Science.gov

Sample records for accelerate bone healing

  1. 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.

  2. 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

  3. Supplementary vitamin C does not accelerate bone healing in a rat tibia fracture model

    PubMed Central

    Giordano, Vincenzo; Albuquerque, Rodrigo Pires e; do Amaral, Ney Pecegueiro; Chame, Cristiano Curcio; de Souza, Fabio; Apfel, Mara Íbis Rodrigues

    2012-01-01

    Objective To investigate the role of ascorbic acid supplementation on bone healing after rat tibia fracture. Methods Thirty male Wistar rats were randomly divided into Vitamin C (Group A) and sham (Group B) groups (15 rats each). Group A received 200 mg intraperitoneally per kg per day of ascorbic acid and Group B was given saline 5 ml per kg per day intraperitoneally once a day. The animals were caged in pairs and allowed free access to tap water and a standard rodent chow ad libitum. Fractures were produced manually, they were not stabilized, and unprotected weight-bearing was allowed. At two, four, and six weeks post-fracture, the rats in both groups were anesthetized and sacrificed by cervical dislocation. Callus tissue was dissected, prepared, and analyzed histologically. Histomorphological analysis was performed at six weeks post-fracture and the extent of fracture healing was determined using a five-point scale. Results There were no histological and histomorphological differences between drug-treated animals and the sham in the three different stages studied. By six weeks post-fracture, the five animals of each group had a complete bone union. Conclusion Under the studied conditions, intraperitoneal Vitamin C supplementation does not accelerate the fracture healing process after experimental tibia fracture in rats. Level of evidence: Level 2, individual study with experimental design. PMID:24453572

  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. Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats.

    PubMed

    Kwon, David S; Gao, Xiaohua; Liu, Yong Bo; Dulchavsky, Deborah S; Danyluk, Andrew L; Bansal, Mona; Chopp, Michael; McIntosh, Kevin; Arbab, Ali S; Dulchavsky, Scott A; Gautam, Subhash C

    2008-06-01

    Bone marrow stem cells participate in tissue repair processes and may have a role in wound healing. Diabetes is characterised by delayed and poor wound healing. We investigated the potential of bone marrow-derived mesenchymal stromal cells (BMSCs) to promote healing of fascial wounds in diabetic rats. After manifestation of streptozotocin (STZ)-induced diabetic state for 5 weeks in male adult Sprague-Dawley rats, healing of fascial wounds was severely compromised. Compromised wound healing in diabetic rats was characterised by excessive polymorphonuclear cell infiltration, lack of granulation tissue formation, deficit of collagen and growth factor [transforming growth factor (TGF-beta), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor PDGF-BB and keratinocyte growth factor (KGF)] expression in the wound tissue and significant decrease in biomechanical strength of wounds. Treatment with BMSC systemically or locally at the wound site improved the wound-breaking strength (WBS) of fascial wounds. The improvement in WBS was associated with an immediate and significant increase in collagen levels (types I-V) in the wound bed. In addition, treatment with BMSCs increased the expression of growth factors critical to proper repair and regeneration of the damaged tissue moderately (TGF-beta, KGF) to markedly (EGF, VEGF, PDGF-BB). These data suggest that cell therapy with BMSCs has the potential to augment healing of the diabetic wounds.

  6. Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing.

    PubMed

    Wang, Liping; Hsiao, Edward C; Lieu, Shirley; Scott, Mark; O'Carroll, Dylan; Urrutia, Ashley; Conklin, Bruce R; Colnot, Celine; Nissenson, Robert A

    2015-10-01

    G-protein-coupled receptors (GPCRs) are key regulators of skeletal homeostasis and are likely important in fracture healing. Because GPCRs can activate multiple signaling pathways simultaneously, we used targeted disruption of G(i) -GPCR or activation of G(s) -GPCR pathways to test how each pathway functions in the skeleton. We previously demonstrated that blockade of G(i) signaling by pertussis toxin (PTX) transgene expression in maturing osteoblastic cells enhanced cortical and trabecular bone formation and prevented age-related bone loss in female mice. In addition, activation of G(s) signaling by expressing the G(s) -coupled engineered receptor Rs1 in maturing osteoblastic cells induced massive trabecular bone formation but cortical bone loss. Here, we test our hypothesis that the G(i) and G(s) pathways also have distinct functions in fracture repair. We applied closed, nonstabilized tibial fractures to mice in which endogenous G(i) signaling was inhibited by PTX, or to mice with activated G(s) signaling mediated by Rs1. Blockade of endogenous G(i) resulted in a smaller callus but increased bone formation in both young and old mice. PTX treatment decreased expression of Dkk1 and increased Lef1 mRNAs during fracture healing, suggesting a role for endogenous G(i) signaling in maintaining Dkk1 expression and suppressing Wnt signaling. In contrast, adult mice with activated Gs signaling showed a slight increase in the initial callus size with increased callus bone formation. These results show that G(i) blockade and G(s) activation of the same osteoblastic lineage cell can induce different biological responses during fracture healing. Our findings also show that manipulating the GPCR/cAMP signaling pathway by selective timing of G(s) and G(i) -GPCR activation may be important for optimizing fracture repair.

  7. Infrared laser therapy after surgically assisted rapid palatal expansion to diminish pain and accelerate bone healing.

    PubMed

    Abreu, Marcelo Emir Requia; Viegas, Vinicius Nery; Pagnoncelli, Rogerio Miranda; de Lima, Eduardo Martinelli Santayama; Farret, Alessandro Marchiori; Kulczynski, Fernando Zugno; Farret, Marcel Marchiori

    2010-01-01

    The aim of this study was to illustrate how gallium arsenite aluminum diode laser (824 nm) irradiation can reduce postsurgical edema and discomfort and accelerate sutural osseous regeneration after surgically assisted rapid palatal expansion (SARPE). An adult patient with an 8-mm transverse maxillary discrepancy was treated with SARPE. Infrared laser therapy was started on the 7th postoperative day, with a total of eight sessions at intervals of 48 hours. The laser probe spot had a size of 0.2827 cm2 and was positioned in contact with the following (bilateral) points: infraorbital foramen, nasal alar, nasopalatine foramen, median palatal suture at the height of the molars, and transverse palatine suture distal to the second molars. The laser was run in continuous mode with a power of 100 mW and a fluency of 1.5 J/cm2 for 20 seconds at each point. Subsequently, an absence of edema and pain was observed. Further, fast bone regeneration in the median palatal suture could be demonstrated by occlusal radiographs. These findings suggest that laser therapy can accelerate bone regeneration of the median palatal suture in patients who have undergone SARPE.

  8. Bone healing in 2016

    PubMed Central

    Buza, John A.; Einhorn, Thomas

    2016-01-01

    Summary Delayed fracture healing and nonunion occurs in up to 5–10% of all fractures, and can present a challenging clinical scenario for the treating physician. Methods for the enhancement of skeletal repair may benefit patients that are at risk of, or have experienced, delayed healing or nonunion. These methods can be categorized into either physical stimulation therapies or biological therapies. Physical stimulation therapies include electrical stimulation, low-intensity pulsed ultrasonography, or extracorporeal shock wave therapy. Biological therapies can be further classified into local or systemic therapy based on the method of delivery. Local methods include autologous bone marrow, autologous bone graft, fibroblast growth factor-2, platelet-rich plasma, platelet-derived growth factor, and bone morphogenetic proteins. Systemic therapies include parathyroid hormone and bisphosphonates. This article reviews the current applications and supporting evidence for the use of these therapies in the enhancement of fracture healing. PMID:27920804

  9. 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

  10. 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.

  11. 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.

  12. Graphene oxide scaffold accelerates cellular proliferative response and alveolar bone healing of tooth extraction socket.

    PubMed

    Nishida, Erika; Miyaji, Hirofumi; Kato, Akihito; Takita, Hiroko; Iwanaga, Toshihiko; Momose, Takehito; Ogawa, Kosuke; Murakami, Shusuke; Sugaya, Tsutomu; Kawanami, Masamitsu

    2016-01-01

    Graphene oxide (GO) consisting of a carbon monolayer has been widely investigated for tissue engineering platforms because of its unique properties. For this study, we fabricated a GO-applied scaffold and assessed the cellular and tissue behaviors in the scaffold. A preclinical test was conducted to ascertain whether the GO scaffold promoted bone induction in dog tooth extraction sockets. For this study, GO scaffolds were prepared by coating the surface of a collagen sponge scaffold with 0.1 and 1 µg/mL GO dispersion. Scaffolds were characterized using scanning electron microscopy (SEM), physical testing, cell seeding, and rat subcutaneous implant testing. Then a GO scaffold was implanted into a dog tooth extraction socket. Histological observations were made at 2 weeks postsurgery. SEM observations show that GO attached to the surface of collagen scaffold struts. The GO scaffold exhibited an interconnected structure resembling that of control subjects. GO application improved the physical strength, enzyme resistance, and adsorption of calcium and proteins. Cytocompatibility tests showed that GO application significantly increased osteoblastic MC3T3-E1 cell proliferation. In addition, an assessment of rat subcutaneous tissue response revealed that implantation of 1 µg/mL GO scaffold stimulated cellular ingrowth behavior, suggesting that the GO scaffold exhibited good biocompatibility. The tissue ingrowth area and DNA contents of 1 µg/mL GO scaffold were, respectively, approximately 2.5-fold and 1.4-fold greater than those of the control. Particularly, the infiltration of ED2-positive (M2) macrophages and blood vessels were prominent in the GO scaffold. Dog bone-formation tests showed that 1 µg/mL GO scaffold implantation enhanced bone formation. New bone formation following GO scaffold implantation was enhanced fivefold compared to that in control subjects. These results suggest that GO was biocompatible and had high bone-formation capability for the scaffold

  13. Graphene oxide scaffold accelerates cellular proliferative response and alveolar bone healing of tooth extraction socket

    PubMed Central

    Nishida, Erika; Miyaji, Hirofumi; Kato, Akihito; Takita, Hiroko; Iwanaga, Toshihiko; Momose, Takehito; Ogawa, Kosuke; Murakami, Shusuke; Sugaya, Tsutomu; Kawanami, Masamitsu

    2016-01-01

    Graphene oxide (GO) consisting of a carbon monolayer has been widely investigated for tissue engineering platforms because of its unique properties. For this study, we fabricated a GO-applied scaffold and assessed the cellular and tissue behaviors in the scaffold. A preclinical test was conducted to ascertain whether the GO scaffold promoted bone induction in dog tooth extraction sockets. For this study, GO scaffolds were prepared by coating the surface of a collagen sponge scaffold with 0.1 and 1 µg/mL GO dispersion. Scaffolds were characterized using scanning electron microscopy (SEM), physical testing, cell seeding, and rat subcutaneous implant testing. Then a GO scaffold was implanted into a dog tooth extraction socket. Histological observations were made at 2 weeks postsurgery. SEM observations show that GO attached to the surface of collagen scaffold struts. The GO scaffold exhibited an interconnected structure resembling that of control subjects. GO application improved the physical strength, enzyme resistance, and adsorption of calcium and proteins. Cytocompatibility tests showed that GO application significantly increased osteoblastic MC3T3-E1 cell proliferation. In addition, an assessment of rat subcutaneous tissue response revealed that implantation of 1 µg/mL GO scaffold stimulated cellular ingrowth behavior, suggesting that the GO scaffold exhibited good biocompatibility. The tissue ingrowth area and DNA contents of 1 µg/mL GO scaffold were, respectively, approximately 2.5-fold and 1.4-fold greater than those of the control. Particularly, the infiltration of ED2-positive (M2) macrophages and blood vessels were prominent in the GO scaffold. Dog bone-formation tests showed that 1 µg/mL GO scaffold implantation enhanced bone formation. New bone formation following GO scaffold implantation was enhanced fivefold compared to that in control subjects. These results suggest that GO was biocompatible and had high bone-formation capability for the scaffold

  14. Parathyroid hormone and bone healing.

    PubMed

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

    2010-07-01

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

  15. 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.

  16. Systemic Treatment with Strontium Ranelate Accelerates the Filling of a Bone Defect and Improves the Material Level Properties of the Healing Bone

    PubMed Central

    Zacchetti, Giovanna; Rizzoli, René

    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

  17. Acceleration of bone formation during fracture healing by injectable collagen powder and human basic fibroblast growth factor containing a collagen-binding domain from Clostridium histolyticum collagenase.

    PubMed

    Saito, Wataru; Uchida, Kentaro; Ueno, Masaki; Matsushita, Osamu; Inoue, Gen; Nishi, Nozomu; Ogura, Takayuki; Hattori, Shunji; Fujimaki, Hisako; Tanaka, Keisuke; Takaso, Masashi

    2014-09-01

    Growth factor delivered with implantable biomaterials has been used to both accelerate and ensure healing of open fractures in human patients. However, a major limitation of implantable biomaterials is the requirement for open surgical placement. Here, we developed an injectable collagen material-based bone formation system consisting of injectable collagen powder with fibril morphology and collagen triple helix conformation, and basic fibroblast growth factor (bFGF) fused to the collagen-binding domain (CBD) of Clostridium histolyticum collagenase. The affinity of the CBD towards collagen was confirmed by the results of collagen-binding assays. Moreover, the combination of the collagen binding-bFGF fusion protein (CB-bFGF) with injectable collagen powder induced bone formation at protein concentrations lower than those required for bFGF alone in mice fracture models. Taken together, these properties suggest that the CB-bFGF/collagen powder composite is a promising injectable material for bone repair in the clinical setting.

  18. Gene therapy for bone healing.

    PubMed

    Evans, Christopher H

    2010-06-23

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

  19. Gene therapy for bone healing

    PubMed Central

    Evans, Christopher H.

    2015-01-01

    Clinical problems in bone healing include large segmental defects, nonunion and delayed union of fractures, and spinal fusions. Gene-transfer technologies have the potential to aid healing by permitting the local delivery and sustained expression of osteogenic gene products within osseous lesions. Key questions for such an approach include the choice of transgene, vector and gene-transfer strategy. Most experimental data have been obtained using cDNAs encoding osteogenic growth factors such as bone morphogenetic protein-2 (BMP-2), BMP-4 and BMP-7, in conjunction with both nonviral and viral vectors using in vivo and ex vivo delivery strategies. Proof of principle has been convincingly demonstrated in small-animal models. Relatively few studies have used large animals, but the results so far are encouraging. Once a reliable method has been developed, it will be necessary to perform detailed pharmacological and toxicological studies, as well as satisfy other demands of the regulatory bodies, before human clinical trials can be initiated. Such studies are very expensive and often protracted. Thus, progress in developing a clinically useful gene therapy for bone healing is determined not only by scientific considerations, but also by financial constraints and the ambient regulatory environment. PMID:20569532

  20. Fracture healing in osteoporotic bone.

    PubMed

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

    2016-06-01

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

  1. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds.

    PubMed

    Falanga, Vincent; Iwamoto, Satori; Chartier, Molly; Yufit, Tatyana; Butmarc, Janet; Kouttab, Nicholas; Shrayer, David; Carson, Polly

    2007-06-01

    The nonhematopoietic component of bone marrow includes multipotent mesenchymal stem cells (MSC) capable of differentiating into fat, bone, muscle, cartilage, and endothelium. In this report, we describe the cell culture and characterization, delivery system, and successful use of topically applied autologous MSC to accelerate the healing of human and experimental murine wounds. A single bone marrow aspirate of 35-50 mL was obtained from patients with acute wounds (n = 5) from skin cancer surgery and from patients with chronic, long-standing, nonhealing lower extremity wounds (n = 8). Cells were grown in vitro under conditions favoring the propagation of MSC, and flow cytometry and immunostaining showed a profile (CD29+, CD44+, CD105+, CD166+, CD34-, CD45-) highly consistent with published reports of human MSC. Functional induction studies confirmed that the MSC could differentiate into bone, cartilage, and adipose tissue. The cultured autologous MSC were applied up to four times to the wounds using a fibrin polymer spray system with a double-barreled syringe. Both fibrinogen (containing the MSC) and thrombin were diluted to optimally deliver a polymerized gel that immediately adhered to the wound, without run-off, and yet allowing the MSC to remain viable and migrate from the gel. Sequential adjacent sections from biopsy specimens of the wound bed after MSC application showed elongated spindle cells, similar to their in vitro counterparts, which immunostained for MSC markers. Generation of new elastic fibers was evident by both special stains and antibodies to human elastin. The application of cultured cells was safe, without treatment-related adverse events. A strong direct correlation was found between the number of cells applied (greater than 1 x 10(6) cells per cm2 of wound area) and the subsequent decrease in chronic wound size (p = 0.0058). Topical application of autologous MSC also stimulated closure of full-thickness wounds in diabetic mice (db

  2. The Biology of Bone and Ligament Healing.

    PubMed

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

    2016-12-01

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

  3. Chemically modified RNA induces osteogenesis of stem cells and human tissue explants as well as accelerates bone healing in rats.

    PubMed

    Balmayor, Elizabeth R; Geiger, Johannes P; Aneja, Manish K; Berezhanskyy, Taras; Utzinger, Maximilian; Mykhaylyk, Olga; Rudolph, Carsten; Plank, Christian

    2016-05-01

    Limitations associated to the use of growth factors represent a major hurdle to musculoskeletal regeneration. On the one hand, they are needed to induce neo-tissue formation for the substitution of a necrotic or missing tissue. On the other hand, these factors are used in supraphysiological concentrations, are short lived and expensive and result in many side effects. Here we develop a gene transfer strategy based on the use of chemically modified mRNA (cmRNA) coding for human bone morphogenetic protein 2 (hBMP-2) that is non-immunogenic and highly stable when compared to unmodified mRNA. Transfected stem cells secrete hBMP-2, show elevated alkaline phosphatase levels and upregulated expression of RunX2, ALP, Osterix, Osteocalcin, Osteopontin and Collagen Type I genes. Mineralization was induced as seen by positive Alizarin red staining. hBMP-2 cmRNA transfected human fat tissue also yielded an osteogenic response in vitro as indicated by expression of hBMP-2, RunX2, ALP and Collagen Type I. Delivering hBMP-2 cmRNA to a femur defect in a rat model results in new bone tissue formation as early as 2 weeks after application of very low doses. Overall, our studies demonstrate the feasibility and therapeutic potential of a new cmRNA-based gene therapy strategy that is safe and efficient. When applied clinically, this approach could overcome BMP-2 growth factor associated limitations in bone regeneration.

  4. 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

  5. Low dose erythropoietin stimulates bone healing in mice.

    PubMed

    Garcia, P; Speidel, V; Scheuer, C; Laschke, M W; Holstein, J H; Histing, T; Pohlemann, T; Menger, M D

    2011-02-01

    Beyond its classical role in regulation of erythropoiesis, erythropoietin (EPO) has been shown to exert protective and regenerative actions in a variety of non-hematopoietic tissues. However, little is known about potential actions in bone regeneration. To analyze fracture healing in mice, a femoral 0.25 mm osteotomy gap was stabilized with a pin-clip technique. Animals were treated with 500 U EPO/kg bw per day or with vehicle only. After 2 and 5 weeks, fracture healing was analyzed biomechanically, radiologically and histologically. Expression of PCNA and NFκB was examined by Western blot analysis. Vascularization was analyzed by immunohistochemical staining of PECAM-1. Circulating endothelial progenitor cells were measured by flow-cytometry. Herein, we demonstrate that EPO-treatment significantly accelerates bone healing in mice. This is indicated by a significantly greater biomechanical stiffness and a higher radiological density of the periosteal callus at 2 and 5 weeks after fracture and stabilization. Histological analysis demonstrated significantly more bone and less cartilage and fibrous tissue in the periosteal callus. Endosteal vascularization was significantly increased in EPO-treated animals when compared to controls. The number of circulating endothelial progenitor cells was significantly greater in EPO-treated animals. The herein shown acceleration of healing by EPO may represent a promising novel treatment strategy for fractures with delayed healing and non-union formation.

  6. A Sheep Model for Cancellous Bone Healing

    PubMed Central

    Malhotra, Angad; Pelletier, Matthew Henry; Yu, Yan; Christou, Chris; Walsh, William Robert

    2014-01-01

    Appropriate well-characterized bone defect animal models remain essential for preclinical research. This pilot study demonstrates a relevant animal model for cancellous bone defect healing. Three different defect diameters (8, 11, 14 mm) of fixed depth (25 mm) were compared in both skeletally immature (18-month-old) and aged sheep (5-year-old). In each animal, four defects were surgically created and placed in the cancellous bone of the medial distal femoral and proximal tibial epiphyses bilaterally. Animals were euthanized at 4 weeks post-operatively to assess early healing and any biological response. Defect sites were graded radiographically, and new bone formation quantified using μCT and histomorphometry. Fibrous tissue was found within the central region in most of the defects with woven bone normally forming near the periphery of the defect. Bone volume fraction [bone volume (BV)/TV] significantly decreased with an increasing defect diameter. Actual BV, however, increased with defect diameter. Bone ingrowth was lower for all defect diameters in the aged group. This pilot study proposes that the surgical creation of 11 mm diameter defects in the proximal tibial and distal femoral epiphyses of aged sheep is a suitable large animal model to study early healing of cancellous bone defects. The refined model allows for the placement of four separate bone defects per animal and encourages a reduction in animal numbers required for preclinical research. PMID:25593961

  7. Acceleration Of Wound Healing Ny Photodynamic Therapy

    SciTech Connect

    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.

  8. 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.

  9. Revascularization in Maxillofacial Bone Healing.

    DTIC Science & Technology

    1985-11-21

    administration of cortisone or acetylsalicylic acid did not affect giant cell or capsule formation around the particles. Therefore, this reparative granuloma was...other aspects of healing have special requirements. Thus sulfur-containing amino acids are important for granulation tissue formation (Edwards and...Dunphy, 1957). Capillary endothelium and collagen fibril formation, essential to revascularization, are decreased by ascorbic acid deficiency; the latter

  10. Surgical approach to bone healing in osteoporosis

    PubMed Central

    Pesce, Vito; Speciale, Domenico; Sammarco, Giulio; Patella, Silvio; Spinarelli, Antonio; Patella, Vittorio

    2009-01-01

    Osteoporotic fractures represent one of the most common cause of disability and one of the major voice in the health economic budget in many countries of the world. Fragility fractures are especially meta-epiphyseal fractures, in skeletal sites with particular biomechanic characteristic (hip, vertebrae), complex and with more fragments, with slow healing process (mineralization and remodeling) and co-morbidity. The healing of a fracture in osteoporotic bone passes through the normal stages and concludes with union of the fracture although the healing process is prolonged. Fractures in the elderly osteoporotic patients represent a challenge to the orthopaedic surgeons. Osteoporosis does not only increase the risk of fracture but also represents a problem in osteofixation of fractures in fracture treatment. The major technical problem that surgeons face, is the difficulty to obtain a stable fixation of an implant due to osteoporotic bone. The load transmitted at the bone-implant interface can often exceed the reduced strain tolerance of osteoporotic bone. In the treatment of osteoporotic fractures it is important to consider different aspects: general conditions of elderly patient and comorbidity, the reduced muscular and bone mass and the increased bone fragility, structural modifications as medullary expansion. The aim of surgical treatment is to obtain a stable fixation that reduces pain and permits an early mobilization. PMID:22461162

  11. Microgrooved Polymer Substrates Promote Collective Cell Migration To Accelerate Fracture Healing in an in Vitro Model.

    PubMed

    Zhang, Qing; Dong, Hua; Li, Yuli; Zhu, Ye; Zeng, Lei; Gao, Huichang; Yuan, Bo; Chen, Xiaofeng; Mao, Chuanbin

    2015-10-21

    Surface topography can affect cell adhesion, morphology, polarity, cytoskeleton organization, and osteogenesis. However, little is known about the effect of topography on the fracture healing in repairing nonunion and large bone defects. Microgrooved topography on the surface of bone implants may promote cell migration into the fracture gap to accelerate fracture healing. To prove this hypothesis, we used an in vitro fracture (wound) healing assay on the microgrooved polycaprolactone substrates to study the effect of microgroove widths and depths on the osteoblast-like cell (MG-63) migration and the subsequent healing. We found that the microgrooved substrates promoted MG-63 cells to migrate collectively into the wound gap, which serves as a fracture model, along the grooves and ridges as compared with the flat substrates. Moreover, the groove widths did not show obvious influence on the wound healing whereas the smaller groove depths tended to favor the collective cell migration and thus subsequent healing. The microgrooved substrates accelerated the wound healing by facilitating the collective cell migration into the wound gaps but not by promoting the cell proliferation. Furthermore, microgrooves were also found to promote the migration of human mesenchymal stem cells (hMSCs) to heal the fracture model. Though osteogenic differentiation of hMSCs was not improved on the microgrooved substrate, collagen I and minerals deposited by hMSCs were organized in a way similar to those in the extracellular matrix of natural bone. These findings suggest the necessity in using microgrooved implants in enhancing fracture healing in bone repair.

  12. Acceleration of bone formation during fracture healing by poly(pro-hyp-gly)10 and basic fibroblast growth factor containing polycystic kidney disease and collagen-binding domains from Clostridium histolyticum collagenase.

    PubMed

    Sekiguchi, Hiroyuki; Uchida, Kentaro; Inoue, Gen; Matsushita, Osamu; Saito, Wataru; Aikawa, Jun; Tanaka, Keisuke; Fujimaki, Hisako; Miyagi, Masayuki; Takaso, Masashi

    2016-06-01

    Growth factor delivered in combination with animal-derived collagen materials has been used to accelerate bone fracture healing in human patients. However, the introduction of bovine proteins into humans carries the risk of zoonotic and immunologic complications. Here, we developed a collagen-like polypeptide-based bone formation system consisting of poly(Pro-Hyp-Gly)10 , which mimics the triple helical conformation of collagen, and basic fibroblast growth factor (bFGF) fused to the polycystic kidney disease (PKD) domain and collagen-binding domain (CBD) of Clostridium histolyticum collagenase. Circular dichroism spectral analysis showed that when pepsin-soluble bovine type I collagen was treated at 50°C, a positive signal corresponding to the collagen triple helix at 220 nm was not detected. In contrast, poly(Pro-Hyp-Gly)10 retained the 220-nm positive peak, even when treated at 80°C. The combination of the collagen binding-bFGF fusion protein (bFGF-PKD-CBD) with poly(Pro-Hyp-Gly)10 induced greater bone formation compared to bFGF alone in mice bone fracture models. Taken together, these properties suggest that the bFGF-PKD-CBD/poly(Pro-Hyp-Gly)10 composite is a promising material for bone repair in the clinical setting. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1372-1378, 2016.

  13. Black bone disease in a healing fracture.

    PubMed

    Thiam, Desmond; Teo, Tse Yean; Malhotra, Rishi; Tan, Kong Bing; Chee, Yu Han

    2016-01-28

    Black bone disease refers to the hyperpigmentation of bone secondary to prolonged usage of minocycline. We present a report of a 34-year-old man who underwent femoral shaft fracture fixation complicated by deep infection requiring debridement. The implants were removed 10 months later after long-term treatment with minocycline and fracture union. A refracture of the femoral shaft occurred 2 days after implant removal and repeat fixation was required. Intraoperatively, abundant heavily pigmented and dark brown bone callus was noted over the old fracture site. There was no evidence of other bony pathology and the appearance was consistent with minocycline-associated pigmentation. As far as we are aware, this is the first case of black bone disease affecting callus within the interval period of bone healing. We also discuss the relevant literature on black bone disease to bring light on this rare entity that is an unwelcomed surprise to operating orthopaedic surgeons.

  14. Do Capacity Coupled Electric Fields Accelerate Tibial Stress Fracture Healing

    DTIC Science & Technology

    2006-12-01

    DAMD17-98-1-8519 TITLE: Do Capacity Coupled Electric Fields Accelerate Tibial Stress Fracture Healing PRINCIPAL INVESTIGATOR...2006 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Do Capacity Coupled Electric Fields Accelerate Tibial Stress Fracture Healing 5b. GRANT NUMBER...To determine the effect of capacitively coupled electric field stimulation on tibial stress fracture healing in men and women. Methods: A

  15. Joint loading modality: its application to bone formation and fracture healing.

    PubMed

    Zhang, P; Malacinski, G M; Yokota, H

    2008-07-01

    Sports-related injuries such as impact and stress fractures often require a rehabilitation programme to stimulate bone formation and accelerate fracture healing. This review introduces a recently developed joint loading modality and evaluates its potential applications to bone formation and fracture healing in post-injury rehabilitation. Bone is a dynamic tissue whose structure is constantly altered in response to its mechanical environments. Indeed, many loading modalities can influence the bone remodelling process. The joint loading modality is, however, able to enhance anabolic responses and accelerate wound healing without inducing significant in situ strain at the site of bone formation or fracture healing. This review highlights the unique features of this loading modality and discusses its potential underlying mechanisms as well as possible clinical applications.

  16. Electromagnetic pulses bone healing booster

    NASA Astrophysics Data System (ADS)

    Sintea, S. R.; Pomazan, V. M.; Bica, D.; Grebenisan, D.; Bordea, N.

    2015-11-01

    Posttraumatic bone restoration triggered by the need to assist and stimulate compensatory bone growth in periodontal condition. Recent studies state that specific electromagnetic stimulation can boost the bone restoration, reaching up to 30% decrease in recovery time. Based on the existing data on the electromagnetic parameters, a digital electronic device is proposed for intra oral mounting and bone restoration stimulation in periodontal condition. The electrical signal is applied to an inductive mark that will create and impregnate magnetic field in diseased tissue. The device also monitors the status of the electromagnetic field. Controlled wave forms and pulse frequency signal at programmable intervals are obtained with optimized number of components and miniaturized using surface mounting devices (SMD) circuits and surface mounting technology (SMT), with enhanced protection against abnormal current growth, given the intra-oral environment. The system is powered by an autonomous power supply (battery), to limit the problems caused by powering medical equipment from the main power supply. Currently the device is used in clinical testing, in cycles of six up to twelve months. Basic principles for the electrical scheme and algorithms for pulse generation, pulse control, electromagnetic field control and automation of current monitoring are presented, together with the friendly user interface, suitable for medical data and patient monitoring.

  17. Cell therapy in bone healing disorders

    PubMed Central

    Jäger, Marcus; Hernigou, Philippe; Zilkens, Christoph; Herten, Monika; Li, Xinning; Fischer, Johannes; Krauspe, Rüdiger

    2010-01-01

    In addition to osteosynthetic stabilizing techniques and autologous bone transplantations, so-called orthobiologics play an increasing role in the treatment of bone healing disorders. Besides the use of various growth factors, more and more new data suggest that cell-based therapies promote local bone regeneration. For ethical and biological reasons, clinical application of progenitor cells on the musculoskeletal system is limited to autologous, postpartum stem cells. Intraoperative one-step treatment with autologous progenitor cells, in particular, delivered promising results in preliminary clinical studies. This article provides an overview of the rationale for, and characteristics of the clinical application of cell-based therapy to treat osseous defects based on a review of existing literature and our own experience with more than 100 patients. Most clinical trials report successful bone regeneration after the application of mixed cell populations from bone marrow. The autologous application of human bone marrow cells which are not expanded ex vivo has medico-legal advantages. However, there is a lack of prospective randomized studies including controls for cell therapy for bone defects. Autologous bone marrow cell therapy seems to be a promising treatment option which may reduce the amount of bone grafting in future. PMID:21808710

  18. Stimulation of bone healing by sustained bone morphogenetic protein 2 (BMP-2) delivery.

    PubMed

    Faßbender, Mirja; Minkwitz, Susann; Strobel, Catrin; Schmidmaier, Gerhard; Wildemann, Britt

    2014-05-14

    The aim of the study was to investigate the effect of a sustained release of bone morphogenetic protein2 (BMP-2) incorporated in a polymeric implant coating on bone healing. In vitro analysis revealed a sustained, but incomplete BMP-2 release until Day 42. For the in vivo study, the rat tibia osteotomy was stabilized either with control or BMP-2 coated wires, and the healing progress was followed by micro computed tomography (µCT), biomechanical testing and histology at Days 10, 28, 42 and 84. MicroCT showed an accelerated formation of mineralized callus, as well as remodeling and an increase of mineralized/total callus volume (p=0.021) at Day 42 in the BMP-2 group compared to the control. Histology revealed an increased callus mineralization at Days 42 and 84 (p=0.006) with reduced cartilage at Day 84 (p=0.004) in the BMP-2 group. Biomechanical stiffness was significantly higher in the BMP-2 group (p=0.045) at Day 42. In summary, bone healing was enhanced after sustained BMP-2 application compared to the control. Using the same drug delivery system, but a burst release of BMP-2, a previous published study showed a similar positive effect on bone healing. Distinct differences in the healing outcome might be explained due to the different BMP release kinetics and dosages. However, further studies are necessary to adapt the optimal release profiles to physiological mechanisms.

