahedifard, Maryam; Tayeby, Faezeh; Awang, Khalijah; Abdulla, Mahmood Ameen; Mohamed, Zahurin

    2015-01-01

    Purpose Curcuma purpurascens BI. is a member of Zingiberaceae family. The purpose of this study is to investigate the wound healing properties of hexane extract of C. purpurascens rhizome (HECP) against excisional wound healing in rats. Materials and methods Twenty four rats were randomly divided into 4 groups: A) negative control (blank placebo, acacia gum), B) low dose of HECP, C) high dose of HECP, and D) positive control, with 6 rats in each group. Full-thickness incisions (approximately 2.00 cm) were made on the neck area of each rat. Groups 1–4 were treated two-times a day for 20 days with blank placebo, HECP (100 mg/kg), HECP (200 mg/kg), and intrasite gel as a positive control, respectively. After 20 days, hematoxylin and eosin and Masson’s trichrome stainings were employed to investigate the histopathological alterations. Protein expressions of Bax and Hsp70 were examined in the wound tissues using immunohistochemistry analysis. In addition, levels of enzymatic antioxidants and malondialdehyde representing lipid peroxidation were measured in wound tissue homogenates. Results Macroscopic evaluation of wounds showed conspicuous elevation in wound contraction after topical administration of HECP at both doses. Moreover, histopathological analysis revealed noteworthy reduction in the scar width correlated with the enhanced collagen content and fibroblast cells, accompanied by a reduction of inflammatory cells in the granulation tissues. At the molecular level, HECP facilitates wound-healing process by downregulating Bax and upregulating Hsp70 protein at the wound site. The formation of new blood vessel was observed in Masson’s trichrome staining of wounds treated with HECP (100 and 200 mg/kg). In addition, HECP administration caused a significant surge in enzymatic antioxidant activities and a decline in lipid peroxidation. Conclusion These findings suggested that HECP accelerated wound-healing process in rats via antioxidant activity, angiogenesis

  8. 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.

  9. Prediction of fracture healing under axial loading, shear loading and bending is possible using distortional and dilatational strains as determining mechanical stimuli

    PubMed Central

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

    2013-01-01

    Numerical models of secondary fracture healing are based on mechanoregulatory algorithms that use distortional strain alone or in combination with either dilatational strain or fluid velocity as determining stimuli for tissue differentiation and development. Comparison of these algorithms has previously suggested that healing processes under torsional rotational loading can only be properly simulated by considering fluid velocity and deviatoric strain as the regulatory stimuli. We hypothesize that sufficient calibration on uncertain input parameters will enhance our existing model, which uses distortional and dilatational strains as determining stimuli, to properly simulate fracture healing under various loading conditions including also torsional rotation. Therefore, we minimized the difference between numerically simulated and experimentally measured courses of interfragmentary movements of two axial compressive cases and two shear load cases (torsional and translational) by varying several input parameter values within their predefined bounds. The calibrated model was then qualitatively evaluated on the ability to predict physiological changes of spatial and temporal tissue distributions, based on respective in vivo data. Finally, we corroborated the model on five additional axial compressive and one asymmetrical bending load case. We conclude that our model, using distortional and dilatational strains as determining stimuli, is able to simulate fracture-healing processes not only under axial compression and torsional rotation but also under translational shear and asymmetrical bending loading conditions. PMID:23825112

  10. Investigation of rat bone fracture healing using pulsed 1.5 MHz, 30 mW/cm(2) burst ultrasound--axial distance dependency.

    PubMed

    Fung, Chak-Hei; Cheung, Wing-Hoi; Pounder, Neill M; de Ana, F Javier; Harrison, Andrew; Leung, Kwok-Sui

    2014-03-01

    This study investigated the effect of LIPUS on fracture healing when fractures were exposed to ultrasound at three axial distances: z=0 mm, 60 mm, and 130 mm. We applied LIPUS to rat fracture at these three axial distances mimicking the exposure condition of human fractures at different depths under the soft tissue. Measurement of LIPUS shows pressure variations in near field (nearby transducer); uniform profile was found beyond it (far field). We asked whether different positions of the fracture within the ultrasound field cause inconsistent biological effect during the healing process. Closed femoral fractured Sprague-Dawley rats were randomized into control, near-field (0mm), mid-near field (60 mm) or far-field (130 mm) groups. Daily LIPUS treatment (plane, but apodized source, see details in the text; 2.2 cm in diameter; 1.5 MHz sine waves repeating at 1 kHz PRF; spatial average temporal average intensity, ISATA=30 mW/cm(2)) was given to fracture site at the three axial distances. Weekly radiographs and endpoint microCT, histomorphometry, and mechanical tests were performed. The results showed that the 130 mm group had the highest tissue mineral density; and significantly higher mechanical properties than control at week 4. The 60 mm and 0 mm groups had significantly higher (i.e. p<0.05) woven bone percentage than control group in radiological, microCT and histomorphometry measurements. In general, LIPUS at far field augmented callus mineralization and mechanical properties; while near field and mid-near field enhanced woven bone formation. Our results indicated the therapeutic effect of LIPUS is dependent on the axial distance of the ultrasound beam. Therefore, the depth of fracture under the soft tissue affects the biological effect of LIPUS. Clinicians have to be aware of the fracture depth when LIPUS is applied transcutaneously.

  11. Investigation of rat bone fracture healing using pulsed 1.5 MHz, 30 mW/cm(2) burst ultrasound--axial distance dependency.

    PubMed

    Fung, Chak-Hei; Cheung, Wing-Hoi; Pounder, Neill M; de Ana, F Javier; Harrison, Andrew; Leung, Kwok-Sui

    2014-03-01

    This study investigated the effect of LIPUS on fracture healing when fractures were exposed to ultrasound at three axial distances: z=0 mm, 60 mm, and 130 mm. We applied LIPUS to rat fracture at these three axial distances mimicking the exposure condition of human fractures at different depths under the soft tissue. Measurement of LIPUS shows pressure variations in near field (nearby transducer); uniform profile was found beyond it (far field). We asked whether different positions of the fracture within the ultrasound field cause inconsistent biological effect during the healing process. Closed femoral fractured Sprague-Dawley rats were randomized into control, near-field (0mm), mid-near field (60 mm) or far-field (130 mm) groups. Daily LIPUS treatment (plane, but apodized source, see details in the text; 2.2 cm in diameter; 1.5 MHz sine waves repeating at 1 kHz PRF; spatial average temporal average intensity, ISATA=30 mW/cm(2)) was given to fracture site at the three axial distances. Weekly radiographs and endpoint microCT, histomorphometry, and mechanical tests were performed. The results showed that the 130 mm group had the highest tissue mineral density; and significantly higher mechanical properties than control at week 4. The 60 mm and 0 mm groups had significantly higher (i.e. p<0.05) woven bone percentage than control group in radiological, microCT and histomorphometry measurements. In general, LIPUS at far field augmented callus mineralization and mechanical properties; while near field and mid-near field enhanced woven bone formation. Our results indicated the therapeutic effect of LIPUS is dependent on the axial distance of the ultrasound beam. Therefore, the depth of fracture under the soft tissue affects the biological effect of LIPUS. Clinicians have to be aware of the fracture depth when LIPUS is applied transcutaneously. PMID:24239510

  12. Collective review: bioactive implants coated with poly(D,L-lactide) and growth factors IGF-I, TGF-beta1, or BMP-2 for stimulation of fracture healing.

    PubMed

    Schmidmaier, Gerhard; Lucke, Martin; Schwabe, Philipp; Raschke, Michael; Haas, Norbert P; Wildemann, Britt

    2006-01-01

    Demographic data reveal that due to the increasing aging of the population, complications with the musculoskeletal system will increase in the next years. One major problem in orthopedic and trauma surgery are the delayed healing or non-unions of long bone fractures. The exogenous application of growth factors can stimulate the bone healing to reduce these complications. Beside the choice of the optimal growth factor the application system is important. Therefore, we developed a new bioactive coating method for implants, which is based on a biodegradable poly(D,L-lactide) (coating thickness: 10 mum). This coating allows the incorporation of growth factors and the controlled release of these factors during the healing process without the need for further devices. The effect of different growth factors (IGF-I, TGF-beta1, and BMP-2) locally released from coated intramedullary implants on fracture healing was investigated with biomechanical and histological analysis in rats. All investigated growth factors stimulated the fracture healing as assessed with biomechanical tests and histological analysis. The local application of combined IGF-I and TGF-beta1 had the most stimulating effect on fracture healing, followed by the effect of BMP-2, IGF-I, and TGF-beta1 alone. Bioactive coating of biomechanical well-established implants can on the one hand stabilize the fracture and on the other hand stimulate healing processes to increase healing and to reduce the rate of complications.

  13. A unique combination of infrared and microwave radiation accelerates wound healing.

    PubMed

    Schramm, J Mark; Warner, Dave; Hardesty, Robert A; Oberg, Kerby C

    2003-01-01

    Light or electromagnetic radiation has been reported to enhance wound healing. The use of selected spectra, including infrared and microwave, has been described; however, no studies to date have examined the potential benefit of combining these spectra. In this study, a device that emits electromagnetic radiation across both the infrared and microwave ranges was used. To test the effects of this unique electromagnetic radiation spectrum on wound healing, two clinically relevant wound-healing models (i.e., tensile strength of simple incisions and survival of McFarlane flaps) were selected. After the creation of a simple full-thickness incision (n = 35 rats) or a caudally based McFarlane flap (n = 33 rats), animals were randomly assigned to one of three treatment groups: untreated control, infrared, or combined electromagnetic radiation. Treatment was administered for 30 minutes, twice daily for 18 days in animals with simple incisions, and 15 days in animals with McFarlane flaps. The wound area or flap was harvested and analyzed, blinded to the treatment regimens. A p value of less than 0.05 obtained by analysis of variance was considered to be statistically significant. Animals receiving combined electromagnetic radiation demonstrated increased tensile strength (2.62 N/mm2) compared with animals receiving infrared radiation (2.36 N/mm2) or untreated controls (1.73 N/mm2, p < 0.001). Animals with McFarlane flaps receiving combined electromagnetic radiation had increased flap survival (78.0 percent) compared with animals receiving infrared radiation (69.7 percent) and untreated controls (63.1 percent, p < 0.01). Thus, combined electromagnetic radiation provided a distinct advantage in wound healing that might augment current treatment regimens.

  14. An innovative bi-layered wound dressing made of silk and gelatin for accelerated wound healing.

    PubMed

    Kanokpanont, Sorada; Damrongsakkul, Siriporn; Ratanavaraporn, Juthamas; Aramwit, Pornanong

    2012-10-15

    In this study, the novel silk fibroin-based bi-layered wound dressing was developed. Wax-coated silk fibroin woven fabric was introduced as a non-adhesive layer while the sponge made of sericin and glutaraldehyde-crosslinked silk fibroin/gelatin was fabricated as a bioactive layer. Wax-coated silk fibroin fabrics showed improved mechanical properties compared with the non-coated fabrics, but less adhesive than the commercial wound dressing mesh. This confirmed by results of peel test on both the partial- and full-thickness wounds. The sericin-silk fibroin/gelatin spongy bioactive layers showed homogeneous porous structure and controllable biodegradation depending on the degree of crosslinking. The bi-layered wound dressings supported the attachment and proliferation of L929 mouse fibroblasts, particularly for the silk fibroin/gelatin ratio of 20/80 and 0.02% GA crosslinked. Furthermore, we proved that the bi-layered wound dressings promoted wound healing in full-thickness wounds, comparing with the clinically used wound dressing. The wounds treated with the bi-layered wound dressings showed the greater extent of wound size reduction, epithelialization, and collagen formation. The superior properties of the silk fibroin-based bi-layered wound dressings compared with those of the clinically used wound dressings were less adhesive and had improved biological functions to promote cell activities and wound healing. This novel bi-layered wound dressing should be a good candidate for the healing of full-thickness wounds.

  15. Melt fracturing and healing: A mechanism for degassing and origin of silicic obsidian

    USGS Publications Warehouse

    Cabrera, A.; Weinberg, R.F.; Wright, H.M.N.; Zlotnik, S.; Cas, Ray A.F.

    2011-01-01

    We present water content transects across a healed fault in pyroclastic obsidian from Lami pumice cone, Lipari, Italy, using synchrotron Fourier transform infrared spectroscopy. Results indicate that rhyolite melt degassed through the fault surface. Transects define a trough of low water content coincident with the fault trace, surrounded on either side by high-water-content plateaus. Plateaus indicate that obsidian on either side of the fault equilibrated at different pressure-temperature (P-T) conditions before being juxtaposed. The curves into the troughs indicate disequilibrium and water loss through diffusion. If we assume constant T, melt equilibrated at pressures differing by 0.74 MPa before juxtaposition, and the fault acted as a low-P permeable path for H2O that diffused from the glass within time scales of 10 and 30 min. Assuming constant P instead, melt on either side could have equilibrated at temperatures differing by as much as 100 ??C, before being brought together. Water content on the fault trace is particularly sensitive to post-healing diffusion. Its preserved value indicates either higher temperature or lower pressure than the surroundings, indicative of shear heating and dynamic decompression. Our results reveal that water contents of obsidian on either side of the faults equilibrated under different P-T conditions and were out of equilibrium with each other when they were juxtaposed due to faulting immediately before the system was quenched. Degassing due to faulting could be linked to cyclical seismic activity and general degassing during silicic volcanic activity, and could be an efficient mechanism of producing low-water-content obsidian. ?? 2011 Geological Society of America.

  16. Effects of Low-Dose Microwave on Healing of Fractures with Titanium Alloy Internal Fixation: An Experimental Study in a Rabbit Model

    PubMed Central

    Zhang, Han; Fu, Tengfei; Jiang, Lan; Bai, Yuehong

    2013-01-01

    Background Microwave is a method for improving fracture repair. However, one of the contraindications for microwave treatment listed in the literature is surgically implanted metal plates in the treatment field. The reason is that the reflection of electromagnetic waves and the eddy current stimulated by microwave would increase the temperature of magnetic implants and cause heat damage in tissues. Comparing with traditional medical stainless steel, titanium alloy is a kind of medical implants with low magnetic permeability and electric conductivity. But the effects of microwave treatment on fracture with titanium alloy internal fixation in vivo were not reported. The aim of this article was to evaluate the security and effects of microwave on healing of a fracture with titanium alloy internal fixation. Methods Titanium alloy internal fixation systems were implanted in New Zealand rabbits with a 3.0 mm bone defect in the middle of femur. We applied a 30-day microwave treatment (2,450MHz, 25W, 10 min per day) to the fracture 3 days after operation. Temperature changes of muscle tissues around implants were measured during the irradiation. Normalized radiographic density of the fracture gap was measured on the 10th day and 30th day of the microwave treatment. All of the animals were killed after 10 and 30 days microwave treatment with histologic and histomorphometric examinations performed on the harvested tissues. Findings The temperatures did not increase significantly in animals with titanium alloy implants. The security of microwave treatment was also supported by histology of muscles, nerve and bone around the implants. Radiographic assessment, histologic and histomorphometric examinations revealed significant improvement in the healing bone. Conclusion Our results suggest that, in the healing of fracture with titanium alloy internal fixation, a low dose of microwave treatment may be a promising method. PMID:24086626

  17. A novel coupled system of non-local integro-differential equations modelling Young's modulus evolution, nutrients' supply and consumption during bone fracture healing

    NASA Astrophysics Data System (ADS)

    Lu, Yanfei; Lekszycki, Tomasz

    2016-10-01

    During fracture healing, a series of complex coupled biological and mechanical phenomena occurs. They include: (i) growth and remodelling of bone, whose Young's modulus varies in space and time; (ii) nutrients' diffusion and consumption by living cells. In this paper, we newly propose to model these evolution phenomena. The considered features include: (i) a new constitutive equation for growth simulation involving the number of sensor cells; (ii) an improved equation for nutrient concentration accounting for the switch between Michaelis-Menten kinetics and linear consumption regime; (iii) a new constitutive equation for Young's modulus evolution accounting for its dependence on nutrient concentration and variable number of active cells. The effectiveness of the model and its predictive capability are qualitatively verified by numerical simulations (using COMSOL) describing the healing of bone in the presence of damaged tissue between fractured parts.

  18. Effects of Platelet Rich Plasma on Healing Rate of Long Bone Non-union Fractures: A Randomized Double-Blind Placebo Controlled Clinical Trial

    PubMed Central

    Ghaffarpasand, Fariborz; Shahrezaei, Mostafa; Dehghankhalili, Maryam

    2016-01-01

    Objective: To determine the effects of platelet rich plasma PRP on healing rates of long bone non-union fracture. Method: This was a randomized double-blind placebo controlled clinical trial being performed in a 12-month period. We included 75 adult (>18 years) patients suffering from long bone (Femur, Tibia, Humerus and Ulna) non-union fracture who were randomly assigned to receive 5mL PRP (n=37) or 5mL normal saline as placebo (n=38) in the site of fracture after intramedullary nailing or open reduction and internal fixation (ORIF) along with autologous bone graft. Patients were followed each 45 days till 9 months and were evaluated both clinically and radiologically in each visit. The healing rate, failure rate, incidence of infection, mal-union and limb shortening were recorded and compared between groups after 9 months of follow-up. Results: The healing rate was significantly higher in PRP group compared to placebo (81.1% vs. 55.3%; p=0.025). The limb shortening was significantly higher in those who received placebo (2.61±1.5 vs. 1.88±1.2mm; p=0.030). Injection of PRP was also associated with lower pain scores ( p=0.003) and shorter healing duration ( p=0.046). The surgical site infection ( p=0.262) and mal-union rate ( p=0.736) were comparable between groups. Conclusion: Application of PRP along with autologous bone graft in the site of non-union of long bone after intramedullary nailing or ORIF results in higher cure rate, shorter healing duration, lower limb shortening and less postoperative pain. Higher infection rate might be a complication of PRP application. Clinical Trial Registry: This trial is registered with the Iranian Clinical Trials Registry (IRCT201208262445N1; www.irct.ir). PMID:27540547

  19. PEDF promotes self-renewal of limbal stem cell and accelerates corneal epithelial wound healing.

    PubMed

    Ho, Tsung-Chuan; Chen, Show-Li; Wu, Ju-Yun; Ho, Mei-Ying; Chen, Lee-Jen; Hsieh, Jui-Wen; Cheng, Huey-Chuan; Tsao, Yeou-Ping

    2013-09-01

    Limbal epithelial stem cell (LSC) transplantation is a prevalent therapeutic method for patients with LSC deficiency. The maintenance of stem cell characteristics in the process of culture expansion is critical for the success of ocular surface reconstruction. Pigment epithelial-derived factor (PEDF) increased the numbers of holoclone in LSC monolayer culture and preserved the stemness of LSC in suspension culture by evidence of ΔNp63α, Bmi-1, and ABCG2 expression. BrdU pulse-labeling assay also demonstrated that PEDF stimulated LSCs proliferation. In air-lift culture of limbal equivalent, PEDF was capable of increasing the numbers of ΔNp63α-positive cells. The mitogenic effect of PEDF was found to be mediated by the phosphorylations of p38 MAPK and STAT3 in LSCs. Synthetic 44-mer PEDF (residues 78-121) was as effective as the full length PEDF in LSC expansion in suspension culture and limbal equivalent formation, as well as the activation of p38 MAPK and STAT3. In mice subjecting to mechanical removal of cornea epithelium, 44-mer PEDF facilitated corneal wound healing. Microscopically, 44-mer PEDF advanced the early proliferative response in limbus, increased the proliferation of ΔNp63α-positive cells both in limbus and in epithelial healing front, and assisted the repopulation of limbus in the late phase of wound healing. In conclusion, the capability of expanding LSC in cell culture and in animal indicates the potential of PEDF and its fragment (e.g., 44-mer PEDF) in ameliorating limbal stem cell deficiency; and their uses as therapeutics for treating corneal wound.

  20. G-CSF Administration after the Intraosseous Infusion of Hypertonic Hydroxyethyl Starches Accelerating Wound Healing Combined with Hemorrhagic Shock

    PubMed Central

    Huang, Hong; Liu, Jiejie; Hao, Haojie; Tong, Chuan; Ti, Dongdong; Liu, Huiling; Song, Haijing; Jiang, Chaoguang; Fu, Xiaobing; Han, Weidong

    2016-01-01

    Objective. To evaluate the therapeutic effects of G-CSF administration after intraosseous (IO) resuscitation in hemorrhagic shock (HS) combined with cutaneous injury rats. Methods. The rats were randomly divided into four groups: (1) HS with resuscitation (blank), (2) HS with resuscitation + G-CSF (G-CSF, 200 μg/kg body weight, subcutaneous injection), (3) HS with resuscitation + normal saline solution injection (normal saline), and (4) HS + G-CSF injection without resuscitation (Unres/G-CSF). To estimate the treatment effects, the vital signs of alteration were first evaluated, and then wound closure rates and homing of MSCs and EPCs to the wound skins and vasculogenesis were measured. Besides, inflammation and vasculogenesis related mRNA expressions were also examined. Results. IO infusion hypertonic hydroxyethyl starch (HHES) exhibited beneficial volume expansion roles and G-CSF administration accelerated wound healing 3 days ahead of other groups under hemorrhagic shock. Circulating and the homing of MSCs and EPCs at wound skins were significantly elevated at 6 h after G-CSF treatment. Inflammation was declined since 3 d while angiogenesis was more obvious in G-CSF treated group on day 9. Conclusions. These results suggested that the synergistical application of HHES and G-CSF has life-saving effects and is beneficial for improving wound healing in HS combined with cutaneous injury rats. PMID:26989687

  1. Electrospun emodin polyvinylpyrrolidone blended nanofibrous membrane: a novel medicated biomaterial for drug delivery and accelerated wound healing.