  19. 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.

  20. Osthole Promotes Endochondral Ossification and Accelerates Fracture Healing in Mice.

    PubMed

    Zhang, Zhongrong; Leung, Wing Nang; Li, Gang; Lai, Yau Ming; Chan, Chun Wai

    2016-12-01

    Osthole has been found to restore bone mass in preclinical osteoporotic models. In the present study, we investigated the effects of osthole on bone fracture repair in mice. Adult C57BL/6 mice were subjected to transverse femoral fractures and administrated orally with 20 mg/kg osthole and vehicle solvent daily from week 1 post-operation. Fracture callus were analyzed by plain radiography, micro-computed tomography, histology, molecular imaging and immunohistochemistry and tartrate-resistant acid phosphatase staining. Results demonstrated that osthole treatment enhanced removal of cartilage and bony union during reparative stage without significant interfering on remodeling process. In vivo molecular imaging showed bone formation rate of the treatment group was almost twofold of control group at week 2 post-operation. Osthole augmented the expression of alkaline phosphatase and collagen type X in hypertrophic chondrocytes as well as expression of bone morphogenetic protein-2, osteocalcin and alkaline phosphatase in osteoblastic cells, indicating it promoted mineralization of hypertrophic cartilage and woven bone growth simultaneously during endochondral healing. In summary, osthole promotes endochondral ossification via upregulation of maturation osteogenic marker genes in chondrocytes and subsequently accelerates fracture repair and bony fusion.

  1. 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.

  2. Bone healing under experimental anemia in rats.

    PubMed

    Giglio, M J; Gorustovich, A; Guglielmotti, M B

    2000-01-01

    The effects of anemia on different physiological parameters have been the object of permanent study. There are no studies in the literature on the effects of this disorder on the process on bone healing. The aim of the present study was to evaluate, histologically and histomorphometrically, the process of osteogenesis in the post-extraction alvcolus of the lower molar, and in the peri-implant environment of rats. Twenty male Wistar rats (body weight (b.w.): 60 +/- 7 g) were grouped into two experimental sets. The control group (n:10) was given 0.5 mL saline solution i.p. The anemic group (n:10) was injected with 6 mg/100 g of b.w. or 3 mg/100 g b.w. phenylhidrazine, a well known hemolytic agent. Under ketamine-xylazine anesthesia the rats were submitted to extraction of the first lower molars, and to implantation in the tibia in keeping with the "laminar test" procedure. Other parameters, i.e. body weight (b.w.), food intake (FI), hematocrit (Htc), and hemoglobinemia (Hb) were monitored every 48 hs. The results showed a reduction in b.w., FI, Htc and Hb in the experimental group. The histological and histomorphometrical data show that the condition of anemia affects osteogenesis quali-quantitatively in the post-extraction alveolus and peri-implant microenvironment. Both bone reparative situations showed that ostegenesis is "sensitive" to anemia and/or the associated conditions, causing a delay in bone healing.

  3. Muscle-bone Interactions During Fracture Healing

    DTIC Science & Technology

    2015-03-01

    equal vascu- larization in healed bone and non-unions in animal studies as well as in human patients20,24-26. In a murine open tibial fracture model...the periosteum is intact, repair occurs largely through endochondral ossification driven by a periosteal supply of cells10,47-50. Indeed, in open...activated to serve as a secondary supply of cells when the periosteal supply becomes compro- mised52,53. These recent findings of muscle’s ability to

  4. An Update into the Application of Nanotechnology in Bone Healing

    PubMed Central

    Brannigan, K.; Griffin, M.

    2016-01-01

    Background Bone differs from other organs in that it can regenerate and remodel without scar formation. There are instances of trauma, congenital bone disorder, bone disease and bone cancer where this is not possible. Without bone grafts and implants, deformity and disability would result. Human bone grafts are limited in their management of large or non-union fractures. In response, synthetic bone grafts and implants are available to the Orthopaedic Surgeon. Unfortunately these also have their limitations and associated complications. Nanotechnology involves the research, design and manufacture of materials with a grain size less than 100nm. Nano-phase materials follow the laws of quantum physics, not classical mechanics, resulting in novel behavioural differences compared to conventional counterparts. Methods: Past, present and future nanotechnology in bone healing literature is reviewed and discussed. The article highlights concepts which are likely to be instrumental to the future of nanotechnology in bone healing. Results: Nanotechnology in bone healing is an emerging field within Orthopaedic Surgery. There is a requirement for bone healing technologies which are biochemically and structurally similar to bone. Nanotechnology is a potential solution as the arrangement of bone includes nanoscopic collagen fibres and hydroxyapatite. This review centers on the novel field of nanotechnology in bone healing with discussion focusing on advances in bone grafts, implants, diagnostics and drug delivery. Conclusion: The concept of nanotechnology was first introduced in 1959. Current nanoproducts for bone healing include nano-HA-paste-ostim and nano-beta-tricalcium phosphate-Vitoss. Nanophase technologies are considered to be superior bone healing solutions. Limited safety data and issues regarding cost and mass scale production require further research into this exciting field. PMID:28217207

  5. Disruption of thrombospondin-2 accelerates ischemic fracture healing.

    PubMed

    Miedel, Emily; Dishowitz, Michael I; Myers, Marc H; Dopkin, Derek; Yu, Yan-Yiu; Miclau, Ted S; Marcucio, Ralph; Ahn, Jaimo; Hankenson, Kurt D

    2013-06-01

    Thrombospondin-2 (TSP2) is a matricellular protein that is highly up-regulated during fracture healing. TSP2 negatively regulates vascularity, vascular reperfusion following ischemia, and cutaneous wound healing. As well, TSP2-null mice show increased endocortical bone formation due to an enhanced number of mesenchymal progenitor cells and show increased cortical thickness. Mice deficient in TSP2 (TSP2-null) show an alteration in fracture healing, that is unrelated to their cortical bone phenotype, which is characterized by enhanced vascularization with a shift towards an intramembranous healing phenotype; thus, we hypothesized that there would be enhanced ischemic fracture healing in the absence of TSP2. We investigated whether an absence of TSP2 would enhance ischemic fracture healing utilizing Laser doppler, µCT and histological analysis. Ischemic tibial fractures were created in wildtype (WT) and TSP2-null mice and harvested 10, 20, or 40 days post-fracture. TSP2-null mice show enhanced vascular perfusion following ischemic fracture. At day 10 post-fracture, TSP2-null mice have 115% greater bone volume than WT mice. This is associated with a 122% increase in vessel density, 20% increase in cell proliferation, and 15% decrease in apoptosis compared to WT. At day 20, TSP2-null mice have 34% more bone volume, 51% greater bone volume fraction, and 37% more bone tissue mineral density than WT. By 40 days after fracture the TSP2-null mice have a 24% increase in bone volume fraction, but other parameters show no significant differences. These findings indicate TSP2 is a negative regulator of ischemic fracture healing and that in the absence of TSP2 bone regeneration is enhanced.

  6. Vibration acceleration promotes bone formation in rodent models

    PubMed Central

    Uchida, Ryohei; Nakata, Ken; Kawano, Fuminori; Yonetani, Yasukazu; Ogasawara, Issei; Nakai, Naoya; Mae, Tatsuo; Matsuo, Tomohiko; Tachibana, Yuta; Yokoi, Hiroyuki; Yoshikawa, Hideki

    2017-01-01

    All living tissues and cells on Earth are subject to gravitational acceleration, but no reports have verified whether acceleration mode influences bone formation and healing. Therefore, this study was to compare the effects of two acceleration modes, vibration and constant (centrifugal) accelerations, on bone formation and healing in the trunk using BMP 2-induced ectopic bone formation (EBF) mouse model and a rib fracture healing (RFH) rat model. Additionally, we tried to verify the difference in mechanism of effect on bone formation by accelerations between these two models. Three groups (low- and high-magnitude vibration and control-VA groups) were evaluated in the vibration acceleration study, and two groups (centrifuge acceleration and control-CA groups) were used in the constant acceleration study. In each model, the intervention was applied for ten minutes per day from three days after surgery for eleven days (EBF model) or nine days (RFH model). All animals were sacrificed the day after the intervention ended. In the EBF model, ectopic bone was evaluated by macroscopic and histological observations, wet weight, radiography and microfocus computed tomography (micro-CT). In the RFH model, whole fracture-repaired ribs were excised with removal of soft tissue, and evaluated radiologically and histologically. Ectopic bones in the low-magnitude group (EBF model) had significantly greater wet weight and were significantly larger (macroscopically and radiographically) than those in the other two groups, whereas the size and wet weight of ectopic bones in the centrifuge acceleration group showed no significant difference compared those in control-CA group. All ectopic bones showed calcified trabeculae and maturated bone marrow. Micro-CT showed that bone volume (BV) in the low-magnitude group of EBF model was significantly higher than those in the other two groups (3.1±1.2mm3 v.s. 1.8±1.2mm3 in high-magnitude group and 1.3±0.9mm3 in control-VA group), but BV in the

  7. Quality of Bone Healing: Perspectives and Assessment Techniques

    DTIC Science & Technology

    2014-01-01

    uniquely restricted to appositional growth; therefore, all activities occur on bone surfaces, either the outer periosteal or marrow- oriented...Standardized scoring systems such as the radio- graphic union score for tibial fractures39 allow for a reduction in the variability of assessing fracture...O’Connor B, Kenwright J. Measuring stiffness can define healing of tibial fractures. J Bone Joint Surg 1994; 76-B: 389–94. Guda et al. Bone healing

  8. Assessment of the Genetic Variation in Bone Fracture Healing

    DTIC Science & Technology

    2004-10-01

    variations in both structural and material properties of bone development will be recapitulated in the developmental mechanism(s) that controls the bone’s... structural geometry and material properties during fracture healing. Two goals were set out in the proposal to test this hypothesis. The first was to...determine how variations in basic bone structure and material properties in three in bred strains of mice is translated into the healing process of

  9. 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.

  10. α-Gal Nanoparticles in Wound and Burn Healing Acceleration

    PubMed Central

    Galili, Uri

    2017-01-01

    Significance: Rapid recruitment and activation of macrophages may accelerate wound healing. Such accelerated healing was observed in wounds and burns of experimental animals treated with α-gal nanoparticles. Recent Advances: α-Gal nanoparticles present multiple α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). α-Gal nanoparticles applied to wounds bind anti-Gal (the most abundant antibody in humans) and generate chemotactic complement peptides, which rapidly recruit macrophages. Fc/Fc receptor interaction between anti-Gal coating the α-gal nanoparticles and recruited macrophages activates macrophages to produce cytokines that accelerate healing. α-Gal nanoparticles applied to burns and wounds in mice and pigs producing anti-Gal, decreased healing time by 40–60%. In mice, this accelerated healing avoided scar formation. α-Gal nanoparticle-treated wounds, in diabetic mice producing anti-Gal, healed within 12 days, whereas saline-treated wounds became chronic wounds. α-Gal nanoparticles are stable for years and may be applied dried, in suspension, aerosol, ointments, or within biodegradable materials. Critical Issues: α-Gal nanoparticle therapy can be evaluated only in mammalian models producing anti-Gal, including α1,3-galactosyltransferase knockout mice and pigs or Old World primates. Traditional experimental animal models synthesize α-gal epitopes and lack anti-Gal. Future Directions: Since anti-Gal is naturally produced in all humans, it is of interest to determine safety and efficacy of α-gal nanoparticles in accelerating wound and burn healing in healthy individuals and in patients with impaired wound healing such as diabetic patients and elderly individuals. In addition, efficacy of α-gal nanoparticle therapy should be studied in healing and regeneration of internal injuries such as surgical incisions, ischemic myocardium following myocardial infarction, and injured nerves. PMID:28289553

  11. Low level diode laser accelerates wound healing.

    PubMed

    Dawood, Munqith S; Salman, Saif Dawood

    2013-05-01

    The effect of wound illumination time by pulsed diode laser on the wound healing process was studied in this paper. For this purpose, the original electronic drive circuit of a 650-nm wavelength CW diode laser was reconstructed to give pulsed output laser of 50 % duty cycle and 1 MHz pulse repetition frequency. Twenty male mice, 3 months old were used to follow up the laser photobiostimulation effect on the wound healing progress. They were subdivided into two groups and then the wounds were made on the bilateral back sides of each mouse. Two sessions of pulsed laser therapy were carried along 15 days. Each mice group wounds were illuminated by this pulsed laser for 12 or 18 min per session during these 12 days. The results of this study were compared with the results of our previous wound healing therapy study by using the same type of laser. The mice wounds in that study received only 5 min of illumination time therapy in the first and second days of healing process. In this study, we found that the wounds, which were illuminated for 12 min/session healed in about 3 days earlier than those which were illuminated for 18 min/session. Both of them were healed earlier in about 10-11 days than the control group did.

  12. The effect of shockwaves on mature and healing cortical bone.

    PubMed

    Forriol, F; Solchaga, L; Moreno, J L; Canãdell, J

    1994-10-01

    It has been proposed that high energy shockwaves could be used to create microfractures in cortical bone. This quality might be exploited clinically to perform closed osteotomies and promote healing in nonunion (15). However, no study has previously documented the effect of shockwaves on cortical bone "in vivo". We report an investigation designed to demonstrate the effect of shockwaves on mature cortical and healing bone. An osteotomy was performed on the tibiae of 37 lambs; two weeks later the operation site was exposed to shockwaves. Three weeks later the lambs were killed and specimens of the bone examined histologically and radiographically. Shockwaves had no effect on the periosteal surface of mature cortical bone, but on the endosteal surface some new trabecular bone was seen. Healing of bone was delayed by the shockwave therapy. We conclude that there is currently little place for shockwave treatment in clinical orthopaedics.

  13. Effects of hyperparathyroidism and dietary calcium supplementation on bone healing.

    PubMed

    Hubbard, G B; Schmidt, R E; Gleiser, C A; MacKenzie, W F

    1979-02-01

    Effects of nutritional secondary hyperparathyroidism and dietary calcium supplementation on bone healing were determined. Groups (n = 4) of 5 mature male dogs each were fed the following diets: group 1, control diet (0.48% Ca, 0.43% P); group 2, test diet (0.12% Ca, 1.14% P): group 3, control diet plus calcium; group 4, test diet plus calcium. The dietary calcium supplementation was calcium gluconate. Lesions were induced in the right tibial cortex by trephinization. Within the time limitations of this study, it was determined that nutritional secondary hyperparathyroidism does not inhibit bone healing and that dietary calcium supplementation does not aid bone healing.

  14. A Perspective: Engineering Periosteum for Structural Bone Graft Healing

    PubMed Central

    Awad, Hani A.; O’Keefe, Regis J.; Guldberg, Robert E.; Schwarz, Edward M.

    2008-01-01

    Autograft is superior to both allograft and synthetic bone graft in repair of large structural bone defect largely due to the presence of multipotent mesenchymal stem cells in periosteum. Recent studies have provided further evidence that activation, expansion and differentiation of the donor periosteal progenitor cells are essential for the initiation of osteogenesis and angiogenesis of donor bone graft healing. The formation of donor cell-derived periosteal callus enables efficient host-dependent graft repair and remodeling at the later stage of healing. Removal of periosteum from bone autograft markedly impairs healing whereas engraftment of multipotent mesenchymal stem cells on bone allograft improves healing and graft incorporation. These studies provide rationale for fabrication of a biomimetic periosteum substitute that could fit bone of any size and shape for enhanced allograft healing and repair. The success of such an approach will depend on further understanding of the molecular signals that control inflammation, cellular recruitment as well as mesenchymal stem cell differentiation and expansion during the early phase of the repair process. It will also depend on multidisciplinary collaborations between biologists, material scientists and bioengineers to address issues of material selection and modification, biological and biomechanical parameters for functional evaluation of bone allograft healing. PMID:18509709

  15. Experimental models for cancellous bone healing in the rat

    PubMed Central

    Bernhardsson, Magnus; Sandberg, Olof; Aspenberg, Per

    2015-01-01

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

  16. Distal radial fractures heal by direct woven bone formation

    PubMed Central

    2013-01-01

    Background Descriptions of fracture healing almost exclusively deal with shaft fractures and they often emphasize endochondral bone formation. In reality, most fractures occur in metaphyseal cancellous bone. Apart from a study of vertebral fractures, we have not found any histological description of cancellous bone healing in humans. Patients and methods We studied histological biopsies from the central part of 12 distal radial fractures obtained during surgery 6–28 days after the injury, using routine hematoxylin and eosin staining. Results New bone formation was seen in 6 cases. It was always in the form of fetal-like, disorganized woven bone. It seldom had contact with old trabeculae and appeared to have formed directly in the marrow. Cartilage was scarce or absent. The samples without bone formation showed only necrosis, scar, or old cancellous bone. Interpretation The histology suggests that cells in the midst of the marrow respond to the trauma by direct formation of bone, independently of trabecular surfaces. PMID:23570338

  17. Low-intensity pulsed ultrasound therapy: a potential strategy to stimulate tendon-bone junction healing.

    PubMed

    Ying, Zhi-min; Lin, Tiao; Yan, Shi-gui

    2012-12-01

    Incorporation of a tendon graft within the bone tunnel represents a challenging clinical problem. Successful anterior cruciate ligament (ACL) reconstruction requires solid healing of the tendon graft in the bone tunnel. Enhancement of graft healing to bone is important to facilitate early aggressive rehabilitation and a rapid return to pre-injury activity levels. No convenient, effective or inexpensive procedures exist to enhance tendon-bone (T-B) healing after surgery. Low-intensity pulsed ultrasound (LIPUS) improves local blood perfusion and angiogenesis, stimulates cartilage maturation, enhances differentiation and proliferation of osteoblasts, and motivates osteogenic differentiation of mesenchymal stem cells (MSCs), and therefore, appears to be a potential non-invasive tool for T-B healing in early stage of rehabilitation of ACL reconstruction. It is conceivable that LIPUS could be used to stimulate T-B tunnel healing in the home, with the aim of accelerating rehabilitation and an earlier return to normal activities in the near future. The purpose of this review is to demonstrate how LIPUS stimulates T-B healing at the cellular and molecular levels, describe studies in animal models, and provide a future direction for research.

  18. Low-intensity pulsed ultrasound therapy: a potential strategy to stimulate tendon-bone junction healing*

    PubMed Central

    Ying, Zhi-min; Lin, Tiao; Yan, Shi-gui

    2012-01-01

    Incorporation of a tendon graft within the bone tunnel represents a challenging clinical problem. Successful anterior cruciate ligament (ACL) reconstruction requires solid healing of the tendon graft in the bone tunnel. Enhancement of graft healing to bone is important to facilitate early aggressive rehabilitation and a rapid return to pre-injury activity levels. No convenient, effective or inexpensive procedures exist to enhance tendon-bone (T-B) healing after surgery. Low-intensity pulsed ultrasound (LIPUS) improves local blood perfusion and angiogenesis, stimulates cartilage maturation, enhances differentiation and proliferation of osteoblasts, and motivates osteogenic differentiation of mesenchymal stem cells (MSCs), and therefore, appears to be a potential non-invasive tool for T-B healing in early stage of rehabilitation of ACL reconstruction. It is conceivable that LIPUS could be used to stimulate T-B tunnel healing in the home, with the aim of accelerating rehabilitation and an earlier return to normal activities in the near future. The purpose of this review is to demonstrate how LIPUS stimulates T-B healing at the cellular and molecular levels, describe studies in animal models, and provide a future direction for research. PMID:23225850

  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. Effects of mouse genotype on bone wound healing and irradiation-induced delay of healing.

    PubMed

    Glowacki, Julie; Mizuno, Shuichi; Kung, Jason; Goff, Julie; Epperly, Michael; Dixon, Tracy; Wang, Hong; Greenberger, Joel S

    2014-01-01

    We tested the effects of mouse genotype (C57BL/6NHsd, NOD/SCID, SAMR1, and SAMP6) and ionizing irradiation on bone wound healing. Unicortical wounds were made in the proximal tibiae, and the time course of spontaneous healing and effects of irradiation were monitored radiographically and histologically. There was reproducible healing beginning with intramedullary osteogenesis, subsequent bone resorption by osteoclasts, gradual bridging of the cortical wound, and re-population of medullary hematopoietic cells. The most rapid wound closure was noted in SAMR1 mice, followed by SAMP6, C57BL/6NHsd, and NOD/SCID. Ionizing irradiation (20 Gy) to the leg significantly delayed bone wound healing in mice of all four genotypes. Mice with genetically-determined predisposition to early osteopenia (SAMP6) or with immune deficiency (NOD/SCID) had impairments in bone wound healing. These mouse models should be valuable for determining the effects of irradiation on bone healing and also for the design and testing of novel bone growth-enhancing drugs and mitigators of ionizing irradiation.

  1. 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.

  2. Mathematical modeling in wound healing, bone regeneration and tissue engineering.

    PubMed

    Geris, Liesbet; Gerisch, Alf; Schugart, Richard C

    2010-12-01

    The processes of wound healing and bone regeneration and problems in tissue engineering have been an active area for mathematical modeling in the last decade. Here we review a selection of recent models which aim at deriving strategies for improved healing. In wound healing, the models have particularly focused on the inflammatory response in order to improve the healing of chronic wound. For bone regeneration, the mathematical models have been applied to design optimal and new treatment strategies for normal and specific cases of impaired fracture healing. For the field of tissue engineering, we focus on mathematical models that analyze the interplay between cells and their biochemical cues within the scaffold to ensure optimal nutrient transport and maximal tissue production. Finally, we briefly comment on numerical issues arising from simulations of these mathematical models.

  3. Accelerated fracture healing in mice lacking the 5-lipoxygenase gene

    PubMed Central

    2010-01-01

    Background and purpose Cyclooxygenase-2 (COX-2) promotes inflammation by synthesizing pro-inflammatory prostaglandins from arachidonic acid. Inflammation is an early response to bone fracture, and ablation of COX-2 activity impairs fracture healing. Arachidonic acid is also converted into leukotrienes by 5-lipoxygenase (5-LO). We hypothesized that 5-LO is a negative regulator of fracture healing and that in the absence of COX-2, excess leukotrienes synthesized by 5-LO will impair fracture healing. Methods Fracture healing was assessed in mice with a targeted 5-LO mutation (5-LOKO mice) and control mice by radiographic and histological observations, and measured by histomorphometry and torsional mechanical testing. To assess effects on arachidonic acid metabolism, prostaglandin E2, F2α, and leukotriene B4 levels were measured in the fracture calluses of control, 5-LOKO COX-1KO, and COX-2KO mice by enzyme linked immunoassays. Results Femur fractures in 5-LOKO mice rapidly developed a cartilaginous callus that was replaced with bone to heal fractures faster than in control mice. Femurs from 5-LOKO mice had substantially better mechanical properties after 1 month of healing than did control mice. Callus leukotriene levels were 4-fold higher in mice homozygous for a targeted mutation in the COX-2 gene (COX-2KO), which indicated that arachidonic acid was shunted into the 5-LO pathway in the absence of COX-2. Interpretation These experiments show that 5-LO negatively regulates fracture healing and that shunting of arachidonic acid into the 5-LO pathway may account, at least in part, for the impaired fracture healing response observed in COX-2KO mice. PMID:21067431

  4. 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.

  5. Multiple Integrated Complementary Healing Approaches: Energetics & Light for bone.

    PubMed

    Gray, Michael G; Lackey, Brett R; Patrick, Evelyn F; Gray, Sandra L; Hurley, Susan G

    2016-01-01

    A synergistic-healing strategy that combines molecular targeting within a system-wide perspective is presented as the Multiple Integrated Complementary Healing Approaches: Energetics And Light (MICHAEL). The basis of the MICHAEL approach is the realization that environmental, nutritional and electromagnetic factors form a regulatory framework involved in bone and nerve healing. The interactions of light, energy, and nutrition with neural, hormonal and cellular pathways will be presented. Energetic therapies including electrical, low-intensity pulsed ultrasound and light based treatments affect growth, differentiation and proliferation of bone and nerve and can be utilized for their healing benefits. However, the benefits of these therapies can be impaired by the absence of nutritional, hormonal and organismal factors. For example, lack of sleep, disrupted circadian rhythms and vitamin-D deficiency can impair healing. Molecular targets, such as the Wnt pathway, protein kinase B and glucocorticoid signaling systems can be modulated by nutritional components, including quercetin, curcumin and Mg(2+) to enhance the healing process. The importance of water and water-regulation will be presented as an integral component. The effects of exercise and acupuncture on bone healing will also be discussed within the context of the MICHAEL approach.

  6. Diabetes and Its Effect on Bone and Fracture Healing

    PubMed Central

    Jiao, Hongli; Xiao, E.; Graves, Dana T.

    2015-01-01

    Diabetes mellitus is a metabolic disorder that increases fracture risk and interferes with bone formation and impairs fracture healing. Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM) both increase fracture risk and have several common features that affect bone including hyperglycemia and increased AGE formation, ROS generation, and inflammation. These factors affect both osteoblasts and osteoclasts lead to increased osteoclasts and reduced numbers of osteoblasts and bone formation. In addition to fracture healing, T1DM and T2DM impair bone formation under conditions of perturbation such as bacteria induced periodontal bone loss, which reduces expression of factors that stimulate osteoblasts such as BMPs and growth factors and increase osteoblast apoptosis. PMID:26254939

  7. Interaction between living bone particles and rhBMP-2 in large segmental defect healing in the rat femur.

    PubMed

    Liu, Fangjun; Wells, James W; Porter, Ryan M; Glatt, Vaida; Shen, Zhenxin; Schinhan, Martina; Ivkovic, Alan; Vrahas, Mark S; Evans, Christopher H; Ferreira, Elisabeth

    2016-12-01

    Orthopedic surgeons sometimes combine recombinant, human BMP-2 with autograft bone when dealing with problematic osseous fractures. Although some case reports indicate success with this off-label strategy, there have been no randomized controlled trials. Moreover, a literature search revealed only one pre-clinical study and this was in a cranial defect model. The present project examined the consequences of combining BMP-2 with particles of living bone in a rat femoral defect model. Human bone particles were recovered with a reamer-irrigator-aspirator (RIA). To allow acceptance of the xenograft as surrogate autograft, rats were administered an immunosuppressive cocktail that does not interfere with bone healing. Implantation of 200 µg living bone particles generated a small amount of new bone and defects did not heal. Graded amounts of BMP-2 that alone provoked no healing (1.1 µg), borderline healing (5.5 µg), or full healing (11 µg) were added to this amount of bone particles. Addition of BMP-2 (1.1 µg) increased osteogenesis, and produced bridging in 2 of 7 defects. The combination of BMP-2 (5.5 µg) and bone particles made healing more reliable and advanced the maturation of the regenerate. Bone formation with BMP-2 (11 µg) and bone particles showed improved maturation. Thus, the combination of autograft and BMP-2 may be helpful clinically under conditions where the healing response is suboptimal. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2137-2145, 2016. Clinical significance These data support the clinical use of recombinant, human BMP-2 with autograft bone when treating large segmental osseous defects. The combination leads to greater bone formation and accelerates the maturation of the regenerate.

  8. The haematoma and its role in bone healing.

    PubMed

    Schell, H; Duda, G N; Peters, A; Tsitsilonis, S; Johnson, K A; Schmidt-Bleek, K

    2017-12-01

    Fracture treatment is an old endeavour intended to promote bone healing and to also enable early loading and regain of function in the injured limb. However, in today's clinical routine the healing potential of the initial fracture haematoma is still not fully recognized. The Arbeitsgemeinschaft für Osteosynthesefragen (AO) formed in Switzerland in 1956 formulated four AO principles of fracture treatment which are still valid today. Fracture treatment strategies have continued to evolve further, as for example the relatively new concept of minimally invasive plate osteosynthesis (MIPO). This MIPO treatment strategy harbours the benefit of an undisturbed original fracture haematoma that supports the healing process. The extent of the supportive effect of this haematoma for the bone healing process has not been considered in clinical practice so far. The rising importance of osteoimmunological aspects in bone healing supports the essential role of the initial haematoma as a source for inflammatory cells that release the cytokine pattern that directs cell recruitment towards the injured tissue. In reviewing the potential benefits of the fracture haematoma, the early development of angiogenic and osteogenic potentials within the haematoma are striking. Removing the haematoma during surgery could negatively influence the fracture healing process. In an ovine open tibial fracture model the haematoma was removed 4 or 7 days after injury and the bone that formed during the first two weeks of healing was significantly reduced in comparison with an undisturbed control. These findings indicate that whenever possible the original haematoma formed upon injury should be conserved during clinical fracture treatment to benefit from the inherent healing potential.

  9. Stem cell therapy: a promising biological strategy for tendon-bone healing after anterior cruciate ligament reconstruction.

    PubMed

    Hao, Zi-Chen; Wang, Shan-Zheng; Zhang, Xue-Jun; Lu, Jun

    2016-04-01

    Tendon-bone healing after anterior cruciate ligament (ACL) reconstruction is a complex process, impacting significantly on patients' prognosis. Natural tendon-bone healing usually results in fibrous scar tissue, which is of inferior quality compared to native attachment. In addition, the early formed fibrous attachment after surgery is often not reliable to support functional rehabilitation, which may lead to graft failure or unsatisfied function of the knee joint. Thus, strategies to promote tendon-bone healing are crucial for prompt and satisfactory functional recovery. Recently, a variety of biological approaches, including active substances, gene transfer, tissue engineering and stem cells, have been proposed and applied to enhance tendon-bone healing. Among these, stem cell therapy has been shown to have promising prospects and draws increasing attention. From commonly investigated bone marrow-derived mesenchymal stem cells (bMSCs) to emerging ACL-derived CD34+ stem cells, multiple stem cell types have been proven to be effective in accelerating tendon-bone healing. This review describes the current understanding of tendon-bone healing and summarizes the current status of related stem cell therapy. Future limitations and perspectives are also discussed.

  10. Tendon to bone healing and its implications for surgery

    PubMed Central

    Bunker, Daniel Lee John; Ilie, Victor; Ilie, Vladimir; Nicklin, Sean

    2014-01-01

    Summary Entheses are complex structures which act to reduce stress concentrations between tendon and skeleton tissues. Understanding the development and function of the enthesis organ has implications for surgical repair, particularly in regards to healing and the regulation of tendon to bone engraftment. In this paper we review the development and function of entheses as well as the enthesis organ concept. Next we examine the process of tendon to bone healing and how this can be regulated, before addressing implications for surgical repair and post-operative care. PMID:25489553

  11. Monitoring Healing Progression and Characterizing the Mechanical Environment in Preclinical Models for Bone Tissue Engineering.