    PubMed

    Dai, Xin-Yi; Nie, Wei; Wang, Yong-Chun; Shen, Yi; Li, Yan; Gan, Shu-Jie

    2012-11-01

    In this work, blended nanofibrous membranes were prepared by an electrospinning technique with polyvinylpyrrolidone (PVP) K90 as the filament-forming polymer, and emodin, an extract of polygonum cuspidate known as a medicinal plant, as the treatment drug. Detailed analysis of the blended nanofibrous membrane by scanning electron microscopy, Differential scanning calorimetry and X-ray diffraction revealed that emodin was well distributed in the ultrafine fibers in the form of amorphous nanosolid dispersions. Results from attenuated total reflectance Fourier transform infrared spectra suggested that the main interactions between PVP and emodin might be mediated through hydrogen bonding. In vitro dissolution tests proved that the blended nanofibrous membrane produced more desired release kinetics of the entrapped drug (emodin) as compared to the pure drug. Furthermore, wound healing test and histological evaluation revealed that the emodin loaded nanofibrous membrane to be more effective as a healing accelerator thereby proving potential strategies to develop composite drug delivery system as well as promising materials for future therapeutic biomedical applications.

  2. Dehydrated Human Amnion/Chorion Grafts May Accelerate the Healing of Ulcers on Free Flaps in Patients With Venous Insufficiency and/or Lymphedema

    PubMed Central

    Friedman, Alex

    2016-01-01

    Objective: Ulceration of free flaps in patients with venous insufficiency and/or lymphedema is an uncommon but challenging problem. We hypothesized that dehydrated human amnion/chorion membrane (Epifix) grafts would accelerate healing of these challenging ulcers. Methods: Retrospective analysis of prospectively acquired data identified 8 lower extremity free flaps with ulcerations in the context of venous insufficiency and/or lymphedema. The first 4 were flaps that had been treated with conservative wound care to healing. The second group was treated conservatively initially but then converted to treatment with dehydrated human amnion/chorion membrane grafts. The primary endpoint was time to healing. Results: Comparison of Kaplan-Meier survival curves revealed a significant difference between the conservatively and dehydrated human amnion/chorion membrane–treated flap ulcers, favoring graft treatment (P = .0361). In those ulcers that healed, the average time to healing was 87 days for the conservative treatment group and 33 days for the dehydrated human amnion/chorion membrane treatment group (with an average of 1.7 grafts per ulcer). Conclusions: Dehydrated human amnion/chorion membrane may accelerate healing of ulcers on lower extremity free flaps in patient with lymphedema and/or venous disease in the treated leg.

  3. Stromal cell-derived factor-1 receptor CXCR4-overexpressing bone marrow mesenchymal stem cells accelerate wound healing by migrating into skin injury areas.

    PubMed

    Yang, Dazhi; Sun, Shijin; Wang, Zhengguo; Zhu, Peifang; Yang, Zailiang; Zhang, Bo

    2013-06-01

    Stromal cell-derived factor-1 (SDF-1) and its membrane receptor C-X-C chemokine receptor type 4 (CXCR4) are involved in the homing and migration of multiple stem cell types, neovascularization, and cell proliferation. This study investigated the hypothesis that bone marrow-derived mesenchymal stem cells (BMSCs) accelerate skin wound healing in the mouse model by overexpression of CXCR4 in BMSCs. We compared SDF-1 expression and skin wound healing times of BALB/c mice, severe combined immunodeficiency (SCID) mice, and immune system-deficient nude mice after (60)Co radiation-induced injury of their bone marrow. The occurrence of transplanted adenovirus-transfected CXCR4-overexpressing male BMSCs in the wound area was compared with the occurrence of untransfected male BALB/c BMSCs in (60)Co-irradiated female mice skin wound healing areas by Y chromosome marker analyses. The wound healing time of BALB/c mice was 14.00±1.41 days, whereas for the nude and SCID mice it was 17.16±1.17 days and 19.83±0.76 days, respectively. Male BMSCs could be detected in the surrounding areas of (60)Co-irradiated female BALB/c mice wounds, and CXCR4-overexpressing BMSCs accelerated the wound healing time. CXCR4-overexpressing BMSCs migrate in an enhanced manner to skin wounds in a SDF-1-expression-dependent manner, thereby reducing the skin wound healing time.

  4. Dehydrated Human Amnion/Chorion Grafts May Accelerate the Healing of Ulcers on Free Flaps in Patients With Venous Insufficiency and/or Lymphedema

    PubMed Central

    Friedman, Alex

    2016-01-01

    Objective: Ulceration of free flaps in patients with venous insufficiency and/or lymphedema is an uncommon but challenging problem. We hypothesized that dehydrated human amnion/chorion membrane (Epifix) grafts would accelerate healing of these challenging ulcers. Methods: Retrospective analysis of prospectively acquired data identified 8 lower extremity free flaps with ulcerations in the context of venous insufficiency and/or lymphedema. The first 4 were flaps that had been treated with conservative wound care to healing. The second group was treated conservatively initially but then converted to treatment with dehydrated human amnion/chorion membrane grafts. The primary endpoint was time to healing. Results: Comparison of Kaplan-Meier survival curves revealed a significant difference between the conservatively and dehydrated human amnion/chorion membrane–treated flap ulcers, favoring graft treatment (P = .0361). In those ulcers that healed, the average time to healing was 87 days for the conservative treatment group and 33 days for the dehydrated human amnion/chorion membrane treatment group (with an average of 1.7 grafts per ulcer). Conclusions: Dehydrated human amnion/chorion membrane may accelerate healing of ulcers on lower extremity free flaps in patient with lymphedema and/or venous disease in the treated leg. PMID:27648116

  5. Fracture Toughness of Carbon Fiber Composites Containing Various Fiber Sizings and a Puncture Self-Healing Thermoplastic Matrix

    NASA Technical Reports Server (NTRS)

    Cano, Roberto J.; Grimsley, Brian W.; Ratcliffe, James G.; Gordon, Keith L.; Smith, Joseph G.; Siochi, Emilie J.

    2015-01-01

    Ongoing efforts at NASA Langley Research Center (LaRC) have resulted in the identification of several commercially available thermoplastic resin systems which self-heal after ballistic impact and through penetration. One of these resins, polybutylene graft copolymer (PBg), was selected as a matrix for processing with unsized carbon fibers to fabricate reinforced composites for further evaluation. During process development, data from thermo-physical analyses was utilized to determine a processing cycle to fabricate laminate panels, which were analyzed by photo microscopy and acid digestion. The process cycle was further optimized based on these results to fabricate panels for mechanical property characterization. The results of the processing development effort of this composite material, as well as the results of the mechanical property characterization, indicated that bonding between the fiber and PBg was not adequate. Therefore, three sizings were investigated in this work to assess their potential to improve fiber/matrix bonding compared to previously tested unsized IM7 fiber. Unidirectional prepreg was made at NASA LaRC from three sized carbon fibers and utilized to fabricate test coupons that were tested in double cantilever beam configurations to determine GIc fracture toughness.

  6. Loss of Epithelial Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Accelerates Skin Wound Healing in Mice

    PubMed Central

    Kalucka, Joanna; Ettinger, Andreas; Franke, Kristin; Mamlouk, Soulafa; Singh, Rashim Pal; Farhat, Katja; Muschter, Antje; Olbrich, Susanne; Breier, Georg; Katschinski, Dörthe M.; Huttner, Wieland; Weidemann, Alexander

    2013-01-01

    Skin wound healing in mammals is a complex, multicellular process that depends on the precise supply of oxygen. Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization. Hence, this study was aimed at understanding the role of PHD2 in cutaneous wound healing using different lines of conditionally deficient mice specifically lacking PHD2 in inflammatory, vascular, or epidermal cells. Interestingly, PHD2 deficiency only in keratinocytes and not in myeloid or endothelial cells was found to lead to faster wound closure, which involved enhanced migration of the hyperproliferating epithelium. We demonstrate that this effect relies on the unique expression of β3-integrin in the keratinocytes around the tip of the migrating tongue in an HIF1α-dependent manner. Furthermore, we show enhanced proliferation of these cells in the stratum basale, which is directly related to their attenuated transforming growth factor β signaling. Thus, loss of the central oxygen sensor PHD2 in keratinocytes stimulates wound closure by prompting skin epithelial cells to migrate and proliferate. Inhibition of PHD2 could therefore offer novel therapeutic opportunities for the local treatment of cutaneous wounds. PMID:23798557

  7. Delayed Fracture Healing and Increased Callus Adiposity in a C57BL/6J Murine Model of Obesity-Associated Type 2 Diabetes Mellitus

    PubMed Central

    Brown, Matthew L.; Yukata, Kiminori; Farnsworth, Christopher W.; Chen, Ding-Geng; Awad, Hani; Hilton, Matthew J.; O'Keefe, Regis J.; Xing, Lianping; Mooney, Robert A.; Zuscik, Michael J.

    2014-01-01

    Introduction Impaired healing and non-union of skeletal fractures is a major public health problem, with morbidity exacerbated in patients with diabetes mellitus (DM). DM is prevalent worldwide and affects approximately 25.8 million US adults, with >90% having obesity-related type 2 DM (T2DM). While fracture healing in type 1 DM (T1DM) has been studied using animal models, an investigation into delayed healing in an animal model of T2DM has not yet been performed. Methods Male C57BL/6J mice at 5 weeks of age were placed on either a control lean diet or an experimental high-fat diet (HFD) for 12 weeks. A mid-diaphyseal open tibia fracture was induced at 17 weeks of age and a spinal needle was used for intra-medullary fixation. Mice were sacrificed at days 7, 10, 14, 21, 28, and 35 for micro-computed tomography (μCT), histology-based histomorphometry and molecular analyses, and biomechanical testing. Results HFD-fed mice displayed increased body weight and impaired glucose tolerance, both characteristic of T2DM. Compared to control mice, HFD-fed mice with tibia fractures showed significantly (p<0.001) decreased woven bone at day 28 by histomorphometry and significantly (p<0.01) decreased callus bone volume at day 21 by μCT. Interestingly, fracture calluses contained markedly increased adiposity in HFD-fed mice at days 21, 28, and 35. HFD-fed mice also showed increased PPARγ immunohistochemical staining at day 14. Finally, calluses from HFD-fed mice at day 35 showed significantly (p<0.01) reduced torsional rigidity compared to controls. Discussion Our murine model of T2DM demonstrated delayed fracture healing and weakened biomechanical properties, and was distinctly characterized by increased callus adiposity. This suggests altered mesenchymal stem cell fate determination with a shift to the adipocyte lineage at the expense of the osteoblast lineage. The up-regulation of PPARγ in fracture calluses of HFD-fed mice is likely involved in the proposed fate switching

  8. Hydrogen-Rich Water Intake Accelerates Oral Palatal Wound Healing via Activation of the Nrf2/Antioxidant Defense Pathways in a Rat Model.

    PubMed

    Tamaki, Naofumi; Orihuela-Campos, Rita Cristina; Fukui, Makoto; Ito, Hiro-O

    2016-01-01

    The wound healing process attempts to restore the integrity and function of the injured tissue. Additionally, proinflammatory cytokines, growth factors, and oxidative stress play important roles in wound healing. The aim of this study was to determine whether hydrogen-rich water intake induces the activation of the Nrf2/antioxidant defense pathway in rat palatal tissue, thereby reducing systemic oxidative stress and proinflammatory cytokine levels and promoting healing-associated genes. A circular excisional wound was created in the oral palatal region, and the wound healing process was observed. The rats were divided into two experimental groups in which either hydrogen-rich water or distilled water was consumed. In the drinking hydrogen-rich water, the palatal wound healing process was accelerated compared to that in the control group. As molecular hydrogen upregulated the Nrf2 pathway, systemic oxidative stresses were decreased by the activation of antioxidant activity. Furthermore, hydrogen-rich water intake reduced proinflammatory cytokine levels and promoted the expression of healing-associated factors in rat palatal tissue. In conclusion, hydrogen-rich water intake exhibited multiple beneficial effects through activation of the Nrf2/antioxidant defense pathway. The results of this study support the hypothesis that oral administration of hydrogen-rich water benefits the wound healing process by decreasing oxidative stress and inflammatory responses.

  9. Hydrogen-Rich Water Intake Accelerates Oral Palatal Wound Healing via Activation of the Nrf2/Antioxidant Defense Pathways in a Rat Model

    PubMed Central

    Orihuela-Campos, Rita Cristina; Fukui, Makoto; Ito, Hiro-O

    2016-01-01

    The wound healing process attempts to restore the integrity and function of the injured tissue. Additionally, proinflammatory cytokines, growth factors, and oxidative stress play important roles in wound healing. The aim of this study was to determine whether hydrogen-rich water intake induces the activation of the Nrf2/antioxidant defense pathway in rat palatal tissue, thereby reducing systemic oxidative stress and proinflammatory cytokine levels and promoting healing-associated genes. A circular excisional wound was created in the oral palatal region, and the wound healing process was observed. The rats were divided into two experimental groups in which either hydrogen-rich water or distilled water was consumed. In the drinking hydrogen-rich water, the palatal wound healing process was accelerated compared to that in the control group. As molecular hydrogen upregulated the Nrf2 pathway, systemic oxidative stresses were decreased by the activation of antioxidant activity. Furthermore, hydrogen-rich water intake reduced proinflammatory cytokine levels and promoted the expression of healing-associated factors in rat palatal tissue. In conclusion, hydrogen-rich water intake exhibited multiple beneficial effects through activation of the Nrf2/antioxidant defense pathway. The results of this study support the hypothesis that oral administration of hydrogen-rich water benefits the wound healing process by decreasing oxidative stress and inflammatory responses. PMID:26798423

  10. Yogurt containing Lactobacillus gasseri OLL 2716 (LG21 yogurt) accelerated the healing of acetic acid-induced gastric ulcer in rats.

    PubMed

    Uchida, Masayuki; Shimizu, Kimiko; Kurakazu, Keiko

    2010-01-01

    We have reported that LG21 yogurt containing Lactobacillus gasseri OLL 2716 (LG21 yogurt) inhibits the formation of HCl-induced acute gastric lesions through the generation of prostaglandin E₂. This study aimed to determine the role of viable Lactobacillus in the healing of acetic acid-induced chronic gastric ulcer. LG21 yogurt or γ-ray radiated LG21 yogurt was administered orally twice a day for 10 d at a dose of 5 ml/kg. LG21 yogurt significantly accelerated the healing of the ulcer, but γ-ray radiated LG21 yogurt did not. However, both yogurts significantly inhibited HCl-induced gastric erosive lesions and enhanced the generation of gastric mucosal prostaglandin E₂. From the above results, it was found that viable bacteria are needed to accelerate the healing of chronic gastric ulcer, but not to inhibit gastric lesions.

  11. Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis

    PubMed Central

    Bilic, R.; Simic, P.; Jelic, M.; Stern-Padovan, R.; Dodig, D.; van Meerdervoort, H. Pompe; Martinovic, S.; Ivankovic, D.; Pecina, M.

    2006-01-01

    We randomly assigned 17 patients with scaphoid non-union at the proximal pole to three treatment groups: (1) autologous iliac graft (n=6), (2) autologous iliac graft + osteogenic protein-1 (OP-1; n=6), and (3) allogenic iliac graft + OP-1 (n=5). Radiographic, scintigraphic, and clinical assessments were performed throughout the follow-up period of 24 months. OP-1 improved the performance of both autologous and allogenic bone implants and reduced radiographic healing time to 4 weeks compared with 9 weeks in group 1. Helical CT scans and scintigraphy showed that in OP-1-treated patients sclerotic bone was replaced by well-vascularised bone. The addition of OP-1 to allogenic bone implant equalised the clinical outcome with the autologous graft procedure. Consequently the harvesting of autologous graft can be avoided. PMID:16506027

  12. Polymer cable/grip-plate system with locking screws for stable fixation to promote healing of trochanteric osteotomies or fractures in revision total hip arthroplasty.

    PubMed

    Berend, Keith R; Willen, Jacob L; Morris, Michael J; Adams, Joanne B; Lombardi, Adolph V

    2014-11-01

    Multiple methods have been proposed to establish stable fixation to promote healing of trochanteric osteotomies or fractures in revision total hip arthroplasty (revTHA), from wiring techniques through cable-plate systems with or without supplemental locking screws. The purpose of this study is to report the clinical results of a single cable-plate system with locked screw fixation in revTHA. Between 2009 and 2012, 27 grip-plates (Supercable® System, Kinamed Inc., Camarillo, CA) were used in 26 patients in 27 revTHA procedures. Utilization was 12 1-hole (50 mm) grip-plates, 10 2-hole (135 mm) grip-plates, four 4-hole (190 mm) grip-plates, and one 6-hole (245 mm) grip-plate. There were 14 women and 12 men. Age averaged 63.2 years and BMI averaged 29.4 kg/m2. At average 2.5 year follow-up, grip-plate fixation was considered successful in 22 hips (81%) with five failures. Three failures consisted of 50 mm/short grip-plates used in one trochanteric slide, and two intraoperative trochanteric fractures during revTHA. The two additional failures were related to pre-revision trochanteric avulsion from bony necrosis of the proximal femur. An additional three grip-plates were removed electively for soft-tissue irritation and pain but with successful fixation and bony healing. Thus 70% of hips were free of reoperation related to the grip-plate. All other hips had successful fixation and the grip-plate was not symptomatic. In this study, the cable-grip system and isoelastic Supercables provided reliable fixation for adequate healing of difficult ETO and trochanteric fractures with an 81% rate of mechanical success with radiographic and clinical healing observed.

  13. Exogenous Ghrelin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats

    PubMed Central

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Ceranowicz, Dagmara; Gałązka, Krystyna; Bonior, Joanna; Jaworek, Jolanta; Bartuś, Krzysztof; Gil, Krzysztof; Olszanecki, Rafał; Dembiński, Artur

    2016-01-01

    Previous studies have shown that ghrelin reduces colonic inflammation induced by trinitrobenzene sulfonic acid and dextran sodium sulfate. In the present study we determined the effect of treatment with ghrelin on the course of acetic acid-induced colitis in rats. Rectal administration of 3% acetic acid solution led to induction of colitis in all animals. Damage of the colonic wall was accompanied by an increase in mucosal concentration of pro-inflammatory interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well mucosal activity of myeloperoxidase. Moreover, induction of colitis led to a reduction in colonic blood flow and DNA synthesis. Administration of ghrelin after induction of colitis led to faster regeneration of the colonic wall and reduction in colonic levels of IL-1β, TNF-α, and myeloperoxidase. In addition, treatment with ghrelin improved mucosal DNA synthesis and blood flow. Our study disclosed that ghrelin exhibits a strong anti-inflammatory and healing effect in acetic acid-induced colitis. Our current observation in association with previous findings that ghrelin exhibits curative effect in trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis suggest that therapeutic effect of ghrelin in the colon is universal and independent of the primary cause of colitis. PMID:27598133

  14. Exogenous Ghrelin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats.

    PubMed

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Ceranowicz, Dagmara; Gałązka, Krystyna; Bonior, Joanna; Jaworek, Jolanta; Bartuś, Krzysztof; Gil, Krzysztof; Olszanecki, Rafał; Dembiński, Artur

    2016-01-01

    Previous studies have shown that ghrelin reduces colonic inflammation induced by trinitrobenzene sulfonic acid and dextran sodium sulfate. In the present study we determined the effect of treatment with ghrelin on the course of acetic acid-induced colitis in rats. Rectal administration of 3% acetic acid solution led to induction of colitis in all animals. Damage of the colonic wall was accompanied by an increase in mucosal concentration of pro-inflammatory interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well mucosal activity of myeloperoxidase. Moreover, induction of colitis led to a reduction in colonic blood flow and DNA synthesis. Administration of ghrelin after induction of colitis led to faster regeneration of the colonic wall and reduction in colonic levels of IL-1β, TNF-α, and myeloperoxidase. In addition, treatment with ghrelin improved mucosal DNA synthesis and blood flow. Our study disclosed that ghrelin exhibits a strong anti-inflammatory and healing effect in acetic acid-induced colitis. Our current observation in association with previous findings that ghrelin exhibits curative effect in trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis suggest that therapeutic effect of ghrelin in the colon is universal and independent of the primary cause of colitis. PMID:27598133

  15. A poly-herbal formulation accelerates normal and impaired diabetic wound healing.

    PubMed

    Gupta, Asheesh; Upadhyay, Nitin K; Sawhney, R C; Kumar, Ratan

    2008-01-01

    In the present study, a poly-herbal formulation (PHF) was prepared by combining the aqueous lyophilized leaf extracts of Hippophae rhamnoides L. and Aloe vera L. and the ethanol rhizome extract of Curcuma longa L., in an optimized ratio (1 : 7 : 1). The efficacy of PHF treatment was studied in normal and impaired diabetic rats using a full-thickness cutaneous wound model. Topical PHF treatment increased cellular proliferation and collagen synthesis at the wound site in normal rats, as evidenced by the significant increase in DNA, total protein, hydroxyproline, and hexosamine contents in comparison with a positive control treated with a povidone-iodine ointment. The histological examinations and matrix metalloproteinases expression also correlated well with the biochemical findings, confirming the efficacy of PHF in normal wounds. In the streptozotocin-induced diabetic rats, PHF treatment increased hydroxyproline and hexosamine content. A faster wound contraction was also observed in PHF-treated normal and diabetic rats. The PHF also promoted angiogenesis as evidenced by an in vitro chick chorioallantoic membrane model and in vivo up-regulated vascular endothelial growth factor expression. The results suggest that PHF possesses significant wound healing potential in both normal as well as chronic diabetic wounds. PMID:19128249

  16. Experimental study in order to assess the effects of limited periosteum stripping on the fracture healing and to compare osteosynthesis using plates and screws with intramedullary Kirschner wire fixation.

    PubMed

    Neagu, Tiberiu Paul; Enache, Valentin; Cocoloş, Ion; Ţigliş, Mirela; Cobilinschi, Cristian; Ţincu, Radu

    2016-01-01

    There are many studies that investigate indirect and direct fracture healing but few mention the effect of periosteum stripping on consolidation of fractures. Most of these studies use only one method of osteosynthesis for each group. Therefore, we reported a new developed murine model in order to assess if limited periosteum stripping influence significantly the quality of the fracture healing process by comparing two different osteosynthesis methods to reduce simultaneously bilateral femur fractures. We applied the experimental protocol for a number of 12 rats. We used plates and screws to reduce femoral osteotomy for the right hind limb and intramedullary Kirschner wire for the left hind limb. Clinical, radiological and histological assessments were made for a period of eight weeks. The absence of a healthy hind limb led to a slower healing process based on the histological findings and to implant failure based on radiological findings. In summary, complete fracture healing was not achieved during this experimental study. Therefore, we consider that future studies are needed for a better understanding of the effects of periosteum removal on the fracture healing process. PMID:27516016

  17. Loss of CAR promotes migration and proliferation of HaCaT cells, and accelerates wound healing in rats via Src-p38 MAPK pathway

    PubMed Central

    Su, Linlin; Fu, Lanqing; Li, Xiaodong; Zhang, Yue; Li, Zhenzhen; Wu, Xue; Li, Yan; Bai, Xiaozhi; Hu, Dahai

    2016-01-01

    The coxsackie and adenovirus receptor (CAR) is a cell adhesion molecule mostly localized to cell-cell contacts in epithelial and endothelial cells. CAR is known to regulate tumor progression, however, its physiological role in keratinocyte migration and proliferation, two essential steps in re-epithelialization during wound healing, has less been investigated. Here we showed that CAR was predominantly expressed in the epidermis of human skin, CAR knockdown by RNAi significantly accelerated HaCaT cell migration and proliferation. In addition, knockdown of CAR in vitro increased p-Src, p-p38, and p-JNK protein levels; however, Src inhibitor PP2 prevented the increase of p-Src and p-p38 induced by CAR RNAi, but not p-JNK, and decelerated cell migration and proliferation. More intriguingly, in vivo CAR RNAi on the skin area surrounding the wounds on rat back visually accelerated wound healing and re-epithelialization process, while treatment with PP2 or p38 inhibitor SB203580 obviously inhibited these effects. By contrast, overexpressing CAR in HaCaT cells significantly decelerated cell migration and proliferation. Above results demonstrate that suppression of CAR could accelerate HaCaT cell migration and proliferation, and promote wound healing in rat skin, probably via Src-p38 MAPK pathway. CAR thus might serve as a novel therapeutic target for facilitating wound healing. PMID:26804208

  18. Transforming Growth Factor Beta Family: Insight into the Role of Growth Factors in Regulation of Fracture Healing Biology and Potential Clinical Applications

    PubMed Central

    Poniatowski, Łukasz A.; Gasik, Robert

    2015-01-01

    The transforming growth factor beta (TGF-β) family forms a group of three isoforms, TGF-β1, TGF-β2, and TGF-β3, with their structure formed by interrelated dimeric polypeptide chains. Pleiotropic and redundant functions of the TGF-β family concern control of numerous aspects and effects of cell functions, including proliferation, differentiation, and migration, in all tissues of the human body. Amongst many cytokines and growth factors, the TGF-β family is considered a group playing one of numerous key roles in control of physiological phenomena concerning maintenance of metabolic homeostasis in the bone tissue. By breaking the continuity of bone tissue, a spread-over-time and complex bone healing process is initiated, considered a recapitulation of embryonic intracartilaginous ossification. This process is a cascade of local and systemic phenomena spread over time, involving whole cell lineages and various cytokines and growth factors. Numerous in vivo and in vitro studies in various models analysing cytokines and growth factors' involvement have shown that TGF-β has a leading role in the fracture healing process. This paper sums up current knowledge on the basis of available literature concerning the role of the TGF-β family in the fracture healing process. PMID:25709154

  19. Transforming growth factor Beta family: insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications.

    PubMed

    Poniatowski, Łukasz A; Wojdasiewicz, Piotr; Gasik, Robert; Szukiewicz, Dariusz

    2015-01-01

    The transforming growth factor beta (TGF-β) family forms a group of three isoforms, TGF-β1, TGF-β2, and TGF-β3, with their structure formed by interrelated dimeric polypeptide chains. Pleiotropic and redundant functions of the TGF-β family concern control of numerous aspects and effects of cell functions, including proliferation, differentiation, and migration, in all tissues of the human body. Amongst many cytokines and growth factors, the TGF-β family is considered a group playing one of numerous key roles in control of physiological phenomena concerning maintenance of metabolic homeostasis in the bone tissue. By breaking the continuity of bone tissue, a spread-over-time and complex bone healing process is initiated, considered a recapitulation of embryonic intracartilaginous ossification. This process is a cascade of local and systemic phenomena spread over time, involving whole cell lineages and various cytokines and growth factors. Numerous in vivo and in vitro studies in various models analysing cytokines and growth factors' involvement have shown that TGF-β has a leading role in the fracture healing process. This paper sums up current knowledge on the basis of available literature concerning the role of the TGF-β family in the fracture healing process.

  20. A mutein of human basic fibroblast growth factor TGP-580 accelerates colonic ulcer healing by stimulating angiogenesis in the ulcer bed in rats.

    PubMed

    Satoh, H; Szabo, S

    2015-10-01

    Previously, we reported that TGP-580, a mutein of human basic fibroblast growth factor (bFGF), accelerated the healing of gastric and duodenal ulcers in rats. In the present study, we examined the effect of TGP-580 on the healing of colonic ulcers. In male Sprague Dawley rats, ulcers were induced in the colon 6 cm from the anus by enema of 50 μl of 3% N-ethylmaleimide, a sulfhydryl alkylator. The lesions were examined under a dissecting microscope (x10). The concentration of bFGF in the ulcerated colon was measured by enzyme immunoassay, and both the distribution of bFGF and the density of microvessels in the ulcer bed were examined by immunohistochemical staining. The content of bFGF in the ulcerated colon was markedly increased associated with ulcer healing, and ulcer healing was significantly delayed by intravenous administration of a monoclonal antibody for bFGF (MAb 3H3) once daily for 10 days. In the ulcer bed, many cells such as fibroblasts, vascular endothelial cells and macrophages were positively stained with bFGF antiserum. TGP-580, human bFGF or dexamethasone was given intracolonally twice daily for 10 days, starting the day after ulcer induction. TGP-580 (0.2 - 20 μg/ml, 200 μl/rat) dose-dependently accelerated ulcer healing, and its effect was more than 10 times stronger than that of human bFGF. Density (μm/0.01 mm(2)) of microvessels in the ulcer bed was significantly increased by treatment with TGP-580, and there was a good correlation between the density of microvessels and the decrease of ulcerated area (R(2) = 0.633). On the other hand dexamethasone (20 μg/ml) inhibited angiogenesis in the ulcer bed and delayed ulcer healing. These results suggest that angiogenesis in the ulcer bed plays an important role in ulcer healing, and that bFGF mutein TGP-580 accelerated colonic ulcer healing, at least in part, by stimulating angiogenesis, whereas glucocorticoids may delay the healing by inhibiting angiogenesis.

  1. Healing Acceleration of Acetic Acid-induced Colitis by Marigold (Calendula officinalis) in Male Rats

    PubMed Central

    Tanideh, Nader; Jamshidzadeh, Akram; Sepehrimanesh, Masood; Hosseinzadeh, Masood; Koohi-Hosseinabadi, Omid; Najibi, Asma; Raam, Mozhdeh; Daneshi, Sajad; Asadi-Yousefabad, Seyedeh-Leili

    2016-01-01

    Background/Aim: Ulcerative colitis (UC) is a type of chronic inflammatory bowel disease with unknown etiology. Several therapeutic strategies such as consumption of medicinal plants have been used for its treatment. The aim of this study was to evaluate healing effects of Calendula officinalis hydroalcoholic extract in experimentally induced UC in rat. Materials and Methods: Ninety-six rats, weighing 200 ± 20 g, were randomly divided into eight equal groups. UC induced by 3% acetic acid and oral doses of C. officinalis extract, 1500 and 3000 mg/kg, and enema (gel 10% and 20%) were given. Two groups as positive controls were given asacol (enema) and oral mesalamine. Negative control groups were given normal saline and base gel. On days 3 and 7, intestinal histopathology and weight changes, plus oxidative stress indices including malondialdehyde (MDA) level and myeloperoxidase (MPO) activity were assayed. Results: A significant increase in the body weight of rats was seen in the group given C. officinalis extract 3000 mg/kg orally, oral mesalamine, and 20% intracolonic gel form of marigold extract compared with negative control and base gel groups during the experimental period. Acute inflammation and granular atrophy after UC induction were resolved completely completely by both 20% intracolonic gel and 3000 mg/kg orally. An increase in MPO activity and a decrease in MDA level in response to oral and intracolonic gel form of C. officinalis were observed 3 and and 7 days after treatment (P < 0.05). Conclusion: Our results indicate that oral and enema forms of hydroalcoholic extract of C. officinalis can be offered as are potential therapeutic agents for UC induced in rats. PMID:26831607

  2. A new growth factor controlled drug release system to promote healing of bone fractures: nanospheres of recombinant human bone morphogenetic-2 and polylactic acid.

    PubMed

    Chen, Lin; Liu, Lei; Li, Cai; Tan, Yinghui; Zhang, Gang

    2011-04-01

    To prepare a new drug control release system, which can markedly promote the healing of bone fractures. Optimized water-in-oil-in-water multiple emulsion evaporation method, prepared nanospheres of recombinant human bone morphogenetic-2 and polylactic acid (rhBMP-2-PLA-Ns). Its physical character was determined by the enzyme linked immunosorbent assay method. Its bioactivity was measured with the microculture tetrazolium test immunohistochemical analyses, alizarin red staining and western blot analysis. rhBMP-2-PLA-Ns exhibited an even and uniform spherical appearance without adhesion, with a particle size distribution between 35 and 65 nm, and a mean size of 45 nm. The drug loading volume and encapsulation efficiency reached ([124.73 +/- 0.41] x 10(-3))% and (90.54 +/- 1.32)%, respectively. The drug release in vitro persisted for 14 days, with a mean concentration of 73.44 +/- 5.38 ng/ml, and corresponded to the Higuichi equation (r = 0.9962). The microculture tetrazolium test showed that 4 days later, the optical density value ranking was rhBMP-2-PLA-N group > rhBMP-2 group > blank control group. Fluorescence immunocytochemical analysis showed that 10 days later the fluorescent density of the rhBMP-2-PLA-N group was significantly higher than the other two groups. Western blot analysis confirmed that the amount of vascular endothelial growth factor in the rhBMP-2-PLA-N group was the greatest. This study showed that rhBMP-2-PLA-Ns have excellent biological activity, can promote proliferation, differentiation and mineralization of osteoblasts. The drug release time is suitable for fracture healing and is an ideal delivery system for fracture healing. PMID:21776677

  3. Overexpression of vascular endothelial growth factor accelerates early vascularization and improves healing of genetically modified cultured skin substitutes.

    PubMed

    Supp, Dorothy M; Boyce, Steven T

    2002-01-01

    Cultured skin substitutes (CSS) lack a vascular plexus, leading to slower vascularization after grafting than split-thickness skin autograft. CSS containing keratinocytes genetically modified to overexpress vascular endothelial growth factor (VEGF) were previously shown to exhibit enhanced vascularization up to 2 weeks after grafting to athymic mice. The present study examines whether enhanced vascularization compared with controls persists after stable engraftment is achieved and analyzes VEGF expression, wound contraction, and engraftment. Control and VEGF-modified (VEGF+) CSS were grafted onto full-thickness wounds in athymic mice. VEGF expression was detected in VEGF+ CSS 14 weeks after grafting. Graft contraction was significantly lower in VEGF+ CSS compared with controls, suggesting more stable engraftment and better tissue development. Positive HLA-ABC staining, indicating persistence of human cells, was seen in 86.7% (13/15) of grafted VEGF+ CSS, compared with 58.3% (7/12) of controls. Differences in dermal vascularization between control and VEGF+ grafts were significant 1 week after surgery, but not at later times. However, the distribution of vessels was different, with more vessels in the upper dermis of VEGF+ grafts. These results suggest that VEGF overexpression in genetically modified CSS acts to accelerate early graft vascularization and can contribute to improved healing of full-thickness skin wounds.

  4. Vacuum-assisted therapy accelerates wound healing in necrotizing soft tissue infections: our experience in two intravenous drug abuse patients.

    PubMed

    Marinis, Athanasios; Voultsos, Mavroudis; Grivas, Paraskevas; Dikeakos, Panagiotis; Liarmakopoulos, Emmanouil; Paschalidis, Nikolaos; Rizos, Spyros

    2013-12-01

    Negative pressure wound therapy using vacuum-assisted closure (VAC) devices is currently a well established technique for managing complicated wounds. Such wounds occur after aggressive surgical debridement for necrotizing soft tissue infections (NSTI). In this report we present our experience in two intravenous drug abusers managed with VAC for NSTIs. The patients were 25 and 34 years old, HCV positive and presented with oedema of the upper femoral compartments and concomitant severe sepsis. Ultrasonography and computed tomography revealed severe cellulitis, fluid collection and necrosis of the affected fasciae and muscles. After emergent and subsequent aggressive surgical debridement during the first 48h, the VAC device was applied. Both patients had an uncomplicated postoperative course and a fast recovery from their multiorgan dysfunction. Suture closure of the wounds was achieved at the 25th and 38th postoperative days respectively and patients were discharged without any motor deficit. Negative pressure wound therapy is a modern therapeutic modality for treating complicated infected wounds. Moreover, it accelerates wound healing and primary closure, facilitating patient ambulation and recovery. A dedicated medical and nursing team is an important prerequisite for a successful outcome.

  5. Mesenchymal stem cell-conditioned medium accelerates skin wound healing: An in vitro study of fibroblast and keratinocyte scratch assays

    SciTech Connect

    Walter, M.N.M.; Wright, K.T.; Fuller, H.R.; MacNeil, S.; Johnson, W.E.B.

    2010-04-15

    We have used in vitro scratch assays to examine the relative contribution of dermal fibroblasts and keratinocytes in the wound repair process and to test the influence of mesenchymal stem cell (MSC) secreted factors on both skin cell types. Scratch assays were established using single cell and co-cultures of L929 fibroblasts and HaCaT keratinocytes, with wound closure monitored via time-lapse microscopy. Both in serum supplemented and serum free conditions, wound closure was faster in L929 fibroblast than HaCaT keratinocyte scratch assays, and in co-culture the L929 fibroblasts lead the way in closing the scratches. MSC-CM generated under serum free conditions significantly enhanced the wound closure rate of both skin cell types separately and in co-culture, whereas conditioned medium from L929 or HaCaT cultures had no significant effect. This enhancement of wound closure in the presence of MSC-CM was due to accelerated cell migration rather than increased cell proliferation. A number of wound healing mediators were identified in MSC-CM, including TGF-{beta}1, the chemokines IL-6, IL-8, MCP-1 and RANTES, and collagen type I, fibronectin, SPARC and IGFBP-7. This study suggests that the trophic activity of MSC may play a role in skin wound closure by affecting both dermal fibroblast and keratinocyte migration, along with a contribution to the formation of extracellular matrix.

  6. Topical treatment with the opioid antagonist naltrexone accelerates the remodeling phase of full-thickness wound healing in type 1 diabetic rats.

    PubMed

    Immonen, Jessica A; Zagon, Ian S; Lewis, Gregory S; McLaughlin, Patricia J

    2013-10-01

    Wound repair involves a series of overlapping phases that include inflammation, proliferation, and tissue remodeling, with the latter phase requiring months for proper healing. Delays in any of these processes can result in infection, chronic ulceration, and possible amputation. Diabetes is a major risk factor for improper wound repair, and impaired wound healing is a major complication for more than 26 million people in the US diagnosed with diabetes. Previous studies have demonstrated that the opioid antagonist naltrexone (NTX) dissolved in moisturizing cream reverses delays in wound closure in streptozotocin-induced type 1 diabetic (T1D) rats. NTX accelerated DNA synthesis and increased the number of epithelial and mast cells, as well as new blood vessel formation. In this study, remodeling was evaluated in T1D rats up to eight weeks after initial wounding. Twenty days following wounding, diabetic rats treated with vehicle had elevated numbers of MMP-2+ fibroblasts, suggesting delayed healing processes; birefringence of granulation tissue stained with Sirius red revealed diminished collagen formation and maturation. Wound tissue from NTX-treated T1D rats had comparable numbers of MMP-2+ fibroblasts to control specimens, as well as accelerated maturation of granulation tissue. The integrity of wounded skin was evaluated by tensile strength measurements. T1D resulted in delayed wound healing, and wounded skin that displayed reduced tensile strength relative to normal rats. Topical NTX applied to wounds in T1D rats resulted in enhanced collagen formation and maturation over a 60-day period of time. Moreover, the force required to tear skin of NTX-treated T1D rats was elevated relative to the force necessary to tear the skin of vehicle-treated T1D rats, and comparable to that for normal rats. These data reveal that complications in wound healing associated with T1D involve the novel OGF-OGFr pathway, and that topical NTX is an effective treatment to enhance wound

  7. Allogeneic Transplantation of an Adipose-Derived Stem Cell Sheet Combined With Artificial Skin Accelerates Wound Healing in a Rat Wound Model of Type 2 Diabetes and Obesity.

    PubMed

    Kato, Yuka; Iwata, Takanori; Morikawa, Shunichi; Yamato, Masayuki; Okano, Teruo; Uchigata, Yasuko

    2015-08-01

    One of the most common complications of diabetes is diabetic foot ulcer. Diabetic ulcers do not heal easily due to diabetic neuropathy and reduced blood flow, and nonhealing ulcers may progress to gangrene, which necessitates amputation of the patient's foot. This study attempted to develop a new cell-based therapy for nonhealing diabetic ulcers using a full-thickness skin defect in a rat model of type 2 diabetes and obesity. Allogeneic adipose-derived stem cells (ASCs) were harvested from the inguinal fat of normal rats, and ASC sheets were created using cell sheet technology and transplanted into full-thickness skin defects in Zucker diabetic fatty rats. The results indicate that the transplantation of ASC sheets combined with artificial skin accelerated wound healing and vascularization, with significant differences observed 2 weeks after treatment. The ASC sheets secreted large amounts of several angiogenic growth factors in vitro, and transplanted ASCs were observed in perivascular regions and incorporated into the newly constructed vessel structures in vivo. These results suggest that ASC sheets accelerate wound healing both directly and indirectly in this diabetic wound-healing model. In conclusion, allogeneic ASC sheets exhibit potential as a new therapeutic strategy for the treatment of diabetic ulcers.

  8. Adenoviral-mediated transfer of human BMP-6 gene accelerates healing in a rabbit ulnar osteotomy model.

    PubMed

    Bertone, A L; Pittman, D D; Bouxsein, M L; Li, J; Clancy, B; Seeherman, H J

    2004-11-01

    This study evaluated healing of rabbit bilateral ulnar osteotomies 6 and 8 weeks after surgery in response to percutaneous injection of transgenic adenoviral (Ad) bone morphogenetic protein-6 (BMP-6) vector or green fluorescent protein vector control (Ad-GFP) administered 7 days after surgery compared to untreated osteotomy controls. The amount, composition and biomechanical properties of the healing bone repair tissue were compared among groups and to historical data for intact rabbit ulnae obtained from similar studies at the same institution. Quantitative computed tomography was used to determine area, density and mineral content of the mineralized callus in the harvested ulnae. Maximum torque, torsional stiffness, and energy absorbed to failure were determined at 1.5 degrees /s. Calcified sections of excised ulnae (5 microm) were stained with Goldner's Trichrome and Von Kossa, and evaluated for callus composition, maturity, cortical continuity, and osteotomy bridging. Radiographic assessment of bone formation indicated greater mineralized callus in the ulnae injected with Ad-hBMP-6 as early as 1 week after treatment (2 weeks after surgery) compared to untreated osteotomy ulnae (p < 0.006) and Ad-GFP treated osteotomy ulnae (p < 0.002). Quantitative computed tomography confirmed greater bone area and bone mineral content at the osteotomy at 6 weeks in Ad-BMP-6 treated osteotomy as compared to untreated osteotomy ulnae (p < 0.001) and Ad-GFP treated osteotomy ulnae (p < 0.01). Ad-BMP-6 treated osteotomy ulnae were stronger (p < 0.001 and 0.003) and stiffer (p < 0.004 and 0.003) in torsion at 6 weeks than untreated osteotomy ulnae or Ad-GFP treated osteotomy ulnae, respectively. Maximum torque, torsional stiffness, and energy absorbed to failure were greater in Ad-BMP-6 treated osteotomy ulnae compared to their respective untreated contralateral osteotomy ulnae at 8 weeks [p < 0.03]. Maximum torque and torsional stiffness in the Ad-BMP-6 treated osteotomy ulnae

  9. Recombinant growth factor mixtures induce cell cycle progression and the upregulation of type I collagen in human skin fibroblasts, resulting in the acceleration of wound healing processes.