    PubMed

    Fountain, Stephanie; Windolf, Markus; Henkel, Jan; Tavakoli, Aramesh; Schuetz, Michael A; Hutmacher, Dietmar W; Epari, Devakara R

    2015-12-15

    The treatment of large segmental bone defects remains a significant clinical challenge. Due to limitations surrounding the use of bone grafts, tissue-engineered constructs for the repair of large bone defects could offer an alternative. Before translation of any newly developed tissue engineering (TE) approach to the clinic, efficacy of the treatment must be shown in a validated preclinical large animal model. Currently, biomechanical testing, histology, and microcomputed tomography are performed to assess the quality and quantity of the regenerated bone. However, in vivo monitoring of the progression of healing is seldom performed, which could reveal important information regarding time to restoration of mechanical function and acceleration of regeneration. Furthermore, since the mechanical environment is known to influence bone regeneration, and limb loading of the animals can poorly be controlled, characterizing activity and load history could provide the ability to explain variability in the acquired data sets and potentially outliers based on abnormal loading. Many approaches have been devised to monitor the progression of healing and characterize the mechanical environment in fracture healing studies. In this article, we review previous methods and share results of recent work of our group toward developing and implementing a comprehensive biomechanical monitoring system to study bone regeneration in preclinical TE studies.

  12. Reaming debris as a novel source of autologous bone to enhance healing of bone defects.

    PubMed

    Bakker, Astrid D; Kroeze, Robert Jan; Korstjens, Clara; de Kleine, Ruben H; Frölke, Jan Paul M; Klein-Nulend, Jenneke

    2011-06-15

    Reaming debris is formed when bone defects are stabilized with an intramedullary nail, and contains viable osteoblast-like cells and growth factors, and might thus act as a natural osteoinductive scaffold. The advantage of using reaming debris over stem cells or autologous bone for healing bone defects is that no extra surgery is needed to obtain the material. To assess the clinical feasibility of using reaming debris to enhance bone healing, we investigated whether reaming debris enhances the healing rate of a bone defect in sheep tibia, compared to an empty gap. As golden standard the defect was filled with iliac crest bone. Bones treated with iliac crest bone and reaming debris showed larger callus volume, increased bone volume, and decreased cartilage volume in the fracture gap, and increased torsional toughness compared to the empty gap group at 3 weeks postoperative. In addition, bones treated with reaming debris showed increased torsional stiffness at 6 weeks postoperatively compared to the empty defect group, while bending stiffness was marginally increased. These results indicate that reaming debris could serve as an excellent alternative to iliac crest bone for speeding up the healing process in bone defects that are treated with an intramedullary nail.

  13. The mechanism of shock wave treatment in bone healing

    NASA Astrophysics Data System (ADS)

    Wang, Ching-Jen

    2005-04-01

    The purpose of this study was to investigate the biological mechanism of shock wave treatment in bone healing in rabbits. A closed fracture of the right femur was created with a three-point bend method and the fracture was stabilized with an intra-medullary pin. Shock waves were applied one week after the fracture. Twenty-four New Zealand white rabbits were randomly divided into 3 groups. Group 1 (the control) received no shock waves; group 2 received low-energy and group 3 high-energy shock waves. The animals were sacrificed at 24 weeks, and a 5-cm segment of the femur bone including the callus was harvested. The specimens were studied with histomorphological examination, biomechanical analysis and immunohistochemical stains. The results showed that high-energy shock waves improved bone healing with significant increases in cortical bone formation and the number neovascularization in histomorphology, better bone strength and bone mass in biomechanics, and increased expressions of angiogenic growth markers including BMP-2, eNOS, VEGF and PCNA than the control and low-energy shock wave groups. The effect of shock wave treatment appears to be dose-dependent. In conclusion, high-energy shock waves promote bone healing associated with ingrowth of neovascularization and increased expressions of angiogenic growth factors.

  14. Ostene, a New Alkylene Oxide Copolymer Bone Hemostatic Material, Does Not Inhibit Bone Healing

    PubMed Central

    Magyar, Clara E.; Aghaloo, Tara L.; Atti, Elisa; Tetradis, Sotirios

    2009-01-01

    OBJECTIVE In this study, we investigate the effects of a soft bone hemostatic wax comprised of water-soluble alkylene oxide copolymers (Ostene; Ceremed, Inc., Los Angeles, CA) on bone healing in a rat calvaria defect model. We compared the effects with a control (no hemostatic agent) and bone wax, an insoluble and nonresorbable material commonly used for bone hemostasis. METHODS Two bilateral 3-mm circular noncritical-sized defects were made in the calvariae of 30 rats. Alkylene oxide copolymer or bone wax was applied or no hemostatic material was used (control). After 3, 6, and 12 weeks, rats were sacrificed and the calvariae excised. Bone healing, expressed as fractional bone volume (± standard error of the mean), was measured by microcomputed tomography. RESULTS Immediate hemostasis was achieved equally with bone wax and alkylene oxide copolymer. Bone wax-filled defects remained unchanged at all time points with negligible healing observed. At 3 weeks, no evidence of alkylene oxide copolymer was observed at the application site, with fractional bone volume significantly greater than bone wax-treated defects (0.20 ± 0.03 versus 0.02 ± 0.01; P = 0.0003). At 6 and 12-weeks, alkylene oxide copolymer-treated defects continued to show significantly greater healing versus bone wax (0.18 ± 0.04 versus 0.05 ± 0.01 and 0.31 ± 0.04 versus 0.06 ± 0.02, respectively). At all time points, alkylene oxide copolymer-treated and control defects showed good healing with no significant difference. CONCLUSION Alkylene oxide copolymer is an effective hemostatic agent that does not inhibit osteogenesis or bone healing. PMID:18981846

  15. Accelerated endothelial wound healing on microstructured substrates under flow.

    PubMed

    Franco, Davide; Milde, Florian; Klingauf, Mirko; Orsenigo, Fabrizio; Dejana, Elisabetta; Poulikakos, Dimos; Cecchini, Marco; Koumoutsakos, Petros; Ferrari, Aldo; Kurtcuoglu, Vartan

    2013-02-01

    Understanding and accelerating the mechanisms of endothelial wound healing is of fundamental interest for biotechnology and of significant medical utility in repairing pathologic changes to the vasculature induced by invasive medical interventions. We report the fundamental mechanisms that determine the influence of substrate topography and flow on the efficiency of endothelial regeneration. We exposed endothelial monolayers, grown on topographically engineered substrates (gratings), to controlled levels of flow-induced shear stress. The wound healing dynamics were recorded and analyzed in various configurations, defined by the relative orientation of an inflicted wound, the topography and the flow direction. Under flow perpendicular to the wound, the speed of endothelial regeneration was significantly increased on substrates with gratings oriented in the direction of the flow when compared to flat substrates. This behavior is linked to the dynamic state of cell-to-cell adhesions in the monolayer. In particular, interactions with the substrate topography counteract Vascular Endothelial Cadherin phosphorylation induced by the flow and the wounding. This effect contributes to modulating the mechanical connection between migrating cells to an optimal level, increasing their coordination and resulting in coherent cell motility and preservation of the monolayer integrity, thus accelerating wound healing. We further demonstrate that the reduction of vascular endothelial cadherin phosphorylation, through specific inhibition of Src activity, enhances endothelial wound healing in flows over flat substrates.

  16. 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.

  17. Ultrasound Won't Help Broken Bones Heal, Expert Panel Says

    MedlinePlus

    ... fullstory_163763.html Ultrasound Won't Help Broken Bones Heal, Expert Panel Says Detailed review suggests it's ... LIPUS) -- to help speed the healing of broken bones. But an international panel of experts now says ...

  18. Induced healing of aneurysmal bone cysts by demineralized bone particles. A report of two cases.

    PubMed

    Delloye, C; De Nayer, P; Malghem, J; Noel, H

    1996-01-01

    Two cases of induced healing of aneurysmal bone cyst (ABC) following intralesional implantation of a bone paste made of autogeneic bone marrow and allogeneic bone powder are reported. The calcaneum in one case and the superior pubic ramus in the other were blown out by an ABC and would have required extensive surgery. Via a minimal exposure, the cyst was partially evacuated and filled with an admixture of a partially demineralized bone particles with bone marrow. Ossification of the peripheral shell was the first sign of healing and was observed within the first 3 postoperative months. Successful healing was observed in both cases. The rationale underlying this intralesional treatment was that the bone grafting material might reverse ABC expansion by promoting ossification through a bone induction mechanism. The concept of this treatment was to retain the ABC tissue, using its own intrinsic osteogenic potential to promote healing. By triggering intralesional new bone formation, the bone paste represented an effective means to reverse the expanding phase of ABC. The particulated bone allograft was easy to handle and to introduced in an irregular cavity. Moreover, as a complete cyst evacuation was not required, a minimal surgical approach could be used so that the risks and morbidity associated with an extensive approach were reduced. Its use is of particular interest in poorly accessible areas like the pelvis and spine.

  19. 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.

  20. Smoking cessation and bone healing: optimal cessation timing.

    PubMed

    Truntzer, Jeremy; Vopat, Bryan; Feldstein, Michael; Matityahu, Amir

    2015-02-01

    Smoking is a worldwide epidemic. Complications related to smoking behavior generate an economic loss around $193 billion annually. In addition to impacting chronic health conditions, smoking is linked to increased perioperative complications in those with current or previous smoking history. Numerous studies have demonstrated more frequent surgical complications including higher rates of infection, poor wound healing, heightened pain complaints, and increased pulmonary morbidities in patients with a smoking history. Longer preoperative cessation periods also seem to correlate with reduced rates. At roughly 4 weeks of cessation prior to surgery, complication rates more closely reflect individuals without a smoking history in comparison with those that smoke within 4 weeks of surgery. In the musculoskeletal system, a similar trend has been observed in smokers with higher rates of fractures, nonunions, malunions, infections, osteomyelitis, and lower functional scores compared to non-smoking patients. Unfortunately, the present literature lacks robust data suggesting a temporal relationship between smoking cessation and bone healing. In our review, we analyze pseudoarthrosis rates following spinal fusion to suggest that bone healing in the context of smoking behavior follows a similar time sequence as observed in wound healing. We also discuss the implications for further clarity on bone healing and smoking cessation within orthopedics including improved risk stratification and better identification of circumstances where adjunct therapy is appropriate.

  1. Cisplatin Inhibits Bone Healing During Distraction Osteogenesis

    PubMed Central

    Stine, Kimo C.; Wahl, Elizabeth C.; Liu, Lichu; Skinner, Robert A.; Schilden, Jaclyn Vander; Bunn, Robert C.; Montgomery, Corey O.; Suva, Larry J.; Aronson, James; Becton, David L.; Nicholas, Richard W.; Swearingen, Christopher J.; Lumpkin, Charles K.

    2014-01-01

    Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non-cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five dose CDP regimen (2mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice (P<0.001). Further, no significant inhibitory effects from the 5 dose CDP regimen were observed in TNFR1KO mice. The two dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri-operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP. PMID:24259375

  2. 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.

  3. Early bone healing events following rat molar tooth extraction.

    PubMed

    Devlin, H

    2000-01-01

    Healing of the rat tooth extraction socket occurs rapidly, indicating a mechanism for cancellous bone formation occurring swiftly throughout the matrix. The residual periodontal ligament is evident at 2 days after extraction and its rich collagen type III fibre content may form a template for future cancellous bone formation. In the remainder of the early tooth extraction socket, fibronectin staining was generalized. The widespread distribution of fibronectin staining has given rise to speculation that the function of fibronectin may be important in granulation tissue formation, by providing a template matrix for fibroblast migration. Osteoprogenitor cells migrated into the socket from the surrounding bone, and produced decorin and proMMP-13 (procollagenase-3). ProMMP-13 was only expressed at sites of new bone formation, e.g. the border of the recently formed trabecular islands or the periphery of the closing socket. Collagen type I fibres were formed later, and were especially evident at 6 days after extraction. The pattern of distribution of both collagen type I and III fibres were similar as they passed from the bone margin towards the centre of the socket - in the same direction as the forming bone trabeculae. Bone formation occurs by rapid movement of the osteoprogenitor cells along these collagen fibres to allow a rapid healing, rather than that of resorption followed by slow bone deposition.

  4. Periosteal BMP2 activity drives bone graft healing.

    PubMed

    Chappuis, Vivianne; Gamer, Laura; Cox, Karen; Lowery, Jonathan W; Bosshardt, Dieter D; Rosen, Vicki

    2012-10-01

    Bone graft incorporation depends on the orchestrated activation of numerous growth factors and cytokines in both the host and the graft. Prominent in this signaling cascade is BMP2. Although BMP2 is dispensable for bone formation, it is required for the initiation of bone repair; thus understanding the cellular mechanisms underlying bone regeneration driven by BMP2 is essential for improving bone graft therapies. In the present study, we assessed the role of Bmp2 in bone graft incorporation using mice in which Bmp2 has been removed from the limb prior to skeletal formation (Bmp2(cKO)). When autograft transplantations were performed in Bmp2cKO mice, callus formation and bone healing were absent. Transplantation of either a vital wild type (WT) bone graft into a Bmp2(cKO) host or a vital Bmp2(cKO) graft into a WT host also resulted in the inhibition of bone graft incorporation. Histological analyses of these transplants show that in the absence of BMP2, periosteal progenitors remain quiescent and healing is not initiated. When we analyzed the expression of Sox9, a marker of chondrogenesis, on the graft surface, we found it significantly reduced when BMP2 was absent in either the graft itself or the host, suggesting that local BMP2 levels drive periosteal cell condensation and subsequent callus cell differentiation. The lack of integrated healing in the absence of BMP2 was not due to the inability of periosteal cells to respond to BMP2. Healing was achieved when grafts were pre-soaked in rhBMP2 protein, indicating that periosteal progenitors remain responsive in the absence of BMP2. In contrast to the requirement for BMP2 in periosteal progenitor activation in vital bone grafts, we found that bone matrix-derived BMP2 does not significantly enhance bone graft incorporation. Taken together, our data show that BMP2 signaling is not essential for the maintenance of periosteal progenitors, but is required for the activation of these progenitors and their subsequent

  5. Thrombospondin-2 influences the proportion of cartilage and bone during fracture healing.

    PubMed

    Taylor, Douglas K; Meganck, Jeffrey A; Terkhorn, Shawn; Rajani, Rajiv; Naik, Amish; O'Keefe, Regis J; Goldstein, Steven A; Hankenson, Kurt D

    2009-06-01

    Thrombospondin-2 (TSP2) is a matricellular protein with increased expression during growth and regeneration. TSP2-null mice show accelerated dermal wound healing and enhanced bone formation. We hypothesized that bone regeneration would be enhanced in the absence of TSP2. Closed, semistabilized transverse fractures were created in the tibias of wildtype (WT) and TSP2-null mice. The fractures were examined 5, 10, and 20 days after fracture using microCT, histology, immunohistochemistry, quantitative RT-PCR, and torsional mechanical testing. Ten days after fracture, TSP2-null mice showed 30% more bone by microCT and 40% less cartilage by histology. Twenty days after fracture, TSP2-null mice showed reduced bone volume fraction and BMD. Mice were examined 5 days after fracture during the stage of neovascularization and mesenchymal cell influx to determine a cellular explanation for the phenotype. TSP2-null mice showed increased cell proliferation with no difference in apoptosis in the highly cellular fracture callus. Although mature bone and cartilage is minimal 5 days after fracture, TSP2-null mice had reduced expression of collagen IIa and Sox9 (chondrocyte differentiation markers) but increased expression of osteocalcin and osterix (osteoblast differentiation markers). Importantly, TSP2-null mice had a 2-fold increase in vessel density that corresponded with a reduction in vascular endothelial growth factor (VEGF) and Glut-1 (markers of hypoxia inducible factor [HIF]-regulated transcription). Finally, by expressing TSP2 using adenovirus starting 3 days after fracture, chondrogenesis was restored in TSP2-null mice. We hypothesize that TSP2 expressed by cells in the fracture mesenchyme regulates callus vascularization. The increase in vascularity increases tissue oxemia and decreases HIF; thus, undifferentiated cells in the callus develop into osteoblasts rather than chondrocytes. This leads to an alternative strategy for achieving fracture healing with reduced

  6. 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.

  7. Modulation of inflammation by Cicaderma ointment accelerates skin wound healing.

    PubMed

    Morin, Christophe; Roumegous, Audrey; Carpentier, Gilles; Barbier-Chassefière, Véronique; Garrigue-Antar, Laure; Caredda, Stéphane; Courty, José

    2012-10-01

    Skin wound healing is a natural and intricate process that takes place after injury, involving different sequential phases such as hemostasis, inflammatory phase, proliferative phase, and remodeling that are associated with complex biochemical events. The interruption or failure of wound healing leads to chronic nonhealing wounds or fibrosis-associated diseases constituting a major health problem where, unfortunately, medicines are not very effective. The objective of this study was to evaluate the capacity of Cicaderma ointment (Boiron, Lyon, France) to accelerate ulcer closure without fibrosis and investigate wound healing dynamic processes. We used a necrotic ulcer model in mice induced by intradermal doxorubicin injection, and after 11 days, when the ulcer area was maximal, we applied Vaseline petroleum jelly or Cicaderma every 2 days. Topical application of Cicaderma allowed a rapid recovery of mature epidermal structure, a more compact and organized dermis and collagen bundles compared with the Vaseline group. Furthermore, the expression of numerous cytokines/molecules in the ulcer was increased 11 days after doxorubicin injection compared with healthy skin. Cicaderma rapidly reduced the level of proinflammatory cytokines, mainly tumor necrosis factor (TNF)-α and others of the TNF pathway, which can be correlated to a decrease of polymorphonuclear recruitment. It is noteworthy that the modulation of inflammation through TNF-α, macrophage inflammatory protein-1α, interleukin (IL)-12, IL-4, and macrophage-colony-stimulating factor was maintained 9 days after the first ointment application, facilitating the wound closure without affecting angiogenesis. These cytokines seem to be potential targets for therapeutic approaches in chronic wounds. Our results confirm the use of Cicaderma for accelerating skin wound healing and open new avenues for sequential treatments to improve healing.

  8. Adipose Stem Cells as Alternatives for Bone Marrow Mesenchymal Stem Cells in Oral Ulcer Healing

    PubMed Central

    Aziz Aly, Lobna Abdel; Menoufy, Hala El-; Ragae, Alyaa; Rashed, Laila Ahmed; Sabry, Dina

    2012-01-01

    Background and Objectives Adipose tissue is now recognized as an accessible, abundant, and reliable site for the isolation of adult stem cells suitable for tissue engineering and regenerative medicine applications. Methods and Results Oral ulcers were induced by topical application of formocresol in the oral cavity of dogs. Transplantation of undifferentiated GFP-labeled Autologous Bone Marrow Stem Cell (BMSCs), Adipose Derived Stem Cell (ADSCs) or vehicle (saline) was injected around the ulcer in each group. The healing process of the ulcer was monitored clinically and histopathologically. Gene expression of vascular endothelial growth factor (VEGF) was detected in MSCs by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Expression of VEGF and collagen genes was detected in biopsies from all ulcers. Results: MSCs expressed mRNA for VEGF MSCs transplantation significantly accelerated oral ulcer healing compared with controls. There was increased expression of both collagen and VEGF genes in MSCs-treated ulcers compared to controls. Conclusions MSCs transplantation may help to accelerate oral ulcer healing, possibly through the induction of angiogenesis by VEGF together with increased intracellular matrix formation as detected by increased collagen gene expression. This body of work has provided evidence supporting clinical applications of adipose-derived cells in safety and efficacy trials as an alternative for bone marrow mesenchymal stem cells in oral ulcer healing. PMID:24298363

  9. Monitoring of bone healing by piezoelectric-EMI method

    NASA Astrophysics Data System (ADS)

    Mazlina, M. H.; Sarpinah, Bibi; Tawie, Rudy; Daho, Claira Dalislone; Annuar, Ishak

    2016-02-01

    Smart Piezoelectric devices which have excellent piezoelectric properties have been employed for various sensor and actuators applications. The work presented here is an attempt to demonstrate the feasibility of bone healing monitoring by using piezoelectric-electromechanical impedance (EMI) method that have several advantages such as low cost, portable, light weight and simplicity in measurement. A Piezoelectric sensor (PZT) has been widely used in damage detection of various structures including concrete, pipes and bones due to their unique sensing and actuating properties. The EMI technique has emerged as a universal Structural Health Monitoring (SHM) tool suitable for almost all engineering materials and structures. The method used for this proposed study consists of put healing agent in the host structure in particular cracks bone to be monitored by PZT-needle sensor which is embedded to the host structure. The measurements were taken in the frequency range between 0.04 to 100 kHz at 1 kHz interval using AD5933 evaluation board. The signals retrieved from the AD5933 evaluation board, were quantify and analyse to obtain Root Mean Square Deviation (RMSD) percentage value. Measurements were taken every hour for 12 hours. The result from the study shows the feasibility of the piezoelectric-EMI method to effectively detect changes during bone-cracks healing process until the cracks bone is fully recovered.

  10. Acceleration of palatal wound healing in Smad3-deficient mice.

    PubMed

    Jinno, K; Takahashi, T; Tsuchida, K; Tanaka, E; Moriyama, K

    2009-08-01

    Wound healing is a well-orchestrated complex process leading to the repair of injured tissues. It is suggested that transforming growth factor (TGF)-beta/Smad3 signaling is involved in wound healing. The purpose of this study was to investigate the role of TGF-beta/Smad3 signaling in palatal wound healing in Smad3-deficient (Smad3(-/-)) mice. Histological examination showed that wound closure was accelerated by the proliferation of epithelium and dermal cells in Smad3(-/-) mice compared with wild-type (WT) mice. Macrophage/monocyte infiltration at wounded regions in Smad3(-/-) mice was decreased in parallel with the diminished production of TGF-beta1, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1alpha compared with WT mice. Fibrocytes, expressing hematopoietic surface marker and fibroblast products, were recruited and produced alpha-smooth-muscle actin in WT mice, but were not observed in Smad3(-/-) mice. These results suggest that TGF-beta/Smad3 signaling may play an important role in the regulation of palatal wound healing.

  11. Vulnerary Factors to Improve Bone Healing

    DTIC Science & Technology

    2007-04-01

    into the sample was achieved by incubation in infiltration media (90% Methyl Methacrylate, 10% Dibutyl Phthalate, and 70% Benzoyl peroxide 1gm...Methacrylate, 10% Dibutyl Phthalate, and 2gm/100ml 70% Benzoyl peroxide . Once bones were embedded, the blocks were trimmed down using a diamond band

  12. 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.

  13. Uncoupled angiogenesis and osteogenesis in nicotine-compromised bone healing.

    PubMed

    Ma, Li; Zheng, Li Wu; Sham, Mai Har; Cheung, Lim Kwong

    2010-06-01

    Nicotine is the main chemical component responsible for tobacco addiction. This study aimed to evaluate the influence of nicotine on angiogenesis and osteogenesis and the associated expression of angiogenic and osteogenic mediators during bone healing. Forty-eight adult New Zealand White rabbits were randomly assigned to a nicotine group and a control group. Nicotine pellets (1.5 g, 60-day time release) or placebo pellets were implanted in the neck subcutaneous tissue. The nicotine or placebo exposure time for all the animals was 7 weeks. Unilateral mandibular distraction osteogenesis was performed. Eight animals in each group were euthanized on day 5, day 11 of active distraction, and week 1 of consolidation, respectively. The mandibular samples were subjected to radiographic, histologic, immunohistochemical, and real-time reverse-transcriptase polymerase chain reaction examinations. Nicotine exposure upregulated the expression of hypoxia inducible factor 1alpha and vascular endothelial growth factor and enhanced angiogenesis but inhibited the expression of bone morphogenetic protein 2 and impaired bone healing. The results indicate that nicotine decouples angiogenesis and osteogenesis in this rabbit model of distraction osteogenesis, and the enhanced angiogenesis cannot compensate for the adverse effects of nicotine on bone healing.

  14. Fractal texture analysis of the healing process after bone loss.

    PubMed

    Borowska, Marta; Szarmach, Janusz; Oczeretko, Edward

    2015-12-01

    Radiological assessment of treatment effectiveness of guided bone regeneration (GBR) method in postresectal and postcystal bone loss cases, observed for one year. Group of 25 patients (17 females and 8 males) who underwent root resection with cystectomy were evaluated. The following combination therapy of intraosseous deficits was used, consisting of bone augmentation with xenogenic material together with covering regenerative membranes and tight wound closure. The bone regeneration process was estimated, comparing the images taken on the day of the surgery and 12 months later, by means of Kodak RVG 6100 digital radiography set. The interpretation of the radiovisiographic image depends on the evaluation ability of the eye looking at it, which leaves a large margin of uncertainty. So, several texture analysis techniques were developed and used sequentially on the radiographic image. For each method, the results were the mean from the 25 images. These methods compute the fractal dimension (D), each one having its own theoretic basis. We used five techniques for calculating fractal dimension: power spectral density method, triangular prism surface area method, blanket method, intensity difference scaling method and variogram analysis. Our study showed a decrease of fractal dimension during the healing process after bone loss. We also found evidence that various methods of calculating fractal dimension give different results. During the healing process after bone loss, the surfaces of radiographic images became smooth. The result obtained show that our findings may be of great importance for diagnostic purpose.

  15. Epidermal Graft Accelerates the Healing of Acute Wound: A Self-controlled Case Report

    PubMed Central

    Bystrzonowski, Nicola; Hachach-Haram, Nadine; Richards, Toby; Mosahebi, Afshin

    2016-01-01

    Summary: Wound care represents a significant socioeconomic burden, with over half of chronic wounds taking up to a year to heal. Measures to accelerate wound healing are beneficial to patients and also reduce the cost and burden of wound management. Epidermal grafting (EG) is an emerging option for autologous skin grafting in the outpatient setting to improve wound healing. Although several case series have previously reported good clinical outcome with EG, the healing rate in comparison to conservative wound management is not known. In this report, we compare the weekly healing rate of 2 separate wounds in the same patient, one treated with EG and the other with dressings. The treated wound showed accelerated healing, with the healing rate being the highest at the first 2 weeks after EG. The average healing time of the treated wound was 40% faster compared with the control wound. EG accelerates healing of acute wounds, potentially reducing the healthcare cost and surgical burden. PMID:27975024

  16. Monitoring of the first stages of bone healing with microdialysis

    PubMed Central

    2013-01-01

    Background and purpose Bone healing is a complex process influenced by growth factors, cytokines, and other mediators. The regulation of this process is not well understood. In this pilot study, we used microdialysis technology in a critical-size bone defect in rat femurs to determine the feasibility of measuring cytokines and growth factors in the first 24 h after injury. Methods A 5-mm defect, stabilized by a plate, was created in the femurs of 30 male Wistar rats. The microdialysis probe (with 100 kDa molecular weight cutoff) was inserted into the defect and microdialysates were collected continuously for up to 24 h. Total protein concentration, interleukin-6 (IL-6) concentration, and transforming growth factor-β1 (TGF-β1) concentration were assessed under different conditions. Results Microdialysis allowed continuous and consistent protein collection over 24 h from a critical-size bone defect starting at the time of injury. IL-6 was secreted within the first 3 h after the injury. The highest IL-6 concentration (344 pg/mL) was measured between 12 and 15 h after surgery. Addition of bovine serum albumin to the perfusate resulted in detectable concentrations of TGF-β1 ranging from 10 to 23 pg/mL. Interpretation Continuous sampling over 24 h of proteins from a bone defect directly after the injury is feasible and provides the opportunity for a detailed analysis of the initial stages of bone healing. PMID:23350578

  17. Effect of early axial dynamization on tibial bone healing: a study in dogs.

    PubMed

    Larsson, S; Kim, W; Caja, V L; Egger, E L; Inoue, N; Chao, E Y

    2001-07-01

    Early axial dynamization and its effect on experimental tibial bone healing was compared with healing under rigid fixation in a time-sequenced manner using dogs. An external fixator that could be rigidly locked or set to allow free axial movement while preventing bending and shear was used. Both tibias were osteotomized and externally fixed, leaving a gap between bone ends of 2 mm. At 1 week, one side was dynamized, whereas the other side was kept rigidly locked as a control. Dogs were euthanized at 1 day and 1, 3, 5, 8, and 11 weeks after dynamization. The outcome measures were static and dynamic load-bearing, periosteal callus development, new bone formation, callus tissue composition, and mechanical strength. Load bearing was higher on the dynamized limbs during standing for the first 5 weeks and during gait for the first 3 weeks after dynamization compared with the controls. Maximum periosteal callus size was reached faster and was distributed more symmetrically on the dynamized side. The periosteal callus area decreased at 12 weeks on the dynamized sides, but there was no significant change in the area on the control sides. Endosteal new bone formation and bone density decreased between 9 and 12 weeks only on the dynamized sides. The dynamized side showed a significantly higher torsional stiffness at 6 weeks than did the controls. There were no significant differences between dynamized and control tibias at other times. Maximum torque also tended to be higher on the dynamized sides at the same time. Early axial dynamization appeared to accelerate callus formation and remodeling and to provide higher mechanical stiffness during early stages of bone healing.

  18. Sustained delivery of transforming growth factor beta three enhances tendon-to-bone healing in a rat model.

    PubMed

    Manning, Cionne N; Kim, H Mike; Sakiyama-Elbert, Shelly; Galatz, Leesa M; Havlioglu, Necat; Thomopoulos, Stavros

    2011-07-01

    Despite advances in surgical technique, rotator cuff repairs are plagued by a high rate of failure. This failure rate is in part due to poor tendon-to-bone healing; rather than regeneration of a fibrocartilaginous attachment, the repair is filled with disorganized fibrovascular (scar) tissue. Transforming growth factor beta 3 (TGF-β3) has been implicated in fetal development and scarless fetal healing and, thus, exogenous addition of TGF-β3 may enhance tendon-to-bone healing. We hypothesized that: TGF-β3 could be released in a controlled manner using a heparin/fibrin-based delivery system (HBDS); and delivery of TGF-β3 at the healing tendon-to-bone insertion would lead to improvements in biomechanical properties compared to untreated controls. After demonstrating that the release kinetics of TGF-β3 could be controlled using a HBDS in vitro, matrices were incorporated at the repaired supraspinatus tendon-to-bone insertions of rats. Animals were sacrificed at 14-56 days. Repaired insertions were assessed using histology (for inflammation, vascularity, and cell proliferation) and biomechanics (for structural and mechanical properties). TGF-β3 treatment in vivo accelerated the healing process, with increases in inflammation, cellularity, vascularity, and cell proliferation at the early timepoints. Moreover, sustained delivery of TGF-β3 to the healing tendon-to-bone insertion led to significant improvements in structural properties at 28 days and in material properties at 56 days compared to controls. We concluded that TGF-β3 delivered at a sustained rate using a HBDS enhanced tendon-to-bone healing in a rat model.

  19. Histomorphometric Study of Alveolar Bone Healing in Rats Fed a Boron-Deficient Diet

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bone healing after tooth extraction in rats is a suitable experimental model to study bone formation. Thus, we performed a study to determine the effects of boron (B) deficiency on bone healing by using this model. Weanling Wistar rats were divided into two groups: control (+B; 3 mg B/kg diet), and ...

  20. Hydrogen sulfide accelerates wound healing in diabetic rats

    PubMed Central

    Wang, Guoguang; Li, Wei; Chen, Qingying; Jiang, Yuxin; Lu, Xiaohua; Zhao, Xue

    2015-01-01

    Aim: The aim of this study was to explore the role of hydrogen sulfide on wound healing in diabetic rats. Methods: Experimental diabetes in rats was induced by intraperitoneal injection of streptozotocin (STZ) (in 0.1 mol/L citrate buffer, Ph 4.5) at dose of 70 mg/kg. Diabetic and age-matched non-diabetic rats were randomly assigned to three groups: untreated diabetic controls (UDC), treated diabetic administrations (TDA), and non-diabetic controls (NDC). Wound Healing Model was prepared by making a round incision (2.0 cm in diameter) in full thickness. Rats from TDA receive 2% sodium bisulfide ointment on wound, and animals from UDC and NDC receive control cream. After treatment of 21 days with sodium bisulfide, blood samples were collected for determination of vascular endothelial growth factor (VEGF), intercellular cell adhesion molecule-1 (ICAM-1), antioxidant effects. Granulation tissues from the wound were processed for histological examination and analysis of western blot. Results: The study indicated a significant increase in levels of VEGF and ICAM-1 and a decline in activity of coagulation in diabetic rats treated with sodium bisulfide. Sodium bisulfide treatment raised the activity of superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) protein expression, and decreased tumor necrosis factor α (TNF-α) protein expression in diabetic rats. Conclusions: The findings in present study suggested that hydrogen sulfide accelerates the wound healing in rats with diabetes. The beneficial effect of H2S may be associated with formation of granulation, anti-inflammation, antioxidant, and the increased level of vascular endothelial growth factor (VEGF). PMID:26191204

  1. Bone healing around nanocrystalline hydroxyapatite, deproteinized bovine bone mineral, biphasic calcium phosphate, and autogenous bone in mandibular bone defects.

    PubMed

    Broggini, Nina; Bosshardt, Dieter D; Jensen, Simon S; Bornstein, Michael M; Wang, Chun-Cheng; Buser, Daniel

    2015-10-01

    The individual healing profile of a given bone substitute with respect to osteogenic potential and substitution rate must be considered when selecting adjunctive grafting materials for bone regeneration procedures. In this study, standardized mandibular defects in minipigs were filled with nanocrystalline hydroxyapatite (HA-SiO), deproteinized bovine bone mineral (DBBM), biphasic calcium phosphate (BCP) with a 60/40% HA/β-TCP (BCP 60/40) ratio, or particulate autogenous bone (A) for histological and histomorphometric analysis. At 2 weeks, percent filler amongst the test groups (DBBM (35.65%), HA-SiO (34.47%), followed by BCP 60/40 (23.64%)) was significantly higher than the more rapidly substituted autogenous bone (17.1%). Autogenous bone yielded significantly more new bone (21.81%) over all test groups (4.91%-7.74%) and significantly more osteoid (5.53%) than BCP 60/40 (3%) and DBBM (2.25%). At 8 weeks, percent filler amongst the test groups (DBBM (31.6%), HA-SiO (31.23%), followed by BCP 60/40 (23.65%)) demonstrated a similar pattern and was again significantly higher as compared to autogenous bone (9.29%). Autogenous bone again exhibited statistically significantly greater new bone (55.13%) over HA-SiO (40.62%), BCP 60/40 (40.21%), and DBBM (36.35%). These results suggest that the osteogenic potential of HA-SiO and BCP is inferior when compared to autogenous bone. However, in instances where a low substitution rate is desired to maintain the volume stability of augmented sites, particularly in the esthetic zone, HA-SiO and DBBM may be favored.

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

    PubMed

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

    2013-02-01

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

  3. Healing pattern of reamed bone following bone harvesting by a RIA device.

    PubMed

    Devine, D M; Arens, D; Thalhauser, M; Schiuma, D; Zeiter, S; Nehrbass, D

    2015-01-29

    Intramedullary nailing has been used for decades to treat fractures of the long bones. However, complications related to the increase in medullary pressure culminated in the development of the Reamer Irrigator Aspirator (RIA). Since its first clinical use, the RIA has moved from a reaming device to a cell and autologous bone-harvesting tool. This increase in use brings with it further clinical questions; namely, does the endosteal bone regenerate sufficiently to allow subsequent reaming procedures. In the current study, endosteal bone regeneration post reaming was assessed in an ovine model. The study included six animals that had one tibia reamed, while the contralateral tibia acted as an intact control. Animals were administered fluorochrome labels in vivo, and bone regeneration was assessed using radiographical analysis. The endpoint of the study was 12 weeks post-surgery, at which time ex vivo analysis consisted of computed tomography and histological assessments. In vivo radiographs indicated limited healing of the reamed bone. However, ex vivo computer tomographical analysis indicated no significant differences in terms of bone volume between the reamed bone and the intact bone. Histological assessment of these regions indicated new bone formation. Fluorescent labelling indicates strong bone formation from 9 weeks post-surgery and as such, the bone formed at 12 weeks was immature in nature and was actively undergoing remodelling. These results indicate that bone regeneration post-reaming was continuing at three months. Therefore, given more time it may have sufficiently healed to allow a surgeon to use the intramedullary canal for a re-reaming procedure.

  4. Platelet-rich plasma for long bone healing

    PubMed Central

    Lenza, Mário; Ferraz, Silvia de Barros; Viola, Dan Carai Maia; dos Santos, Oscar Fernando Pavão; Cendoroglo, Miguel; Ferretti, Mario

    2013-01-01

    ABSTRACT Objective: To evaluate effectiveness of the use of platelet-rich plasma as coadjuvant for union of long bones. Methods: The search strategy included the Cochrane Library (via Central) and MEDLINE (via PubMed). There were no limits as to language or publication media. The latest search strategy was conducted in December 2011. It included randomized clinical trials that evaluated the use of platelet-rich plasma as coadjuvant medication to accelerate union of long bones (acute fractures, pseudoarthrosis and bone defects). The outcomes of interest for this review include bone regeneration, adverse events, costs, pain, and quality of life. The authors selected eligible studies, evaluated the methodological quality, and extracted the data. It was not possible to perform quantitative analysis of the grouped studies (meta-analyses). Results: Two randomized prospective clinical trials were included, with a total of 148 participants. One of them compared recombinant human morphogenic bone protein-7 versus platelet-rich plasma for the treatment of pseudoarthrosis; the other evaluated the effects of three coadjuvant treatments for union of valgising tibial osteotomies (platelet-rich plasma, platelet-rich plasma plus bone marrow stromal cells, and no coadjuvant treatment). Both had low statistical power and moderate to high risk of bias. Conclusion: There was no conclusive evidence that sustained the use of platelet-rich plasma as a coadjuvant to aid bone regeneration of fractures, pseudoarthrosis, or bone defects. PMID:23579757

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

    PubMed

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

    2014-01-01

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

  6. Improved Bone Healing by Angiogenic Factor-Enriched Platelet-Rich Plasma and Its Synergistic Enhancement by Bone Morphogenetic Protein-2

    PubMed Central

    Park, Eun-Jin; Kim, Eun-Seok; Weber, Hans-Peter; Wright, Robert F.

    2010-01-01

    (1) Purpose The purpose of this study was to modify the method of platelet-rich plasma (PRP) preparation for obtaining optimal angiogenic potential and accelerate bone healing. Also, the potential synergistic effect of a suboptimal concentration of bone morphogenic protein-2 (BMP-2) and modified PRP (mPRP) on bone healing was evaluated in vivo. (2) Materials and Methods The angiogenic factor-enriched PRP which includes peripheral blood mononuclear cells (mostly lymphocytes and monocytes fraction, excluding polymorphonuclear leukocyte, PMNs) was achieved by lowering concentrations of thrombin and CaCl2, after pre-activation with shear stress using a table-top vortex machine and collagen. In vitro, endothelial cell migration activity in the mPRP group was compared to conventional PRP preparation using a modified Boyden chamber assay. In an animal study, PGA scaffold, PGA scaffold + mPRP, PGA scaffold + mPRP + rhBMP-2, and PGA scaffold + rhBMP-2 were applied to 28 NIH nude rats’ critical size calvarial defects. At 2 weeks, periosteal blood flow was measured using LDPI, and bone formation was evaluated at 8 weeks by histology, DEXA, and μCT. (3) Results mPRP induced faster migration of cord blood-derived outgrowth endothelial-like cells. In vivo, mPRP with low dose rhBMP-2 group showed significantly increased numbers of blood vessels at 2 weeks, and notable synergistic effect on bone healing at 8 weeks as evaluated with histology, bone mineral density (BMD) and bone mineral content (BMC, and μCT. (4) Conclusion mPRP used in this study improved vascular perfusion around the defect, and resulted in enhanced bone healing. Also, combining mPRP with a suboptimal dosage of rhBMP-2 improved bone formation and enhanced bone density. PMID:19014150

  7. Critical Size Bone Defect Healing Using Collagen–Calcium Phosphate Bone Graft Materials

    PubMed Central

    Walsh, William Robert; Oliver, Rema A.; Christou, Chris; Lovric, Vedran; Walsh, Emma Rose; Prado, Gustavo R.; Haider, Thomas

    2017-01-01

    The need for bone graft materials to fill bony voids or gaps that are not related to the intrinsic stability of the bone that arise due to trauma, tumors or osteolysis remains a clinically relevant and significant issue. The in vivo response of collagen–tricalcium phosphate bone graft substitutes was evaluated in a critical size cancellous defect model in skeletally mature rabbits. While the materials were chemically virtually identical, new bone formation, implant resorption and local in vivo responses were significantly different. Differences in the in vivo response may be due, in part, collagen source and processing which influences resorption profiles. Continued improvements in processing and manufacturing techniques of collagen—tricalcium phosphate bone graft substitutes can result in osteoconductive materials that support healing of critical size bone defects even in challenging pre-clinical models. PMID:28045946

  8. Proteomic Analysis of Gingival Tissue and Alveolar Bone during Alveolar Bone Healing*

    PubMed Central

    Yang, Hee-Young; Kwon, Joseph; Kook, Min-Suk; Kang, Seong Soo; Kim, Se Eun; Sohn, Sungoh; Jung, Seunggon; Kwon, Sang-Oh; Kim, Hyung-Seok; Lee, Jae Hyuk; Lee, Tae-Hoon

    2013-01-01

    Bone tissue regeneration is orchestrated by the surrounding supporting tissues and involves the build-up of osteogenic cells, which orchestrate remodeling/healing through the expression of numerous mediators and signaling molecules. Periodontal regeneration models have proven useful for studying the interaction and communication between alveolar bone and supporting soft tissue. We applied a quantitative proteomic approach to analyze and compare proteins with altered expression in gingival soft tissue and alveolar bone following tooth extraction. For target identification and validation, hard and soft tissue were extracted from mini-pigs at the indicated times after tooth extraction. From triplicate experiments, 56 proteins in soft tissue and 27 proteins in alveolar bone were found to be differentially expressed before and after tooth extraction. The expression of 21 of those proteins was altered in both soft tissue and bone. Comparison of the activated networks in soft tissue and alveolar bone highlighted their distinct responsibilities in bone and tissue healing. Moreover, we found that there is crosstalk between identified proteins in soft tissue and alveolar bone with respect to cellular assembly, organization, and communication. Among these proteins, we examined in detail the expression patterns and associated networks of ATP5B and fibronectin 1. ATP5B is involved in nucleic acid metabolism, small molecule biochemistry, and neurological disease, and fibronectin 1 is involved in cellular assembly, organization, and maintenance. Collectively, our findings indicate that bone regeneration is accompanied by a profound interaction among networks regulating cellular resources, and they provide novel insight into the molecular mechanisms involved in the healing of periodontal tissue after tooth extraction. PMID:23824910

  9. [Bone fracture and the healing mechanisms. The mechanical stress for fracture healing in view of distraction osteogenesis].

    PubMed

    Yukata, Kiminori; Takahashi, Mitsuhiko; Yasui, Natsuo

    2009-05-01

    It is generally accepted that moderate mechanical stress influences the course of fracture healing. A flexible fixation of the fractured site can induce fracture callus formation, whereas an unstable fixation can lead to a nonunion. The relationship between mechanical stress and the process of bone regeneration or healing remains incompletely understood. Distraction osteogenesis is a surgical technique that, using appropriate mechanical tension-stress, does not break the callus but rather it stimulates and maintains osteogenesis. The common principles of distraction osteogenesis are osteotomy and slow progressive distraction by an external fixation device. Interest in bone regeneration associated with mechanical stress might lead to better understanding of the fracture healing process.

  10. A review of techniques for gene therapy in bone healing.

    PubMed

    Tarassoli, Payam; Khan, Wasim S; Hughes, Adrian; Heidari, Nima

    2013-05-01

    Gene therapy has been successfully used in several areas of medicine as a technique to either alter defective genes or as method to enable delivery of therapeutic proteins. Despite advances in surgical and pharmaceutical interventions for diseases of bone regeneration and healing, results in certain patient groups remain sub-optimal. With this consideration, gene therapy is currently being investigated as a means of facilitating healing and improving outcomes. Two broad techniques which are currently utilised by research teams are discussed in this review; ex vivo and in vivo. The underlying principle is similar in each case; the use of gene therapy to alter target cells to deliver proteins which facilitate bone regeneration. However, whereas ex vivo techniques involve performing genetic manipulations outside the body and then introducing the altered cells to the desired site, in vivo techniques execute genetic manipulations inside the body by the introduction of vectors directly to the desired location. Results from small animal models for both techniques are promising, however, further research is required to demonstrate both safety and efficacy prior to any future clinical application.

  11. Early bone healing events in the human extraction socket.

    PubMed

    Devlin, H; Sloan, P

    2002-12-01

    The tooth extraction socket is unique in terms of a bone-healing defect in that it contains the remnants of periodontal ligament fibroblasts attached to the socket wall. Although these cells have an osteogenic potential in vitro, the origin of cells populating the human extraction socket is unknown and may include bone marrow, periosteum and pericytic cells. Recently, monoclonal antibodies (AML-3, SB-10 and SB-20) have become available which can identify cells undergoing osteogenic differentiation. The aim of this work was to investigate the pattern of osteoblast differentiation in the human extraction socket using these markers. Immunolocalization was used to identify the osteoprogenitor cell population in the extraction sockets of three patients. Runx2 was most strongly expressed by the osteoblasts at the socket margin and in the surrounding marrow spaces. Osteoprogenitor, pre-osteoblast and osteoblast cells surrounded the newly formed trabeculae, and expressed on their cell surface antigens which reacted with the SB-10 and SB-20 antibodies. In a specimen with the tooth and periodontium present, both osteo-blasts and periodontal ligament fibroblasts were immunoreactive with SB-10, and SB-20 and also expressed Runx2. There was heterogeneity of expression of these osteogenic markers e.g. not all osteoblasts expressed Runx2. We have shown that osteoprogenitor cells in the residual periodontal ligament and bone marrow may contribute to bone regeneration following tooth extraction.

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

    PubMed

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

    2016-12-01

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

  13. Influence of ultrasound and physical activity on bone healing.

    PubMed

    Guerino, Marcelo R; Santi, Francisco P; Silveira, Rafael F; Luciano, Eliete

    2008-09-01

    The aim of this study was to investigate the effects of ultrasound treatment of experimental bone fractures and the effects of physical exercise on the speed of bone consolidation. Osteotomy was performed on the upper third of the right tibia of rats. Physical training consisted of swimming 1 h per d with a load of 5% body weight and therapy with medium-intensity ultrasound was applied for 5 min daily. Young adult male Wistar rats were divided into four groups: (1) osteotomized sedentary animals with no ultrasound treatment (OSnUS); (2) trained with no ultrasound treatment (OTnUS); (3) sedentary with ultrasound treatment (OSwUS); and (4) trained with ultrasound treatment (OTwUS). The animals were sacrificed for the following analyses: muscle glycogen and serum alkaline phosphatase on the 5th, 10th, 20th and 30th days and histological slices of the bone on the 5th and 20th days. The results show that ultrasound is better in the initial phases of the process of bone tissue repair and physical exercise at the end of bone consolidation. These facts suggest that the treatments herein used prove favorable to the bone regenerative process, as the overall ossification process has been accelerated.

  14. A Longitudinal Low Dose μCT Analysis of Bone Healing in Mice: A Pilot Study

    PubMed Central

    Di, Lu-Zhao; Leblanc, Élisabeth; Alinejad, Yasaman; Beaudoin, Jean-François; Lecomte, Roger; Berthod, François; Faucheux, Nathalie; Balg, Frédéric

    2014-01-01

    Low dose microcomputed tomography (μCT) is a recently matured technique that enables the study of longitudinal bone healing and the testing of experimental treatments for bone repair. This imaging technique has been used for studying craniofacial repair in mice but not in an orthopedic context. This is mainly due to the size of the defects (approximately 1.0 mm) in long bone, which heal rapidly and may thus negatively impact the assessment of the effectiveness of experimental treatments. We developed a longitudinal low dose μCT scan analysis method combined with a new image segmentation and extraction software using Hounsfield unit (HU) scores to quantitatively monitor bone healing in small femoral cortical defects in live mice. We were able to reproducibly quantify bone healing longitudinally over time with three observers. We used high speed intramedullary reaming to prolong healing in order to circumvent the rapid healing typical of small defects. Bone healing prolongation combined with μCT imaging to study small bone defects in live mice thus shows potential as a promising tool for future preclinical research on bone healing. PMID:25431676

  15. Biocompatibility, bone healing, and safety evaluation in rabbits with an IlluminOss bone stabilization system.

    PubMed

    McSweeney, Amanda L; Zani, Brett G; Baird, Rose; Stanley, James R L; Hayward, Alison; Markham, Peter M; Kopia, Gregory A; Edelman, Elazer R; Rabiner, Robert

    2017-01-30

    Bone healing, biocompatibility, and safety employing the IlluminOss System (IS), comprised of an inflatable balloon filled with photopolymerizable liquid monomer, was evaluated in New Zealand white rabbits. Successful bone healing and callus remodeling over 6 months was demonstrated radiologically and histologically with IS implants in fenestrated femoral cortices. Biocompatibility was demonstrated with IS implants in brushed, flushed femoral intramedullary spaces, eliciting no adverse, local, or systemic responses and with similar biocompatibility to K-wires in contralateral femurs up to 1 year post-implant. Lastly simulated clinical failures demonstrated the safety of IS implants up to 1 year in the presence of liquid or polymerized polymer within the intramedullary space. Polymerized material displayed cortical bone and vasculature effects comparable to mechanical disruption of the endosteum. In the clinically unlikely scenario with no remediation or polymerization, a high dose monomer injection resulted in marked necrosis of cortical bone, as well as associated vasculature, endosteum, and bone marrow. Overall, when polymerized and hardened within bone intramedullary spaces, this light curable monomer system may provide a safe and effective method for fracture stabilization. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

  16. Porous decellularized tissue engineered hypertrophic cartilage as a scaffold for large bone defect healing.

    PubMed

    Cunniffe, Gráinne M; Vinardell, Tatiana; Murphy, J Mary; Thompson, Emmet M; Matsiko, Amos; O'Brien, Fergal J; Kelly, Daniel J

    2015-09-01

    Clinical translation of tissue engineered therapeutics is hampered by the significant logistical and regulatory challenges associated with such products, prompting increased interest in the use of decellularized extracellular matrix (ECM) to enhance endogenous regeneration. Most bones develop and heal by endochondral ossification, the replacement of a hypertrophic cartilaginous intermediary with bone. The hypothesis of this study is that a porous scaffold derived from decellularized tissue engineered hypertrophic cartilage will retain the necessary signals to instruct host cells to accelerate endogenous bone regeneration. Cartilage tissue (CT) and hypertrophic cartilage tissue (HT) were engineered using human bone marrow derived mesenchymal stem cells, decellularized and the remaining ECM was freeze-dried to generate porous scaffolds. When implanted subcutaneously in nude mice, only the decellularized HT-derived scaffolds were found to induce vascularization and de novo mineral accumulation. Furthermore, when implanted into critically-sized femoral defects, full bridging was observed in half of the defects treated with HT scaffolds, while no evidence of such bridging was found in empty controls. Host cells which had migrated throughout the scaffold were capable of producing new bone tissue, in contrast to fibrous tissue formation within empty controls. These results demonstrate the capacity of decellularized engineered tissues as 'off-the-shelf' implants to promote tissue regeneration.

  17. Fracture induced mobilization and incorporation of bone marrow-derived endothelial progenitor cells for bone healing.

    PubMed

    Matsumoto, Tomoyuki; Mifune, Yutaka; Kawamoto, Atsuhiko; Kuroda, Ryosuke; Shoji, Taro; Iwasaki, Hiroto; Suzuki, Takahiro; Oyamada, Akira; Horii, Miki; Yokoyama, Ayumi; Nishimura, Hiromi; Lee, Sang Yang; Miwa, Masahiko; Doita, Minoru; Kurosaka, Masahiro; Asahara, Takayuki

    2008-04-01

    We recently reported that systemic administration of peripheral blood (PB) CD34+ cells, an endothelial progenitor cell (EPC)-enriched population, contributed to fracture healing via vasculogenesis/angiogenesis. However, pathophysiological role of EPCs in fracture healing process has not been fully clarified. Therefore, we investigated the hypothesis whether mobilization and incorporation of bone marrow (BM)-derived EPCs may play a pivotal role in appropriate fracture healing. Serial examinations of Laser doppler perfusion imaging and histological capillary density revealed that neovascularization activity at the fracture site peaked at day 7 post-fracture, the early phase of endochondral ossifification. Fluorescence-activated cell sorting (FACS) analysis demonstrated that the frequency of BM cKit+Sca1+Lineage- (Lin-) cells and PB Sca1+Lin- cells, which are EPC-enriched fractions, significantly increased post-fracture. The Sca1+ EPC-derived vasuculogenesis at the fracture site was confirmed by double immunohistochemistry for CD31 and Sca1. BM transplantation from transgenic donors expressing LacZ transcriptionally regulated by endothelial cell-specific Tie-2 promoter into wild type also provided direct evidence that EPCs contributing to enhanced neovascularization at the fracture site were specifically derived from BM. Animal model of systemic administration of PB Sca1+Lin- Green Fluorescent Protein (GFP)+ cells further confirmed incorporation of the mobilized EPCs into the fracture site for fracture healing. These findings indicate that fracture may induce mobilization of EPCs from BM to PB and recruitment of the mobilized EPCs into fracture sites, thereby augment neovascularization during the process of bone healing. EPCs may play an essential role in fracture healing by promoting a favorable environment through neovascularization in damaged skeletal tissue.

  18. Alteration of blood clot structures by interleukin-1 beta in association with bone defects healing

    PubMed Central

    Wang, Xin; Friis, Thor E.; Masci, Paul P.; Crawford, Ross W.; Liao, Wenbo; Xiao, Yin

    2016-01-01

    The quality of hematomas are crucial for successful early bone defect healing, as the structure of fibrin clots can significantly influence the infiltration of cells, necessary for bone regeneration, from adjacent tissues into the fibrin network. This study investigated if there were structural differences between hematomas from normal and delayed healing bone defects and whether such differences were linked to changes in the expression of IL-1β. Using a bone defect model in rats, we found that the hematomas in the delayed healing model had thinner fibers and denser clot structures. Moreover, IL-1β protein levels were significantly higher in the delayed healing hematomas. The effects of IL-1β on the structural properties of human whole blood clots were evaluated by thrombelastograph (TEG), scanning electronic microscopy (SEM), compressive study, and thrombolytic assays. S-nitrosoglutathione (GSNO) was applied to modulate de novo hematoma structure and the impact on bone healing was evaluated in the delayed healing model. We found that GSNO produced more porous hematomas with thicker fibers and resulted in significantly enhanced bone healing. This study demonstrated that IL-1β and GSNO had opposing effects on clot architecture, the structure of which plays a pivotal role in early bone healing. PMID:27767056

  19. Irradiated human chondrocytes expressing bone morphogenetic protein 2 promote healing of osteoporotic bone fracture in rats.

    PubMed

    Yi, Youngsuk; Choi, Kyoung Baek; Lim, Chae-Lyul; Hyun, Jong-Pil; Lee, Hyeon-Youl; Lee, Kun Bok; Yun, Lillian; Ayverdi, Asli; Hwang, Sally; Yip, Vivian; Noh, Moon Jong; Lee, Kwan Hee

    2009-10-01

    Bone morphogenetic protein 2 (BMP2) was selected as a transgene to regenerate osteoporotic bone defects after several BMPs were tested using a bone formation study in nude mice. Human chondrocytes were transduced with a BMP2-containing retroviral vector, and single clones were selected. The cells were characterized over numerous passages for growth and BMP2 expression. The single clones were irradiated and tested for viability. BMP2 expression lasted for 3 weeks before dying off completely after approximately 1 month. Irradiated and non-irradiated transduced chondrocytes successfully healed fractures in osteoporotic rats induced by ovariectomy. The osteoinducing effect of irradiated cells was better than that of their non-irradiated counterparts or a chondrocytes-only control. This study showed that delivering BMP2 from the transduced and irradiated chondrocytes could be an effective and safe method of repairing osteoporotic bone fractures.

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

    PubMed Central

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

    2012-01-01

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

  1. Evaluation of a Topical Herbal Agent for the Promotion of Bone Healing

    PubMed Central

    Siu, Wing-Sum; Ko, Chun-Hay; Lam, Ka-Wing; Shum, Wai-Ting; Lau, Clara Bik-San; Ko, Kam-Ming; Hung, Leung-Kim; Lau, David Tai-Wai; Leung, Ping-Chung

    2015-01-01

    A topically used Chinese herbal paste, namely, CDNR, was designed to facilitate fracture healing which is usually not addressed in general hospital care. From our in vitro studies, CDNR significantly inhibited the release of nitric oxide from RAW264.7 cells by 51 to 77%. This indicated its anti-inflammatory effect. CDNR also promoted the growth of bone cells by stimulating the proliferation of UMR106 cells up to 18%. It also increased the biomechanical strength of the healing bone in a drill-hole defect rat model by 16.5% significantly. This result revealed its in vivo efficacy on facilitation of bone healing. Furthermore, the detection of the chemical markers of CDNR in the skin and muscle of the treatment area demonstrated its transdermal properties. However, CDNR did not affect the bone turnover markers in serum of the rats. With its anti-inflammatory and bone formation properties, CDNR is found effective in promoting bone healing. PMID:25810746

  2. The effect of platelet concentrates on graft maturation and graft-bone interface healing in ACL reconstruction in human patients

    PubMed Central

    Vavken, Patrick; Sadoghi, Patrick; Murray, Martha M

    2011-01-01

    Purpose To systematically review the current evidence for effects of platelet concentrates on (1) graft maturation and (2) graft-bone interface healing in ACL reconstruction in human, controlled trials, and for ensuing differences in clinical outcomes. Methods A systematic search of PubMed, CINAHL, EMBASE, CCTR and CDSR was performed for controlled trials of human ACL reconstruction with and without platelet concentrates. Data validity was assessed and data were collected on graft maturation, graft-bone interface healing and clinical outcome. Results Eight studies met the inclusion criteria. Seven studies reported on graft maturation with significantly better outcomes in the platelet groups in four, and large differences in means in two (underpowered) studies. Five studies report on tunnel healing, but four found no difference between groups. Three studies assessed clinical outcome but found no differences, regardless whether they had shown a benefical (1/3) or no effect (2/3) of platelets on graft and tunnel healing. Conclusion The current best evidence suggests that the addition of platelet concentrates to ACL reconstruction may have a beneficial effect on graft maturation and could improve it by 20–30% on average, but with substantial variability. The most likely mode of action is that treatment with platelets accelerates graft repopulation and remodeling, and this interpretation is supported by the existing data and biologically plausible. However, the current evidence also shows only a very limited influence of platelet concentrates on graft-bone interface healing and no significant difference in clinical outcomes. Clinical Relevance This systematic review collected evidence that the use of platelet concentrates may be a safe and inexpensive way to optimize graft maturation after ACL reconstruction, but there is no evidence for improved graft-bone interface healing or a significant difference in clinical outcomes. Level of Evidence Level IV, systematic

  3. Molecular signaling in bone fracture healing and distraction osteogenesis.

    PubMed

    Liu, Z; Luyten, F P; Lammens, J; Dequeker, J

    1999-04-01

    The process of fracture healing has been described in detail in many histological studies. Recent work has focused on the mechanisms by which growth and differentiation factors regulate the fracture healing process. Rapid progress in skeletal cellular and molecular biology has led to the identification of many signaling molecules associated with the formation of skeletal tissues, including members of the transforming growth factor-beta (TGF-beta) superfamily and the insulin-like growth factor (IGF) family. Increasing evidence indicates that they are critical regulators of cellular proliferation, differentiation, extracellular matrix biosynthesis and mineralization. Limb lengthening procedure (distraction osteogenesis) is a relevant model to investigate the in vivo correlation between mechanical stimulation and biological responses as the callus is stretched by a proper rate and rhythm of mechanical strain. This model also provides additional insights into the molecular and cellular events during bone fracture repair. TGF-beta 1 was significantly increased in both the distracted callus and the fracture callus. The increased level of TGF-beta 1, together with a low concentration of calcium and an enhanced level of collagen synthesis, was maintained in the distracted callus as long as mechanical strain was applied. Less mineralization is also associated with a low level of osteocalcin production. These observations provide further insights into the molecular basis for the cellular events during distraction osteogenesis.

  4. Circadian rhythms accelerate wound healing in female Siberian hamsters.

    PubMed

    Cable, Erin J; Onishi, Kenneth G; Prendergast, Brian J

    2017-03-15

    Circadian rhythms (CRs) provide temporal regulation and coordination of numerous physiological traits, including immune function. CRs in multiple aspects of immune function are impaired in rodents that have been rendered circadian-arrhythmic through various methods. In Siberian hamsters, circadian arrhythmia can be induced by disruptive light treatments (DPS). Here we examined CRs in wound healing, and the effects of circadian disruption on wound healing in DPS-arrhythmic hamsters. Circadian entrained/rhythmic (RHYTH) and behaviorally-arrhythmic (ARR) female hamsters were administered a cutaneous wound either 3h after light onset (ZT03) or 2h after dark onset (ZT18); wound size was quantified daily using image analyses. Among RHYTH hamsters, ZT03 wounds healed faster than ZT18 wounds, whereas in ARR hamsters, circadian phase did not affect wound healing. In addition, wounds healed slower in ARR hamsters. The results document a clear CR in wound healing, and indicate that the mere presence of organismal circadian organization enhances this aspect of immune function. Faster wound healing in CR-competent hamsters may be mediated by CR-driven coordination of the temporal order of mechanisms (inflammation, leukocyte trafficking, tissue remodeling) underlying cutaneous wound healing.

  5. An electronically instrumented internal fixator for the assessment of bone healing

    PubMed Central

    Kowald, B.; Seide, K.; Aljudaibi, M.; Faschingbauer, M.; Juergens, C.; Gille, J.

    2016-01-01

    Objectives The monitoring of fracture healing is a complex process. Typically, successive radiographs are performed and an emerging calcification of the fracture area is evaluated. The aim of this study was to investigate whether different bone healing patterns can be distinguished using a telemetric instrumented femoral internal plate fixator. Materials and Methods An electronic telemetric system was developed to assess bone healing mechanically. The system consists of a telemetry module which is applied to an internal locking plate fixator, an external reader device, a sensor for measuring externally applied load and a laptop computer with processing software. By correlation between externally applied load and load measured in the implant, the elasticity of the osteosynthesis is calculated. The elasticity decreases with ongoing consolidation of a fracture or nonunion and is an appropriate parameter for the course of bone healing. At our centre, clinical application has been performed in 56 patients suffering nonunion or fracture of the femur. Results A total of 39 cases of clinical application were reviewed for this study. In total, four different types of healing curves were observed: fast healing; slow healing; plateau followed by healing; and non-healing. Conclusion The electronically instrumented internal fixator proved to be valuable for the assessment of bone healing in difficult healing situations. Cost-effective manufacturing is possible because the used electronic components are derived from large-scale production. The incorporation of microelectronics into orthopaedic implants will be an important innovation in future clinical care. Cite this article: B. Kienast, B. Kowald, K. Seide, M. Aljudaibi, M. Faschingbauer, C. Juergens, J. Gille. An electronically instrumented internal fixator for the assessment of bone healing. Bone Joint Res 2016;5:191–197. DOI: 10.1302/2046-3758.55.2000611. PMID:27226357

  6. Study of nano-hydroxyapatite/zirconia stabilized with yttria in bone healing: histopathological study in rabbit model.