    PubMed

    Lee, Do Hyun; Choi, Kyung-Ha; Cho, Jae-We; Kim, So Young; Kwon, Tae Rin; Choi, Sun Young; Choi, Yoo Mi; Lee, Jay; Yoon, Ho Sang; Kim, Beom Joon

    2014-05-01

    Application of growth factor mixtures has been used for wound healing and anti-wrinkles agents. The aim of this study was to evaluate the effect of recombinant growth factor mixtures (RGFM) on the expression of cell cycle regulatory proteins, type I collagen, and wound healing processes of acute animal wound models. The results showed that RGFM induced increased rates of cell proliferation and cell migration of human skin fibroblasts (HSF). In addition, expression of cyclin D1, cyclin E, cyclin-dependent kinase (Cdk)4, and Cdk2 proteins was markedly increased with a growth factor mixtures treatment in fibroblasts. Expression of type I collagen was also increased in growth factor mixtures-treated HSF. Moreover, growth factor mixtures-induced the upregulation of type I collagen was associated with the activation of Smad2/3. In the animal model, RGFM-treated mice showed accelerated wound closure, with the closure rate increasing as early as on day 7, as well as re-epithelization and reduced inflammatory cell infiltration than phosphate-buffered saline (PBS)-treated mice. In conclusion, the results indicated that RGFM has the potential to accelerate wound healing through the upregulation of type I collagen, which is partly mediated by activation of Smad2/3-dependent signaling pathway as well as cell cycle progression in HSF. The topical application of growth factor mixtures to acute and chronic skin wound may accelerate the epithelization process through these molecular mechanisms.

  10. Proximal fifth metatarsal fractures.

    PubMed

    Ramponi, Denise R

    2013-01-01

    The most common fracture of the foot is a fracture of the proximal fifth metatarsal. In general, there are 3 types of fractures involving the proximal fifth metatarsal area, including a proximal diaphyseal stress fracture, a Jones fracture, and an avulsion fracture of the tuberosity. Some fractures of the fifth metatarsal heal without difficulty, whereas some have the potential for nonunion or delayed healing. Each fracture has some variation in the anatomical location on the fifth metatarsal, the mechanism of injury, the radiographic findings, and the treatment plan. Avulsion fractures of the tuberosity often heal without difficulty, yet fractures distal to the area of insertion of the peroneus brevis tendon are prone to nonunion and delayed healing (). Differential diagnosis of a fifth metatarsal midfoot injury includes ankle sprains, midfoot sprains, plantar facial ruptures, peroneus tendon ruptures, and other foot fractures.

  11. Effect of a bioabsorbable, super-high molecular weight poly-D,L-lactic acid plate containing recombinant human bone morphogenetic protein-2 for fracture healing

    PubMed Central

    ZHOU, NING-FENG; HUANG, YU-FENG; WANG, JIN-WU

    2015-01-01

    The aim of this study was to investigate the effect of a bioabsorbable, super-high molecular weight poly-D,L-lactic acid (PDLLA) plate exhibiting the sustained release of recombinant human bone morphogenetic protein-2 (rhBMP-2) (PDLLA-rhBMP-2) on the treatment of fracture with internal fixation. A total of 32 New Zealand rabbits were randomly allocated to one of four groups (2, 4, 8 and 12 weeks), and a 2.5-mm middle ulnar osteotomy was performed bilaterally. The right side (experimental side) was fixed internally with PDLLA-rhBMP-2, and the left side (control side) was fixed with a normal PDLLA plate. At 2, 4, 8 and 12 weeks after surgery, the gross pathology of the ulnas was examined and radiographic, histological and computer image analyses were performed. The results demonstrated that the ulna fractures were fixed stably with the two bioactive plates at 2, 4, 8 and 12 weeks after surgery. At the 8-week time-point, 7 rabbits exhibited good healing at the osteotomy site on the experimental side. At 12 weeks after surgery, 8 rabbits exhibited good healing at the osteotomy site on both sides, but the experimental side showed enhanced compatibility between the plates and surrounding tissue, faster bone formation, a greater bone regeneration mass and better medullary canal structure compared with the control side. In conclusion, PPLLA-rhBMP-2 may be effectively used to treat fracture or nonunion at a non-weight-bearing site. PMID:26640559

  12. Tocotrienol Supplementation Improves Late-Phase Fracture Healing Compared to Alpha-Tocopherol in a Rat Model of Postmenopausal Osteoporosis: A Biomechanical Evaluation

    PubMed Central

    Mohamad, Sharlina; Shuid, Ahmad Nazrun; Mokhtar, Sabarul Afian; Abdullah, Shahrum; Soelaiman, Ima Nirwana

    2012-01-01

    This study investigated the effects of α-tocopherol and palm oil tocotrienol supplementations on bone fracture healing in postmenopausal osteoporosis rats. 32 female Sprague-Dawley rats were divided into four groups. The first group was sham operated (SO), while the others were ovariectomised. After 2 months, the right femora were fractured under anesthesia and fixed with K-wire. The SO and ovariectomised-control rats (OVXC) were given olive oil (vehicle), while both the alpha-tocopherol (ATF) and tocotrienol-enriched fraction (TEF) groups were given alpha-tocopherol and tocotrienol-enriched fraction, respectively, at the dose of 60 mg/kg via oral gavages 6 days per week for 8 weeks. The rats were then euthanized and the femora dissected out for bone biomechanical testing to assess their strength. The callous of the TEF group had significantly higher stress parameter than the SO and OVXC groups. Only the SO group showed significantly higher strain parameter compared to the other treatment groups. The load parameter of the OVXC and ATF groups was significantly lower than the SO group. There was no significant difference in the Young's modulus between the groups. In conclusion, tocotrienol is better than α-tocopherol in improving the biomechanical properties of the fracture callous in postmenopausal osteoporosis rat model. PMID:22829855

  13. Hierarchically micro-patterned nanofibrous scaffolds with a nanosized bio-glass surface for accelerating wound healing

    NASA Astrophysics Data System (ADS)

    Xu, He; Lv, Fang; Zhang, Yali; Yi, Zhengfang; Ke, Qinfei; Wu, Chengtie; Liu, Mingyao; Chang, Jiang

    2015-11-01

    A composite scaffold with a controlled micro-pattern, nano-sized fiber matrix and surface-modified nanobioglass component was successfully prepared for skin wound healing by combining the patterning electrospinning with pulsed laser deposition strategies, and the hierarchical micro/nano structures and nano-sized bioglass in the scaffolds could synergistically improve the efficiency and re-epithelialization of wound healing.A composite scaffold with a controlled micro-pattern, nano-sized fiber matrix and surface-modified nanobioglass component was successfully prepared for skin wound healing by combining the patterning electrospinning with pulsed laser deposition strategies, and the hierarchical micro/nano structures and nano-sized bioglass in the scaffolds could synergistically improve the efficiency and re-epithelialization of wound healing. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr04802h

  14. Stem Cell-Mediated Accelerated Bone Healing Observed with In Vivo Molecular and Small Animal Imaging Technologies in a Model of Skeletal Injury

    PubMed Central

    Lee, Sheen-Woo; Padmanabhan, Parasuraman; Ray, Pritha; Gambhir, Sanjiv Sam; Doyle, Timothy; Contag, Christopher; Goodman, Stuart B.; Biswal, Sandip

    2014-01-01

    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), [18F]FHBG (9-(fluoro-hydroxy-methyl-butyl-guanine)-micro-PET, [18F]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. PMID:18752273

  15. Accelerated wound healing and anti-inflammatory effects of physically cross linked polyvinyl alcohol-chitosan hydrogel containing honey bee venom in diabetic rats.

    PubMed

    Amin, Mohamed A; Abdel-Raheem, Ihab T

    2014-08-01

    Diabetes is one of the leading causes of impaired wound healing. The objective of this study was to develop a bee venom-loaded wound dressing with an enhanced healing and anti-inflammatory effects to be examined in diabetic rats. Different preparations of polyvinyl alcohol (PVA), chitosan (Chit) hydrogel matrix-based wound dressing containing bee venom (BV) were developed using freeze-thawing method. The mechanical properties such as gel fraction, swelling ratio, tensile strength, percentage of elongation and surface pH were determined. The pharmacological activities including wound healing and anti-inflammatory effects in addition to primary skin irritation and microbial penetration tests were evaluated. Moreover, hydroxyproline, glutathione and IL-6 levels were measured in the wound tissues of diabetic rats. The bee venom-loaded wound dressing composed of 10 % PVA, 0.6 % Chit and 4 % BV was more swellable, flexible and elastic than other formulations. Pharmacologically, the bee venom-loaded wound dressing that has the same previous composition showed accelerated healing of wounds made in diabetic rats compared to the control. Moreover, this bee venom-loaded wound dressing exhibited anti-inflammatory effect that is comparable to that of diclofenac gel, the standard anti-inflammatory drug. Simultaneously, wound tissues covered with this preparation displayed higher hydroxyproline and glutathione levels and lower IL-6 levels compared to control. Thus, the bee venom-loaded hydrogel composed of 10 % PVA, 0.6 % Chit and 4 % BV is a promising wound dressing with excellent forming and enhanced wound healing as well as anti-inflammatory activities. PMID:24293065

  16. Fractures

    MedlinePlus

    ... commonly happen because of car accidents, falls, or sports injuries. Other causes are low bone density and osteoporosis, which cause weakening of the bones. Overuse can cause stress fractures, which are very small cracks in the ...

  17. Multiple actions of Lucilia sericata larvae in hard-to-heal wounds: larval secretions contain molecules that accelerate wound healing, reduce chronic inflammation and inhibit bacterial infection.

    PubMed

    Cazander, Gwendolyn; Pritchard, David I; Nigam, Yamni; Jung, Willi; Nibbering, Peter H

    2013-12-01

    In Europe ≈15,000 patients receive larval therapy for wound treatment annually. Over the past few years, clinical studies have demonstrated the success of larvae of Lucilia sericata as debridement agents. This is based on a combination of physical and biochemical actions. Laboratory investigations have advanced our understanding of the biochemical mechanisms underlying the beneficial effects of larval secretions, including removal of dead tissue, reduction of the bacterial burden, and promotion of tissue regeneration. The present article summarizes our current understanding of the microbiological, immunological, and wound healing actions of larval therapy, and the molecules involved in these beneficial effects. Future studies will focus on the isolation, identification, and (pre)clinical testing of the effective molecules of L. sericata larvae. These molecules may be candidates for the development of new agents for the treatment of several infectious and inflammatory diseases, including chronic wounds.

  18. Expression of sclerostin scFv and the effect of sclerostin scFv on healing of osteoporotic femur fracture in rats.

    PubMed

    Yao, Qi; Ni, Jie; Hou, Yu; Ding, Lixiang; Zhang, Licheng; Jiang, Hua

    2014-06-01

    Osteoporosis is a systemic metabolic disease characterized by low bone mass with deterioration of the bony microstructure which leads to both bone brittleness and increased risk of fracture. Sclerostin is a protein encoded by the SOST gene which is specifically expressed in osteocyte. Monoclonal antibodies of sclerostin can promote bone formation by antagonizing its inhibitory action. However, the effectiveness of monoclonal antibodies to exert such effects are limited by the large molecular mass and high immunogenicity. Here, we report that we purified a high immune affinity, single-chain antibody of SOST: SOST-single-chain Fv (scFv). Real-time polymerase chain reaction amplification of the variable regions of the heavy- and light-chain gene from a secretory anti-SOST antibody was performed. Animal experiments showed that SOST-scFv promoted bone healing in a rat model of osteoporosis.

  19. Ankle fracture - aftercare

    MedlinePlus

    ... that surgery can allow faster and more reliable healing. In children, the fracture involves the part of ... will use a special walking boot as the healing progresses. You will need to learn: How to ...

  20. Ciliary neurotrophic factor promotes the activation of corneal epithelial stem/progenitor cells and accelerates corneal epithelial wound healing.

    PubMed

    Zhou, Qingjun; Chen, Peng; Di, Guohu; Zhang, Yangyang; Wang, Yao; Qi, Xia; Duan, Haoyun; Xie, Lixin

    2015-05-01

    Ciliary neurotrophic factor (CNTF), a well-known neuroprotective cytokine, has been found to play an important role in neurogenesis and functional regulations of neural stem cells. As one of the most innervated tissue, however, the role of CNTF in cornea epithelium remains unclear. This study was to explore the roles and mechanisms of CNTF in the activation of corneal epithelial stem/progenitor cells and wound healing of both normal and diabetic mouse corneal epithelium. In mice subjecting to mechanical removal of corneal epithelium, the corneal epithelial stem/progenitor cell activation and wound healing were promoted by exogenous CNTF application, while delayed by CNTF neutralizing antibody. In cultured corneal epithelial stem/progenitor cells, CNTF enhanced the colony-forming efficiency, stimulated the mitogenic proliferation, and upregulated the expression levels of corneal epithelial stem/progenitor cell-associated transcription factors. Furthermore, the promotion of CNTF on the corneal epithelial stem/progenitor cell activation and wound healing was mediated by the activation of STAT3. Moreover, in diabetic mice, the content of CNTF in corneal epithelium decreased significantly when compared with that of normal mice, and the supplement of CNTF promoted the diabetic corneal epithelial wound healing, accompanied with the advanced activation of corneal epithelial stem/progenitor cells and the regeneration of corneal nerve fibers. Thus, the capability of expanding corneal epithelial stem/progenitor cells and promoting corneal epithelial wound healing and nerve regeneration indicates the potential application of CNTF in ameliorating limbal stem cell deficiency and treating diabetic keratopathy.

  1. Antioxidant and anti-inflammatory potential of curcumin accelerated the cutaneous wound healing in streptozotocin-induced diabetic rats.

    PubMed

    Kant, Vinay; Gopal, Anu; Pathak, Nitya N; Kumar, Pawan; Tandan, Surendra K; Kumar, Dinesh

    2014-06-01

    Prolonged inflammation and increased oxidative stress impairs healing in diabetics and application of curcumin, a well known antioxidant and anti-inflammatory agent, could be an important strategy in improving impaired healing in diabetics. So, the present study was conducted to evaluate the cutaneous wound healing potential of topically applied curcumin in diabetic rats. Open excision skin wound was created in streptozotocin induced diabetic rats and wounded rats were divided into three groups; i) control, ii) gel-treated and iii) curcumin-treated. Pluronic F-127 gel (25%) and curcumin (0.3%) in pluronic gel were topically applied in the gel- and curcumin-treated groups, respectively, once daily for 19 days. Curcumin application increased the wound contraction and decreased the expressions of inflammatory cytokines/enzymes i.e. tumor necrosis factor-alpha, interleukin (IL)-1beta and matrix metalloproteinase-9. Curcumin also increased the levels of anti-inflammatory cytokine i.e. IL-10 and antioxidant enzymes i.e. superoxide dismutase, catalase and glutathione peroxidase. Histopathologically, the curcumin-treated wounds showed better granulation tissue dominated by marked fibroblast proliferation and collagen deposition, and wounds were covered by thick regenerated epithelial layer. These findings reveal that the anti-inflammatory and antioxidant potential of curcumin caused faster and better wound healing in diabetic rats and curcumin could be an additional novel therapeutic agent in the management of impaired wound healing in diabetics.

  2. Does human immunodeficiency virus status affect early wound healing in open surgically stabilised tibial fractures?: A prospective study.

    PubMed

    Howard, N E; Phaff, M; Aird, J; Wicks, L; Rollinson, P

    2013-12-01

    We compared early post-operative rates of wound infection in HIV-positive and -negative patients presenting with open tibial fractures managed with surgical fixation. The wounds of 84 patients (85 fractures), 28 of whom were HIV positive and 56 were HIV negative, were assessed for signs of infection using the ASEPIS wound score. There were 19 women and 65 men with a mean age of 34.8 years. A total of 57 fractures (17 HIV-positive, 40 HIV-negative) treated with external fixation were also assessed using the Checkett score for pin-site infection. The remaining 28 fractures were treated with internal fixation. No significant difference in early post-operative wound infection between the two groups of patients was found (10.7% (n = 3) vs 19.6% (n = 11); relative risk (RR) 0.55 (95% confidence interval (CI) 0.17 to 1.8); p = 0.32). There was also no significant difference in pin-site infection rates (17.6% (n = 3) vs 12.5% (n = 5); RR 1.62 (95% CI 0.44 to 6.07); p = 0.47). The study does not support the hypothesis that HIV significantly increases the rate of early wound or pin-site infection in open tibial fractures. We would therefore suggest that a patient's HIV status should not alter the management of open tibial fractures in patients who have a CD4 count > 350 cells/μl. PMID:24293603

  3. Bone Morphogenetic Protein for the Healing of Tibial Fracture: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Jiang, Chaoyin; Wang, Chunyang; Chen, Hua; Chai, Yimin

    2015-01-01

    Purpose To review the evidence from RCTs on clinical outcomes and benefit of acute tibial fracture and nonunion treated with and without BMPs. Material We searched multiple databases (MEDLINE, EMABSE, BIOSIS and Cochrane central) as well as reference lists of articles and contacted authors. Evaluated outcomes included union rate, revision rate, hardware failure and infection. The weighted and standard mean difference (WMD and SMD) or the relative risk (RR) was calculated for continuous or dichotomous data respectively. The quality of the trial was assessed, and meta-analyses were performed with the Cochrane Collaboration’s REVMAN 5.0 software. Results Eight RCTs involving 1113 patients were included. For acute tibial fracture, BMP group was associated with a higher rate of union (RR, 1.16; 95% CI, 1.04 to 1.30) and a lower rate of revision (RR, 0.68; 95% CI, 0.54 to 0.85) compared with control group. No significant differences were found in rate of hardware failure and infection. The pooled RR for achieving union for tibial fracture nonunion was 0.98 (95% CI, 0.86 to 1.13). There was no significant difference between the two groups in the rate of revision (RR, 0.48; 95% CI, 0.13 to 1.85) and infection (RR, 0.61; 95% CI, 0.37 to 1.02). Conclusion Study on acute tibial fractures suggests that BMP is more effective that controls, for bone union and for decreasing the rate of surgical revision to achieve union. For the treatment of tibial fracture nonunion, BMP leads to similar results to as autogenous bone grafting. Finally, well-designed RCTs of BMP for tibial fracture treatment are also needed. PMID:26509264

  4. Polysaccharides-Rich Extract of Ganoderma lucidum (M.A. Curtis:Fr.) P. Karst Accelerates Wound Healing in Streptozotocin-Induced Diabetic Rats

    PubMed Central

    Cheng, Poh-Guat; Sabaratnam, Vikineswary; Kuppusamy, Umah Rani

    2013-01-01

    Ganoderma lucidum (M.A. Curtis:Fr.) P. Karst is a popular medicinal mushroom. Scientific reports had shown that the wound healing effects of G. lucidum were partly attributed to its rich polysaccharides. However, little attention has been paid to its potential effects on wounds associated with diabetes mellitus. In this study, we evaluated the wound healing activity of the hot aqueous extract of G. lucidum in streptozotocin-induced diabetic rats. The extract of G. lucidum was standardised based on chemical contents (w/w) of total polysaccharides (25.1%), ganoderic acid A (0.45%), and adenosine (0.069%). Six groups of six rats were experimentally wounded in the posterior neck region. Intrasite gel was used as a positive control and aqueous cream as the placebo. Topical application with 10% (w/w) of mushroom extract-incorporated aqueous cream was more effective than that with Intrasite gel in terms of wound closure. The antioxidant activity in serum of rats treated with aqueous extract of G. lucidum was significantly higher; whereas the oxidative protein products and lipid damage were lower when compared to those of the controls. These findings strongly support the beneficial effects of standardised aqueous extract of G. lucidum in accelerating wound healing in streptozotocin-induced diabetic rats. PMID:24348715

  5. Collagen Hydrogel Scaffold and Fibroblast Growth Factor-2 Accelerate Periodontal Healing of Class II Furcation Defects in Dog

    PubMed Central

    Momose, Takehito; Miyaji, Hirofumi; Kato, Akihito; Ogawa, Kosuke; Yoshida, Takashi; Nishida, Erika; Murakami, Syusuke; Kosen, Yuta; Sugaya, Tsutomu; Kawanami, Masamitsu

    2016-01-01

    Objective: Collagen hydrogel scaffold exhibits bio-safe properties and facilitates periodontal wound healing. However, regenerated tissue volume is insufficient. Fibroblast growth factor-2 (FGF2) up-regulates cell behaviors and subsequent wound healing. We evaluated whether periodontal wound healing is promoted by application of collagen hydrogel scaffold in combination with FGF2 in furcation defects in beagle dogs. Methods: Collagen hydrogel was fabricated from bovine type I collagen with an ascorbate-copper ion cross-linking system. Collagen hydrogel was mingled with FGF2 and injected into sponge-form collagen. Subsequently, FGF2 (50 µg)/collagen hydrogel scaffold and collagen hydrogel scaffold alone were implanted into class II furcation defects in dogs. In addition, no implantation was performed as a control. Histometric parameters were assessed at 10 days and 4 weeks after surgery. Result: FGF2 application to scaffold promoted considerable cell and tissue ingrowth containing numerous cells and blood vessel-like structure at day 10. At 4 weeks, reconstruction of alveolar bone was stimulated by implantation of scaffold loaded with FGF2. Furthermore, periodontal attachment, consisting of cementum-like tissue, periodontal ligament-like tissue and Sharpey’s fibers, was also repaired, indicating that FGF2-loaded scaffold guided self-assembly and then re-established the function of periodontal organs. Aberrant healing, such as ankylosis and root resorption, was not observed. Conclusion: FGF2-loaded collagen hydrogel scaffold possessed excellent biocompatibility and strongly promoted periodontal tissue engineering, including periodontal attachment re-organization. PMID:27583044

  6. Use of teriparatide in osteoporotic fracture patients.

    PubMed

    Collinge, Cory; Favela, Juan

    2016-01-01

    Teriparatide [PTH (1-34)] is a genetically engineered analog of human parathyroid hormone that acts as an anabolic drug by increasing activity in both osteoblasts and osteoclasts. Intermittent (once-daily) doses of teriparatide seem to stimulate osteoblast activity and therefore result in a net increase of bone formation. It is recommended for use in post-menopausal women (PMW), men with hypogonadal osteoporosis, as well as men and women with glucocorticoid-induced osteoporosis. In vivo studies have generated important findings regarding teriparatide's role in the enhancement of fracture healing. The intention of this article is to review the clinical findings of teriparatide to stimulate fracture healing. The drug was shown in a prospective randomized, double blind study to achieve earlier radiographic cortical bridging of three of four cortices (7.4 weeks) compared to patients who were assigned to the placebo group (9.1 weeks). Another study compared mean time for healing and functional outcome in two groups of elderly women who had suffered osteoporotic pelvic fractures: one group received daily 100 μg parathyroid hormone (1-84) injections, while the other group received no treatment. Patients who received the PTH (1-84) injections accelerated radiographic and clinical fracture healing (7.8 weeks) when compared to patients who received no treatment (12.6 weeks, p<0.001). Numerous case series state the safety and potential benefits of teriparatide use in patients recovering from fractures. In the following scenarios, teriparatide might be considered in patients with osteoporosis and a fracture: (1) patients with severe osteoporosis with use of bisphosphonates for a number of years with a fracture not expected to predictably unite, e.g. atypical femur fracture or open tibia fracture, (2) in cases where an osteoporotic patient has failed fracture healing and is considering surgical treatment e.g. non-union surgery. It seems prudent to reevaluate these patients

  7. Effect of Pulsed Wave Low-Level Laser Therapy on Tibial Complete Osteotomy Model of Fracture Healing With an Intramedullary Fixation

    PubMed Central

    Mostafavinia, Atarodalsadat; Masteri Farahani, Reza; Abbasian, Mohammadreza; Vasheghani Farahani, Mohammadmehdi; Fridoni, Mohammadjavad; Zandpazandi, Sara; Ghoreishi, Seyed Kamran; Abdollahifar, Mohammad Amin; Pouriran, Ramin; Bayat, Mohammad

    2015-01-01

    Background: Fractures pose a major worldwide challenge to public health, causing tremendous disability for the society and families. According to recent studies, many in vivo and in vitro experiments have shown the positive effects of PW LLLT on osseous tissue. Objectives: The aim of this study was to evaluate the outcome of infrared pulsed wave low-level laser therapy (PW LLLT) on the fracture healing process in a complete tibial osteotomy in a rat model, which was stabilized by an intramedullary pin. Materials and Methods: This experimental study was conducted at Shahid Beheshti University of Medical Sciences in Tehran, Iran. We performed complete tibial osteotomies in the right tibias for the population of 15 female rats. The rats were divided randomly into three different groups: I) Control rats with untreated bone defects; II) Rats irradiated by a 0.972 J/cm2 PW LLLT; and III) Rats irradiated by a 1.5 J/cm2 PW LLLT. The right tibias were collected six weeks following the surgery and a three-point bending test was performed to gather results. Immediately after biomechanical examination, the fractured bones were prepared for histological examinations. Slides were examined using stereological method. Results: PW LLLT significantly caused an increase in maximum force (N) of biomechanical repair properties for osteotomized tibias in the first and second laser groups (30.0 ± 15.9 and 32.4 ± 13.8 respectively) compared to the control group (8.6 ± 4.5) LSD test, P = 0.019, P = 0.011 respectively). There was a significant increase in the osteoblast count of the first and second laser groups (0.53 ± 0.06, 0.41 ± 0.06 respectively) compared to control group (0.31 ± 0.04) (LSD test, P = 0001, P = 0.007 respectively). Conclusions: This study confirmed the efficacy of PW LLLT on biomechanical strength, trabecular bone volume, callus volume, and osteoblast number of repairing callus in a complete tibial osteotomy animal model at a relatively late stage of the bone

  8. Mesenchymal Stromal Cells form Vascular Tubes when Placed in Fibrin Sealant and Accelerate Wound Healing in Vivo

    PubMed Central

    Mendez, Julio J.; Ghaedi, Mahboobe; Sivarapatna, Amogh; Dimitrievska, Sashka; Shao, Zhen; Osuji, Chinedum; Steinbacher, Derek M.; Leffell, David J.; Niklason, Laura E.

    2014-01-01

    Non-healing, chronic wounds are a growing public health problem and may stem from insufficient angiogenesis in affected sites. Here, we have developed a fibrin formulation that allows adipose-derived mesenchymal stromal cells (ADSCs) to form tubular structures in vitro. The tubular structures express markers of endothelium, including CD31 and VE-Cadherin, as well as the pericyte marker NG2. The ability for the MSCs to form tubular structures within the fibrin gels was directly dependent on the stoichiometric ratios of thrombin and fibrinogen and the resulting gel concentration, as well as on the presence of bFGF. Fibrin gel formulations that varied in stiffness were tested. ADSCs that are embedded in a stiff fibrin formulation express VE-cadherin and CD31 as shown by PCR, FACS and immunostaining. Confocal imaging analysis demonstrated that tubular structures formed, containing visible lumens, in the stiff fibrin gels in vitro. There was also a difference in the amounts of bFGF secreted by ADSCs grown in the stiffer gels as compared to softer gels. Additionally, hAT-MSCs gave rise to perfusable vessels that were VE-cadherin positive after subcutaneous injection into mice, whereas the softer fibrin formulation containing ADSCs did not. The application of ADSCs delivered in the stiff fibrin gels allowed for the wounds to heal more quickly, as assessed by wound size, amount of granulation tissue and collagen content. Interestingly, following 5 days of healing, the ADSCs remained within the fibrin gel and did not integrate into the granulation tissue of healing wounds in vivo. These data show that ADSCs are able to form tubular structures within fibrin gels, and may also contribute to faster wound healing, as compared with no treatment or to wounds treated with fibrin gels devoid of ADSCs. PMID:25433608

  9. Comparison of laser and diode sources for acceleration of in vitro wound healing by low-level light therapy.

    PubMed

    Spitler, Ryan; Berns, Michael W

    2014-03-01

    Low-level light therapy has been shown to improve in vitro wound healing. However, well-defined parameters of different light sources for this therapy are lacking. The goal of this study was (1) to determine if the wavelengths tested are effective for in vitro wound healing and (2) to compare a laser and a light-emitting diode (LED) source at similar wavelengths. We show four wavelengths, delivered by either a laser or LED array, improved in vitro wound healing in A549, U2OS, and PtK2 cells. Improved wound healing occurred through increased cell migration demonstrated through scratch wound and transwell assays. Cell proliferation was tested by the (3-(4,5-dimethylthiazol-2-yl)-5-(3-car-boxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay and was found generally not to be involved in the wound healing process. The laser and LED sources were found to be comparable when equal doses of light were applied. The biological response measured was similar in most cases. We conclude that the laser at 652 (5.57  mW/cm2, 10.02  J/cm2) and 806 nm (1.30  mW/cm2, 2.334  J/cm2) (full bandwidth 5 nm), and LED at 637 (5.57  mW/cm2, 10.02  J/cm2) and 901 nm (1.30  mW/cm2, 2.334  J/cm2) (full bandwidth 17 and 69 nm respectively) induce comparable levels of cell migration and wound closure.

  10. rhBMP-2 injected in a calcium phosphate paste (alpha-BSM) accelerates healing in the rabbit ulnar osteotomy model.

    PubMed

    Li, R H; Bouxsein, M L; Blake, C A; D'Augusta, D; Kim, H; Li, X J; Wozney, J M; Seeherman, H J

    2003-11-01

    This study evaluated the ability of recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered in an injectable calcium phosphate carrier (alpha-BSM) to accelerate healing in a rabbit ulna osteotomy model compared to untreated surgical controls. Healing was assessed by radiography, histology and biomechanics. Bilateral mid-ulnar osteotomies were created in 16 skeletally mature rabbits. One limb in each animal was injected with either 0.1 mg rhBMP-2/alpha-BSM (BMP) (N=8) or buffer/alpha-BSM (BSM) (N=8). Contralateral osteotomies served as untreated surgical controls (SXCT). Gamma scintigraphy showed 75%, 45% and 5% of the initial 125I-rhBMP-2 dose was retained at the osteotomy site at 3 h, 1 week and 3 weeks. The biological activity of rhBMP-2 (alkaline phosphatase activity from bioassay) extracted from alpha-BSM incubated in vitro up to 30 days at 37 degrees C was unchanged. Radiographs demonstrated complete bridging of the BMP limbs at 4 weeks whereas none of the BSM or SXCT limbs were bridged. Post-mortem peripheral quantitative computed tomography determined mineralized callus area was 62% greater in BMP limbs compared to SXCT limbs. Torsional stiffness and strength were 63% and 103% greater in BMP limbs compared to SXCT limbs. There was no difference in torsional properties between BSM and SXCT limbs. Failure occurred outside the osteotomy in four out of seven of the BMP limbs. All BSM and SXCT limbs failed through the osteotomy. Histology showed bony bridging of the osteotomy and no residual carrier in the BMP limbs. BSM and SXCT groups showed less mature calluses composed of primarily fibrocartilaginous tissue and immature bone in the osteotomy gap. These data indicate rhBMP-2 delivered in alpha-BSM accelerated healing in a rabbit ulna osteotomy model compared to BSM and SXCT groups.

  11. Acceleration of tendon-bone healing in anterior cruciate ligament reconstruction using an enamel matrix derivative in a rat model.

    PubMed

    Kadonishi, Y; Deie, M; Takata, T; Ochi, M

    2012-02-01

    We examined whether enamel matrix derivative (EMD) could improve healing of the tendon-bone interface following reconstruction of the anterior cruciate ligament (ACL) using a hamstring tendon in a rat model. ACL reconstruction was performed in both knees of 30 Sprague-Dawley rats using the flexor digitorum tendon. The effect of commercially available EMD (EMDOGAIN), a preparation of matrix proteins from developing porcine teeth, was evaluated. In the left knee joint the space around the tendon-bone interface was filled with 40 µl of EMD mixed with propylene glycol alginate (PGA). In the right knee joint PGA alone was used. The ligament reconstructions were evaluated histologically and biomechanically at four, eight and 12 weeks (n = 5 at each time point). At eight weeks, EMD had induced a significant increase in collagen fibres connecting to bone at the tendon-bone interface (p = 0.047), whereas the control group had few fibres and the tendon-bone interface was composed of cellular and vascular fibrous tissues. At both eight and 12 weeks, the mean load to failure in the treated specimens was higher than in the controls (p = 0.009). EMD improved histological tendon-bone healing at eight weeks and biomechanical healing at both eight and 12 weeks. EMD might therefore have a human application to enhance tendon-bone repair in ACL reconstruction.

  12. Clinical evaluation of Cissus quadrangularis as osteogenic agent in maxillofacial fracture: A pilot study

    PubMed Central

    Brahmkshatriya, Hemal R.; Shah, Kruti A.; Ananthkumar, G. B.; Brahmkshatriya, Mansi H.

    2015-01-01

    Introduction: Cissus quadrangularis Linn. is an indigenous medicinal plant, grown in India, which helps to increase healing process of fractured bone. Fracture of maxillofacial skeletal takes reasonably long time to heal. Many attempts have been made till today to reduce the healing period of 6–8 weeks, by means of improved surgical technology or by inhibiting the physiological mechanism of bone healing. Aim: To evaluate the effect of C. quadrangularis in healing process of maxillofacial fracture. Materials and Methods: All the patients were treated by open reduction internal fixation method and in postoperative management, antibiotics, and analgesics. Patients were divided into two groups. In Group 1, one capsule of C. quadrangularis (500 mg) thrice a day for 6 weeks was administered (n = 5), and in Group 2 (control group), no supplementary medication was administered (n = 4). Pain, swelling, fragment mobility, serum calcium, and serum phosphorus were evaluated pre- and post-operatively on day-1, -21, and -45. Results: Pain, swelling, and fragment mobility were low in Group 1 compared to Group 2. Serum calcium and serum phosphorus were also high, and healing of bone was clearly seen in Group 1 on day 21 as compared to control group. Conclusion: C. quadrangularis helps in reducing pain, swelling, and fracture mobility and accelerate the healing of fracture jaw bones. PMID:27011718

  13. The history of the walls of the Acropolis of Athens and the natural history of secondary fracture healing process.

    PubMed

    Lyritis, G P

    2000-09-01

    During its long and adventurous history, the Acropolis of Athens has been a site of many dramatic events. It suffered its most disastrous destruction during the Persian wars. Under the command of King Xerxes, the Persians invaded Athens and ruined the Temple of the Parthenon and the walls of the Acropolis. After their victorious sea battle at Salamis, the Athenians, led by Themistocles, returned home and tried to repair the damage. Their priority still was to defend their city by restoring the walls of the Acropolis. Materials of all kinds were salvaged from the ruins of the Acropolis and used for an immediate reconstruction of the walls. Later, when the Athenians became the leaders of the Greek world, it was decided that the walls should be rebuilt in a proper artistic way. Themistocles suggested that a small section of the walls, which had formerly been a part of the urgent restoration, should remain in place so as to remind the citizens of this historical event. This is a characteristic example of the biological and mechanical adaptation of fracture callus to musculoskeletal function. After a period of urgency with the fixation of a fracture by means of a primitive secondary callus formation, the broken limb gradually returns to its usual function. Increased mechanical loading enhances the remodelling of the callus and the replacement of woven bone with lamellar bone. PMID:15758516

  14. Local release of pioglitazone (a peroxisome proliferator-activated receptor γ agonist) accelerates proliferation and remodeling phases of wound healing.

    PubMed

    Sakai, Shigeki; Sato, Keisuke; Tabata, Yasuhiko; Kishi, Kazuo

    2016-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily known for its anti-inflammatory and macrophage differentiation effects, as well as its ability to promote fat cell differentiation and reduce insulin resistance. Pioglitazone (Pio) is a PPARγ agonist used clinically as an anti-diabetic agent for improving insulin sensitivity in patients with diabetes. The objective of this study was to develop a drug delivery system (DDS) for the local release of Pio to promote wound healing. Pio of low aqueous solubility was water-solubilized by micelles formed from gelatin grafted with L-lactic acid oligomers, and incorporated into a biodegradable gelatin hydrogel. An 8-mm punch biopsy tool was used to prepare two skin wounds on either side of the midline of 8-week-old mice. Wounds were treated by the hydrogels with (Pio-hydrogel group) or without (control group) Pio, and the wound area were observed 1, 4, 7, and 14 days after treatment. In addition, a protein assay and immunohistological stain were performed to determine the effects of the Pio-hydrogel on inflammation and macrophage differentiation. The Pio-hydrogels promote wound healing. Moreover, Western blotting analysis demonstrated that treatment with Pio-hydrogels resulted in decreased levels of the cytokines MIP-2 and TGF-β, and increased levels of glucose-regulating adiponectin. It is concluded that Pio-incorporated hydrogels promote the proliferation and remodeling phases of wound healing, and may prove to be effective as wound dressings. PMID:26710090

  15. Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth.

    PubMed

    Staresinic, M; Sebecic, B; Patrlj, L; Jadrijevic, S; Suknaic, S; Perovic, D; Aralica, G; Zarkovic, N; Borovic, S; Srdjak, M; Hajdarevic, K; Kopljar, M; Batelja, L; Boban-Blagaic, A; Turcic, I; Anic, T; Seiwerth, S; Sikiric, P

    2003-11-01

    In studies intended to improve healing of transected Achilles tendon, effective was a stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419). Currently in clinical trials for inflammatory bowel disease (PLD-116, PL 14736, Pliva), it ameliorates internal and external wound healing. In rats, the right Achilles tendon transected (5 mm proximal to its calcaneal insertion) presents with a large tendon defect between cut ends. Agents (/kg b.w., i.p., once time daily) (BPC 157 (dissolved in saline, with no carrier addition) (10 microg, 10 ng or 10 pg) or saline (5.0 ml)), were firstly applied at 30 min after surgery, the last application at 24 h before autopsy. Achilles functional index (AFI) was assessed once time daily. Biomechanical, microscopical and macroscopical assessment was on day 1, 4, 7, 10 and 14. Controls generally have severely compromised healing. In comparison, pentadecapeptide BPC 157 fully improves recovery: (i) biomechanically, increased load of failure, load of failure per area and Young's modulus of elasticity; (ii) functionally, significantly higher AFI-values; (iii) microscopically, more mononuclears and less granulocytes, superior formation of fibroblasts, reticulin and collagen; (iv) macroscopically, smaller size and depth of tendon defect, and subsequently the reestablishment of full tendon integrity. Likewise, unlike TGF-beta, pentadecapeptide BPC 157, presenting with no effect on the growth of cultured cell of its own, consistently opposed 4-hydroxynonenal (HNE), a negative modulator of the growth. HNE-effect is opposed in both combinations: BPC 157+HNE (HNE growth inhibiting effect reversed into growth stimulation of cultured tendocytes) and HNE+BPC 157(abolished inhibiting activity of the aldehyde), both in the presence of serum and serum deprived conditions. In conclusion, these findings, particularly, Achilles tendon transection fully recovered in rats, peptide stability suitable delivery, usefully favor gastric

  16. Combined application of low-intensity pulsed ultrasound and functional electrical stimulation accelerates bone-tendon junction healing in a rabbit model.

    PubMed

    Hu, Jianzhong; Qu, Jin; Xu, Daqi; Zhang, Tao; Qin, Ling; Lu, Hongbin

    2014-02-01

    The objective of this study was to elucidate the combined use of low-intensity pulsed ultrasound (LIPUS) and functional electrical stimulation (FES) on patella-patellar tendon (PPT) junction healing using a partial patellectomy model in rabbits. LIPUS was delivered continuously starting day 3 postoperative until week 6. FES was applied on quadriceps muscles to induce tensile force to the repaired PPT junction 5 days per week for 6 weeks since week 7 postoperatively. Forty rabbits with partial patellectomy were randomly divided into four groups: control, LIPUS alone, FES alone, and LIPUS + FES groups. At week 12, the PPT complexes were harvested for histology, radiographs, peripheral quantitative computed tomography, and biomechanical testing. There was better remodeling of newly formed bone and fibrocartilage zone in the three treatment groups compared with the control group. LIPUS and/or FES treatments significantly increased the area and bone mineral content of new bone. The failure load and ultimate strength of PPT complex were also highly improved in the three treatment groups. More new bone formed and higher tensile properties were showed in the LIPUS + FES group compared with the LIPUS or FES alone groups. Early LIPUS treatment and later FES treatment showed the additive effects of accelerating PPT junction healing.

  17. Dinitrosyl iron complexes with glutathione incorporated into a collagen matrix as a base for the design of drugs accelerating skin wound healing.

    PubMed

    Shekhter, Anatoly B; Rudenko, Tatyana G; Istranov, Leonid P; Guller, Anna E; Borodulin, Rostislav R; Vanin, Anatoly F

    2015-10-12

    Composites of a collagen matrix and dinitrosyl iron complexes with glutathione (DNIC-GS) (in a dose of 4.0 μmoles per item) in the form of spongy sheets (DNIC-Col) were prepared and then topically applied in rat excisional full-thickness skin wound model. The effects of DNIC-Col were studied in comparison with spontaneously healing wounds (SpWH) and wounds treated with collagen sponges (Col) without DNIC-GS. The composites induced statistically and clinically significant acceleration of complete wound closure (21±1 day versus 23±1 day and 26±1 day for DNIC-Col, Col and SpWH, respectively). Histological examination of wound tissues on days 4, 14, 18 and 21 after surgery demonstrated that this improvement was supported by enhanced growth, maturation and fibrous transformation of granulation tissue and earlier epithelization of the injured area in rats treated with DNIC-Col composites benchmarked against Col and SpWH. It is suggested that the positive effect of the new pharmaceutical material on wound healing is based on the release of NO from decomposing DNIC. This effect is believed to be potentiated by the synergy of DNIC and collagen.

  18. Osteogenic gene regulation and relative acceleration of healing by adenoviral-mediated transfer of human BMP-2 or -6 in equine osteotomy and ostectomy models.

    PubMed

    Ishihara, Akikazu; Shields, Kathleen M; Litsky, Alan S; Mattoon, John S; Weisbrode, Steven E; Bartlett, Jeffrey S; Bertone, Alicia L

    2008-06-01

    This study evaluated healing of equine metatarsal osteotomies and ostectomies in response to percutaneous injection of adenoviral (Ad) bone morphogenetic protein (BMP)-2, Ad-BMP-6, or beta-galactosidase protein vector control (Ad-LacZ) administered 14 days after surgery. Radiographic and quantitative computed tomographic assessment of bone formation indicated greater and earlier mineralized callus in both the osteotomies and ostectomies of the metatarsi injected with Ad-BMP-2 or Ad-BMP-6. Peak torque to failure and torsional stiffness were greater in osteotomies treated with Ad-BMP-2 than Ad-BMP-6, and both Ad-BMP-2- and Ad-BMP-6-treated osteotomies were greater than Ad-LacZ or untreated osteotomies. Gene expression of ostectomy mineralized callus 8 weeks after surgery indicated upregulation of genes related to osteogenesis compared to intact metatarsal bone. Expression of transforming growth factor beta-1, cathepsin H, and gelsolin-like capping protein were greater in Ad-BMP-2- and Ad-BMP-6-treated callus compared to Ad-LacZ-treated or untreated callus. Evidence of tissue biodistribution of adenovirus in distant organs was not identified by quantitative PCR, despite increased serum antiadenoviral vector antibody. This study demonstrated a greater relative potency of Ad-BMP-2 over Ad-BMP-6 in accelerating osteotomy healing when administered in this regimen, although both genes were effective at increasing bone at both osteotomy and ostectomy sites.

  19. Comparison between different methods for biomechanical assessment of ex vivo fracture callus stiffness in small animal bone healing studies.