    PubMed

    Abedi, Gholamreza; Jahanshahi, Amirali; Fathi, Mohamad Hosein; Haghdost, Iraj Sohrabi; Veshkini, Abas

    2014-03-01

    Acceleration of bone healing has always been a major challenge in orthopedic surgery, the aim of this study was an evaluation of the biological effects of zirconia-stabilized yttria on bone healing, using an in vivo model. Nano-hydroxyapatite powder with zirconia-stabilized yttria were inserted in rabbit tibia and then histologically analyzed and compared with non-treated controls so thirty six. New Zealand white male rabbits randomly divided into two groups of 18 rabbits each. A cortical hole of 4 mm diameter and 8 mm depth in each tibia was drilled. In group I, the defect was left empty, whereas in group II, the bone defect was packed with nano-hydroxyapatite/5% zirconia stabilized with yttria. Histological evaluations were performed at two, four and six weeks after the implantation. Microscopic changes on two groups along with the time course were scored and statistical analysis showed that the average scores in group II were significantly higher than the other groups (p < 0.05). Histological analysis was shown to be significantly improved by the nano-hydroxyapatite/5% zirconia stabilized with yttria compared with the control group, suggesting that this biomaterial promote the healing of cortical bone, presumably by acting as an osteoconductive.

  7. Effect of thrombin peptide 508 (TP508) on bone healing during distraction osteogenesis in rabbit tibia.

    PubMed

    Amir, Lisa R; Li, Gang; Schoenmaker, Ton; Everts, Vincent; Bronckers, Antonius L J J

    2007-10-01

    Thrombin-related peptide 508 (TP508) accelerates bone regeneration during distraction osteogenesis (DO). We have examined the effect of TP508 on bone regeneration during DO by immunolocalization of Runx2 protein, a marker of osteoblast differentiation, and of osteopontin (OPN) and bone sialoprotein (BSP), two late markers of the osteoblast lineage. Distraction was performed in tibiae of rabbits over a period of 6 days. TP508 (30 or 300 microg) or vehicle was injected into the distraction gap at the beginning and end of the distraction period. Two weeks after active distraction, tissue samples were harvested and processed for immunohistochemical analysis. We also tested the in vitro effect of TP508 on Runx2 mRNA expression in osteoblast-like (MC3T3-E1) cells by polymerase chain reaction analysis. Runx2 and OPN protein were observed in preosteoblasts, osteoblasts, osteocytes of newly formed bone, blood vessel cells and many fibroblast-like cells of the soft connective tissue. Immunostaining for BSP was more restricted to osteoblasts and osteocytes. Significantly more Runx2- and OPN-expressing cells were seen in the group treated with 300 microg TP508 than in the control group injected with saline or with 30 microg TP508. However, TP508 failed to increase Runx2 mRNA levels significantly in MC3T3-E1 cells after 2-3 days of exposure. Our data suggest that TP508 enhances bone regeneration during DO by increasing the proportion of cells of the osteoblastic lineage. Clinically, TP508 may shorten the healing time during DO; this might be of benefit when bone regeneration is slow.

  8. Targeting Epithelial Cell Migration to Accelerate Wound Healing

    DTIC Science & Technology

    2012-02-01

    consisting of the proteins Rsu1, Integrin Linked Kinase (ILK), PINCH, and Parvin. The correct association of these proteins in a functional complex...impacting integrin function and actin polymerization. 15. SUBJECT TERMS Wound healing, cell migration, protein kinase C, protein kinase A 16. SECURITY...epithelial cell migration in wound healing. In addition, the correct association of these proteins in a functional complex depends on their phosphorylation

  9. Matrix Metalloproteinase-3 Accelerates Wound Healing following Dental Pulp Injury

    PubMed Central

    Zheng, Li; Amano, Kazuharu; Iohara, Koichiro; Ito, Masataka; Imabayashi, Kiyomi; Into, Takeshi; Matsushita, Kenji; Nakamura, Hiroshi; Nakashima, Misako

    2009-01-01

    Matrix metalloproteinases (MMPs) are implicated in a wide range of physiological and pathological processes, including morphogenesis, wound healing, angiogenesis, inflammation, and cancer. Angiogenesis is essential for reparative dentin formation during pulp wound healing. The mechanism of angiogenesis, however, still remains unclear. We hypothesized that certain MMPs expressed during pulp wound healing may support recovery processes. To address this issue, a rat pulp injury model was established to investigate expression of MMPs during wound healing. Real-time RT-PCR analysis showed that expression MMP-3 and MMP-9 (albeit lower extent) was up-regulated at 24 and 12 hours after pulp injury, respectively, whereas expression of MMP-2 and MMP-14 was not changed. MMP-3 mRNA and protein were localized in endothelial cells and/or endothelial progenitor cells in injured pulp in vivo. In addition, MMP-3 enhanced proliferation, migration, and survival of human umbilical vein endothelial cells in vitro. Furthermore, the topical application of MMP-3 protein on the rat-injured pulp tissue in vivo induced angiogenesis and reparative dentin formation at significantly higher levels compared with controls at 24 and 72 hours after treatment, respectively. Inhibition of endogenous MMP-3 by N-Isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid resulted in untoward wound healing. These results provide suggestive evidence that MMP-3 released from endothelial cells and/or endothelial progenitor cells in injured pulp plays critical roles in angiogenesis and pulp wound healing. PMID:19834065

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

    PubMed

    Argyros, George C; Roth, Aaron J

    2016-09-01

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

  11. The immunosuppressive effect of Siglecs on tendon-bone healing after ACL reconstruction.

    PubMed

    Hu, Jiang; Yao, Bin; Yang, Xiao; Ma, Fang

    2015-01-01

    The quality of the bone-tendon healing is very important to the surgery outcome after anterior cruciate ligament reconstruction. The necrosis of autograft and local new blood vessels occur after the surgery. The fibroblasts and mesenchymal cells presenting in the tendon-bone interface as well as the infiltrated of neutrophils and macrophages improve the biomechanical properties of the healing. We hypothesize that immunosuppressive effect of Siglecs which present on the surface of neutrophils and macrophages play the important roles to regulate acute local inflammatory reaction, maintain the physiological environment and induce the differentiation of the pluripotent cells to form the accepted histologic structure healing of the tendon-bone interface. It might be helpful to understand the mechanism of tendon-bone healing.

  12. 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

    2015-12-08

    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.

  13. 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

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

    PubMed Central

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

    2017-01-01

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

  15. 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.

  16. Electrical Stimulation in Bone Healing: Critical Analysis by Evaluating Levels of Evidence

    PubMed Central

    Griffin, Michelle; Bayat, Ardeshir

    2011-01-01

    Objectives: Direct current, capacitive coupling, and inductive coupling are modes of electrical stimulation (ES) used to enhance bone healing. It is important to assess the effectiveness of ES for bone healing to ensure optimization for clinical practice. This review aims to examine the level of evidence (LOE) for the application of ES to enhance bone healing and investigate the proposed mechanism for its stimulatory effect. Methods: MEDLINE and EMBASE searches were conducted to identify clinical and in vitro studies utilizing ES for bone healing since 1959. A total of 105 clinical studies and 35 in vitro studies were evaluated. Clinical studies were assigned LOE according to Oxford Centre for Evidence Based Medicine (LOE-1, highest; LOE-5, lowest). Results: Direct current was found to be effective in enhancing bone healing in spinal fusion but only LOE-4 supported its use for nonunions. Eleven studies were retrieved for capacitive coupling with LOE-1 demonstrating its effectiveness for treating nonunions. The majority of studies utilized inductive coupling with LOE-1 supporting its application for healing osteotomies and nonunions. In vitro studies demonstrate that ES enhances bone healing by changes in growth factors and transmembrane signaling although no clear mechanism has been defined. Conclusion: Overall, the studies, although in favor of ES application in bone repair, displayed variability in treatment regime, primary outcome measures, follow-up times, and study design, making critical evaluation and assessment difficult. Electrical stimulation shows promise in enhancement of bone healing; however, better-designed clinical studies will enable the optimization for clinical practice. PMID:21847434

  17. Enhanced Healing of Segmental Bone Defects by Modulation of the Mechanical Environment

    DTIC Science & Technology

    2013-10-01

    AE, Kenwright J. The influence of induced micromovement upon the healing of experimental tibial fractures. J Bone Joint Surg Br 1985;67-4:650-5. 4...Kenwright J, Goodship AE. Controlled mechanical stimulation in the treatment of tibial fractures. Clin Orthop Relat Res 1989-241:36-47. 5. Perren...7. Larsson S, Kim W, Caja VL, Egger EL, Inoue N, Chao EY. Effect of early axial dynamization on tibial bone healing: a study in dogs. Clin Orthop

  18. Bone healing of commercial oral implants with RGD immobilization through electrodeposited poly(ethylene glycol) in rabbit cancellous bone.

    PubMed

    Park, Jin-Woo; Kurashima, Kazuya; Tustusmi, Yusuke; An, Chang-Hyeon; Suh, Jo-Young; Doi, Hisashi; Nomura, Naoyuki; Noda, Kazuhiko; Hanawa, Takao

    2011-08-01

    Immobilization of RGD peptides on titanium (Ti) surfaces enhances implant bone healing by promoting early osteoblastic cell attachment and subsequent differentiation by facilitating integrin binding. Our previous studies have demonstrated the efficacy of RGD peptide immobilization on Ti surfaces through the electrodeposition of poly(ethylene glycol) (PEG) (RGD/PEG/Ti), which exhibited good chemical stability and bonding. The RGD/PEG/Ti surface promoted differentiation and mineralization of pre-osteoblasts. This study investigated the in vivo bone healing capacity of the RGD/PEG/Ti surface for biomedical application as a more osteoconductive implant surface in dentistry. The RGD/PEG/Ti surface was produced on an osteoconductive implant surface, i.e. the grit blasted micro-rough surface of a commercial oral implant. The osteoconductivity of the RGD/PEG/Ti surface was compared by histomorphometric evaluation with an RGD peptide-coated surface obtained by simple adsorption in rabbit cancellous bone after 2 and 4 weeks healing. The RGD/PEG/Ti implants displayed a high degree of direct bone apposition in cancellous bone and achieved greater active bone apposition, even in areas of poor surrounding bone. Significant increases in the bone to implant contact percentage were observed for RGD/PEG/Ti implants compared with RGD-coated Ti implants obtained by simple adsorption both after 2 and 4 weeks healing (P<0.05). These results demonstrate that RGD peptide immobilization on a Ti surface through electrodeposited PEG may be an effective method for enhancing bone healing with commercial micro-rough surface oral implants in cancellous bone by achieving rapid bone apposition on the implant surface.

  19. Small molecule GS-nitroxide ameliorates ionizing irradiation-induced delay in bone wound healing in a novel murine model.

    PubMed

    Gokhale, Abhay; Rwigema, Jean-Claude; Epperly, Michael W; Glowacki, Julie; Wang, Hong; Wipf, Peter; Goff, Julie P; Dixon, Tracy; Patrene, Ken; Greenberger, Joel S

    2010-01-01

    We studied radioprotection and mitigation by mitochondrial-targeted Tempol (GS-nitroxide, JP4-039), in a mouse injury/irradiation model of combined injury (fracture/irradiation). Right hind legs of control C57BL/6NHsd female mice, mice pretreated with MnSOD-PL, JP4-039, or with amifostine were irradiated with single and fractionated doses of 0 to 20 Gy. Twenty-four hours later, unicortical holes were drilled into the tibiae of both hind legs; at intervals, tibias were excised, radiographed, and processed for histology. Bone wounds irradiated to 20 or 30 Gy showed delayed healing at 21 to 28 days. Treatment with JP4-039 MnSOD-PL or amifostine, before or after single fraction 20 Gy or during fractionated irradiation followed by drilling accelerated wound healing at days 21 and 28. Orthotopic 3LL tumors were not protected by JP4-039 or amifostine. In nonirradiated mice, pretreatment with JP4-039 accelerated bone wound healing. This test system should be useful for the development of new small molecule radioprotectors.

  20. Small Molecule GS-Nitroxide Ameliorates Ionizing Irradiation-Induced Delay in Bone Wound Healing in a Novel Murine Model

    PubMed Central

    Gokhale, Abhay; Rwigema, Jean-Claude; Epperly, Michael; Glowacki, Julie; Wang, Hong; Wipf, Peter; Goff, Julie P.; Dixon, Tracy; Patrene, Ken; Greenberger, Joel S.

    2010-01-01

    We studied radioprotection and mitigation by mitochondrial-targeted Tempol (GS-nitroxide, JP4-039), in a mouse injury/irradiation model of combined injury (fracture/irradiation). Right hind legs of control C57BL/6NHsd female mice, mice pretreated with MnSOD-PL, JP4-039, or with amifostine were irradiated with single and fractionated doses of 0 to 20 Gy. Twenty-four hours later, unicortical holes were drilled into the tibiae of both hind legs; at intervals, tibias were excised, radiographed, and processed for histology. Bone wounds irradiated to 20 or 30 Gy showed delayed healing at 21 to 28 days. Treatment with JP4-039 MnSOD-PL or amifostine, before or after single fraction 20 Gy or during fractionated irradiation followed by drilling accelerated wound healing at days 21 and 28. Orthotopic 3LL tumors were not protected by JP4-039 or amifostine. In nonirradiated mice, pretreatment with JP4-039 accelerated bone wound healing. This test system should be useful for the development of new small molecule radioprotectors. PMID:20668303

  1. 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

  2. Accelerated wound healing with combined NPWT and IPC: a case series.

    PubMed

    Arvesen, Kristian; Nielsen, Camilla Bak; Fogh, Karsten

    2017-03-01

    Negative pressure wound therapy (NPWT) and intermittent pneumatic compression (IPC) have traditionally been used in patients with chronic complicated non-healing wounds. The aim of this study (retrospective case series) was to describe the use of NPWT in combination with IPC in patients with a relatively short history (2-6 months) of ulcers. All wounds showed improved healing during the treatment period with marked or moderate reduction in ulcer size, and granulation tissue formation was markedly stimulated. Oedema was markedly reduced due to IPC. Treatment was generally well tolerated. The results of this study indicate that combined NPWT and IPC can accelerate wound healing and reduce oedema, thus shortening the treatment period. Therefore, patients may have a shorter healing period and may avoid entering a chronic wound phase. However, controlled studies of longer duration are needed in order to show the long-term effect of a more accelerated treatment course.

  3. The Effect of Orthognathic Surgery on Osteoprotegerin as Immunological Caliper of Bone Healing

    PubMed Central

    Soliman, Sara; Ahmed, Mamdouh

    2016-01-01

    BACKGROUND: Osteoprotegerin (OPG) is considered to be the cytokine that plays an important role in the healing process. OPG regulates bone cell biology, osteoblast–osteoclast, bone-immune cross-talk and maintenance of bone mass. It plays an important role in the development, induction, and repair of bone. Orthognathic surgery as multiples segmental osteotomies has been taken as a model surgery to assess the changes in osteoprotegerin levels in the post-operative bone healing period. AIM: The aim of the study was to evaluate OPG as immunological caliper of bone healing. MATERIAL AND METHODS: OPG was evaluated in nine patients seeking orthognathic surgery. Patients were examined and checked to be medically and immunologically free prior to surgery. Blood samples were collected immediate pre-operative as control group and for six weeks post-operative as study group. RESULTS: Data were collected from nine consecutive patients. The results showed higher levels of OPG. it showed significant increase in the immediate post-operative value (p = 0.001) which started to increase gradually during the six weeks (p < 0.001). CONCLUSIONS: Significant higher levels of OPG during the healing period of orthognathic surgery suggest the its use as immunological caliper of bone healing. PMID:28028419

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

    PubMed Central

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

    2012-01-01

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

  5. Effect of steroidal saponins-loaded nano-bioglass/phosphatidylserine/collagen bone substitute on bone healing.

    PubMed

    Yang, Chunrong; Wu, Huazhong; Wang, Jianhua

    2016-11-10

    The objective of this study was to investigate the therapeutic potential of nano-bioglass/phosphatidylserine/collagen (nBG/PS/COL) scaffolds loaded with steroidal saponins as an inducer factor for skeletal defects. The drugs-encapsulated bone substitute was prepared by loading steroidal saponins-collagen microsphere suspension in nano-bioglass and phosphatidylserine (PS) composite. The scaffolds possess an interconnected porous structure with a porosity of about 82.3%. The pore size ranges from several micrometers up to about 400 μm. The drug release assays showed the long-term sustained release of steroidal saponins from the scaffolds with effective and safe bioactivity. Moreover, in vitro and in vivo studies showed that the involvement of steroidal saponins contributed to the secretion of nerve growth factor (NGF) in MC3T3-E1 cells, which may be the possible factor that greatly enhanced bone healing. The results suggest that the bone substitute is an effective implantable drug-delivery system for use in bone repair.

  6. N-Acetylcysteine accelerates amputation stump healing in the setting of diabetes.

    PubMed

    Zayed, Mohamed A; Wei, Xiachao; Park, Kyoung-Mi; Belaygorod, Larisa; Naim, Uzma; Harvey, Joseph; Yin, Li; Blumer, Kendall; Semenkovich, Clay F

    2017-03-09

    Over 60% of lower extremity amputations are performed in patients with diabetes and peripheral arterial disease, and at least 25% require subsequent reamputation due to poor surgical site healing. The mechanisms underlying poor amputation stump healing in the setting of diabetes are not understood. N-acetylcysteine (NAC) is known to promote endothelial cell function and angiogenesis and may have therapeutic benefits in the setting of diabetes. We tested the hypothesis that NAC alters the vascular milieu to improve healing of amputation stumps in diabetes using a novel in vivo murine hindlimb ischemia-amputation model. Amputation stump tissue perfusion and healing were evaluated in C57BL/6J adult mice with streptozotocin-induced diabetes. Compared with controls, mice treated with daily NAC demonstrated improved postamputation stump healing, perfusion, adductor muscle neovascularization, and decreased muscle fiber damage. Additionally, NAC stimulated HUVEC migration and proliferation in a phospholipase C β-dependent fashion and decreased Gαq palmitoylation. Similarly, NAC treatment also decreased Gαq palmitoylation in ischemic and nonischemic hindlimbs in vivo In summary, we demonstrate that NAC accelerates healing of amputation stumps in the setting of diabetes and ischemia. The underlying mechanism appears to involve a previously unrecognized effect of NAC on Gαq palmitoylation and phospholipase C β-mediated signaling in endothelial cells.-Zayed, M. A., Wei, X., Park, K., Belaygorod, L., Naim, U., Harvey, J., Yin, L., Blumer, K., Semenkovich, C. F. N-acetylcysteine accelerates amputation stump healing in the setting of diabetes.

  7. Collagen scaffolds loaded with collagen-binding NGF-beta accelerate ulcer healing.

    PubMed

    Sun, Wenjie; Lin, Hang; Chen, Bing; Zhao, Wenxue; Zhao, Yannan; Xiao, Zhifeng; Dai, Jianwu

    2010-03-01

    Studies have shown that exogenous nerve growth factor (NGF) accelerates ulcer healing, but the inefficient growth factor delivery system limits its clinical application. In this report, we found that the native human NGF-beta fused with a collagen-binding domain (CBD) could form a collagen-based NGF targeting delivery system, and the CBD-fused NGF-beta could bind to collagen membranes efficiently. Using the rabbit dermal ischemic ulcer model, we have found that this targeting delivery system maintains a higher concentration and stronger bioactivity of NGF-beta on the collagen membranes by promoting peripheral nerve growth. Furthermore, it enhances the rate of ulcer healing through accelerating the re-epithelialization of dermal ulcer wounds and the formation of capillary lumens within the newly formed tissue area. Thus, collagen membranes loaded with collagen-targeting human NGF-beta accelerate ulcer healing efficiently.

  8. Bone-to-bone Fixation Enhances Functional Healing of the Porcine Anterior Cruciate Ligament Using a Collagen-Platelet Composite

    PubMed Central

    Murray, Martha M.; Magarian, Elise; Zurakowski, David; Fleming, Braden C.

    2010-01-01

    Purpose The purpose of this study was to determine if providing bony stabilization between the tibia and femur would improve the structural properties of an “enhanced” ACL repair using a collagen-platelet composite when compared to the traditional (Marshall) suture technique. Methods Twelve pigs underwent unilateral ACL transection and were treated with sutures connecting the bony femoral ACL attachment site to the distal ACL stump (LIGAMENT group), or to the tibia via a bone tunnel (TIBIA group). A collagen-platelet composite was placed around the sutures to enhance the biologic repair in both groups. Anteroposterior (AP) knee laxity and the graft structural properties were measured after 15 weeks of healing in both the ACL-repaired and contralateral ACL-intact joints. Results Enhanced ACL repair with bone-to-bone fixation significantly improved yield load and linear stiffness of the ACL repairs (p<0.05) after 15 weeks of healing. However, laxity values of the knees were similar in both groups of repaired knees (p>0.10). Conclusions Using an enhanced ACL suture repair technique that includes bone-to-bone fixation to protect the repair in the initial healing stages resulted in an ACL with improved structural properties after 15 weeks in the porcine model. Clinical Relevance The healing response of an ACL suture repair using a collagen-platelet composite can be enhanced by providing bony stabilization between the tibia and femur to protect the graft during the initial healing process in a translational model. PMID:20810092

  9. Bioglass as a carrier for reindeer bone protein extract in the healing of rat femur defect.

    PubMed

    Tölli, Hanna; Kujala, Sauli; Levonen, Katri; Jämsä, Timo; Jalovaara, Pekka

    2010-05-01

    Bioactive glasses have been developed as scaffolds for bone tissue engineering but combination with reindeer bone protein extract has not been evaluated. We investigated the effects of bone protein extract implants (5-40 mg dosages) with bioglass (BG) carrier on the healing of rat femur defects. Bioglass implants and untreated defects served as controls. All doses of extract increased bone formation compared with the control groups, and bone union was enhanced with doses of 10 mg or more. In comparison with untreated defect, mean cross-sectional bone area at the defect site was greater when implants with BG + 15 mg of extract or bioglass alone were used, bone density at the defect site was higher in all bioglass groups with and without bone extract, and the BG + 15 mg extract dosage marginally increased bone torsional stiffness in mechanical testing. Bioglass performed well as a carrier candidate for reindeer bone protein extract.

  10. Targeting Epithelial Cell Migration to Accelerate Wound Healing

    DTIC Science & Technology

    2010-12-01

    the protein kinase C (PKC) family and the process can be enhanced or inhibited by modulating the levels of the RIPP complex proteins as well by...HACAT cells indicates that PKC may modulate migration on two-dimensional surface. 15. SUBJECT TERMS Wound healing, cell migration, protein kinase C ...ABSTRACT U c . THIS PAGE U UU 11 19b. TELEPHONE NUMBER (include area code) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18

  11. Trabecular bone formation in the healing of the rodent molar tooth extraction socket.

    PubMed

    Devlin, H; Hoyland, J; Newall, J F; Ayad, S

    1997-12-01

    The aim of this study was to investigate the nature of the template structure on which trabecular bone formation occurs during healing of the rodent tooth extraction socket, a well studied bone healing system. The presence of collagen type II mRNA has previously been described in the healing socket, although the formation of the protein or cartilage has not been observed. However, recent evidence from developmental and other bone healing studies indicates that collagen type III may be important in forming the preliminary scaffold on which bone trabeculae are formed. The maxillary right molar teeth were removed from rats under general anaesthesia and the animals killed at various times afterward. The tissues were examined using histological, in situ hybridization, and immunohistochemical staining techniques. It was concluded that collagen type IIA mRNA was produced by osteoblast cells of the socket, but that collagen type II, if present, would account for less than 0.01% of the total proteins extracted. During bone formation, Sharpey's fibers were seen radiating from the peripheral bone toward the center of the socket. These optically active collagen fibers were inserted into the forming bone trabeculae and were recognized by antibodies raised against collagen type III. The arrangement and composition of these fibers therefore suggest that they form a preliminary framework on which deposition of woven bone trabeculae occurs.

  12. Healing of segmental bone defects with granular porous hydroxyapatite augmented with recombinant human osteogenic protein-1 or autologous bone marrow.

    PubMed

    den Boer, Frank C; Wippermann, Burkhard W; Blokhuis, Taco J; Patka, Peter; Bakker, Fred C; Haarman, Henk J Th M

    2003-05-01

    Hydroxyapatite is a synthetic bone graft, which is used for the treatment of bone defects and nonunions. However, it is a rather inert material with no or little intrinsic osteoinductive activity. Recombinant human osteogenic protein-1 (rhOP-1) is a very potent biological agent, that enhances osteogenesis during bone repair. Bone marrow contains mesenchymal stem cells, which are capable of new bone formation. Biosynthetic bone grafts were created by the addition of rhOP-1 or bone marrow to granular porous hydroxyapatite. The performance of these grafts was tested in a sheep model and compared to the results of autograft, which is clinically the standard treatment of bone defects and nonunions. A 3 cm segmental bone defect was made in the tibia and fixed with an interlocking intramedullary nail. There were five treatment groups: no implant (n=6), autograft (n=8), hydroxyapatite alone (n=8), hydroxyapatite loaded with rhOP-1 (n=8), and hydroxyapatite loaded with autologous bone marrow (n=8). At 12 weeks, healing of the defect was evaluated with radiographs, a torsional test to failure, and histological examination of longitudinal sections through the defect. Torsional strength and stiffness of the healing tibiae were about two to three times higher for autograft and hydroxyapatite plus rhOP-1 or bone marrow compared to hydroxyapatite alone and empty defects. The mean values of both combination groups were comparable to those of autograft. There were more unions in defects with hydroxyapatite plus rhOP-1 than in defects with hydroxyapatite alone. Although the differences were not significant, histological examination revealed that there was more often bony bridging of the defect in both combination groups and the autograft group than in the group with hydroxyapatite alone. Healing of bone defects, treated with porous hydroxyapatite, can be enhanced by the addition of rhOP-1 or autologous bone marrow. The results of these composite biosynthetic grafts are equivalent to

  13. 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.

  14. Evaluation of laser photobiomodulation on healing of bone defects grafted with bovine bone in diabetic rats

    NASA Astrophysics Data System (ADS)

    Paraguassú, Gardênia Matos; da Costa Lino, Maíra Doria Martinez; de Carvalho, Fabíola Bastos; Cangussu, Maria Cristina; Pinheiro, Antônio Luiz Barbosa; Ramalho, Luciana Maria Pedreira

    2012-09-01

    Previous studies have shown positive effects of Low Level Laser Therapy (LLLT) on the repair of bone defects, but there is a few that associates bone healing in the presence of a metabolic disorder such as Diabetes Mellitus, a systemic disorder associated to impair of the repair of different tissues. The aim of this study was to assess, histologically, the repair of surgical defects created in the femur of diabetic and non-diabetic rats treated or not with LLLT (λ780nm, 70mW, CW, o/˜0.4mm, 16J/cm2 per session) associated or not to the use of a biomaterial. Surgical tibial bone defects were created in 60 animals that were divided into 4 groups: Group B (non-diabetic + biomaterial); Group BL (non-diabetic + biomaterial + LLLT); Group BD (diabetic + biomaterial); Group BDL (diabetic + biomaterial + LLLT). The irradiated group received 16 J/cm2 per session divided into 4 points around the defect, being the first irradiation carried out immediately after surgery and repeated every 48h for 14 days. The animals were killed 15, 21 and 30 days after surgery. The specimens underwent a semi-quantitative analysis. The results showed inflammation more intense in the BD and BDL groups than in the B and BL groups in the period of 15 days (p = 0.02), however the cortical repair in the BDL group was below 25% in more than half of the specimens, while in the BD group, the repair was more than to 25% in all specimens. At 30 days, both osteoblastic activity and collagen deposition were significantly higher in the B group when compared to the BD group (p=0.04). Bone deposition was significantly higher in the BL group (p=0.023) than in BDL group. It is concluded that LLLT has a positive biomodulative effect in the early stages of the healing process of bone defects grafted with biomaterial in diabetic and non-diabetic rats.

  15. Effects of pre- and postoperative irradiation on the healing of bone grafts in the rabbit

    SciTech Connect

    Morales, M.J.; Marx, R.E.; Gottlieb, C.F.

    1987-01-01

    Healing of cellular bone grafts irradiated at various times in the postsurgical course was compared to the healing characteristics of bone grafts placed into already irradiated tissue and to controls of irradiated host mandible in a rabbit model. Physical graft consolidation was assessed by load stress characteristics and serial histologic examination. Results indicated that grafts placed into already irradiated tissues failed to form bone in both phases of expected regeneration resulting in structurally weakened and histologically deficient ossicles. Bone grafts irradiated after placement were tolerant of irradiation. Bone grafts irradiated after four weeks were found to be less affected by irradiation than those irradiated within the first four weeks, forming an ossicle structurally and histologically superior to that of bone ossicles developed from grafts placed into irradiated tissues.

  16. Mobilization of bone marrow mesenchymal stem cells in vivo augments bone healing in a mouse model of segmental bone defect.

    PubMed

    Kumar, Sanjay; Ponnazhagan, Selvarangan

    2012-04-01

    Although the number of mesenchymal stem cells (MSC) in the bone marrow is sufficient to maintain skeletal homeostasis, in osteopenic pathology, aggravated osteoclast activity or insufficient osteoblast numbers ensue, affecting normal bone remodeling. Most of the currently available therapies are anti-resorptive with limited osteogenic potential. Since mobilization of stem/progenitors from the BM is a prerequisite for their participation in tissue repair, amplification of endogenous stem cells may provide an alternative approach in these conditions. The present study determined the potential of MSC mobilization in vivo, using combinations of different growth factors with the CXCR4 antagonist, AMD3100, in a mouse model of segmental bone defect. Results indicated that among several factors tested IGF1 had maximum proliferative ability of MSC in vitro. Results of the in vivo studies indicated that the combination of IGF1 and AMD3100 provided significant augmentation of bone growth as determined by DXA, micro-CT and histomorphometry in mice bearing segmental fractures. Further, characterization of MSC isolated from mice treated with IGF1 and AMD3100 indicated Akt/PI3K, MEK1/2-Erk1/2 and smad2/3 as key signaling pathways mediating this effect. These data indicate the potential of in vivo stem cell mobilization as a novel alternative for bone healing.

  17. Arginine Silicate Inositol Complex Accelerates Cutaneous Wound Healing.

    PubMed

    Durmus, Ali Said; Tuzcu, Mehmet; Ozdemir, Oguzhan; Orhan, Cemal; Sahin, Nurhan; Ozercan, Ibrahim Hanifi; Komorowski, James Richard; Ali, Shakir; Sahin, Kazim

    2016-10-14

    Arginine silicate inositol (ASI) complex is a composition of arginine, silicon, and inositol that has been shown to have beneficial effects on vascular health. This study reports the effects of an ASI ointment on wound healing in rats. A full-thickness excision wound was created by using a disposable 5 mm diameter skin punch biopsy tool. In this placebo-controlled study, the treatment group's wound areas were covered by 4 or 10 % ASI ointments twice a day for 5, 10, or 15 days. The rats were sacrificed either 5, 10, or 15 days after the wounds were created, and biopsy samples were taken for biochemical and histopathological analysis. Granulation tissue appeared significantly faster in the ASI-treated groups than in the control groups (P < 0.05). The mean unhealed wound area was significantly smaller, and the mean percentage of total wound healing was significantly higher in ASI-treated wounds than in the control wounds. Hydroxyproline, collagen, and matrix metalloproteinases were measured in the granulated tissue and found to be affected. Inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), collagen, matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and various cytokines (TNF-α and IL-1β) measured in this study showed a significant fall in expression level in ASI-treated wounds. The results suggest that topical application of ASI ointment (especially 4 % concentration) has beneficial effects on the healing response of an excisional wound.