    PubMed

    Steiner, Malte; Volkheimer, David; Meyers, Nicholaus; Wehner, Tim; Wilke, Hans-Joachim; Claes, Lutz; Ignatius, Anita

    2015-01-01

    For ex vivo measurements of fracture callus stiffness in small animals, different test methods, such as torsion or bending tests, are established. Each method provides advantages and disadvantages, and it is still debated which of those is most sensitive to experimental conditions (i.e. specimen alignment, directional dependency, asymmetric behavior). The aim of this study was to experimentally compare six different testing methods regarding their robustness against experimental errors. Therefore, standardized specimens were created by selective laser sintering (SLS), mimicking size, directional behavior, and embedding variations of respective rat long bone specimens. For the latter, five different geometries were created which show shifted or tilted specimen alignments. The mechanical tests included three-point bending, four-point bending, cantilever bending, axial compression, constrained torsion, and unconstrained torsion. All three different bending tests showed the same principal behavior. They were highly dependent on the rotational direction of the maximum fracture callus expansion relative to the loading direction (creating experimental errors of more than 60%), however small angular deviations (<15°) were negligible. Differences in the experimental results between the bending tests originate in their respective location of maximal bending moment induction. Compared to four-point bending, three-point bending is easier to apply on small rat and mouse bones under realistic testing conditions and yields robust measurements, provided low variation of the callus shape among the tested specimens. Axial compressive testing was highly sensitive to embedding variations, and therefore cannot be recommended. Although it is experimentally difficult to realize, unconstrained torsion testing was found to be the most robust method, since it was independent of both rotational alignment and embedding uncertainties. Constrained torsional testing showed small errors (up to

  20. Trefoil peptide TFF2 (spasmolytic polypeptide) potently accelerates healing and reduces inflammation in a rat model of colitis

    PubMed Central

    Tran, C; Cook, G; Yeomans, N; Thim, L; Giraud, A

    1999-01-01

    BACKGROUND—The trefoil peptides are major secretory products of mucus cells of the gastrointestinal tract and show increased expression after inflammatory or ulcerative damage. Recombinant human TFF2 (spasmolytic polypeptide) has been shown to be cytoprotective, and enhances repair in models of gastric injury. 
AIMS—To test the healing effects of recombinant human (h)TFF2 in a rat model of chronic colitis. 
METHODS—Colitis was induced by intracolonic administration of dinitrobenzene sulphonic acid in ethanol. Mucosal repair was quantified macroscopically, microscopically by image analysis of tissue histology, and by measuring myeloperoxidase activity. 
RESULTS—Initial validation studies showed that maximal injury and inflammation occurred at the end of the first week after colitis induction (active phase), and that spontaneous healing was complete by eight weeks. Once daily intrarectal application of hTFF2 (2.5 mg/kg; approximately 0.5 mg/rat) for five days after maximal damage had been sustained, reduced both microscopic and macroscopic injury by 80% and inflammatory index by 50% compared with vehicle controls. In addition, endogenous concentrations of rat TFF2 and TFF3 (intestinal trefoil factor) were increased in the active phase of colitis and were reduced to basal levels by hTFF2 treatment. 
CONCLUSIONS—This study has shown that hTFF2 enhances the rate of colonic epithelial repair, and reduces local inflammation in a rat model of colitis, and suggests that luminal application of trefoil peptides may have therapeutic potential in the treatment of inflammatory bowel disease. 

 Keywords: trefoil peptide; TFF2; spasmolytic polypeptide; colitis; repair PMID:10205199

  1. Wnt Signaling During Fracture Repair

    PubMed Central

    Secreto, Frank J.; Hoeppner, Luke H.; Westendorf, Jennifer J.

    2010-01-01

    Bone is one of the few tissues in the body with the capacity to regenerate and repair itself. In most cases, fractures are completely repaired in a relatively short period of time; however, in a small percentage of cases, healing never occurs and non-union is the result. Fracture repair and bone regeneration require the localized re-activation of signaling cascades that are crucial for skeletal development. The Wnt/β-catenin signaling pathway is one such developmental pathway whose role in bone formation and regeneration has been recently appreciated. During the last decade, much has learned about how Wnt pathways regulate bone mass. Small molecules and biologics aimed at this pathway are now being tested as potential new anabolic agents. Here we review recent data demonstrating that Wnt pathways are active during fracture repair and that increasing the activities of Wnt pathway components accelerates bone regeneration. PMID:19631031

  2. Laser-assisted skin closure (LASC) using a 815-nm diode laser system: determination of an optimal dose to accelerate wound healing

    NASA Astrophysics Data System (ADS)

    Capon, Alexandre; Mitchell, Valerie A.; Sumian, Chryslain C.; Gauthier, Beatrice; Mordon, Serge R.

    1999-01-01

    This study aimed to evaluate a 815 nm diode-laser system to assist wound closure. It was proposed to determine an optimal fluence being able to accelerate and improve heating process without thermal damage after laser irradiation. Male hairless rats with dorsal skin incisions were used for the study. Different fluences were screened (76 to 346 J/cm2) in a first phase with clinical examination at 3, 7, 15 and 21 days after surgery. Best results were obtained for a fluence of 145 J/cm2 and 3 sec time of exposure. A second phase was conducted to valid these parameters with histological study and determination of tensile strength at 3, 7, 15 and 21 days after surgery. LASC was 4 times faster to process than conventional suture. In the laser group with an optimal fluence of 145 J/cm2, healing was accelerated. The resulting scar was more indiscernible than in the control groups. Histological aspect was better with continuous epidermis and dermis at 3 days in most cases. Tensile strength was 30 to 58% greater than in control groups (1141 g/cm2 at 7 days in the laser group versus 856 g/cm2 and 724 g/cm2 in the control groups, p < 0.001).

  3. Commercially available topical platelet-derived growth factor as a novel agent to accelerate burn-related wound healing.

    PubMed

    Travis, Taryn E; Mauskar, Neil A; Mino, Matthew J; Prindeze, Nick; Moffatt, Lauren T; Fidler, Philip E; Jordan, Marion H; Shupp, Jeffrey W

    2014-01-01

    The authors investigated whether the application of platelet-derived growth factor (PDGF) to donor site wounds would speed healing in a porcine model. In a red duroc pig model, three wounds that were 3 inches × 3 inches were created with a dermatome (0.06-inch depth) on one side of two different animals. These wounds were digitally and laser Doppler (LDI) imaged and biopsied immediately pre- and postwound creation and every 2 days for 2 weeks. A set of identical wounds were subsequently created on the opposite side of the same animals and treated with topical PDGF (becaplermin gel 0.01%, 4 g/wound) immediately on wounding. PDGF-treated wounds were imaged and biopsied as above. Digital images of wounds were assessed for epithelialization by clinicians using an ordinal scale. Perfusion units (PU) were evaluated by LDI. Wound healing was evaluated by hematoxylin and eosin histological visualization of an epithelium and intact basement membrane. First evidence of partial epithelialization was seen in control and PDGF-treated wounds within 7.7 ± 1.4 and 6.4 ± 1.1 days postwounding, respectively (P=.03). Completely epithelialized biopsies were seen in control and PDGF-treated wounds at 11.7 ± 2.6 and 9.6 ± 1.5 days, respectively (P=.02). Clinician evaluation of digital images showed that on day 9, control wounds were, on average, 48.3 ± 18.5% epithelialized vs 57.2 ± 20.2% epithelialized for PDGF-treated wounds. At day 16, control wounds showed an average of 72.9 ± 14.6% epithelialization and PDGF-treated wounds showed an average of 90 ± 11.8%epithelialization. Overall, PDGF-treated wounds had statistically significantly higher scores across all timepoints (P=.02). Average perfusion units as measured by LDI were similar for control and PDGF-treated wounds at time of excision (225 ± 81and 257 ± 100, respectively). On day 2 postwounding, average PU for control wounds were 803 and were 764 for PDGF-treated wounds. Control wounds maintained higher PU values

  4. Self-Healing of Polymer Networks with Reversible Bonds

    NASA Astrophysics Data System (ADS)

    Rubinstein, Michael

    2015-03-01

    Self-healing polymeric materials are systems that after damage can revert to their original state with full or partial recovery of mechanical strength. Using scaling theory we study a simple model of autonomic self-healing of polymer networks. In this model one of the two end monomers of each polymer chain is fixed in space mimicking dangling chains attachment to a polymer network, while the sticky monomer at the other end of each chain can form pairwise reversible bond with the sticky end of another chain. We study the reaction kinetics of reversible bonds in this simple model and analyze the different stages in the self-repair process. The formation of bridges and the recovery of the material strength across the fractured interface during the healing period occur appreciably faster after shorter waiting time, during which the fractured surfaces are kept apart. We observe the slowest formation of bridges for self-adhesion after bringing into contact two bare surfaces with equilibrium (very low) density of open stickers in comparison with self-healing. The primary role of anomalous diffusion in material self-repair for short waiting times is established, while at long waiting times the recovery of bonds across fractured interface is due to hopping diffusion of stickers between different bonded partners. Acceleration in bridge formation for self-healing compared to self-adhesion is due to excess nonequilibrium concentration of open stickers. Full recovery of reversible bonds across fractured interface (formation of bridges) occurs after appreciably longer time than the equilibration time of the concentration of reversible bonds in the bulk. The model is extended to describe enhanced toughness of dual networks with both permanent and reversible cross-links. This work was done in collaboration with Drs. Ludwik Leibler, Li-Heng Cai, Evgeny B. Stukalin, N. Arun Kumar and supported by the National Science Foundation.

  5. Self-Healing of Unentangled Polymer Networks with Reversible Bonds

    PubMed Central

    Stukalin, Evgeny B.; Cai, Li-Heng; Kumar, N. Arun; Leibler, Ludwik; Rubinstein, Michael

    2013-01-01

    Self-healing polymeric materials are systems that after damage can revert to their original state with full or partial recovery of mechanical strength. Using scaling theory we study a simple model of autonomic self-healing of unentangled polymer networks. In this model one of the two end monomers of each polymer chain is fixed in space mimicking dangling chains attachment to a polymer network, while the sticky monomer at the other end of each chain can form pairwise reversible bond with the sticky end of another chain. We study the reaction kinetics of reversible bonds in this simple model and analyze the different stages in the self-repair process. The formation of bridges and the recovery of the material strength across the fractured interface during the healing period occur appreciably faster after shorter waiting time, during which the fractured surfaces are kept apart. We observe the slowest formation of bridges for self-adhesion after bringing into contact two bare surfaces with equilibrium (very low) density of open stickers in comparison with self-healing. The primary role of anomalous diffusion in material self-repair for short waiting times is established, while at long waiting times the recovery of bonds across fractured interface is due to hopping diffusion of stickers between different bonded partners. Acceleration in bridge formation for self-healing compared to self-adhesion is due to excess non-equilibrium concentration of open stickers. Full recovery of reversible bonds across fractured interface (formation of bridges) occurs after appreciably longer time than the equilibration time of the concentration of reversible bonds in the bulk. PMID:24347684

  6. Acceleration of diabetic wound healing by a cryopreserved living dermal substitute created by micronized amnion seeded with fibroblasts

    PubMed Central

    Zheng, Yongjun; Ji, Shizhao; Wu, Haibin; Tian, Song; Wang, Xingtong; Luo, Pengfei; Fang, He; Wang, Zhihong; Wang, Junjie; Wang, Zhongshan; Xiao, Shichu; Xia, Zhaofan

    2015-01-01

    Bioengineered dermal substitutes have been used for the treatment of diabetic ulcers in clinics and achieved satisfactory results. However, constructing traditional tissue engineered dermal substitutes with two-step method is high-cost, time-consuming and greatly decreases fibroblast proliferative activity because of repeated trypsinization. Inthisstudy, we created a 3D micronized amniotic membrane (mAM) and used it as a natural microcarrier for ex vivo culture and amplification of human dermal fibroblasts (HDF) combined with the rotary cell culture system (RCCS). This one-step mAM-RCCS method couldamplify HDF quickly and construct a dermal substitute HDF-mAM simultaneously. To facilitate the clinical application of mAM-RCCS, anoptimized storage method was used.Post-thawing HDF-mAM retained high cell viability, intact cell morphology and active peptide secretion. When transplanted to the wounds of db/db mice, cryopreserved HDF-mAM promoted vascularization and diabetic wound healing significantly. These results demonstrate the potential application of cryopreserved HDF-mAM as a living dermal substitutefor treating diabetic ulcers and other chronic wounds in clinics. PMID:26885266

  7. Development of an Electromagnetic Acceleration Facility for Impact and Fracture Studies at High Strain Rates

    NASA Astrophysics Data System (ADS)

    Pahari, S.; Suryaprasad, I. V. V.; Shiv, N.; Madhavan, S.; Sijoy, C. D.; Chaturvedi, S.

    2011-07-01

    Experimental studies of strain time history and fracture & penetration resulting from the high velocity impact of solid projectiles on solid targets have been initiated. Design, fabrication, testing and commissioning of an electromagnetic impact facility driven by a capacitor bank have been carried out in this regard. The facility presently has an induction coil gun driving a cylindrical hollow/solid projectile on to a target. 3-7 kJ capacitor banks have been used to drive the launchers. The parameters of the coil gun are in consonance with a computer code developed in-house for the validation and optimization of the coil dimension and bank parameters. Systematic studies have been carried out for validation of code and understanding and benchmarking coil performance. Reproducible velocities of the order of 100 m/s have been successfully achieved with projectiles of masses 20 gm. Preliminary impact studies carried out on Alumnium target plates have given the strain time history.

  8. Fracture After Total Hip Replacement

    MedlinePlus

    ... er Total Hip Replacement cont. • Dislocation • Limb length inequality • Poor fracture healing • Repeat fracture • Lack of in- ... Surgeons (AAOS). To learn more about your orthopaedic health, please visit orthoinfo.org. Page ( 5 ) AAOS does ...

  9. Anti-alpha-toxin monoclonal antibody and antibiotic combination therapy improves disease outcome and accelerates healing in a Staphylococcus aureus dermonecrosis model.

    PubMed

    Hilliard, Jamese J; Datta, Vivekananda; Tkaczyk, Christine; Hamilton, Melissa; Sadowska, Agnieszka; Jones-Nelson, Omari; O'Day, Terrence; Weiss, William J; Szarka, Szabolcs; Nguyen, Vien; Prokai, Laszlo; Suzich, JoAnn; Stover, C Kendall; Sellman, Bret R

    2015-01-01

    Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.

  10. Anti-alpha-toxin monoclonal antibody and antibiotic combination therapy improves disease outcome and accelerates healing in a Staphylococcus aureus dermonecrosis model.

    PubMed

    Hilliard, Jamese J; Datta, Vivekananda; Tkaczyk, Christine; Hamilton, Melissa; Sadowska, Agnieszka; Jones-Nelson, Omari; O'Day, Terrence; Weiss, William J; Szarka, Szabolcs; Nguyen, Vien; Prokai, Laszlo; Suzich, JoAnn; Stover, C Kendall; Sellman, Bret R

    2015-01-01

    Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections. PMID:25348518

  11. Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

    PubMed Central

    Hilliard, Jamese J.; Datta, Vivekananda; Tkaczyk, Christine; Hamilton, Melissa; Sadowska, Agnieszka; Jones-Nelson, Omari; O'Day, Terrence; Weiss, William J.; Szarka, Szabolcs; Nguyen, Vien; Prokai, Laszlo; Suzich, JoAnn; Stover, C. Kendall

    2014-01-01

    Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections. PMID:25348518

  12. Platelet-Rich Fibrin Promotes an Accelerated Healing of Achilles Tendon When Compared to Platelet-Rich Plasma in Rat

    PubMed Central

    Dietrich, Franciele; L. Duré, Gustavo; P. Klein, Caroline; F. Bampi, Vinícius; V. Padoin, Alexandre; D. Silva, Vinícius; Braga-Silva, Jefferson

    2015-01-01

    BACKGROUND Autologous platelet concentrate has been used to improve the function and regeneration of injured tissues. Tendinopathies are common in clinical practice, although long-term treatment is required. On the basis of lead time, we compared the effect of using platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) in repairing rat Achilles tendon. METHODS The effectiveness of using PRP and PRF was evaluated after 14 and 28 postoperative days by histological analysis. The quantification of collagen types I and III was performed by Sirius red staining. Qualitatively, the data were verified with hematoxylin-eosin (H&E) staining. RESULTS In Sirius red staining, no significant treatment differences were found between groups. Statistical difference was observed only between PRP (37.2% collagen) and the control group (16.2%) 14 days after treatment. Intra-groups compared twice showed a difference for collagen I (27.8% and 47.7%) and III (66.9% and 46.0%) in the PRF group. The control group showed differences only in collagen I (14.2% and 40.9%) and no other finding was observed in the PRP group. In H&E staining, PRF showed a better cellular organization when compared to the other groups at 28 days. CONCLUSION Our study suggests that PRF promotes accelerated regeneration of the Achilles tendon in rats, offering promising prospects for future clinical use. PMID:26284178

  13. Wormwood (Artemisia absinthium) suppresses tumour necrosis factor alpha and accelerates healing in patients with Crohn's disease - A controlled clinical trial.

    PubMed

    Krebs, Simone; Omer, Talib N; Omer, Bilal

    2010-04-01

    Suppression of tumour necrosis factor alpha (TNF-alpha) and other interleukins by wormwood (Artemisia absinthium) extracts were reported recently in in vitro studies. The aim of the present study was to find out if this effect can be also be observed in Crohn's Disease (CD) patients where TNF-alpha appears to play an important role. In a controlled trial, 10 randomly selected patients suffering from CD were given in addition to their basic CD therapy 3x750mg dried powdered wormwood for 6 weeks. Ten patients, also randomly selected who met the inclusion criteria served as control group. Minimum score of 200 on Crohn's Disease Activity Index (CDAI) was required at baseline for inclusion in each group. Patients who received infliximab or similar were excluded from the trial. TNF-alpha level in serum were measured at baseline, and after three and six weeks. During this period all concomitant CD medications was maintained at the baseline dose levels. Average serum TNF-alpha level fell from 24.5+/-3.5pg/ml at baseline to 8.0+/-2.5pg/ml after six weeks. The corresponding levels in the control group were 25.7+/-4.6 (week 0), and 21.1+/-3.2 (week 6). On the clinical side, CDAI scores fell from 275+/-15 to below 175+/-12 in wormwood group with remission of symptoms in eight patients (CDAI score below 170 or reduction by 70 points), compared to only two in the placebo group (CDAI of placebo group 282+/-11 at baseline and 230+/-14 on week 6). IBDQ also reflected accelerated clinical response with wormwood. Of clinical significance were the findings that wormwood also improved mood of the CD patients, as reflected in Hamilton's Depression Scale. These findings provide a base to test wormwood in clinical conditions thought to be mediated by increased production of pro-inflammatory cytokines such as TNF-alpha.

  14. Displaced patella fractures.

    PubMed

    Della Rocca, Gregory J

    2013-10-01

    Displaced patella fractures often result in disruption of the extensor mechanism of the knee. An intact extensor mechanism is a requirement for unassisted gait. Therefore, operative treatment of the displaced patella fracture is generally recommended. The evaluation of the patella fracture patient includes examination of extensor mechanism integrity. Operative management of patella fractures normally includes open reduction with internal fixation, although partial patellectomy is occasionally performed, with advancement of quadriceps tendon or patellar ligament to the fracture bed. Open reduction with internal fixation has historically been performed utilizing anterior tension band wiring, although comminution of the fracture occasionally makes this fixation construct inadequate. Supplementation or replacement of the tension band wire construct with interfragmentary screws, cerclage wire or suture, and/or plate-and-screw constructs may add to the stability of the fixation construct. Arthrosis of the patellofemoral joint is very common after healing of patella fractures, and substantial functional deficits may persist long after fracture healing has occurred.

  15. In Vivo Wound Healing Studies.

    PubMed

    2016-01-01

    Wound healing has emerged as a major treatment issue which has provoked the development of drugs that can improve the healing process. Studies using plant drugs have revealed many interesting results about existing commercial drugs. Effective wound healing leads to the restoration of tissue integrity and occurs through a highly organized multistage. Use of plant-derived medicines against excision, incision, and dead space models accelerates the wound healing process, which is briefly discussed in a manner to be followed easily during experimental sessions.

  16. In Vivo Wound Healing Studies.

    PubMed

    2016-01-01

    Wound healing has emerged as a major treatment issue which has provoked the development of drugs that can improve the healing process. Studies using plant drugs have revealed many interesting results about existing commercial drugs. Effective wound healing leads to the restoration of tissue integrity and occurs through a highly organized multistage. Use of plant-derived medicines against excision, incision, and dead space models accelerates the wound healing process, which is briefly discussed in a manner to be followed easily during experimental sessions. PMID:26939282

  17. Saliva and wound healing.

    PubMed

    Brand, Henk S; Veerman, Enno C I

    2013-01-01

    Wounds in the oral cavity heal faster and with less scarring than wounds in other parts of the body. One of the factors implicated in this phenomenon is the presence of saliva, which promotes the healing of oral wounds in several ways. Saliva creates a humid environment, which improves the survival and functioning of inflammatory cells that are crucial for wound healing. Furthermore, saliva contains a variety of proteins that play a role in the various stages of the intraoral wound healing. Tissue factor, present in salivary exosomes, accelerates the clotting of blood dramatically. The subsequent proliferation of epithelial cells is promoted by growth factors in saliva, especially epidermal growth factor. The importance of secretory leucocyte protease inhibitor is demonstrated by the observation that in the absence of this salivary protein, oral wound healing is considerably delayed. Members of the salivary histatin family promote wound closure in vitro by enhancing cell spreading and cell migration. Cell proliferation is not enhanced by histatin. Cyclization of histatin increased its biological activity approximately 1,000-fold compared to linear histatin. These studies suggest that histatins could potentially be used for the development of new wound healing medications.

  18. Rejuvenation of the inflammatory system stimulates fracture repair in aged mice

    PubMed Central

    Xing, Zhiqing; Lu, Chuanyong; Hu, Diane; Miclau, Theodore; Marcucio, Ralph S.

    2010-01-01

    Age significantly reduces the regenerative capacity of the skeleton, but the underlying causes are unknown. Here, we tested whether the functional status of inflammatory cells contributes to delayed healing in aged animals. We created chimeric mice by bone marrow transplantation after lethal irradiation. In this model chondrocytes and osteoblasts in the regenerate are derived exclusively from host cells while inflammatory cells are derived from the donor. Using this model, the inflammatory system of middle-aged mice (12-month-old) was replaced by transplanted bone marrow from juvenile mice (4-week-old), or age-matched controls. We found that the middle-aged mice receiving juvenile bone marrow had larger calluses and more bone formation during early stages and faster callus remodeling at late stages of fracture healing, indicating that inflammatory cells derived from the juvenile bone marrow accelerated bone repair in the middle-aged animals. In contrast, transplanting bone marrow from middle-age mice to juvenile mice did not alter the process of fracture healing in juvenile mice. Thus, the roles of inflammatory cells in fracture healing may be age-related, suggesting the possibility of enhancing fracture healing in aged animals by manipulating the inflammatory system. PMID:20108320

  19. Spontaneous calcaneal fracture in patients with diabetic foot ulcer: Four cases report and review of literature

    PubMed Central

    Evran, Mehtap; Sert, Murat; Tetiker, Tamer; Akkuş, Gamze; Biçer, Ömer Sunkar

    2016-01-01

    Spontaneous calcaneal fractures in diabetic patients without obvious trauma may occur, sometimes accompanying diabetic foot ulcers. In the current study we report four cases who were hospitalized for diabetic foot ulcer with concomitant calcaneal fractures. There were four diabetic patients (one type 1 and three type 2) who registered with diabetic foot ulcers with coexisting calcaneal fractures, all of which were classified as Type A according to Essex Lopresti Calcaneal Fracture Classification. Two of the patients with renal failure were in a routine dialysis program, as well as vascular compromise and osteomyelitis in all of the patients. The diabetic foot ulcer of the 61 years old osteoporotic female patient healed with local debridement, vacuum assisted closure and then epidermal growth factor while the calcaneal fracture was then followed by elastic bandage. In two patients could not prevent progression of diabetic foot ulcers and calcaneal fractures to consequent below-knee amputation. The only patient with type 1 diabetes mellitus improved with antibiotic therapy and split thickness skin grafting, while the calcaneal fracture did not heal. In the current study we aimed to emphasize the spontaneous calcaneal fractures as possible co-existing pathologies in patients with diabetic foot ulcers. After all the medical treatment, amputation below knee had to be performed in 2 patients. It should be noted that other accompanying conditions such as impaired peripheral circulation, osteomyelitis, chronic renal failure, and maybe osteoporosis is a challenge of the recovery of calcaneal fractures and accelerate the progress to amputation in diabetic patients. PMID:27458594

  20. Spontaneous calcaneal fracture in patients with diabetic foot ulcer: Four cases report and review of literature.

    PubMed

    Evran, Mehtap; Sert, Murat; Tetiker, Tamer; Akkuş, Gamze; Biçer, Ömer Sunkar

    2016-07-16

    Spontaneous calcaneal fractures in diabetic patients without obvious trauma may occur, sometimes accompanying diabetic foot ulcers. In the current study we report four cases who were hospitalized for diabetic foot ulcer with concomitant calcaneal fractures. There were four diabetic patients (one type 1 and three type 2) who registered with diabetic foot ulcers with coexisting calcaneal fractures, all of which were classified as Type A according to Essex Lopresti Calcaneal Fracture Classification. Two of the patients with renal failure were in a routine dialysis program, as well as vascular compromise and osteomyelitis in all of the patients. The diabetic foot ulcer of the 61 years old osteoporotic female patient healed with local debridement, vacuum assisted closure and then epidermal growth factor while the calcaneal fracture was then followed by elastic bandage. In two patients could not prevent progression of diabetic foot ulcers and calcaneal fractures to consequent below-knee amputation. The only patient with type 1 diabetes mellitus improved with antibiotic therapy and split thickness skin grafting, while the calcaneal fracture did not heal. In the current study we aimed to emphasize the spontaneous calcaneal fractures as possible co-existing pathologies in patients with diabetic foot ulcers. After all the medical treatment, amputation below knee had to be performed in 2 patients. It should be noted that other accompanying conditions such as impaired peripheral circulation, osteomyelitis, chronic renal failure, and maybe osteoporosis is a challenge of the recovery of calcaneal fractures and accelerate the progress to amputation in diabetic patients. PMID:27458594

  1. Clavicle fractures: individualizing treatment for fracture type.

    PubMed

    Housner, Jeffrey A; Kuhn, John E

    2003-12-01

    Clavicle fractures are common injuries in both children and adults. In most cases, the diagnosis can be made readily from the patient's history and physical examination. X-rays are helpful to confirm the diagnosis, to assess the severity of the fracture, and to follow interval healing. Most fractures are treated nonoperatively, and surgical intervention is typically reserved for unstable distal clavicle fractures. Nonoperative options involve either a sling-and-swathe or figure-of-eight splint. Return-to-play decisions should be individualized based on the age of the patient, location and severity of the fracture, degree of clinical and radiographic healing, and the sport in which the athlete will be participating.

  2. Osteosynthesis of fragility fractures.

    PubMed

    Tarantino, Umberto; Iundusi, Riccardo; Lecce, Domenico; Tempesta, Valerio; Perrone, Fabio Luigi; Rao, Cecilia; Cerocchi, Irene; Gasbarra, Elena

    2011-04-01

    The deepening knowledge about bone pathophysiology, together with the development of less invasive bone implants, fitted for the treatment of fragility fractures, the continuous advances in the creation of osteoconductive and osteoinductive biomaterials, the availability of bone active agents, capable of modulating fracture healing, actually represent the orthopaedic "weapons" to improve the surgical outcome and quality of life in patients with osteoporosis.

  3. Magnet Healing?

    NASA Astrophysics Data System (ADS)

    Finegold, Leonard

    2000-03-01

    Many people are convinced that static magnets—applied to their skin—will heal ills, and many businesses sell such magnets. The biophysics of such healing was reviewed [1] together with the general biophysics of static fields. Birds and insects do use the earth’s magnetic field for navigation. While insect and frog egg development can clearly be influenced by high fields (7 T and 17 T respectively), there is no experimental evidence that small magnetic fields (of less than 0.5 T) might heal, and much evidence that they cannot heal. A puzzle to the physics community is: How to show laypersons that simple magnets (very probably) do not heal, however attractive that idea might be. [1] L. Finegold, The Physics of "Alternative Medicine": Magnet Therapy, The Scientific Review of Alternative Medicine 3:26-33 (1999).

  4. Archetypal healing.

    PubMed

    Jones, D; Churchill, J E

    1994-01-01

    With emphasis on healing versus curing, the authors draw from a wide assortment of treatment methods for psychospiritual relief of pain in the terminally ill. These archetypal methods include: life-review therapy; ministry of presence; clinical hypnosis; myths, symbols, rituals, and community; creative therapies. In life-review therapy, the ill person shares his/her life story with the provider much like the healing rituals of the ancient storyteller did in his community. In the ministry of presence, the caregiver focuses on sharing his vulnerability, not his professional skills. Clinical hypnosis emphasizes the naturalness and simplicity of accessing the unconscious along with problem areas of the hypnoclinician. Myths, symbols, rituals, and community serve as nurturing agents in the intervention of pain, while creative therapies such as music, drama, crafts, and art continue to be powerful healing instruments. Archetypal healing produces relief of pain in the caregiver, as well as the ill, with emphasis on healing versus curing. PMID:8117487

  5. The Impact of Strontium Ranelate on Metaphyseal Bone Healing in Ovariectomized Rats.

    PubMed

    Komrakova, Marina; Weidemann, Anna; Dullin, Christian; Ebert, Joachim; Tezval, Mohammad; Stuermer, Klaus Michael; Sehmisch, Stephan

    2015-10-01

    The following questions were addressed: whether therapy with strontium ranelate (SR) should be continued or interrupted if the fractures occur during SR treatment and whether SR could be applied directly after fracture to improve bone healing. Sprague-Dawley rats (3 month old) were ovariectomized (Ovx, n = 48) or left intact (n = 12). After 8 weeks, a bilateral transverse osteotomy of the tibia metaphysis was created in all rats. Ovx rats were divided into four groups: Ovx; SR applied directly after Ovx until osteotomy (prophylaxis, SR pr, 8 weeks); SR applied after osteotomy (therapy, SR th, 5 weeks); SR applied during the whole experiment (pr + th, 13 weeks). SR dosage was 625 mg/kg body weight/day, administered in the feed. Five weeks later, tibiae were analyzed by biomechanical, histological, micro-CT, and gene expression analyses. The SR pr + th treatment increased total bone mineral density (BMD), bone volume fraction, cortical BMD and volume, callus area and density, serum alkaline phosphatase, tartrate-resistant acid phosphatase mRNA, accelerated osteotomy bridging, and callus formation at weeks 2 and 3 of healing and decreased the osteoprotegerin/receptor activator of nuclear factor kB ligand mRNA ratio. SR th enlarged callus area and improved callus formation during the 5th week of healing. SR pr improved cortical BMD preserving bone after SR discontinuation (5-week rest); the bone healing was not affected. SR content in the tibia metaphysis was the highest in SR pr + th group and was not different between SR pr and SR th. SR has a positive effect on osteoporotic bone healing in rat and SR treatment can be continued after the fracture occurs or applied directly after the fracture. PMID:26084691

  6. Metatarsal shaft fractures and fractures of the proximal fifth metatarsal.

    PubMed

    Fetzer, Gary B; Wright, Rick W

    2006-01-01

    Metatarsal fractures represent a relatively common injury, especially in athletes. The pertinent anatomy, evaluation, diagnosis, classification, and treatment of acute and chronic (stress) metatarsal shaft fractures are discussed. Fractures of the proximal fifth metatarsal, which are unique and important injuries, are also discussed. Treatment remains relatively straightforward for the traumatic metatarsal injury, whereas traditional stress fractures typically heal with decreased activity. The problematic proximal fifth metatarsal fracture (Jones fracture) frequently requires surgical intervention in patients who want to avoid non-weight-bearing cast immobilization. The authors' current treatment for this fracture includes the option of intramedullary fixation versus cast immobilization.

  7. 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

  8. Wound Healing and Care

    MedlinePlus

    ... heal through natural scar formation. continue The Healing Process Before healing begins, the body gears up to ... dry at all times to help the healing process. As the body does its healing work on ...

  9. How wounds heal

    MedlinePlus

    ... How scrapes heal; How puncture wounds heal; How burns heal; How pressure sores heal; How lacerations heal ... from germs. Not all wounds bleed. For example, burns, some puncture wounds, and pressure sores do not ...

  10. TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds.

    PubMed

    Qi, Yu; Jiang, Dongsheng; Sindrilaru, Anca; Stegemann, Agatha; Schatz, Susanne; Treiber, Nicolai; Rojewski, Markus; Schrezenmeier, Hubert; Vander Beken, Seppe; Wlaschek, Meinhard; Böhm, Markus; Seitz, Andreas; Scholz, Natalie; Dürselen, Lutz; Brinckmann, Jürgen; Ignatius, Anita; Scharffetter-Kochanek, Karin

    2014-02-01

    Proper activation of macrophages (Mφ) in the inflammatory phase of acute wound healing is essential for physiological tissue repair. However, there is a strong indication that robust Mφ inflammatory responses may be causal for the fibrotic response always accompanying adult wound healing. Using a complementary approach of in vitro and in vivo studies, we here addressed the question of whether mesenchymal stem cells (MSCs)-due to their anti-inflammatory properties-would control Mφ activation and tissue fibrosis in a murine model of full-thickness skin wounds. We have shown that the tumor necrosis factor-α (TNF-α)-stimulated protein 6 (TSG-6) released from MSCs in co-culture with activated Mφ or following injection into wound margins suppressed the release of TNF-α from activated Mφ and concomitantly induced a switch from a high to an anti-fibrotic low transforming growth factor-β1 (TGF-β1)/TGF-β3 ratio. This study provides insight into what we believe to be a previously undescribed multifaceted role of MSC-released TSG-6 in wound healing. MSC-released TSG-6 was identified to improve wound healing by limiting Mφ activation, inflammation, and fibrosis. TSG-6 and MSC-based therapies may thus qualify as promising strategies to enhance tissue repair and to prevent excessive tissue fibrosis.

  11. Self-healing polymers

    NASA Technical Reports Server (NTRS)

    Klein, Daniel J. (Inventor)

    2011-01-01

    A three dimensional structure fabricated from a self-healing polymeric material, comprising poly(ester amides) obtained from ethylene glycol, azelaic acid and 1,1-aminoundecanoic acid, wherein polymeric material has a melt index above 2.5 g/10 min. as determined by ASTM D1238 at 190.degree. C. and 2.16kg, impact resistance and ductility sufficient to resist cracking and brittle fracture upon impact by a 9 mm bullet fired at a temperature of about 29.degree. C. at subsonic speed in a range from about 800 feet/sec to about 1000 feet/sec. It has been determined that the important factors necessary for self-healing behavior of polymers include sufficient impact strength, control of the degree of crystallinity, low melting point and the ability to instantly melt at impacted area.

  12. Use of a strontium-enriched calcium phosphate cement in accelerating the healing of soft-tissue tendon graft within the bone tunnel in a rabbit model of anterior cruciate ligament reconstruction.

    PubMed

    Kuang, G M; Yau, W P; Lu, W W; Chiu, K Y

    2013-07-01

    We investigated whether strontium-enriched calcium phosphate cement (Sr-CPC)-treated soft-tissue tendon graft results in accelerated healing within the bone tunnel in reconstruction of the anterior cruciate ligament (ACL). A total of 30 single-bundle ACL reconstructions using tendo Achillis allograft were performed in 15 rabbits. The graft on the tested limb was treated with Sr-CPC, whereas that on the contralateral limb was untreated and served as a control. At timepoints three, six, nine, 12 and 24 weeks after surgery, three animals were killed for histological examination. At six weeks, the graft-bone interface in the control group was filled in with fibrovascular tissue. However, the gap in the Sr-CPC group had already been completely filled in with new bone, and there was evidence of the early formation of Sharpey fibres. At 24 weeks, remodelling into a normal ACL-bone-like insertion was found in the Sr-CPC group. Coating of Sr-CPC on soft tissue tendon allograft leads to accelerated graft healing within the bone tunnel in a rabbit model of ACL reconstruction using Achilles tendon allograft.

  13. Measurement of ulnar variance and radial inclination on X-rays of healed distal radius fractures. With the axis of the distal radius or ulna?

    PubMed

    Thuysbaert, Gilles; Ringburg, Akkie; Petronilia, Steven; Vanden Berghe, Alex; Hollevoet, Nadine

    2015-06-01

    Ulnar variance and radial inclination are radiological parameters frequently used to evaluate displacement of distal radius fractures. In most studies measurements are based on the long central axis of the distal radius, although the axis of the distal ulna can also be used. The purpose of this study was to determine which axis is more reliable. Four observers performed measurements on standard anteroposterior digital wrist X-rays of 20 patients taken 1 and 2 months after sustaining an extra-articular distal radius fracture. Intraobserver reliability was similar with both methods. No difference was found in interobserver reliability between both methods for ulnar variance, but for radial inclination it was better with the axis through the radius. Measurements on two X-rays of the same wrist taken at a different moment were similar with both methods. It can be concluded that the central axis of the distal radius can remain the basis to determine ulnar variance and radial inclination.

  14. Comparative study of the effect of ultrasound and electrostimulation on bone healing in rats.

    PubMed

    Zorlu, U; Tercan, M; Ozyazgan, I; Taşkan, I; Kardaş, Y; Balkar, F; Oztürk, F

    1998-01-01

    This study was performed to compare the effects of direct current with ultrasound on fracture healing. Thirty-two rats were subjected to the experiment. Each rat's right legs were used as the experimental sample, and their left legs were used as the control. Four groups were formed, each consisting of 16 ultrasound, 16 electrostimulation, 16 ultrasound control, and 16 electrostimulation control animals. Fibular osteotome was applied to the rats under anesthesia. In the electrostimulation and electrostimulation control groups, a stainless steel cathode electrode was installed in the fractured side. In the electrostimulation group, 10 microA of direct current for 30 min, using a semi-invasive method, was given one day after fracture, for 15 days. On the control side, the aforementioned protocol was followed but sham treated. The ultrasound group was treated with 0.1 W/cm2 ultrasound for 2 min every second day for 6 days after fracture (4 times). Rats were killed on the 7th and 14th days to investigate the macroscopic, radiologic, and histopathologic parameters of fracture healing. There was a difference (P < 0.05) between the electrostimulation and the electrostimulation control groups on the 7th day. There was a difference (P < 0.05) between the ultrasound and ultrasound control groups on the 14th day. After statistical evaluation of the experimental results, it was found that in both the ultrasound and the electrostimulation groups, the fracture healing had been accelerated more so than in the control groups. There was no observed statistical difference between ultrasound and electrostimulation effects.

  15. Low-intensity pulsed ultrasound accelerated bone-tendon junction healing through regulation of vascular endothelial growth factor expression and cartilage formation.

    PubMed

    Lu, Hongbin; Qin, Ling; Cheung, Winghoi; Lee, Kwongman; Wong, Wannar; Leung, Kwoksui

    2008-08-01

    The purpose of this study was to use our established partial patellectomy rabbit model to study the effects of low-intensity pulsed ultrasound (LIPUS) on patella-patellar tendon (PPT) junction repair through hypothesized pathways including regulation of vascular endothelial growth factor (VEGF) and chondrogenesis. Standard partial patellectomy was conducted in sixty-four 18 wk-old rabbits that were subsequently divided into LIPUS and control group. The PPT complex was harvested at week 2, 4, 8 and 16 postoperatively (n = 8 for each time point) for preparation of sagittal sections that were evaluated for angiogenesis by analyzing VEGF expression and chondrogenesis. Results showed differences in the pattern of VEGF expression between LIPUS and control groups during the entire healing process, i.e., significant differences in the average percentage of VEGF expression found in between the LIPUS and the control groups. At postoperative week 4, the chondrocytes and osteoblasts in woven bone expressed significantly more VEGF in the LIPUS group than that in the control group (35.6% +/- 7.0% versus 28.0% +/- 4.6%, p < 0.05). Compared with the control group, the development of cartilaginous metaplasia was found more advanced in the scar tissue next to the articular cartilage of the remaining patella in the LIPUS group that was expressed with VEGF in the chondrocytes (38.8% +/- 12.3%). However, the specimens in the control group just showed the similar cartilaginous metaplasia region until postoperative week 8. Histomorphometry revealed thicker fibrocartilage zone and larger cartilaginous metaplasia field at PPT healing interface in LIPUS group compared with those of the control group at week 8 and 16. In conclusion, this was the first quantitative study to demonstrate that LIPUS improved B-T junction healing through regulation of VEGF expression in early healing phase and subsequent chondrogenesis.

  16. Amino acids from Mytilus galloprovincialis (L.) and Rapana venosa molluscs accelerate skin wounds healing via enhancement of dermal and epidermal neoformation.

    PubMed

    Badiu, Diana L; Luque, Rafael; Dumitrescu, Elena; Craciun, Anca; Dinca, Danut

    2010-02-01

    Wound healing consists of re-epithelialization, contraction and formation of granulation and scar tissue. Amino acids from proteins are involved in these events, but their exact roles are not well understood. The present study was undertaken to investigate the anti-inflammatory effects of some amino acids from two molluscs, Mytilus galloprovincialis (L.) (Mediterranean mussel) and Rapana venosa (hard shell-clam) employed in induced skin burn injuries in Wistar rats. The treatment was evaluated in terms of essential amino acids composition which rendered the extracts very efficient in healing skin burns. The healing process was examined by periodic acid Schiff's, Verhoeff's Van Gieson and immunohistochemistry stains for collagen IV, CD 34 and CD 117 antibodies. According to the obtained results, as expressed by histological studies, the most abundant blood vessels, collagen fibres, basal and stem cells were found only for treated animals with amino acids from Rapana venosa extracts. The rich composition of amino acids from the two molluscs merits consideration as therapeutic agents in the treatment of skin burns.

  17. Astragulus polysaccharide-loaded fibrous mats promote the restoration of microcirculation in/around skin wounds to accelerate wound healing in a diabetic rat model.

    PubMed

    Yang, Ye; Wang, Fei; Yin, Dengke; Fang, Zhaohui; Huang, Lu

    2015-12-01

    Tissue engineering scaffolds (TES) can carry numerous biomacromolecules and cells, and they have been widely used in diabetic skin wound healing with positive effects. However, the bioactive retention of biomacromolecules and cells during fabrication and storage is still a factor restricting their use. Moreover, impaired blood supply in/around poorly healing diabetic skin wounds has not been considered. In the present study, a bioactive natural substance of Astragalus polysaccharide (APS), which has stable and confirmed effects on endothelial protection, was embedded into fibrous TES by electrospinning. The administration of APS-loaded TES on the skin wound in a diabetic rat model led to a dose-dependent promotion in skin blood flow around wounds and an increase in endoglin expression and microvessel density in regenerated skin tissues. Furthermore, the higher loading of APS in TES led to faster collagen synthesis, appendage and epidermal differentiation, and wound closure. In summary, the combination of APS with TES is a potentially novel therapeutic strategy for diabetic skin wound healing, as it not only mimics the ultrastructure of extracellular matrixes but also restores skin microcirculation.

  18. Healing fractured families: parents' and elders' perspectives on the impact of colonization and youth suicide prevention in a pacific northwest American Indian tribe.

    PubMed

    Strickland, C June; Walsh, Elaine; Cooper, Michelle

    2006-01-01

    Suicide rates among American Indian youth in the United States are two to three times the national average. Risk factors for American Indian youth include depression, alcohol use, hopelessness and stress, and family conflict, abuse, poverty, and instability. In this descriptive study, the authors aimed to obtain parents' and elders' perspectives on community needs and to identify strengths on which the community might build to reduce youth suicide risk. Data were collected from focus groups with 40 American Indian parents and from individual interviews with 9 American Indian elders. The major task participants addressed was holding the family together and healing intergenerational pains. Topics parents discussed were holding onto cultural values, holding the family together, getting through school, and getting a job. These findings substantiate previous research and provide useful information for the design of culturally appropriate family or community-based interventions to prevent American Indian youth suicide.