  18. The effect of muscle loading on flexor tendon-to-bone healing in a canine model.

    PubMed

    Thomopoulos, Stavros; Zampiakis, Emmanouil; Das, Rosalina; Silva, Matthew J; Gelberman, Richard H

    2008-12-01

    Previous tendon and ligament studies have demonstrated a role for mechanical loading in tissue homeostasis and healing. In uninjured musculoskeletal tissues, increased loading leads to an increase in mechanical properties, whereas decreased loading leads to a decrease in mechanical properties. The role of loading on healing tissues is less clear. We studied tendon-to-bone healing in a canine flexor tendon-to-bone injury and repair model. To examine the effect of muscle loading on tendon-to-bone healing, repaired tendons were either cut proximally (unloaded group) to remove all load from the distal phalanx repair site or left intact proximally (loaded group). All paws were casted postoperatively and subjected to daily passive motion rehabilitation. Specimens were tested to determine functional properties, biomechanical properties, repair-site gapping, and bone mineral density. Loading across the repair site led to improved functional and biomechanical properties (e.g., stiffness for the loaded group was 8.2 +/- 3.9 versus 5.1 +/- 2.5 N/mm for the unloaded group). Loading did not affect bone mineral density or gapping. The formation of a gap between the healing tendon and bone correlated with failure properties. Using a clinically relevant model of flexor tendon injury and repair, we found that muscle loading was beneficial to healing. Complete removal of load by proximal transection resulted in tendon-to-bone repairs with less range of motion and lower biomechanical properties compared to repairs in which the muscle-tendon-bone unit was left intact.

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

    PubMed

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

    2013-03-01

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

  20. Effect of Alendronate on Bone Formation during Tooth Extraction Wound Healing.

    PubMed

    Tanoue, R; Koi, K; Yamashita, J

    2015-09-01

    Alendronate (ALN) is an antiresorptive agent widely used for the treatment of osteoporosis. Its suppressive effect on osteoclasts has been extensively studied. However, the effect of ALN on bone formation is not as clear as its effect on resorption. The objective was to determine the effect of short-term ALN on bone formation and tooth extraction wound healing. Molar tooth extractions were performed in mice. ALN, parathyroid hormone (PTH), or saline (vehicle control) was administered. PTH was used as the bone anabolic control. Mice were euthanized at 3, 5, 7, 10, and 21 d after extractions. Hard tissue healing was determined histomorphometrically. Neutrophils and lymphatic and blood vessels were quantified to evaluate soft tissue healing. Gene expression in the wounds was assessed at the RNA level. Furthermore, the vossicle bone transplant system was used to verify findings from extraction wound analysis. Alkaline phosphatase (ALP) was visualized in the vossicles to assess osteoblast activity. ALN exhibited no negative effect on bone formation. In intact tibiae, ALN increased bone mass significantly more than PTH did. Consistently, significantly elevated osteoblast numbers were noted. In the extraction sockets, bone fill in the ALN-treated mice was equivalent to the control. Genes associated with bone morphogenetic protein signaling, such as bmp2, nog, and dlx5, were activated in the extraction wounds of the ALN-treated animals. Bone formation in vossicles was significantly enhanced in the ALN versus PTH group. In agreement with this, ALN upregulated ALP activity considerably in vossicles. Neutrophil aggregation and suppressed lymphangiogenesis were evident in the soft tissue at 21 d after extraction, although gross healing of extraction wounds was uneventful. Bone formation was not impeded by short-term ALN treatment. Rather, short-term ALN treatment enhanced bone formation. ALN did not alter bone fill in extraction sockets.

  1. Effect of Alendronate on Bone Formation during Tooth Extraction Wound Healing

    PubMed Central

    Tanoue, R.; Koi, K.

    2015-01-01

    Alendronate (ALN) is an antiresorptive agent widely used for the treatment of osteoporosis. Its suppressive effect on osteoclasts has been extensively studied. However, the effect of ALN on bone formation is not as clear as its effect on resorption. The objective was to determine the effect of short-term ALN on bone formation and tooth extraction wound healing. Molar tooth extractions were performed in mice. ALN, parathyroid hormone (PTH), or saline (vehicle control) was administered. PTH was used as the bone anabolic control. Mice were euthanized at 3, 5, 7, 10, and 21 d after extractions. Hard tissue healing was determined histomorphometrically. Neutrophils and lymphatic and blood vessels were quantified to evaluate soft tissue healing. Gene expression in the wounds was assessed at the RNA level. Furthermore, the vossicle bone transplant system was used to verify findings from extraction wound analysis. Alkaline phosphatase (ALP) was visualized in the vossicles to assess osteoblast activity. ALN exhibited no negative effect on bone formation. In intact tibiae, ALN increased bone mass significantly more than PTH did. Consistently, significantly elevated osteoblast numbers were noted. In the extraction sockets, bone fill in the ALN-treated mice was equivalent to the control. Genes associated with bone morphogenetic protein signaling, such as bmp2, nog, and dlx5, were activated in the extraction wounds of the ALN-treated animals. Bone formation in vossicles was significantly enhanced in the ALN versus PTH group. In agreement with this, ALN upregulated ALP activity considerably in vossicles. Neutrophil aggregation and suppressed lymphangiogenesis were evident in the soft tissue at 21 d after extraction, although gross healing of extraction wounds was uneventful. Bone formation was not impeded by short-term ALN treatment. Rather, short-term ALN treatment enhanced bone formation. ALN did not alter bone fill in extraction sockets. PMID:26124220

  2. Carbon nanohorns accelerate bone regeneration in rat calvarial bone defect.

    PubMed

    Kasai, Takao; Matsumura, Sachiko; Iizuka, Tadashi; Shiba, Kiyotaka; Kanamori, Takeshi; Yudasaka, Masako; Iijima, Sumio; Yokoyama, Atsuro

    2011-02-11

    A recent study showed that carbon nanohorns (CNHs) have biocompatibility and possible medical uses such as in drug delivery systems. It was reported that some kinds of carbon nanomaterials such as carbon nanotubes were useful for bone formation. However, the effect of CNHs on bone tissue has not been clarified. The purpose of this study was to evaluate the effect of CNHs on bone regeneration and their possible application for guided bone regeneration (GBR). CNHs dispersed in ethanol were fixed on a porous polytetrafluoroethylene membrane by vacuum filtration. Cranial defects were created in rats and covered by a membrane with/without CNHs. At two weeks, bone formation under the membrane with CNHs had progressed more than under that without CNHs and numerous macrophages were observed attached to CNHs. At eight weeks, there was no significant difference in the amount of newly formed bone between the groups and the appearance of macrophages was decreased compared with that at two weeks. Newly formed bone attached to some CNHs directly. These results suggest that macrophages induced by CNHs are related to bone regeneration. In conclusion, the present study indicates that CNHs are compatible with bone tissue and effective as a material for GBR.

  3. Carbon nanohorns accelerate bone regeneration in rat calvarial bone defect

    NASA Astrophysics Data System (ADS)

    Kasai, Takao; Matsumura, Sachiko; Iizuka, Tadashi; Shiba, Kiyotaka; Kanamori, Takeshi; Yudasaka, Masako; Iijima, Sumio; Yokoyama, Atsuro

    2011-02-01

    A recent study showed that carbon nanohorns (CNHs) have biocompatibility and possible medical uses such as in drug delivery systems. It was reported that some kinds of carbon nanomaterials such as carbon nanotubes were useful for bone formation. However, the effect of CNHs on bone tissue has not been clarified. The purpose of this study was to evaluate the effect of CNHs on bone regeneration and their possible application for guided bone regeneration (GBR). CNHs dispersed in ethanol were fixed on a porous polytetrafluoroethylene membrane by vacuum filtration. Cranial defects were created in rats and covered by a membrane with/without CNHs. At two weeks, bone formation under the membrane with CNHs had progressed more than under that without CNHs and numerous macrophages were observed attached to CNHs. At eight weeks, there was no significant difference in the amount of newly formed bone between the groups and the appearance of macrophages was decreased compared with that at two weeks. Newly formed bone attached to some CNHs directly. These results suggest that macrophages induced by CNHs are related to bone regeneration. In conclusion, the present study indicates that CNHs are compatible with bone tissue and effective as a material for GBR.

  4. Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice

    PubMed Central

    Marrotte, Eric J.; Chen, Dan-Dan; Hakim, Jeffrey S.; Chen, Alex F.

    2010-01-01

    Amputation as a result of impaired wound healing is a serious complication of diabetes. Inadequate angiogenesis contributes to poor wound healing in diabetic patients. Endothelial progenitor cells (EPCs) normally augment angiogenesis and wound repair but are functionally impaired in diabetics. Here we report that decreased expression of manganese superoxide dismutase (MnSOD) in EPCs contributes to impaired would healing in a mouse model of type 2 diabetes. A decreased frequency of circulating EPCs was detected in type 2 diabetic (db/db) mice, and when isolated, these cells exhibited decreased expression and activity of MnSOD. Wound healing and angiogenesis were markedly delayed in diabetic mice compared with normal controls. For cell therapy, topical transplantation of EPCs onto excisional wounds in diabetic mice demonstrated that diabetic EPCs were less effective than normal EPCs at accelerating wound closure. Transplantation of diabetic EPCs after MnSOD gene therapy restored their ability to mediate angiogenesis and wound repair. Conversely, siRNA-mediated knockdown of MnSOD in normal EPCs reduced their activity in diabetic wound healing assays. Increasing the number of transplanted diabetic EPCs also improved the rate of wound closure. Our findings demonstrate that cell therapy using diabetic EPCs after ex vivo MnSOD gene transfer accelerates their ability to heal wounds in a mouse model of type 2 diabetes. PMID:21060152

  5. Potential use of blood bank platelet concentrates to accelerate wound healing of diabetic ulcers.

    PubMed

    Han, Seung-Kyu; Kim, Deok-Woo; Jeong, Seong-Ho; Hong, Yong-Taek; Woo, Hong-Suh; Kim, Woo-Kyung; Gottrup, Finn

    2007-11-01

    Many clinical trials have shown the effectiveness of platelet releasates on diabetic wound healing, but large volumes of blood must be aspirated from patients and a platelet separator is required. This study was undertaken to investigate the potential of blood bank platelet concentrate (BBPC) for accelerating diabetic wound healing. Platelet-derived growth factor-BB (PDGF-BB) contents in BBPC were determined by enzyme-linked immunosorbent assay in vitro, and the in vivo study involved comparing extents of wound healing in BBPC-treated and control groups using diabetic mouse wound models. In the in vitro study, 5.2 +/- 1.2 pg of PDGF-BB was found to be released by 1 million platelets in fresh BBPC, and adding thrombin to BBPC significantly increased the levels of PDGF-BB released. Our in vivo study in diabetic mice revealed that BBPC treatment greatly accelerated wound healing. Our results suggest that BBPC has potential to accelerate the healing of diabetic ulcers.

  6. O-phospho-L-serine: a modulator of bone healing in calcium-phosphate cements.

    PubMed

    Mai, Ronald; Lux, Romy; Proff, Peter; Lauer, Günter; Pradel, Winnie; Leonhardt, Henry; Reinstorf, Antje; Gelinsky, Michael; Jung, Roland; Eckelt, Uwe; Gedrange, Tomasz; Stadlinger, Bernd

    2008-10-01

    Bone substitution materials are seen as an alternative to autogenous bone transplants in the reconstruction of human bone structures. The aim of the present animal study was to evaluate the clinical handling and the conditions of bone healing after the application of a phosphoserine and collagen-I-modified calcium-phosphate cement (Biozement D). The application of phosphoserine is supposed to influence the texture of the extracellular matrix. Standardised bone defects were created in the lower jaw of 10 adult minipigs. These defects were reconstructed with a pasty calcium-phosphate cement mixture. After a healing time of 4 months, the animals were sacrificed. The mandibles of all animals were resected and non-decalcified histological sections of the areas of interest were prepared. The experiment was evaluated by means of qualitative histology and histomorphometry. The hydroxyapatite cement entirely hardened intraoperatively. Modelling and handling of the cement was facile and the margin fit to the host bone was excellent. Histology showed that resorption started in the periphery and proceeded exceptionally fast. The bony substitution, especially in phosphoserine-endowed cements, was very promising. After a healing period of 4 months, phosphoserine cements showed a bone regeneration of nearly two-thirds of the defect sizes. In the applied animal experiment, the newly developed hydroxyapatite collagen-I cement is well suited for bone substitution due to its easy handling, its excellent integration and good resorption characteristics. The addition of phosphoserine is very promising in terms of influencing resorption features and bone regeneration.

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

    PubMed

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

    2014-09-22

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

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

    PubMed Central

    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. PMID:26230411

  9. Effect of cell-based VEGF gene therapy on healing of a segmental bone defect.

    PubMed

    Li, Ru; Stewart, Duncan J; von Schroeder, Herbert P; Mackinnon, Erin S; Schemitsch, Emil H

    2009-01-01

    Fracture healing requires coordinated coupling between osteogenesis and angiogenesis in which vascular endothelial growth factor (VEGF) plays a key role. We hypothesized that targeted over-expression of angiogenic and osteogenic factors within the fracture would promote bone healing by inducing development of new blood vessels and stimulating/affecting proliferation, survival, and activity of skeletal cells. Using a cell-based method of gene transfer, without viral vector, 5.0 x 10(6) fibroblasts transfected with VEGF were delivered to a 10-mm bone defect in rabbit tibiae (Group 1) (n = 9); control groups were treated with fibroblasts (Group 2) (n = 7), or saline (Group 3) (n = 7) only. After 12 weeks, eight tibial fractures healed in Group 1, compared to four each in Groups 2 and 3. In Group 1, ossification was seen across the entire defect; in Groups 2 and 3, the defects were fibrous and sparsely ossified. Group 1 had more positively stained (CD31) vessels than Groups 2 and 3. MicroCT 3-D showed complete bridging of the new bone for Group 1, but incomplete healing for Groups 2 and 3. MicroCT bone structural parameters showed significant differences between VEGF treatment and control groups (p < 0.05). These results indicate that the cell-based VEGF gene therapy has significant angiogenic and osteogenic effects to enhance healing of a segmental defect in the long bone of rabbits.

  10. 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

  11. Biafine topical emulsion accelerates excisional and burn wound healing in mice.

    PubMed

    Krausz, Aimee E; Adler, Brandon L; Landriscina, Angelo; Rosen, Jamie M; Musaev, Tagai; Nosanchuk, Joshua D; Friedman, Adam J

    2015-09-01

    Macrophages play a fundamental role in wound healing; therefore, employing a strategy that enhances macrophage recruitment would be ideal. It was previously suggested that the mechanism by which Biafine topical emulsion improves wound healing is via enhanced macrophage infiltration into the wound bed. The purpose of this study was to confirm this observation through gross and histologic assessments of wound healing using murine full-thickness excisional and burn wound models, and compare to common standards, Vaseline and silver sulfadiazine (SSD). Full-thickness excisional and burn wounds were created on two groups of 60 mice. In the excisional arm, mice were divided into untreated control, Biafine, and Vaseline groups. In the burn arm, mice were divided into untreated control, Biafine, and SSD groups. Daily treatments were administered and healing was measured over time. Wound tissue was excised and stained to appropriately visualize morphology, collagen, macrophages, and neutrophils. Collagen deposition was measured and cell counts were performed. Biafine enhanced wound healing in murine full-thickness excisional and burn wounds compared to control, and surpassed Vaseline and SSD in respective wound types. Biafine treatment accelerated wound closure clinically, with greater epidermal/dermal maturity, granulation tissue formation, and collagen quality and arrangement compared to other groups histologically. Biafine application was associated with greater macrophage and lower neutrophil infiltration at earlier stages of healing when compared to other study groups. In conclusion, Biafine can be considered an alternative topical therapy for full-thickness excisional and burn wounds, owing to its advantageous biologically based wound healing properties.

  12. Continuous delivery of stromal cell-derived factor-1 from alginate scaffolds accelerates wound healing.

    PubMed

    Rabbany, Sina Y; Pastore, Joseph; Yamamoto, Masaya; Miller, Tim; Rafii, Shahin; Aras, Rahul; Penn, Marc

    2010-01-01

    Proper wound diagnosis and management is an increasingly important clinical challenge and is a large and growing unmet need. Pressure ulcers, hard-to-heal wounds, and problematic surgical incisions are emerging at increasing frequencies. At present, the wound-healing industry is experiencing a paradigm shift towards innovative treatments that exploit nanotechnology, biomaterials, and biologics. Our study utilized an alginate hydrogel patch to deliver stromal cell-derived factor-1 (SDF-1), a naturally occurring chemokine that is rapidly overexpressed in response to tissue injury, to assess the potential effects SDF-1 therapy on wound closure rates and scar formation. Alginate patches were loaded with either purified recombinant human SDF-1 protein or plasmid expressing SDF-1 and the kinetics of SDF-1 release were measured both in vitro and in vivo in mice. Our studies demonstrate that although SDF-1 plasmid- and protein-loaded patches were able to release therapeutic product over hours to days, SDF-1 protein was released faster (in vivo K(d) 0.55 days) than SDF-1 plasmid (in vivo K(d) 3.67 days). We hypothesized that chronic SDF-1 delivery would be more effective in accelerating the rate of dermal wound closure in Yorkshire pigs with acute surgical wounds, a model that closely mimics human wound healing. Wounds treated with SDF-1 protein (n = 10) and plasmid (n = 6) loaded patches healed faster than sham (n = 4) or control (n = 4). At day 9, SDF-1-treated wounds significantly accelerated wound closure (55.0 +/- 14.3% healed) compared to nontreated controls (8.2 +/- 6.0%, p < 0.05). Furthermore, 38% of SDF-1-treated wounds were fully healed at day 9 (vs. none in controls) with very little evidence of scarring. These data suggest that patch-mediated SDF-1 delivery may ultimately provide a novel therapy for accelerating healing and reducing scarring in clinical wounds.

  13. Histomorphological characteristics of accelerated healing of acetate ulcers under the effect of glyprolines.

    PubMed

    Trufanova, A V; Baglikova, K E; Bakaeva, Z V; Samonina, G E; Guseva, A A

    2007-08-01

    Glyprolines (PGP, GPG, GPGP, PGPGP, and GPGPGP) modulated histomorphological characteristics of acetate ulcers. They accelerated healing of acetate ulcers, promote complete differentiation of the surface epithelium and glands in the gastric mucosa, contributed to the appearance of a considerable number of fibroblasts at the site of the regenerating mucosa, and significantly decreased the count of macrophages.

  14. The effect of muscle loading on flexor tendon-to-bone healing in a canine model

    PubMed Central

    Thomopoulos, Stavros; Zampiakis, Emmanouil; Das, Rosalina; Silva, Matthew J.; Gelberman, Richard H.

    2008-01-01

    SUMMARY Previous tendon and ligament studies demonstrated a role for mechanical loading in tissue homeostasis and healing. In uninjured musculoskeletal tissues, increased loading leads to an increase in mechanical properties, while decreased loading leads to a decrease in properties. The role of loading on healing tissues is less clear. We studied tendon-to-bone healing in a canine flexor tendon-to-bone injury and repair model. To examine the effect of muscle loading on healing, repaired tendons were either cut proximally to remove all load from the distal phalanx repair site (unloaded group) or left intact proximally (loaded group). All paws were cast post-operatively and subjected to daily passive motion rehabilitation. Specimens were tested to determine functional properties, biomechanical properties, repair-site gapping, and bone mineral density. Loading across the repair site led to improved functional and biomechanical properties (e.g., stiffness for the loaded group was 8.2 ± 3.9 vs. 5.1 ± 2.5 N/mm for the unloaded group). Loading did not affect bone mineral density or gapping. The formation of a gap between the healing tendon and bone correlated with failure properties. Using a clinically relevant model of flexor tendon injury and repair, we found that muscle loading was beneficial to healing. Complete removal of load by proximal transection resulted in tendon-to-bone repairs with less range of motion and lower biomechanical properties compared to repairs in which the muscle-tendon-bone unit was left intact. PMID:18524009

  15. 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.

  16. 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.

  17. Bioceramic Implant Induces Bone Healing of Cranial Defects.

    PubMed

    Engstrand, Thomas; Kihlström, Lars; Lundgren, Kalle; Trobos, Margarita; Engqvist, Håkan; Thomsen, Peter

    2015-08-01

    Autologous bone or inert alloplastic materials used in cranial reconstructions are techniques that are associated with resorption, infection, and implant exposure. As an alternative, a calcium phosphate-based implant was developed and previously shown to potentially stimulate bone growth. We here uncover evidence of induced bone formation in 2 patients. Histological examination 9 months postoperatively showed multinuclear cells in the central defect zone and bone ingrowth in the bone-implant border zone. An increased expression of bone-associated markers was detected. The other patient was investigated 50 months postoperatively. Histological examination revealed ceramic materials covered by vascularized compact bone. The bone regenerative effect induced by the implant may potentially improve long-term clinical outcome compared with conventional techniques, which needs to be verified in a clinical study.

  18. The effect of three hemostatic agents on early bone healing in an animal model

    PubMed Central

    2010-01-01

    Background Resorbable bone hemostasis materials, oxidized regenerated cellulose (ORC) and microfibrillar collagen (MFC), remain at the site of application for up to 8 weeks and may impair osteogenesis. Our experimental study compared the effect of a water-soluble alkylene oxide copolymer (AOC) to ORC and MFC versus no hemostatic material on early bone healing. Methods Two circular 2.7 mm non-critical defects were made in each tibia of 12 rabbits. Sufficient AOC, ORC or MFC was applied to achieve hemostasis, and effectiveness recorded. An autologous blood clot was applied to control defects. Rabbits were sacrificed at 17 days, tibiae excised and fixed. Bone healing was quantitatively measured by micro-computed tomography (micro-CT) expressed as fractional bone volume, and qualitatively assessed by histological examination of decalcified sections. Results Hemostasis was immediate after application of MFC and AOC, after 1-2 minutes with ORC, and >5 minutes for control. At 17 days post-surgery, micro-CT analysis showed near-complete healing in control and AOC groups, partial healing in the ORC group and minimal healing in the MFC group. Fractional bone volume was 8 fold greater in the control and AOC groups than in the MFC group (0.42 ± 0.06, 0.40 ± 0.03 vs 0.05 ± 0.01, P < 0.001) and over 1.5-fold greater than in the ORC group (0.25 ± 0.03, P < 0.05). By histology, MFC remained at the application site with minimal healing at the defect margins and early fibrotic tissue within the defect. ORC-treated defects showed partial healing but with early fibrotic tissue in the marrow space. Conversely, control and AOC-treated defects demonstrated newly formed woven bone rich in cellular activity with no evidence of AOC remaining at the application site. Conclusions Early healing appeared to be impaired by the presence of MFC and impeded by the presence of ORC. In contrast, AOC did not inhibit bone healing and suggest that AOC may be a better bone hemostatic material for

  19. Present status and future potential of enhancing bone healing using nanotechnology.

    PubMed

    Stylios, George; Wan, Taoyu; Giannoudis, Peter

    2007-03-01

    An overview of the current state of tissue engineering material systems used in bone healing is presented. A variety of fabrication processes have been developed that have resulted in porous implant substrates that can address unresolved clinical problems. The merits of these biomaterial systems are evaluated in the context of the mechanical properties and biomedical performances most suitable for bone healing. An optimal scaffold for bone tissue engineering applications should be biocompatible and act as a 3D template for in vitro and in vivo bone growth; in addition, its degradation products should be non-toxic and easily excreted by the body. To achieve these features, scaffolds must consist of an interconnected porous network of micro- and nanoscale to allow extensive body fluid transport through the pores, which will trigger bone ingrowth, cell migration, tissue ingrowth, and eventually vascularization.

  20. Residual (ghost) sockets in bisphosphonate use--evidence of poor healing and slow bone turnover.

    PubMed

    Shetty, Kishore; Bouquot, J

    2009-01-01

    Patients taking bisphosphonate drug therapy have demonstrated extremely poor alveolar bone healing after relatively minor oral surgical procedures. It would seem logical that extraction sockets could remain visible radiographically for an extended period after surgery, even in cases with soft tissue healing. This article chronicles the case of a patient who had been taking zoledronic acid chronically for metastatic cancer and who demonstrated numerous residual sockets (also known as ghost sockets), with lamina dura outlines that were visible radiographically.

  1. Bone marrow-derived cells serve as proangiogenic macrophages but not endothelial cells in wound healing.

    PubMed

    Okuno, Yuji; Nakamura-Ishizu, Ayako; Kishi, Kazuo; Suda, Toshio; Kubota, Yoshiaki

    2011-05-12

    Bone marrow-derived cells (BMDCs) contribute to postnatal vascular growth by differentiating into endothelial cells or secreting angiogenic factors. However, the extent of their endothelial differentiation highly varies according to the angiogenic models used. Wound healing is an intricate process in which the skin repairs itself after injury. As a process also observed in cancer progression, neoangiogenesis into wound tissues is profoundly involved in this healing process, suggesting the contribution of BMDCs. However, the extent of the differentiation of BMDCs to endothelial cells in wound healing is unclear. In this study, using the green fluorescent protein-bone marrow chim-eric experiment and high resolution confocal microscopy at a single cell level, we observed no endothelial differentiation of BMDCs in 2 acute wound healing models (dorsal excisional wound and ear punch) and a chronic wound healing model (decubitus ulcer). Instead, a major proportion of BMDCs were macrophages. Indeed, colony-stimulating factor 1 (CSF-1) inhibition depleted approximately 80% of the BMDCs at the wound healing site. CSF-1-mutant (CSF-1(op/op)) mice showed significantly reduced neoangiogenesis into the wound site, supporting the substantial role of BMDCs as macrophages. Our data show that the proangiogenic effects of macrophages, but not the endothelial differentiation, are the major contribution of BMDCs in wound healing.

  2. 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

  3. The effect of ultrasound on the healing of muscle-pediculated bone graft in scaphoid non-union.

    PubMed

    Ricardo, Monreal

    2006-04-01

    The use of pedicled vascularised bone grafts from the distal radius makes it possible to transfer bone with a preserved circulation and viable osteoclasts and osteoblasts. Experiments performed at the basic science level has provided substantial evidence that low-intensity ultrasound can accelerate and augment the fracture healing process. Only an adequate double-blind trial comparing treatment by ultrasound stimulation in patients treated by similar surgical techniques can provide evidence of the true effect of ultrasound. This paper describes the results of such a trial. From 1999 to 2004, 21 fractures of the scaphoid with established non-union treated with vascularised pedicle bone graft were selected for inclusion in a double-blind trial. All patients were males, with an average age of 26.7 years (range 17-42 years) and an average interval between injury and surgery of 38.4 months (range 3 months-10 years). Low-intensity ultrasound was delivered using a TheraMed 101-B bone-growth stimulator (30 mW/cm2, 20 min/day), which was modified to accomplish double-blinding. These modifications did not affect the designated active units. The placebo units were adjusted to give no ultrasound signal output across the transducer. Externally, all units appeared identical but were marked with individual code numbers. Patients were randomly allocated to either an active or placebo stimulation. Follow-up averaged 2.3 years (range 1-4 years). All patients achieved fracture union (active and placebo groups), but compared with the placebo device (11 patients), the active device (ten patients) accelerated healing by 38 days (56+/-3.2 days compared with 94+/-4.8 days, p<0.0001, analysis of variance).

  4. Coating with a Modular Bone Morphogenetic Peptide Promotes Healing of a Bone-Implant Gap in an Ovine Model

    PubMed Central

    Lu, Yan; Lee, Jae Sung; Nemke, Brett; Graf, Ben K.; Royalty, Kevin; Illgen, Richard; Vanderby, Ray; Markel, Mark D.; Murphy, William L.

    2012-01-01

    Despite the potential for growth factor delivery strategies to promote orthopedic implant healing, there is a need for growth factor delivery methods that are controllable and amenable to clinical translation. We have developed a modular bone growth factor, herein termed “modular bone morphogenetic peptide (mBMP)”, which was designed to efficiently bind to the surface of orthopedic implants and also stimulate new bone formation. The purpose of this study was to coat a hydroxyapatite-titanium implant with mBMP and evaluate bone healing across a bone-implant gap in the sheep femoral condyle. The mBMP molecules efficiently bound to a hydroxyapatite-titanium implant and 64% of the initially bound mBMP molecules were released in a sustained manner over 28 days. The results demonstrated that the mBMP-coated implant group had significantly more mineralized bone filling in the implant-bone gap than the control group in C-arm computed tomography (DynaCT) scanning (25% more), histological (35% more) and microradiographic images (50% more). Push-out stiffness of the mBMP group was nearly 40% greater than that of control group whereas peak force did not show a significant difference. The results of this study demonstrated that mBMP coated on a hydroxyapatite-titanium implant stimulates new bone formation and may be useful to improve implant fixation in total joint arthroplasty applications. PMID:23185610

  5. Bioimaging assessment and effect of skin wound healing using bone-marrow-derived mesenchymal stromal cells with the artificial dermis in diabetic rats.

    PubMed

    Inoue, Hirokazu; Murakami, Takashi; Ajiki, Takashi; Hara, Mayumi; Hoshino, Yuichi; Kobayashi, Eiji

    2008-01-01

    We investigate the relationship between the fate and healing effect of transplanted mesenchymal stromal cells (MSCs) in a rat diabetic skin wound model. Rats are treated with streptozotocin to induce diabetic conditions. A full-thickness skin defect is surgically made on the head of diabetic rats, and covered with an artificial dermis impregnated with either bone marrow cells (BMCs) or bone-marrow-derived MSCs from firefly luciferase (luc) transgenic (Tg) rats. Wound healing is evaluated using planimetry and immunohistochemistry, and the fate of transplanted MSCs is determined using in-vivo luminescent imaging. The diabetic wound treated with MSCs-impregnated artificial dermis is significantly smaller than that treated with artificial dermis alone at 1 week postoperation. Photons of luc+ MSCs are detected at the transplanted site during healing (3 weeks), whereas those of luc+ MSCs are depleted only after 1 week postimplantation. Immunohistochemistry at the healing site treated with MSCs demonstrates that CD31+ vessels increase with expression of vascular endothelial growth factor, suggesting that MSCs accelerate angiogenesis. These findings suggest that transplanted MSCs could be retained at wound sites during the healing process in a diabetic rat model, and subsequently promote wound healing through angiogenesis.

  6. Monitoring the healing process of rat bones using Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Gamulin, O.; Serec, K.; Bilić, V.; Balarin, M.; Kosović, M.; Drmić, D.; Brčić, L.; Seiwerth, S.; Sikirić, P.

    2013-07-01

    The healing effect of BPC 157 on rat femoral head osteonecrosis was monitored by Raman spectroscopy. Three groups of rats were defined: an injured group treated with BPC 157 (10 μg/kg/daily ip), an injured control group (treated with saline, 5 ml/kg/daily ip), and an uninjured healthy group. The spectra were recorded and the healing effect assessed on samples harvested from animals which were sacrificed 3 and 6 weeks after being injured. The statistical analysis of the recorded spectra showed statistical differences between the BPC 157-treated, control, and healthy groups of animals. In particular, after 6 weeks the spectral resemblance between the healthy and BPC 157 samples indicated a positive BPC 157 influence on the healing process of rat femoral head.

  7. 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.

  8. A synthetic uric acid analog accelerates cutaneous wound healing in mice.

    PubMed

    Chigurupati, Srinivasulu; Mughal, Mohamed R; Chan, Sic L; Arumugam, Thiruma V; Baharani, Akanksha; Tang, Sung-Chun; Yu, Qian-Sheng; Holloway, Harold W; Wheeler, Ross; Poosala, Suresh; Greig, Nigel H; Mattson, Mark P

    2010-04-06

    Wound healing is a complex process involving intrinsic dermal and epidermal cells, and infiltrating macrophages and leukocytes. Excessive oxidative stress and associated inflammatory processes can impair wound healing, and antioxidants have been reported to improve wound healing in animal models and human subjects. Uric acid (UA) is an efficient free radical scavenger, but has a very low solubility and poor tissue penetrability. We recently developed novel UA analogs with increased solubility and excellent free radical-scavenging properties and demonstrated their ability to protect neural cells against oxidative damage. Here we show that the uric acid analog (6, 8 dithio-UA, but not equimolar concentrations of UA or 1, 7 dimethyl-UA) modified the behaviors of cultured vascular endothelial cells, keratinocytes and fibroblasts in ways consistent with enhancement of the wound healing functions of all three cell types. We further show that 6, 8 dithio-UA significantly accelerates the wound healing process when applied topically (once daily) to full-thickness wounds in mice. Levels of Cu/Zn superoxide dismutase were increased in wound tissue from mice treated with 6, 8 dithio-UA compared to vehicle-treated mice, suggesting that the UA analog enhances endogenous cellular antioxidant defenses. These results support an adverse role for oxidative stress in wound healing and tissue repair, and provide a rationale for the development of UA analogs in the treatment of wounds and for modulation of angiogenesis in other pathological conditions.

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

    PubMed

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

    2015-02-01

    In this study we investigated if Wnt/β-catenin signaling in mesenchymal progenitor cells plays a role in bone fracture repair and if DKK1-Ab promotes fracture healing through activation of β-catenin signaling. Unilateral open transverse tibial fractures were created in CD1 mice and in β-catenin(Prx1ER) conditional knockout (KO) and Cre-negative control mice (C57BL/6 background). Bone fracture callus tissues were collected and analyzed by radiography, micro-CT (μCT), histology, biomechanical testing and gene expression analysis. The results demonstrated that treatment with DKK1-Ab promoted bone callus formation and increased mechanical strength during the fracture healing process in CD1 mice. DKK1-Ab enhanced fracture repair by activation of endochondral ossification. The normal rate of bone repair was delayed when the β-catenin gene was conditionally deleted in mesenchymal progenitor cells during the early stages of fracture healing. DKK1-Ab appeared to act through β-catenin signaling to enhance bone repair since the beneficial effect of DKK1-Ab was abrogated in β-catenin(Prx1ER) conditional KO mice. Further understanding of the signaling mechanism of DKK1-Ab in bone formation and bone regeneration may facilitate the clinical translation of this anabolic agent into therapeutic intervention.

  10. 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

  11. Platelet derived growth factor secretion and bone healing after Er:YAG laser bone irradiation.

    PubMed

    Kesler, Gavriel; Shvero, Dana Kesler; Tov, Yariv Siman; Romanos, George

    2011-03-01

    Er:YAG laser irradiation has been reported to enhance wound healing. However, no studies have evaluated the synthesis of growth factors after laser irradiation. The present study investigated the effects of laser irradiation on the amount of secretion of platelet derived growth factor (PDGF) in the wound, clarifying the effects of the Er:YAG laser on the bone healing. Osteotomies were prepared in the tibiae of 28 rats using an Er:YAG laser (test group). Maximum power of 8 watts, energy per pulse of 700 mJ, and frequency up to 50 Hz were used. The laser was used with external water irrigation, a spot size of 2 mm, energy per pulse of 500 to 1000 mJ/pulse, and energy density of 32 J/cm(2). Twenty eight additional rats served as a control group and their osteotomies were prepared with a drill 1.3 mm in diameter at 1000 rpm, with simultaneous saline irrigation. Two rats from the tested group and 2 from the control group were sacrificed on each day following surgery (1-14 days), and the tissue specimens were prepared for histologic evaluation. Immunohistochemical staining with anti-PDGF was performed after histologic examination. The difference between the PDGF staining intensities of the 2 treatment groups was analyzed using a multivariate logistic regression test. A significant rise in PDGF staining occurred in both groups 2-3 days following surgery. However, while high PDGF counts remained for the 2-week experimental period in the laser group, PDGF levels in the control group returned to baseline levels 8 days post surgery. The 2 groups (laser and control) were found to be different throughout the experiment, and the rat type was found to be a significant predictor (P  =  .000011). The present study demonstrated that Er:YAG laser irradiation seems to stimulate the secretion of PDGF in osteotomy sites in a rat model. It is possible that the high levels of PDGF are part of the mechanism that Er:YAG irradiation enhances and improves the healing of

  12. Histomorphometric evaluation of the effect of systemic and topical ozone on alveolar bone healing following tooth extraction in rats.

    PubMed

    Erdemci, F; Gunaydin, Y; Sencimen, M; Bassorgun, I; Ozler, M; Oter, S; Gulses, A; Gunal, A; Sezgin, S; Bayar, G R; Dogan, N; Gider, I K

    2014-06-01

    The aim of this study was to investigate the effects of systemic and topical ozone applications on alveolar bone healing following tooth extraction. One hundred and twelve male Wistar rats were divided into eight groups of 14 rats each; seven groups were experimental (A-G) and one formed the control group (K). The experimental groups were further divided into two sub-groups, with seven rats in each - sacrificed on days 14 and 28 (subgroups 1 and 2). The maxillary right central incisors were extracted under general anaesthesia following the administration of local anaesthesia. After sacrifice, semi-serial histological sections were prepared, and mineralized and trabecular bone and osteoid and osteoblast surfaces were measured. Measurements of the trabecular bone showed statistically higher values in the groups treated with systemic ozone (D(2): 50.01 ± 2.12; E(2): 49.03 ± 3.03; F(2): 48.76 ± 2.61; G(2): 50.24 ± 3.37) than in the groups that underwent topical ozone administration (A(2): 46.01 ± 3.07; B(2): 46.79 ± 3.09; C(2): 47.07 ± 2.12; P = 0.030 (G(2)-A(2), G(2)-B(2), G(2)-C(2))). Within the limitations of the current study, it may be concluded that postoperative long-term systemic ozone application can accelerate alveolar bone healing following extraction. However, additional studies are required to clarify the effects of the different ozone applications on new bone formation.

  13. The effects of photobiomodulation and low-amplitude high-frequency vibration on bone healing process: a comparative study.

    PubMed

    Rajaei Jafarabadi, M; Rouhi, G; Kaka, G; Sadraie, S H; Arum, J

    2016-12-01

    critical size defects in the presence of a stainless steel implant. But their combination, i.e., low-level laser therapy and low-amplitude high-frequency whole body vibration (LV), interestingly did not accelerate the fractured bone healing process.

  14. 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.

  15. 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

  16. NSAID therapy effects on healing of bone, tendon, and the enthesis.

    PubMed

    Su, Bailey; O'Connor, J Patrick

    2013-09-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of skeletal injuries. The ability of NSAIDs to reduce pain and inflammation is well-established. However, the effects of NSAID therapy on healing of skeletal injuries is less defined. NSAIDs inhibit cyclooxygenase activity to reduce synthesis of prostaglandins, which are proinflammatory, lipid-signaling molecules. Inhibition of cyclooxygenase activity can impact many physiological processes. The effects of NSAID therapy on healing of bone, tendon, and the tendon-to-bone junction (enthesis) have been studied in animal and cell culture models, but human studies are few. Use of different NSAIDs with different pharmacological properties, differences in dosing regimens, and differences in study models and outcome measures have complicated comparisons between studies. In this review, we summarize the mechanisms by which bone, tendon, and enthesis healing occurs, and describe the effects of NSAID therapy on each of these processes. Determining the impact of NSAID therapy on healing of skeletal tissues will enable clinicians to appropriately manage the patient's condition and improve healing outcomes.

  17. The effects of photobiomodulation on healing of bone defects in streptozotocin induced diabetic rats

    NASA Astrophysics Data System (ADS)

    Martinez Costa Lino, Maíra D.; Bastos de Carvalho, Fabíola; Ferreira Moraes, Michel; Augusto Cardoso, José; Pinheiro, Antônio L. B.; Maria Pedreira Ramalho, Luciana

    2011-03-01

    Previous studies have shown positive effects of Low level laser therapy (LLLT) on the repair of bone defects, but there are only a few that associates bone healing in the presence of a metabolic disorder as Diabetes Melitus and LLLT. The aim of this study was to assess histologically the effect of LLLT (AsGaAl), 780nm, 70mW, CW, Ø~0.4mm, 16J/cm2 per session) on the repair of surgical defects created in the femur of diabetic and non-diabetic Wistar Albinus rats. Surgical bone defects were created in 60 animals divided into four groups of 15 animals each: Group C (non-diabetic - control); Group CL (non-diabetic + LLLT); Group CD (diabetic); Group CDL (diabetic + LLLT). The animals on the irradiated group received 16 J/cm2 per session divided into four points around the defect, being the first irradiation immediately after surgery and repeated every 48h for 14 days. The animals were killed 15, 21 and 30 days after surgery. The results of the present investigation showed histological evidence of improved amount of collagen fibers at early stages of the bone healing (15 days) and increased amount of well organized bone trabeculae at the end of the experimental period (30 days) on irradiated animals, (diabetic and non-diabetic) compared to non irradiated ones. It is concluded that LLLT has a positive biomodulative effect on the healing process of bone defects, even when diabetes mellitus was present.

  18. Differential regulation of blood vessel formation between standard and delayed bone healing.

    PubMed

    Lienau, Jasmin; Schmidt-Bleek, Katharina; Peters, Anja; Haschke, Franek; Duda, Georg N; Perka, Carsten; Bail, Hermann J; Schütze, Norbert; Jakob, Franz; Schell, Hanna

    2009-09-01

    Blood vessel formation is a prerequisite for bone healing. In this study, we tested the hypothesis that a delay in bone healing is associated with an altered regulation of blood vessel formation. A tibial osteotomy was performed in two groups of sheep and stabilized with either a rigid external fixator leading to standard healing or with a highly rotationally unstable one leading to delayed healing. At days 4, 7, 9, 11, 14, 21, and 42 after surgery, total RNA was extracted from the callus. Gene expressions of vWF, an endothelial cell marker, and of several molecules related to blood vessel formation were studied by qPCR. Furthermore, histology was performed on fracture hematoma and callus sections. Histologically, the first blood vessels were detected at day 7 in both groups. mRNA expression levels of vWF, Ang1, Ang2, VEGF, CYR61, FGF2, MMP2, and TIMP1 were distinctly lower in the delayed compared to the standard healing group at several time points. Based on differential expression patterns, days 7 and 21 postoperatively were revealed to be essential time points for vascularization of the ovine fracture callus. This work demonstrates for the first time a differential regulation of blood vessel formation between standard and mechanically induced delayed healing in a sheep osteotomy model.

  19. Acceleration of wound healing by growth hormone-releasing hormone and its agonists.

    PubMed

    Dioufa, Nikolina; Schally, Andrew V; Chatzistamou, Ioulia; Moustou, Evi; Block, Norman L; Owens, Gary K; Papavassiliou, Athanasios G; Kiaris, Hippokratis

    2010-10-26

    Despite the well-documented action of growth hormone-releasing hormone (GHRH) on the stimulation of production and release of growth hormone (GH), the effects of GHRH in peripheral tissues are incompletely explored. In this study, we show that GHRH plays a role in wound healing and tissue repair by acting primarily on wound-associated fibroblasts. Mouse embryonic fibroblasts (MEFs) in culture and wound-associated fibroblasts in mice expressed a splice variant of the receptors for GHRH (SV1). Exposure of MEFs to 100 nM and 500 nM GHRH or the GHRH agonist JI-38 stimulated the expression of α-smooth muscle actin (αSMA) based on immunoblot analyses as well as the expression of an αSMA-β-galactosidase reporter transgene in primary cultures of fibroblasts isolated from transgenic mice. Consistent with this induction of αSMA expression, results of transwell-based migration assays and in vitro wound healing (scratch) assays showed that both GHRH and GHRH agonist JI-38 stimulated the migration of MEFs in vitro. In vivo, local application of GHRH or JI-38 accelerated healing in skin wounds of mice. Histological evaluation of skin biopsies showed that wounds treated with GHRH and JI-38 were both characterized by increased abundance of fibroblasts during the early stages of wound healing and accelerated reformation of the covering epithelium at later stages. These results identify another function of GHRH in promoting skin tissue wound healing and repair. Our findings suggest that GHRH may have clinical utility for augmenting healing of skin wounds resulting from trauma, surgery, or disease.

  20. The effects of amlodipine and platelet rich plasma on bone healing in rats

    PubMed Central

    Atalay, Yusuf; Bozkurt, Mehmet Fatih; Gonul, Yucel; Cakmak, Omer; Agacayak, Kamil Serkan; Köse, Ibrahim; Hazman, Omer; Keles, Hikmet; Turamanlar, Ozan; Eroglu, Mehmet

    2015-01-01

    Aim The aim of this study was to evaluate the effects of calcium channel blocker (CCB) amlodipine (AML), platelet rich plasma (PRP), and a mixture of both materials on bone healing. Materials and methods Fifty-six male Wistar rats were randomly divided into four groups: group A, tibia defect model with no treatment; group B, tibia defect model treated with AML, 0.04 mg daily by oral gavage; group C, tibia defect model treated with local PRP; group D, tibia defect model treated with local PRP and AML, 0.04 mg daily by oral gavage. Results At day 21, bone healing was significantly better in groups C and D compared to group A (P<0.05), but comparisons showed no statistically significant difference in group B (P>0.05). At day 30, groups B and C showed no statistically significant difference (P>0.05) compared to group A, but bone healing in group D was significantly better than in group A (P<0.05). Statistically, AML did not affect alkaline phosphatase (ALP) activity at 21 and 30 days (P>0.05), but PRP and AML + PRP increased ALP activity statistically (P<0.05). Conclusion It can be concluded that AML had neither a positive nor a negative effect on bone healing, but when used in combination with PRP, it may be beneficial. PMID:25897207

  1. Accelerated healing of full-thickness wounds by genipin-crosslinked silk sericin/PVA scaffolds.

    PubMed

    Aramwit, Pornanong; Siritienthong, Tippawan; Srichana, Teerapol; Ratanavaraporn, Juthamas

    2013-01-01

    Silk sericin has recently been studied for its advantageous biological properties, including its ability to promote wound healing. This study developed a delivery system to accelerate the healing of full-thickness wounds. Three-dimensional scaffolds were fabricated from poly(vinyl alcohol) (PVA), glycerin (as a plasticizer) and genipin (as a crosslinking agent), with or without sericin. The physical and biological properties of the genipin-crosslinked sericin/PVA scaffolds were investigated and compared with those of scaffolds without sericin. The genipin-crosslinked sericin/PVA scaffolds exhibited a higher compressive modulus and greater swelling in water than the scaffolds without sericin. Sericin also exhibited controlled release from the scaffolds. The genipin-crosslinked sericin/PVA scaffolds promoted the attachment and proliferation of L929 mouse fibroblasts. After application to full-thickness rat wounds, the wounds treated with genipin-crosslinked sericin/PVA scaffolds showed a significantly greater reduction in wound size, collagen formation and epithelialization compared with the control scaffolds without sericin but lower numbers of macrophages and multinucleated giant cells. These results indicate that the delivery of sericin from the novel genipin-crosslinked scaffolds efficiently healed the wound. Therefore, these genipin-crosslinked sericin/PVA scaffolds represent a promising candidate for the accelerated healing of full-thickness wounds.

  2. A bioengineered drug-Eluting scaffold accelerated cutaneous wound healing In diabetic mice.

    PubMed

    Yin, Hao; Ding, Guoshan; Shi, Xiaoming; Guo, Wenyuan; Ni, Zhijia; Fu, Hong; Fu, Zhiren

    2016-09-01

    Hyperglycemia in diabetic patients can greatly hinder the wound healing process. In this study we investigated if the engagement of F4/80(+) murine macrophages could accelerate the cutaneous wound healing in streptozotocin induced diabetic mice. To facilitate the engagement of macrophages, we engineered a drug-eluting electrospun scaffold with a payload of monocyte chemoattractant protein-1 (MCP-1). MCP-1 could be readily released from the scaffold within 3 days. The electrospun scaffold showed no cytotoxic effects on human keratinocytes in vitro. Full-thickness excisional cutaneous wound was created in diabetic mice. The wound fully recovered within 10 days in mice treated with the drug-eluting scaffold. In contrast, the wound took 14 days to fully recover in control groups. The use of drug-eluting scaffold also improved the re-epithelialization. Furthermore, we observed a larger population of F4/80(+) macrophages in the wound bed of mice treated with drug-eluting scaffolds on day 3. This marked increase of macrophages in the wound bed could have contributed to the accelerated wound healing. Our study shed new light on an immuno-engineering solution for wound healing management in diabetic patients.

  3. IL-33 accelerates cutaneous wound healing involved in upregulation of alternatively activated macrophages.

    PubMed

    Yin, Hui; Li, Xiangyong; Hu, Shilian; Liu, Tao; Yuan, Baohong; Gu, Hongbiao; Ni, Qian; Zhang, Xiaofan; Zheng, Fang

    2013-12-01

    IL-33 is a recently recognized member of the IL-1 family and has been best identified as a potent inducer of Th2-type immune responses. Increasing evidence, however, indicates that IL-33 also represents an important mediator of mucosal healing and epithelial restoration and repair. In this study, we further explore the potential effect of IL-33 in cutaneous wound healing. A full-thickness skin wound was generated on the back of mice and treated with IL-33 or vehicle intraperitoneally. Our results revealed that the levels of IL-33 mRNA and protein were significantly enhanced in incisional wound skin. Meantime, administration of IL-33 obviously accelerated wound healing with wounds gaping narrower and exhibiting enhanced reepithelialization. IL-33 upregulation also promoted the collagen deposition and the expression of extracellular matrix (ECM)-associated genes such as fibronectin and collagen IIIa, which implies a direct effect of IL-33 on matrix synthesis. Furthermore, IL-33 facilitated the development of alternatively activated macrophages (AAM) in incisional wound tissue, which closely related to resolution of inflammation and promotion of wound repair. Taken together, these findings suggest that IL-33 may play a pivotal role in maintenance of cutaneous homeostasis and acceleration of normal wound healing.

  4. Carbon nanotubes with high bone-tissue compatibility and bone-formation acceleration effects.

    PubMed

    Usui, Yuki; Aoki, Kaoru; Narita, Nobuyo; Murakami, Narumichi; Nakamura, Isao; Nakamura, Koichi; Ishigaki, Norio; Yamazaki, Hiroshi; Horiuchi, Hiroshi; Kato, Hiroyuki; Taruta, Seiichi; Kim, Yoong Ahm; Endo, Morinobu; Saito, Naoto

    2008-02-01

    Carbon nanotubes (CNTs) have been used in various fields as composites with other substances or alone to develop highly functional materials. CNTs hold great interest with respect to biomaterials, particularly those to be positioned in contact with bone such as prostheses for arthroplasty, plates or screws for fracture fixation, drug delivery systems, and scaffolding for bone regeneration. Accordingly, bone-tissue compatibility of CNTs and CNT influence on bone formation are important issues, but the effects of CNTs on bone have not been delineated. Here, it is found that multi-walled CNTs adjoining bone induce little local inflammatory reaction, show high bone-tissue compatibility, permit bone repair, become integrated into new bone, and accelerate bone formation stimulated by recombinant human bone morphogenetic protein-2 (rhBMP-2). This study provides an initial investigational basis for CNTs in biomaterials that are used adjacent to bone, including uses to promote bone regeneration. These findings should encourage development of clinical treatment modalities involving CNTs.

  5. CaMKK2 Inhibition in Enhancing Bone Fracture Healing

    DTIC Science & Technology

    2016-05-01

    Einhorn, 1986) in the right femurs of 10- week old anesthetized male mice after first inserting an intramedullary pin (25 gauge needle, approx. 0.5...intraperitoneal (i.p.) injections of saline or STO-609 (10 µmol/kg mouse body weight) were performed for 6 weeks . Progression of fracture healing was...permeable inhibitor STO-609 protects from ovariectomy-induced osteoporosis. Moreover, treatment of 32 week old male mice with STO-609 reverses age

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

    DTIC Science & Technology

    2014-10-01

    Long Bone Fracture: Influence of Method of Repair and External Beam Irradiation on the Pathway and Efficacy of Fracture Healing 5a. CONTRACT NUMBER...in the fifth quarter of the award. 15. SUBJECT TERMS Fracture healing , bone healing , endochondral ossification, intramembranous ossification...irradiation, radiotherapy, pathologic fractures, bony metastasis, bone cancer, animal model , rat model 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF

  7. Effect of Obesity on Bone Healing After Foot and Ankle Long Bone Fractures.

    PubMed

    Thorud, Jakob C; Mortensen, Spencer; Thorud, Jennifer L; Shibuya, Naohiro; Maldonado, Yolanda Munoz; Jupiter, Daniel C

    As obesity has become more common, fractures in the obese population have become more frequent. Concern exists regarding alterations in bone health and healing in obese patients. A matched case-control study was performed at 1 institution to evaluate whether an association exists between nonunion and a high body mass index in metatarsal and ankle fractures. A total of 48 patients with nonunion were identified, and control patients matched 2 to 1 (n = 96) were selected. The control patients were matched for age, sex, and fracture type. No association was identified between nonunion and the continuous body mass index (p = .23) or morbid obesity, with a body mass index of ≥40 kg/m(2) (p = .51). However, the results from both univariate and multivariate analysis suggested that patients with a current alcohol problem or a history of an alcohol problem might have a greater risk of nonunion. The odds ratio of a patient with a history of alcohol use experiencing nonunion was 2.7 (95% confidence interval 1.2 to 6.2). Further studies are warranted to confirm these findings.

  8. Dual-Purpose Bone Grafts Improve Healing and Reduce Infection

    DTIC Science & Technology

    2011-08-01

    al. Enhancement of ectopic bone formation by bone morphogenetic protein-2 released from a heparin-conjugated poly(- L- lactic -co-glycolic acid ...release of antibiotic at an effective dose from the scaffolds for at least 6 weeks to ensure protection of the graft from colonization by bacteria . The...irrigated with 60 mL of saline.13 This period was chosen because it is clinically relevant14 and allows the bacteria enough time to attach to the

  9. Reduced FOXO1 expression accelerates skin wound healing and attenuates scarring.

    PubMed

    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

    2014-09-01

    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.

  10. Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis.

    PubMed

    Asai, Jun; Takenaka, Hideya; Hirakawa, Satoshi; Sakabe, Jun-ichi; Hagura, Asami; Kishimoto, Saburo; Maruyama, Kazuichi; Kajiya, Kentaro; Kinoshita, Shigeru; Tokura, Yoshiki; Katoh, Norito

    2012-12-01

    Impaired wound healing is a major complication of diabetes. Recent studies have reported reduced lymphangiogenesis and angiogenesis during diabetic wound healing, which are thought to be new therapeutic targets. Statins have effects beyond cholesterol reduction and can stimulate angiogenesis when used systemically. However, the effects of topically applied statins on wound healing have not been well investigated. The present study tested the hypothesis that topical application of simvastatin would promote lymphangiogenesis and angiogenesis during wound healing in genetically diabetic mice. A full-thickness skin wound was generated on the back of the diabetic mice and treated with simvastatin or vehicle topically. Simvastatin administration resulted in significant acceleration of wound recovery, which was notable for increases in both angiogenesis and lymphangiogenesis. Furthermore, simvastatin promoted infiltration of macrophages, which produced vascular endothelial growth factor C in granulation tissues. In vitro, simvastatin directly promoted capillary morphogenesis and exerted an antiapoptotic effect on lymphatic endothelial cells. These results suggest that the favorable effects of simvastatin on lymphangiogenesis are due to both a direct influence on lymphatics and indirect effects via macrophages homing to the wound. In conclusion, a simple strategy of topically applied simvastatin may have significant therapeutic potential for enhanced wound healing in patients with impaired microcirculation such as that in diabetes.

  11. Intramembranous bone healing process subsequent to tooth extraction in mice: micro-computed tomography, histomorphometric and molecular characterization.

    PubMed

    Vieira, Andreia Espindola; Repeke, Carlos Eduardo; Ferreira Junior, Samuel de Barros; Colavite, Priscila Maria; Biguetti, Claudia Cristina; Oliveira, Rodrigo Cardoso; Assis, Gerson Francisco; Taga, Rumio; Trombone, Ana Paula Favaro; Garlet, Gustavo Pompermaier

    2015-01-01

    Bone tissue has a significant potential for healing, which involves a significant the interplay between bone and immune cells. While fracture healing represents a useful model to investigate endochondral bone healing, intramembranous bone healing models are yet to be developed and characterized. In this study, a micro-computed tomography, histomorphometric and molecular (RealTimePCRarray) characterization of post tooth-extraction alveolar bone healing was performed on C57Bl/6 WT mice. After the initial clot dominance (0 h), the development of a provisional immature granulation tissue is evident (7 d), characterized by marked cell proliferation, angiogenesis and inflammatory cells infiltration; associated with peaks of growth factors (BMP-2-4-7,TGFβ1,VEGFa), cytokines (TNFα, IL-10), chemokines & receptors (CXCL12, CCL25, CCR5, CXCR4), matrix (Col1a1-2, ITGA4, VTN, MMP1a) and MSCs (CD105, CD106, OCT4, NANOG, CD34, CD146) markers expression. Granulation tissue is sequentially replaced by more mature connective tissue (14 d), characterized by inflammatory infiltrate reduction along the increased bone formation, marked expression of matrix remodeling enzymes (MMP-2-9), bone formation/maturation (RUNX2, ALP, DMP1, PHEX, SOST) markers, and chemokines & receptors associated with healing (CCL2, CCL17, CCR2). No evidences of cartilage cells or tissue were observed, strengthening the intramembranous nature of bone healing. Bone microarchitecture analysis supports the evolving healing, with total tissue and bone volumes as trabecular number and thickness showing a progressive increase over time. The extraction socket healing process is considered complete (21 d) when the dental socket is filled by trabeculae bone with well-defined medullary canals; it being the expression of mature bone markers prevalent at this period. Our data confirms the intramembranous bone healing nature of the model used, revealing parallels between the gene expression profile and the

  12. Intramembranous Bone Healing Process Subsequent to Tooth Extraction in Mice: Micro-Computed Tomography, Histomorphometric and Molecular Characterization

    PubMed Central

    Vieira, Andreia Espindola; Repeke, Carlos Eduardo; Ferreira Junior, Samuel de Barros; Colavite, Priscila Maria; Biguetti, Claudia Cristina; Oliveira, Rodrigo Cardoso; Assis, Gerson Francisco; Taga, Rumio; Trombone, Ana Paula Favaro; Garlet, Gustavo Pompermaier

    2015-01-01

    Bone tissue has a significant potential for healing, which involves a significant the interplay between bone and immune cells. While fracture healing represents a useful model to investigate endochondral bone healing, intramembranous bone healing models are yet to be developed and characterized. In this study, a micro-computed tomography, histomorphometric and molecular (RealTimePCRarray) characterization of post tooth-extraction alveolar bone healing was performed on C57Bl/6 WT mice. After the initial clot dominance (0h), the development of a provisional immature granulation tissue is evident (7d), characterized by marked cell proliferation, angiogenesis and inflammatory cells infiltration; associated with peaks of growth factors (BMP-2-4-7,TGFβ1,VEGFa), cytokines (TNFα, IL-10), chemokines & receptors (CXCL12, CCL25, CCR5, CXCR4), matrix (Col1a1-2, ITGA4, VTN, MMP1a) and MSCs (CD105, CD106, OCT4, NANOG, CD34, CD146) markers expression. Granulation tissue is sequentially replaced by more mature connective tissue (14d), characterized by inflammatory infiltrate reduction along the increased bone formation, marked expression of matrix remodeling enzymes (MMP-2-9), bone formation/maturation (RUNX2, ALP, DMP1, PHEX, SOST) markers, and chemokines & receptors associated with healing (CCL2, CCL17, CCR2). No evidences of cartilage cells or tissue were observed, strengthening the intramembranous nature of bone healing. Bone microarchitecture analysis supports the evolving healing, with total tissue and bone volumes as trabecular number and thickness showing a progressive increase over time. The extraction socket healing process is considered complete (21d) when the dental socket is filled by trabeculae bone with well-defined medullary canals; it being the expression of mature bone markers prevalent at this period. Our data confirms the intramembranous bone healing nature of the model used, revealing parallels between the gene expression profile and the histomorphometric

  13. BMP2-coprecipitated calcium phosphate granules enhance osteoinductivity of deproteinized bovine bone, and bone formation during critical-sized bone defect healing.

    PubMed

    Liu, Tie; Zheng, Yuanna; Wu, Gang; Wismeijer, Daniel; Pathak, Janak L; Liu, Yuelian

    2017-01-31

    Most materials used clinically for filling critical-sized bone defects (CSBD), such as deproteinized bovine bone (DBB), lack osteoinductivity so that their therapeutic effects are far from satisfactory. The effect of bone morphogenic protein 2 (BMP2)-coprecipitated biomimetic calcium phosphate granules (BMP2-cop.BioCaP) on osteoinduction of DBB graft(s) during CSBD healing is still unknown. We investigated whether BMP2-cop.BioCaP affects the osteoinductivity of DBB, bone formation, and foreign body reaction during CSBD healing. DBB + BMP2-cop.BioCaP, DBB, DBB + BMP2, DBB + BioCaP, and autologous bone grafts were implanted in the CSBD of sheep. Bone formation, DBB/BioCaP degradability, foreign body reaction, and osteoinductivity of DBB were analyzed histologically and histomorphometrically at week 4 and 8. Combination of BMP2-cop.BioCaP and DBB healed CSBD as effectively as autologous bone grafts. About 95% of the BMP2-cop.BioCaP had been degraded and replaced by new bone at week 8 in the DBB + BMP2-cop.BioCaP-group. Foreign body reaction was reduced in the DBB + BMP2-cop.BioCaP-group compared to the other groups. The independent use of the BMP2-cop.BioCaP did not achieve a satisfactory bone repair. In conclusion, the BMP2-cop.BioCaP showed good degradability and biocompatibility, and enhanced osteoinductivity of DBB during CSBD healing in sheep, suggesting BMP2-cop.BioCaP as a potential osteoinducer to enhance the therapeutic effects of the graft materials in clinic.