  19. Randomised controlled trial evaluating the efficacy of wrap therapy for wound healing acceleration in patients with NPUAP stage II and III pressure ulcer

    PubMed Central

    Mizuhara, Akihiro; Oonishi, Sandai; Takeuchi, Kensuke; Suzuki, Masatsune; Akiyama, Kazuhiro; Kobayashi, Kazuyo; Matsunaga, Kayoko

    2012-01-01

    Objectives To evaluate if ‘wrap therapy’ using food wraps, which is widely used in Japanese clinical sites, is not inferior when compared to guideline adhesion treatments. Design Multicentre, prospective, randomised, open, blinded endpoint clinical trial. Setting 15 hospitals in Japan. Patients 66 older patients with new National Pressure Ulcer Advisory Panel stage II or III pressure ulcers. Interventions Of these 66 patients, 31 were divided into the conventional treatment guidelines group and 35 into the wrap therapy group. Main outcome measures The primary end point was the period until the pressure ulcers were cured. The secondary end point was a comparison of the speed of change in the Pressure Ulcer Scale for Healing score. Results 64 of the 66 patients were analysed. The estimated mean period until healing was 57.5 days (95% CI 45.2 to 69.8) in the control group as opposed to 59.8 days (95% CI 49.7 to 69.9) in the wrap therapy group. By the extent of pressure ulcer infiltration, the mean period until healing was 16.0 days (95% CI 8.1 to 23.9) in the control group as opposed to 18.8 days (95% CI 10.3 to 27.2) in the wrap therapy group with National Pressure Ulcer Advisory Panel stage II ulcers, and 71.8 days (95% CI 61.4 to 82.3) as opposed to 63.2 days (95% CI 53.0 to 73.4), respectively, with stage III ulcers. There is no statistical significance in difference in Pressure Ulcer Scale for Healing scores. Conclusions It might be possible to consider wrap therapy as an alternative choice in primary care settings as a simple and inexpensive dressing care. Clinical Trial registration UMIN Clinical Trials Registry UMIN000002658. Summary protocol is available on https://upload.umin.ac.jp/cgi-bin/ctr/ctr.cgi?function=brows&action=brows&type=detail&recptno=R000003235&admin=0&language=J PMID:22223842

  20. Pressurized vascular systems for self-healing materials

    PubMed Central

    Hamilton, A. R.; Sottos, N. R.; White, S. R.

    2012-01-01

    An emerging strategy for creating self-healing materials relies on embedded vascular networks of microchannels to transport reactive fluids to regions of damage. Here we investigate the use of active pumping for the pressurized delivery of a two-part healing system, allowing a small vascular system to deliver large volumes of healing agent. Different pumping strategies are explored to improve the mixing and subsequent polymerization of healing agents in the damage zone. Significant improvements in the number of healing cycles and in the overall healing efficiency are achieved compared with prior passive schemes that use only capillary forces for the delivery of healing agents. At the same time, the volume of the vascular system required to achieve this superior healing performance is significantly reduced. In the best case, nearly full recovery of fracture toughness is attained throughout 15 cycles of damage and healing, with a vascular network constituting just 0.1 vol% of the specimen. PMID:21957119

  1. Biomechanical Concepts for Fracture Fixation.

    PubMed

    Bottlang, Michael; Schemitsch, Christine E; Nauth, Aaron; Routt, Milton; Egol, Kenneth A; Cook, Gillian E; Schemitsch, Emil H

    2015-12-01

    Application of the correct fixation construct is critical for fracture healing and long-term stability; however, it is a complex issue with numerous significant factors. This review describes a number of common fracture types and evaluates their currently available fracture fixation constructs. In the setting of complex elbow instability, stable fixation or radial head replacement with an appropriately sized implant in conjunction with ligamentous repair is required to restore stability. For unstable sacral fractures with vertical or multiplanar instabilities, "standard" iliosacral screw fixation is not sufficient. Periprosthetic femur fractures, in particular Vancouver B1 fractures, have increased stability when using 90/90 fixation versus a single locking plate. Far cortical locking combines the concept of dynamization with locked plating to achieve superior healing of a distal femur fracture. Finally, there is no ideal construct for syndesmotic fracture stabilization; however, these fractures should be fixed using a device that allows for sufficient motion in the syndesmosis. In general, orthopaedic surgeons should select a fracture fixation construct that restores stability and promotes healing at the fracture site, while reducing the potential for fixation failure.

  2. Nose fracture

    MedlinePlus

    Fracture of the nose; Broken nose; Nasal fracture; Nasal bone fracture; Nasal septal fracture ... A fractured nose is the most common fracture of the face. It ... with other fractures of the face. Sometimes a blunt injury can ...

  3. Ghrelin accelerates wound healing through GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways in combined radiation and burn injury in rats

    PubMed Central

    Liu, Cong; Huang, Jiawei; Li, Hong; Yang, Zhangyou; Zeng, Yiping; Liu, Jing; Hao, Yuhui; Li, Rong

    2016-01-01

    The therapeutic effect of ghrelin on wound healing was assessed using a rat model of combined radiation and burn injury (CRBI). Rat ghrelin, anti-rat tumor necrosis factor (TNF) α polyclonal antibody (PcAb), or selective antagonists of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and growth hormone secretagogue receptor (GHS-R) 1a (SB203580, SP600125, and [D-Lys3]-GHRP-6, respectively), were administered for seven consecutive days. Levels of various signaling molecules were assessed in isolated rat peritoneal macrophages. The results showed that serum ghrelin levels and levels of macrophage glucocorticoid receptor (GR) decreased, while phosphorylation of p38MAPK, JNK, and p65 nuclear factor (NF) κB increased. Ghrelin inhibited the serum induction of proinflammatory mediators, especially TNF-α, and promoted wound healing in a dose-dependent manner. Ghrelin treatment decreased phosphorylation of p38MAPK, JNK, and p65NF-κB, and increased GR levels in the presence of GHS-R1a. SB203580 or co-administration of SB203580 and SP600125 decreased TNF-α level, which may have contributed to the inactivation of p65NF-κB and increase in GR expression, as confirmed by western blotting. In conclusion, ghrelin enhances wound recovery in CRBI rats, possibly by decreasing the induction of TNF-α or other proinflammatory mediators that are involved in the regulation of GHS-R1a-mediated MAPK-NF-κB/GR signaling pathways. PMID:27271793

  4. [Healing "booster" dressings].

    PubMed

    Fromantin, Isabelle; Téot, Luc; Meaume, Sylvie

    2011-09-01

    The relationship between the dressing and the wound is vital to clinical effectiveness. The more-or-less standard wound-surface coverings have been replaced with initial dressings, referred to as modern dressings, which contain an oily and sticky compound. They provide a moist medium by applying the basic mechanistic principles (liquid absorption and release). Other types of products and techniques modify the behaviour of wound cells by acting directly through irritation, biochemical stimulation or genetic modification of the cells, which accelerates the healing process.

  5. 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

  6. Low-Magnitude High-Frequency Mechanical Signals Accelerate and Augment Endochondral Bone Repair: Preliminary Evidence of Efficacy

    PubMed Central

    Goodship, Allen E.; Lawes, Timothy J.; Rubin, Clinton T.

    2010-01-01

    Fracture healing can be enhanced by load bearing, but the specific components of the mechanical environment which can augment or accelerate the process remain unknown. The ability of low-magnitude, high-frequency mechanical signals, anabolic in bone tissue, are evaluated here for their ability to influence fracture healing. The potential for short duration (17 min), extremely low-magnitude (25 μm), high-frequency (30 Hz) interfragmentary displacements to enhance fracture healing was evaluated in a mid-diaphyseal, 3-mm osteotomy of the sheep tibia. In a pilot study of proof of concept and clinical relevance, healing in osteotomies stabilized with rigid external fixation (Control: n = 4), were compared to the healing status of osteotomies with the same stiffness of fixation, but supplemented with daily mechanical loading (Experimental: n = 4). These 25-μm displacements, induced by a ferroactive shape-memory alloy (“smart” material) incorporated into the body of the external fixator, were less than 1% of the 3-mm fracture gap, and less than 6% of the 0.45-mm displacement measured at the site during ambulation (p <0.001). At 10-weeks post-op, the callus in the Experimental group was 3.6-fold stiffer (p <0.03), 2.5-fold stronger (p =0.05), and 29% larger (p <0.01) than Controls. Bone mineral content was 52% greater in the Experimental group (p <0.02), with a 2.6-fold increase in bone mineral content (BMC) in the region of the periosteum (p <0.001). These data reinforce the critical role of mechanical factors in the enhancement of fracture healing, and emphasize that the signals need not be large to be influential and potentially clinically advantageous to the restoration of function. PMID:19117066

  7. Closed reduction of the mandibular fracture.

    PubMed

    Blitz, Meredith; Notarnicola, Kurt

    2009-03-01

    The search for the ideal method of treatment for mandibular fractures has continued for thousands of years. These injuries have unique and problematic features for adequate reliable wound healing. Oral and maxillofacial surgeons must learn and master several techniques for mandibular fracture treatment. The age-old successful management of these injuries using closed reduction techniques always should be considered when mandibular trauma presents. The closed reduction remains a mainstay of mandibular fracture treatment. An adequate knowledge of anatomy, multiple closed reduction techniques, and the physiology of fracture healing must be adequately understood and technically mastered by the oral and maxillofacial surgical team for the present and future of mandibular fracture management.

  8. Self-healing of hierarchical materials.

    PubMed

    Bosia, Federico; Abdalrahman, Tamer; Pugno, Nicola M

    2014-02-01

    We present a theoretical and numerical analysis of the mechanical behavior of self-healing materials using an analytical model and numerical calculations both based on a Hierarchical Fiber Bundle Model, and applying them to graphene- or carbon-nanotube-based materials. The self-healing process can be described essentially through a single parameter, that is, the healing rate, but numerical simulations also highlight the influence of the location of the healing process on the overall strengthening and toughening of the material. The role of hierarchy is discussed, showing that full-scale hierarchical structures can in fact acquire more favorable properties than smaller, nonhierarchical ones through interaction with the self-healing process, thus inverting the common notion in fracture mechanics that specimen strength increases with decreasing size. Further, the study demonstrates that the developed analytical and numerical tools can be useful to develop strategies for the optimization of strength and toughness of synthetic bioinspired materials. PMID:24364755

  9. Systemic treatment with strontium ranelate accelerates the filling of a bone defect and improves the material level properties of the healing bone.

    PubMed

    Zacchetti, Giovanna; Dayer, Romain; Rizzoli, René; Ammann, Patrick

    2014-01-01

    Rapid bone defect filling with normal bone is a challenge in orthopaedics and dentistry. Strontium ranelate (SrRan) has been shown to in vitro decrease bone resorption and increase bone formation, and represents a potential agent with the capacity to accelerate bone defect filling. In this study, bone tibial defects of 2.5 mm in diameter were created in 6-month-old female rats orally fed SrRan (625 mg/kg/d; 5/7 days) or vehicle for 4, 8, or 12 weeks (10 rats per group per time point) from the time of surgery. Tibias were removed. Micro-architecture was determined by micro-computed tomography (µCT) and material level properties by nanoindentation analysis. µCT analysis showed that SrRan administration significantly improved microarchitecture of trabecular bone growing into the defect after 8 and 12 weeks of treatment compared to vehicle. SrRan treatment also accelerated the growth of cortical bone over the defect, but with different kinetics compared to trabecular bone, as the effects were already significant after 4 weeks. Nanoindentation analysis demonstrated that SrRan treatment significantly increased material level properties of both trabecular bone and cortical bone filling the defect compared to vehicle. SrRan accelerates the filling of bone defect by improving cortical and trabecular bone microarchitecture both quantitatively and qualitatively. PMID:25243150

  10. Progress in corneal wound healing.

    PubMed

    Ljubimov, Alexander V; Saghizadeh, Mehrnoosh

    2015-11-01

    Corneal wound healing is a complex process involving cell death, migration, proliferation, differentiation, and extracellular matrix remodeling. Many similarities are observed in the healing processes of corneal epithelial, stromal and endothelial cells, as well as cell-specific differences. Corneal epithelial healing largely depends on limbal stem cells and remodeling of the basement membrane. During stromal healing, keratocytes get transformed to motile and contractile myofibroblasts largely due to activation of transforming growth factor-β (TGF-β) system. Endothelial cells heal mostly by migration and spreading, with cell proliferation playing a secondary role. In the last decade, many aspects of wound healing process in different parts of the cornea have been elucidated, and some new therapeutic approaches have emerged. The concept of limbal stem cells received rigorous experimental corroboration, with new markers uncovered and new treatment options including gene and microRNA therapy tested in experimental systems. Transplantation of limbal stem cell-enriched cultures for efficient re-epithelialization in stem cell deficiency and corneal injuries has become reality in clinical setting. Mediators and course of events during stromal healing have been detailed, and new treatment regimens including gene (decorin) and stem cell therapy for excessive healing have been designed. This is a very important advance given the popularity of various refractive surgeries entailing stromal wound healing. Successful surgical ways of replacing the diseased endothelium have been clinically tested, and new approaches to accelerate endothelial healing and suppress endothelial-mesenchymal transformation have been proposed including Rho kinase (ROCK) inhibitor eye drops and gene therapy to activate TGF-β inhibitor SMAD7. Promising new technologies with potential for corneal wound healing manipulation including microRNA, induced pluripotent stem cells to generate corneal

  11. Ethanolic extract of roots from Arctium lappa L. accelerates the healing of acetic acid-induced gastric ulcer in rats: Involvement of the antioxidant system.

    PubMed

    da Silva, Luisa Mota; Allemand, Alexandra; Mendes, Daniel Augusto G B; Dos Santos, Ana Cristina; André, Eunice; de Souza, Lauro Mera; Cipriani, Thales Ricardo; Dartora, Nessana; Marques, Maria Consuelo Andrade; Baggio, Cristiane Hatsuko; Werner, Maria Fernanda

    2013-01-01

    We evaluate the curative efficacy of the ethanolic extract (EET) of roots from Arctium lappa (bardana) in healing of chronic gastric ulcers induced by 80% acetic acid in rats and additionally studies the possible mechanisms underlying this action. Oral administration of EET (1, 3, 10 and 30mg/kg) reduced the gastric lesion area in 29.2%, 41.4%, 59.3% and 38.5%, respectively, and at 10mg/kg promoted significant regeneration of the gastric mucosa, which was confirmed by proliferating cell nuclear antigen immunohistochemistry. EET (10mg/kg) treatment did not increase the gastric mucus content but restored the superoxide dismutase activity, prevented the reduction of glutathione levels, reduced lipid hydroperoxides levels, inhibited the myeloperoxidase activity and reduced the microvascular permeability. In addition, EET reduced the free radical generation and increased scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals in vitro. Furthermore, intraduodenal EET (10 and 30mg/kg) decreased volume and acidity of gastric secretion. Total phenolic compounds were high in EET (Folin-Ciocalteau assay) and the analysis by liquid chromatography-mass spectrometry revealed that the main compounds present in EET were a serie of hydroxycinnamoylquinic acid isomers. In conclusion, these data reveal that EET promotes regeneration of damaged gastric mucosa, probably through its antisecretory and antioxidative mechanisms.

  12. Ethanolic extract of roots from Arctium lappa L. accelerates the healing of acetic acid-induced gastric ulcer in rats: Involvement of the antioxidant system.

    PubMed

    da Silva, Luisa Mota; Allemand, Alexandra; Mendes, Daniel Augusto G B; Dos Santos, Ana Cristina; André, Eunice; de Souza, Lauro Mera; Cipriani, Thales Ricardo; Dartora, Nessana; Marques, Maria Consuelo Andrade; Baggio, Cristiane Hatsuko; Werner, Maria Fernanda

    2013-01-01

    We evaluate the curative efficacy of the ethanolic extract (EET) of roots from Arctium lappa (bardana) in healing of chronic gastric ulcers induced by 80% acetic acid in rats and additionally studies the possible mechanisms underlying this action. Oral administration of EET (1, 3, 10 and 30mg/kg) reduced the gastric lesion area in 29.2%, 41.4%, 59.3% and 38.5%, respectively, and at 10mg/kg promoted significant regeneration of the gastric mucosa, which was confirmed by proliferating cell nuclear antigen immunohistochemistry. EET (10mg/kg) treatment did not increase the gastric mucus content but restored the superoxide dismutase activity, prevented the reduction of glutathione levels, reduced lipid hydroperoxides levels, inhibited the myeloperoxidase activity and reduced the microvascular permeability. In addition, EET reduced the free radical generation and increased scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals in vitro. Furthermore, intraduodenal EET (10 and 30mg/kg) decreased volume and acidity of gastric secretion. Total phenolic compounds were high in EET (Folin-Ciocalteau assay) and the analysis by liquid chromatography-mass spectrometry revealed that the main compounds present in EET were a serie of hydroxycinnamoylquinic acid isomers. In conclusion, these data reveal that EET promotes regeneration of damaged gastric mucosa, probably through its antisecretory and antioxidative mechanisms. PMID:23036453

  13. Mechanisms and Management of Stress Fractures in Physically Active Persons

    PubMed Central

    Romani, William A.; Gieck, Joe H.; Perrin, David H.; Saliba, Ethan N.; Kahler, David M.

    2002-01-01

    Objective: To describe the anatomy of bone and the physiology of bone remodeling as a basis for the proper management of stress fractures in physically active people. Data Sources: We searched PubMed for the years 1965 through 2000 using the key words stress fracture, bone remodeling, epidemiology, and rehabilitation. Data Synthesis: Bone undergoes a normal remodeling process in physically active persons. Increased stress leads to an acceleration of this remodeling process, a subsequent weakening of bone, and a higher susceptibility to stress fracture. When a stress fracture is suspected, appropriate management of the injury should begin immediately. Effective management includes a cyclic process of activity and rest that is based on the remodeling process of bone. Conclusions/Recommendations: Bone continuously remodels itself to withstand the stresses involved with physical activity. Stress fractures occur as the result of increased remodeling and a subsequent weakening of the outer surface ofthe bone. Once a stress fracture is suspected, a cyclic management program that incorporates the physiology of bone remodeling should be initiated. The cyclic program should allow the physically active person to remove the source of the stress to the bone, maintain fitness, promote a safe return to activity, and permit the bone to heal properly. PMID:16558676

  14. Mathematical model for wound healing following autologous keratinocyte transplantation.

    PubMed

    Renner, Regina; Teuwen, Isabell; Gebhardt, Carl; Simon, Jan C

    2008-06-01

    In times of increasing economical pressure on the health care systems, it is important to optimise the outpatient treatment of chronic wounds. Another aim of wound healing research is to discover agents to accelerate healing. Wound healing trajectories or healing velocities can provide information to demonstrate the endpoints for wound healing. A great problem in clinical trials is to specify these parameters. Therefore, we developed a mathematical model for more transparency. In this initial project, we observed 19 wounds to construct the wound healing trajectories after transplantation of autologous keratinocytes, and the results are so encouraging that investigation in this area will continue. The developed mathematical model describes the clinical observed healing process. It was possible to find parameters to distinguish between old and young patients, retrospectively or prospectively calculate the healing rates and to determine exactly the endpoint of healing. Therefore, our model might be very useful in practices or for studies.

  15. Tibial Stress Fractures in Athletes.

    PubMed

    Feldman, John J; Bowman, Eric N; Phillips, Barry B; Weinlein, John C

    2016-10-01

    Tibial stress fractures are common in the athlete. There are various causes of these fractures, the most common being a sudden increase in training intensity. Most of these injuries are treated conservatively; however, some may require operative intervention. Intervention is mostly dictated by location of the fracture and failure of conservative treatment. There are several surgical options available to the treating surgeon, each with advantages and disadvantages. The physician must understand the nature of the fracture and the likelihood for it to heal in a timely manner in order to best treat these fractures in this patient subset. PMID:27637660

  16. Femur fracture repair - discharge

    MedlinePlus

    ... surgery, your surgeon will make a cut to open your fracture. Your surgeon will then use special metal devices to hold your bones in place while they heal. These devices are called ... is open reduction and internal fixation (ORIF). In the most ...

  17. Dorsal radiocarpal fracture dislocation.

    PubMed

    Tanzer, T L; Horne, J G

    1980-11-01

    A case of a rare radiocarpal fracture dislocation in a 17-year-old girl, with persisting loss of radiocarpal joint space following reduction under hematoma block, is described. The wrist joint was exposed, and two osteochondral fragments were rotated 90 degrees and secured with 2.7-mm AO screws. Satisfactory healing followed 3 months postinjury.

  18. Acceleration of cutaneous healing by electrical stimulation: degenerate electrical waveform down-regulates inflammation, up-regulates angiogenesis and advances remodeling in temporal punch biopsies in a human volunteer study.

    PubMed

    Sebastian, Anil; Syed, Farhatullah; Perry, Donna; Balamurugan, Vinayagapriya; Colthurst, James; Chaudhry, Iskander H; Bayat, Ardeshir

    2011-11-01

    We previously demonstrated the beneficial effect of a novel electrical stimulation (ES) waveform, degenerate wave (DW) on skin fibroblasts, and now hypothesize that DW can enhance cutaneous wound healing in vivo. Therefore, a punch biopsy was taken from the upper arm of 20 volunteers on day 0 and repeated on day 14 (NSD14). A contralateral upper arm biopsy was taken on day 0 and treated with DW for 14 days prior to a repeat biopsy on day 14 (ESD14). A near-completed inflammatory stage of wound healing in ESD14, compared to NSD14 was demonstrated by up-regulation of interleukin-10 and vasoactive intestinal peptide using quantitative real time polymerase chain reaction and down-regulation of CD3 by immunohist