  14. BMP2-coprecipitated calcium phosphate granules enhance osteoinductivity of deproteinized bovine bone, and bone formation during critical-sized bone defect healing

    PubMed Central

    Liu, Tie; Zheng, Yuanna; Wu, Gang; Wismeijer, Daniel; Pathak, Janak L.; Liu, Yuelian

    2017-01-01

    Most materials used clinically for filling critical-sized bone defects (CSBD), such as deproteinized bovine bone (DBB), lack osteoinductivity so that their therapeutic effects are far from satisfactory. The effect of bone morphogenic protein 2 (BMP2)-coprecipitated biomimetic calcium phosphate granules (BMP2-cop.BioCaP) on osteoinduction of DBB graft(s) during CSBD healing is still unknown. We investigated whether BMP2-cop.BioCaP affects the osteoinductivity of DBB, bone formation, and foreign body reaction during CSBD healing. DBB + BMP2-cop.BioCaP, DBB, DBB + BMP2, DBB + BioCaP, and autologous bone grafts were implanted in the CSBD of sheep. Bone formation, DBB/BioCaP degradability, foreign body reaction, and osteoinductivity of DBB were analyzed histologically and histomorphometrically at week 4 and 8. Combination of BMP2-cop.BioCaP and DBB healed CSBD as effectively as autologous bone grafts. About 95% of the BMP2-cop.BioCaP had been degraded and replaced by new bone at week 8 in the DBB + BMP2-cop.BioCaP-group. Foreign body reaction was reduced in the DBB + BMP2-cop.BioCaP-group compared to the other groups. The independent use of the BMP2-cop.BioCaP did not achieve a satisfactory bone repair. In conclusion, the BMP2-cop.BioCaP showed good degradability and biocompatibility, and enhanced osteoinductivity of DBB during CSBD healing in sheep, suggesting BMP2-cop.BioCaP as a potential osteoinducer to enhance the therapeutic effects of the graft materials in clinic. PMID:28139726

  15. Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis.

    PubMed

    Ai-Aql, Z S; Alagl, A S; Graves, D T; Gerstenfeld, L C; Einhorn, T A

    2008-02-01

    Fracture healing and distraction osteogenesis have important applications in orthopedic, maxillofacial, and periodontal treatment. In this review, the cellular and molecular mechanisms that regulate fracture repair are contrasted with bone regeneration that occurs during distraction osteogenesis. While both processes have many common features, unique differences are observed in the temporal appearance and expression of specific molecular factors that regulate each. The relative importance of inflammatory cytokines in normal and diabetic healing, the transforming growth factor beta superfamily of bone morphogenetic mediators, and the process of angiogenesis are discussed as they relate to bone repair. A complete summary of biological activities and functions of various bioactive factors may be found at COPE (Cytokines & Cells Online Pathfinder Encyclopedia), http://www.copewithcytokines.de/cope.cgi.

  16. Effects of Trypsinization and Mineralization on Intrasynovial Tendon Allograft Healing to Bone

    PubMed Central

    Qu, Jin; van Alphen, Nick A.; Thoreson, Andrew R.; Chen, Qingshan; An, Kai-Nan; Amadio, Peter C.; Schmid, Thomas M.; Zhao, Chunfeng

    2014-01-01

    The purpose of the current study was to develop a novel technology to enhance tendon-to-bone interface healing by trypsinizing and mineralizing (TM) an intrasynovial tendon allograft in a rabbit bone tunnel model. Eight rabbit flexor digitorum profundus (FDP) tendons were used to optimize the trypsinization process. An additional 24 FDP tendons were stratified into control and TM groups; in each group, 4 tendons were used for in vitro evaluation of TM and 8 were transplanted into proximal tibial bone tunnels in rabbits. The samples were evaluated histologically and with mechanical testing at postoperative week 8. Maximum failure strength and linear stiffness were not significantly different between the control and TM tendons. A thin fibrous band of scar tissue formed at the graft-to-bone interface in the control group. However, only the TM group showed obvious new bone formation inside the tendon graft and a visible fibrocartilage layer at the bone tunnel entrance. This study is the first to explore effects of TM on the intrasynovial allograft healing to a bone tunnel. TM showed beneficial effects on chondrogenesis, osteogenesis, and integration of the intrasynovial tendon graft, but mechanical strength was the same as the control tendons in this short-term in vivo study. PMID:25611186

  17. Evaluation of bioactive glass and platelet-rich plasma for bone healing in rabbit calvarial defects.

    PubMed

    Penteado, Luiz A M; Colombo, Carlos E D; Penteado, Roberta A P M; Assis, Angélica O; Gurgel, Bruno C V

    2013-09-01

    Bone regeneration is an important objective in clinical dental practice and has been used for different applications. The aim of this study was to evaluate the effectiveness of platelet-rich plasma (PRP) and bioactive glass (BG) for bone healing of surgical calvarial defects in rabbits. Two 8-mm defects were prepared in the parietal bones of ten animals, and the animals were randomly assigned to two groups. In each group, two subgroups were created with five defects each: BC - blood clot, BG, PRP and PRP + BG. Thus, four treatments were performed with five specimens each. The animals were sacrificed after 12 weeks and the specimens were analyzed radiographically, histologically and histomorphometrically. Data were subjected to ANOVA and Tukey's tests (α = 0.05). Outcomes demonstrated that the PRP group had higher bone density (%) values than the groups not treated with PRP (P < 0.05). Histometrically, both groups treated with PRP (PRP: 25.6 ± 9.9; PRP+BG: 25.8 ± 12.4) demonstrated higher percentages of new bone formation than the groups not treated with PRP (BG: 6.1 ± 4.3; BC: 7.8 ± 5.6) (P < 0.05). The results suggested that PRP improved bone repair and that bioactive glass alone, or in association with PRP, did not improve bone healing.

  18. Ozone treatment of alveolar bone in the cape chacma baboon does not enhance healing following trauma.

    PubMed

    Kotze, Marthinus; Bütow, Kürt-W; Olorunju, Steve A; Kotze, Harry F

    2014-06-01

    In the international literature, the role of Ozone (O3) in the advancement in alveolar bone healing in the absence of bone pathology was not tested before. The purpose of this study was to evaluate alveolar bone regeneration after a bone defect was created and treated with a single topical administration of O3. Alveolar bone defects were created on five healthy chacma baboons. One side of the maxilla and mandible was topically treated with a single treatment of an O3/O2 mixture (3,5-4 % O3), while the opposite sides were not treated and thus served as control. Regeneration was measured radiologically, using a standardized gray scale, as the increase in bone density in the treatment area at 3 and 6 weeks post-operative and was statistically analyzed using multivariate analysis of variance (MANOVA). There were no significant differences in densities observed between the O3/O2 mixture treatment and the control (p > 0.05). A single O3 treatment did not increase alveolar bone healing over a 3- and 6-week period in the mandible and the maxilla.

  19. Effects of trypsinization and mineralization on intrasynovial tendon allograft healing to bone.

    PubMed

    Qu, Jin; van Alphen, Nick A; Thoreson, Andrew R; Chen, Qingshan; An, Kai-Nan; Amadio, Peter C; Schmid, Thomas M; Zhao, Chunfeng

    2015-04-01

    The purpose of the current study was to develop a novel technology to enhance tendon-to-bone interface healing by trypsinizing and mineralizing (TM) an intrasynovial tendon allograft in a rabbit bone tunnel model. Eight rabbit flexor digitorum profundus (FDP) tendons were used to optimize the trypsinization process. An additional 24 FDP tendons were stratified into control and TM groups; in each group, 4 tendons were used for in vitro evaluation of TM and 8 were transplanted into proximal tibial bone tunnels in rabbits. The samples were evaluated histologically and with mechanical testing at postoperative week 8. Maximum failure strength and linear stiffness were not significantly different between the control and TM tendons. A thin fibrous band of scar tissue formed at the graft-to-bone interface in the control group. However, only the TM group showed obvious new bone formation inside the tendon graft and a visible fibrocartilage layer at the bone tunnel entrance. This study is the first to explore effects of TM on the intrasynovial allograft healing to a bone tunnel. TM showed beneficial effects on chondrogenesis, osteogenesis, and integration of the intrasynovial tendon graft, but mechanical strength was the same as the control tendons in this short-term in vivo study.

  20. Healing

    PubMed Central

    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

  1. Use of Bioresorbable Hydrogels and Genetic Engineering to Accomplish Rapid Stabilization and Healing in Segmental Long Bone Defects

    DTIC Science & Technology

    2013-04-29

    also suggests that the lymphatics play a critical role in fracture repair. With normal healing of tibial fracture, foci of ossification are...Effectiveness in segmental tibial defects in rats. Tissue Eng 12:489–497. Finkemeier CG. 2002. Bone-grafting and bone-graft substitutes. J Bone Joint...Vogelin E, Brekke JH, Jones NF. 2000. Heterotopic and orthotopic bone formation with a vascularized periosteal flap, a matrix and rh-BMP- 2 (bone

  2. Gelatin powders accelerate the resorption of calcium phosphate cement and improve healing in the alveolar ridge.

    PubMed

    Matsumoto, Goichi; Sugita, Yoshihiko; Kubo, Katsutoshi; Yoshida, Waka; Ikada, Yoshito; Sobajima, Satoshi; Neo, Masashi; Maeda, Hatsuhiko; Kinoshita, Yukihiko

    2014-05-01

    The aim of this study was to show the effectiveness of combining calcium phosphate cement and gelatin powders to promote bone regeneration in the canine mandible. We mixed gelatin powders with calcium phosphate cement to create a macroporous composite. In four beagle dogs, two saddle-type bone defects were created on each side of the mandible, and calcium phosphate cement alone or calcium phosphate cement containing composite gelatin powders was implanted in each of the defects. After a healing period of six months, mandibles were removed for µCT and histological analyses. The µCT and histological analyses showed that at experimental sites at which calcium phosphate cement alone had been placed new bone had formed only around the periphery of the residual calcium phosphate cement and that there had been little or no ingrowth into the calcium phosphate cement. On the other hand, at experimental sites at which calcium phosphate cement containing composite gelatin powders had been placed, we observed regenerated new bone in the interior of the residual calcium phosphate cement as well as around its periphery. The amount of resorption of calcium phosphate cement and bone regeneration depended on the mixing ratio of gelatin powders to calcium phosphate cement. New bone replacement was significantly better in the sites treated with calcium phosphate cement containing composite gelatin powders than in those treated with calcium phosphate cement alone.

  3. 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.

  4. CXC receptor knockout mice: characterization of skeletal features and membranous bone healing in the adult mouse.

    PubMed

    Bischoff, David S; Sakamoto, Taylor; Ishida, Kenji; Makhijani, Nalini S; Gruber, Helen E; Yamaguchi, Dean T

    2011-02-01

    The potential role of CXC chemokines bearing the glu-leu-arg (ELR) motif in bone repair was studied using a cranial defect (CD) model in mice lacking the CXC receptor (mCXCR(-/-) knockout mice), which is homologous to knockout of the human CXC receptor 2 (CXCR2) gene. During the inflammatory stage of bone repair, ELR CXC chemokines are released by inflammatory cells and serve as chemotactic and angiogenic factors. mCXCR(-/-) mice were smaller in weight and length from base of tail to nose tip, compared to WT littermates. DEXA analysis indicated that bone mineral density (BMD), bone mineral content (BMC), total area (TA), bone area (BA), and total tissue mass (TTM) were decreased in the mCXCR(-/-) mice at 6, 12, and 18 weeks of age. Trabecular bone characteristics in mCXCR(-/-) (% bone, connectivity, number, and thickness) were reduced, and trabecular spacing was increased as evidenced by μCT. There was no difference in bone formation or resorption indices measured by bone histomorphometry. Trabecular BMD was not altered. Cortical bone volume, BMD, and thickness were reduced; whereas, bone marrow volume was increased in mCXCR(-/-). Decreased polar moment of inertia (J) in the tibias/femurs suggested that the mCXCR(-/-) long bones are weaker. This was confirmed by three-point bending testing of the femurs. CDs created in 6-week-old male mCXCR(-/-) and WT littermates were not completely healed at 12 weeks; WT animals, however, had significantly more bone in-growth than mCXCR(-/-). New bone sites were identified using polarized light and assessed for numbers of osteocyte (OCy) lacunae and blood vessels (BlV) around the original CD. In new bone, the number of BlV in WT was >2× that seen in mCXCR(-/-). Bone histomorphometry parameters in the cranial defect did not show any difference in bone formation or resorption markers. In summary, studies showed that mCXCR(-/-) mice have (1) reduced weight and size; (2) decreased BMD and BMC; (3) decreased amounts of trabecular

  5. Accelerated Bone Mass Senescence After Hematopoietic Stem Cell Transplantation

    PubMed Central

    Serio, B; Pezzullo, L; Fontana, R; Annunziata, S; Rosamilio, R; Sessa, M; Giudice, V; Ferrara, I; Rocco, M; De Rosa, G; Ricci, P; Tauchmanovà, L; Montuori, N; Selleri, C.

    2013-01-01

    Osteoporosis and avascular necrosis (AVN) are long-lasting and debilitating complications of hematopoietic stem cell transplantation (HSCT). We describe the magnitude of bone loss, AVN and impairment in osteogenic cell compartment following autologous (auto) and allogeneic (allo) HSCT, through the retrospective bone damage revaluation of 100 (50 auto- and 50 allo-HSCT) long-term survivors up to 15 years after transplant. Current treatment options for the management of these complications are also outlined. We found that auto- and allo-HSCT recipients show accelerated bone mineral loss and micro-architectural deterioration during the first years after transplant. Bone mass density (BMD) at the lumbar spine, but not at the femur neck, may improve in some patients after HSCT, suggesting more prolonged bone damage in cortical bone. Phalangeal BMD values remained low for even more years, suggesting persistent bone micro-architectural alterations after transplant. The incidence of AVN was higher in allo-HSCT recipients compared to auto-HSCT recipients. Steroid treatment length, but not its cumulative dose was associated with a higher incidence of bone loss. Allo-HSCT recipients affected by chronic graft versus host disease seem to be at greater risk of continuous bone loss and AVN development. Reduced BMD and higher incidence of AVN was partly related to a reduced regenerating capacity of the normal marrow osteogenic cell compartment. Our results suggest that all patients after auto-HSCT and allo-HSCT should be evaluated for their bone status and treated with anti-resorptive therapy as soon as abnormalities are detected. PMID:23905076

  6. Enhancement of bone-titanium integration profile with UV-photofunctionalized titanium in a gap healing model.

    PubMed

    Ueno, Takeshi; Yamada, Masahiro; Suzuki, Takeo; Minamikawa, Hajime; Sato, Naoko; Hori, Norio; Takeuchi, Kazuo; Hattori, Masami; Ogawa, Takahiro

    2010-03-01

    In this study, we tested the potential of UV-photofunctionalized titanium surfaces to overcome compromised bone-titanium integration in a gap healing model. Titanium in rod and disk forms was acid etched and then stored for 4 weeks under dark ambient conditions. Titanium rods with and without UV pretreatment were placed into a rat femur with (contact healing) or without (gap healing) contact with the innate cortical bone. The titanium implants were subjected to a biomechanical push-in test, micro-CT bone morphometry, and surface elemental analysis after 2 weeks of healing. The strength of bone-titanium integration in the gap healing model was one-third of that in the contact healing model. However, UV-treated implants in the gap healing condition produced a strength of bone-titanium integration equivalent to that of untreated implants in the contact healing condition. Bone volume around UV-treated implants was 2- to 3-fold greater than that around the untreated implants in the gap healing model. A bone generation profile drawn along the long axis of the implant exhibited greater contrast between the untreated and UV-treated surfaces in the cortical area than in the bone marrow area. The bone tissue formed on UV-treated implants showed a higher Ca/P ratio than that formed on untreated titanium. The rate of cell proliferation, alkaline phosphatase activity, and calcium deposition in femoral periosteal cells and in bone marrow-derived osteoblasts were greater in cultures on UV-treated titanium disks than in cultures on untreated disks. The UV-enhanced function in periosteal cells was more pronounced when they were co-cultured with bone marrow-derived osteoblasts, indicating a synergistic effect of UV-treated titanium with biological signals from bone marrow-derived osteoblasts. Within the limitation of the model used in this study, UV-photofunctionalized titanium surfaces may overcome the challenging condition of bone-titanium integration without cortical bone support

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

    PubMed

    Ribeiro, Frederico O; Gómez-Benito, María José; Folgado, João; Fernandes, Paulo R; García-Aznar, José Manuel

    2015-01-01

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

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

    PubMed Central

    2015-01-01

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

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

    PubMed

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

    2015-06-01

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

  10. Ultrasound imaging of long bone fractures and healing with the split-step fourier imaging method.

    PubMed

    Li, Hongjiang; Le, Lawrence H; Sacchi, Mauricio D; Lou, Edmond H M

    2013-08-01

    We applied the split-step Fourier imaging method to back-propagate the ultrasound zero-offset wavefields acquired on the bone surface to the sources of scatterers, which are the reflecting interfaces. The method required, as an input, an estimated slowness (reciprocal of half the velocity) model to map the time-dependent sonogram to the depth image, which provides the geometric properties of the interfaces. The slowness was approximated by a depth-dependent term and a first-order spatially varying perturbation. Simulated data sets were used to validate the method. The reconstructed images show proper mapping of the interfaces and the fracture, and a reasonable cortical thickness measurement with 8.3% error. The images also illustrate clearly the bone fracture healing process of a 1-mm-wide 45° inclined crack with different in-filled tissue velocities for various healing stages. Reconstruction of a fractured bone plate using data from an in vitro experiment is also presented. This study suggests that the proposed imaging method has good potential in quantification of bone fractures and monitoring of the fracture healing process.

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

    PubMed

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

    1999-03-01

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

  12. Accelerated wound healing in tumor necrosis factor receptor p55-deficient mice with reduced leukocyte infiltration.

    PubMed

    Mori, Ryoichi; Kondo, Toshikazu; Ohshima, Tohru; Ishida, Yuko; Mukaida, Naofumi

    2002-07-01

    To clarify biological roles of tumor necrosis factor receptor p55 (TNF-Rp55) -mediated signals in wound healing, skin excisions were prepared in BALB/c (WT) and TNF-Rp55-deficient (KO) mice. In WT mice, the wound area was reduced to 50% of the original area 6 days after injury, with angiogenesis and collagen accumulation. Histopathologically, reepithelialization rate was approximately 80% 6 days. Myeloperoxidase activity and macrophage recruitment were the most evident 1 and 6 days after injury, respectively. Gene expression of adhesion molecules, interleukin 1alpha (IL-1alpha), IL-1beta, monocyte chemoattractant protein 1, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-2, transforming growth factor beta1 (TGF-beta1) connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), Flt-1, and Flk-1 was enhanced at the wound site. In KO mice, an enhancement in angiogenesis, collagen content, and reepithelialization was accelerated with the increased gene expression of TGF-beta1, CTGF, VEGF, Flt-1, and Flk-1 at the wound sites, resulting in accelerated wound healing compared with WT mice. In contrast, leukocyte infiltration, mRNA expression of adhesion molecules, and cytokines were significantly reduced in KO mice. These observations suggest that TNF-Rp55-mediated signals have some role in promoting leukocyte infiltration at the wound site and negatively affect wound healing, probably by reducing angiogenesis and collagen accumulation.

  13. Salidroside accelerates fracture healing through cell-autonomous and non-autonomous effects on osteoblasts.

    PubMed

    Guo, Xiao Qin; Qi, Lin; Yang, Jing; Wang, Yue; Wang, Chuan; Li, Zong Min; Li, Ling; Qu, Ye; Wang, Dan; Han, Ze Min

    2017-02-01

    Salidroside (SAL), a major active component of Rhodiola rosea L., exhibits diverse pharmacological effects. However, the direct roles of SAL in fracture healing remain largely unknown. Here, we demonstrate that SAL significantly promotes proliferation by altering the cell-cycle distribution of osteoblastic cells. SAL also greatly stimulates osteoblast differentiation and mineralization by inducing the expression of Runx2 and Osterix. In addition to its osteoblast-autonomous effects, SAL can activate the HIF-1α pathway coupling of angiogenesis and osteogenesis through cell-non-autonomous effects. Our in vitro results suggest that SAL significantly up-regulates HIF-1α expression at the mRNA and protein levels. Furthermore, the nuclear translocation and transcriptional activity of HIF-1α and the HIF-responsive gene VEGF increase following SAL treatment. Our mechanistic study revealed that the regulation of osteoblastic proliferation and HIF-1α expression partly involves MAPK/ERK and PI3K/Akt signaling. Our in vivo analysis also demonstrated that SAL can promote angiogenesis within the callus and accelerate fracture healing. Thus, SAL promotes skeletal regeneration in cell-autonomous and cell-non-autonomous ways and might be a potential therapy for accelerating fracture healing.

  14. Bone-Healing Capacity of PCL/PLGA/Duck Beak Scaffold in Critical Bone Defects in a Rabbit Model

    PubMed Central

    Lee, Jae Yeon; Son, Soo Jin; Son, Jun Sik; Kang, Seong Soo; Choi, Seok Hwa

    2016-01-01

    Bone defects are repaired using either natural or synthetic bone grafts. Poly(ϵ-caprolactone) (PCL), β-tricalcium phosphate (TCP), and poly(lactic-co-glycolic acid) (PLGA) are widely used as synthetic materials for tissue engineering. This study aimed to investigate the bone-healing capacity of PCL/PLGA/duck beak scaffold in critical bone defects and the oxidative stress status of the graft site in a rabbit model. The in vivo performance of 48 healthy New Zealand White rabbits, weighing between 2.5 and 3.5 kg, was evaluated. The rabbits were assigned to the following groups: group 1 (control), group 2 (PCL/PLGA hybrid scaffolds), group 3 (PCL/PLGA/TCP hybrid scaffolds), and group 4 (PCL/PLGA/DB hybrid scaffolds). A 5 mm critical defect was induced in the diaphysis of the left radius. X-ray, micro-CT, and histological analyses were conducted at (time 0) 4, 8, and 12 weeks after implantation. Furthermore, bone formation markers (bone-specific alkaline phosphatase, carboxyterminal propeptide of type I procollagen, and osteocalcin) were measured and oxidative stress status was determined. X-ray, micro-CT, biochemistry, and histological analyses revealed that the PCL/PLGA/duck beak scaffold promotes new bone formation in rabbit radius by inducing repair, suggesting that it could be a good option for the treatment of fracture. PMID:27042660

  15. Identification of a vibration regime favorable for bone healing and muscle in estrogen-deficient rats.

    PubMed

    Komrakova, Marina; Sehmisch, Stephan; Tezval, Mohammad; Ammon, Jan; Lieberwirth, Peggy; Sauerhoff, Cordula; Trautmann, Lukas; Wicke, Michael; Dullin, Christian; Stuermer, Klaus M; Stuermer, Ewa K

    2013-06-01

    Numerous whole-body vibration (WBV) devices of various forces are available on the market, although their influence on the musculoskeletal system is not yet understood. The effect of different WBVs on bone healing and muscle function was evaluated in rats ovariectomized at 3 months of age. 2 months after ovariectomy, bilateral metaphyseal tibia osteotomy and T-plate osteosynthesis were performed. Rats were divided into groups: intact, OVX, and OVX exposed to vertical WBVs of 35, 50, 70, or 90 Hz (experiment 1) or horizontal WBVs of 30, 50, 70, or 90 Hz (experiment 2) 5 days after osteotomy (0.5 mm, 15 min/day for 30 days). The tibia and gastrocnemius and soleus muscles were collected. Vertical vibrations (>35 Hz) improved cortical and callus densities, enlarged callus area and width, suppressed the tartrate-resistant acid phosphatase gene, enhanced citrate synthase activity, accelerated osteotomy bridging (35 and 50 Hz), upregulated the osteocalcin (Oc) gene (70 Hz), and increased relative muscle weight (50 Hz). Horizontal vibrations reduced cortical width (<90 Hz) and callus density (30 Hz), enhanced alkaline phosphatase (Alp) gene expression (50 Hz), decreased the size of oxidative fibers (35 and 70 Hz), and increased capillary density (70, 90 Hz). Biomechanical data; serum Oc, Alp, and creatine kinase activities; body weight; and food intake did not change after WBVs. Vertical WBVs of 35 and 50 Hz produced more favorable results than the higher frequencies. Horizontal WBV showed no positive or negative effects. Further studies are needed to elucidate the effects of WBV on different physiological systems, and precautions must be taken when implementing WBV in the treatment of patients.

  16. 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

  17. Knockout of Endothelial Cell-Derived Endothelin-1 Attenuates Skin Fibrosis but Accelerates Cutaneous Wound Healing

    PubMed Central

    Makino, Katsunari; Jinnin, Masatoshi; Aoi, Jun; Kajihara, Ikko; Makino, Takamitsu; Fukushima, Satoshi; Sakai, Keisuke; Nakayama, Kazuhiko; Emoto, Noriaki; Yanagisawa, Masashi; Ihn, Hironobu

    2014-01-01

    Endothelin (ET)-1 is known for the most potent vasoconstrictive peptide that is released mainly from endothelial cells. Several studies have reported ET-1 signaling is involved in the process of wound healing or fibrosis as well as vasodilation. However, little is known about the role of ET-1 in these processes. To clarify its mechanism, we compared skin fibrogenesis and wound repair between vascular endothelial cell-specific ET-1 knockout mice and their wild-type littermates. Bleomycin-injected fibrotic skin of the knockout mice showed significantly decreased skin thickness and collagen content compared to that of wild-type mice, indicating that bleomycin-induced skin fibrosis is attenuated in the knockout mice. The mRNA levels of transforming growth factor (TGF)-β were decreased in the bleomycin-treated skin of ET-1 knockout mice. On the other hand, skin wound healing was accelerated in ET-1 knockout mice, which was indicated by earlier granulation tissue reduction and re-epithelialization in these mice. The mRNA levels of TGF-β, tumor necrosis factor (TNF)-α and connective tissue growth factor (CTGF) were reduced in the wound of ET-1 knockout mice. In endothelial ET-1 knockout mouse, the expression of TNF-α, CTGF and TGF-β was down-regulated. Bosentan, an antagonist of dual ET receptors, is known to attenuate skin fibrosis and accelerate wound healing in systemic sclerosis, and such contradictory effect may be mediated by above molecules. The endothelial cell-derived ET-1 is the potent therapeutic target in fibrosis or wound healing, and investigations of the overall regulatory mechanisms of these pathological conditions by ET-1 may lead to a new therapeutic approach. PMID:24853267

  18. Local gentamicin application does not interfere with bone healing in a rat model.

    PubMed

    Fassbender, M; Minkwitz, S; Kronbach, Z; Strobel, C; Kadow-Romacker, A; Schmidmaier, G; Wildemann, B

    2013-08-01

    For the prophylaxis and treatment of bony infections antibiotics are locally used. Since several decades antibiotics mixed with bone cement (methylmethacrylate) are successfully used in prosthetic surgery and a gentamicin coated tibial nail is approved in Europe for fracture stabilization. The goal of the present study was to investigate if gentamicin, locally applied from a polymeric coating of intramedullary nails, might interfere with the bone healing process. Female Sprague Dawley rats (n = 72) were used and the tibiae were intramedullary stabilized with Kirschner-wires (k-wires) after osteotomy. This model was established earlier and shows a delayed healing with a prolonged inflammatory reaction. The open approach is clinically more relevant compared to a closed one because it mimics the clinically critical case of an open fracture, which has a higher risk of infection. The k-wire was either coated with the polymer poly(d,l-lactide) (control group) or with 10% gentamicin incorporated into the polymer (gentamicin group). In vivo μCT analyses were performed at days 10, 28, 42, and 84 after osteotomy. Mechanical torsional testing and histological evaluation were done at the days of sacrifice: 28, 42, and 84. The μCT analyses revealed an increase in tissue mineral density (TMD) over the healing period in both groups. In the control group, the torsional stiffness and maximum load did not reach the values of the intact contralateral side at any time point. At day 84 the gentamicin treated tibiae, however, showed significantly better maximum load compared to the control group. The histology showed no bony bridging in the control, whereas in 2 of 5 calluses of the gentamicin group mineralized bridging occurred. Significantly more mineralized tissue was measured in the gentamicin group. This study shows that the local gentamicin application does not negatively interfere with the long term healing process. Local infection prophylaxis is effective without negative

  19. 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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:25299783

  1. Boric Acid Reduces the Formation of DNA Double Strand Breaks and Accelerates Wound Healing Process.

    PubMed

    Tepedelen, Burcu Erbaykent; Soya, Elif; Korkmaz, Mehmet

    2016-12-01

    Boron is absorbed by the digestive and respiratory system, and it was considered that it is converted to boric acid (BA), which was distributed to all tissues above 90 %. The biochemical essentiality of boron element is caused by boric acid because it affects the activity of several enzymes involved in the metabolism. DNA damage repair mechanisms and oxidative stress regulation is quite important in the transition stage from normal to cancerous cells; thus, this study was conducted to investigate the protective effect of boric acid on DNA damage and wound healing in human epithelial cell line. For this purpose, the amount of DNA damage occurred with irinotecan (CPT-11), etoposide (ETP), doxorubicin (Doxo), and H2O2 was determined by immunofluorescence through phosphorylation of H2AX((Ser139)) and pATM((Ser1981)) in the absence and presence of BA. Moreover, the effect of BA on wound healing has been investigated in epithelial cells treated with these agents. Our results demonstrated that H2AX((Ser139)) foci numbers were significantly decreased in the presence of BA while wound healing was accelerated by BA compared to that in the control and only drug-treated cells. Eventually, the results indicate that BA reduced the formation of DNA double strand breaks caused by agents as well as improving the wound healing process. Therefore, we suggest that boric acid has important therapeutical effectiveness and may be used in the treatment of inflammatory diseases where oxidative stress and wound healing process plays an important role.

  2. Healing of fracturing-bone disease occurring in patients on dialysis. A prospective study.

    PubMed

    Milne, F J; Hudson, G A; Meyers, A M; Baily, P; Barmeir, E; Dubowitz, B; Reis, P

    1982-06-19

    Ten patients developed fracturing-bone disease (osteomalacia) while on dialysis against water with high levels of aluminium. Eight patients remained on dialysis, using de-ionized or reverse-osmosis water, and 2 received a renal transplant. Clinical improvement as regards bone pain and proximal muscle weakness occurred in 6 months and radiographic evidence of healing of the pseudofractures was seen at approximately 12 months. Associated osteopenia and hyperparathyroidism were found in most patients, but no significant change in either was noted during the study period. The serum parathyroid hormone levels rose significantly in the patients who remained on dialysis. The chest and pelvic deformities typical of healed osteomalacia were seen. This dramatic improvement can only be attributed to the removal of some water-borne element, either by changing the water used in the dialysis or by successful renal transplantation. Aluminium-containing phosphate binders were used throughout the study in the patients on dialysis, and hypophosphataemia was never a feature.

  3. Enhanced Healing of Segmental Bone Defects by Modulation of the Mechanical Environment

    DTIC Science & Technology

    2012-10-01

    enhances healing of a 2-mm tibial osteotomy in dogs16 but not a 1-mm femoral osteotomy in rats17. Using the latter model, however, Claes et al.18 showed that...defect. In the groups with the two lower-stiffness fixators, there was evidence of a periosteal reaction adjacent to the defect gap around the periosteum...the collagen sponge, with periosteal new bone formation on the bone adjacent to the defect. This presented as the for- mation of external callus, with

  4. Synchrotron imaging reveals bone healing and remodelling strategies in extinct and extant vertebrates

    PubMed Central

    Anné, Jennifer; Edwards, Nicholas P.; Wogelius, Roy A.; Tumarkin-Deratzian, Allison R.; Sellers, William I.; van Veelen, Arjen; Bergmann, Uwe; Sokaras, Dimosthenis; Alonso-Mori, Roberto; Ignatyev, Konstantin; Egerton, Victoria M.; Manning, Phillip L.

    2014-01-01

    Current understanding of bone healing and remodelling strategies in vertebrates has traditionally relied on morphological observations through the histological analysis of thin sections. However, chemical analysis may also be used in such interpretations, as different elements are known to be absorbed and used by bone for different physiological purposes such as growth and healing. These chemical signatures are beyond the detection limit of most laboratory-based analytical techniques (e.g. scanning electron microscopy). However, synchrotron rapid scanning–X-ray fluorescence (SRS–XRF) is an elemental mapping technique that uniquely combines high sensitivity (ppm), excellent sample resolution (20–100 µm) and the ability to scan large specimens (decimetre scale) approximately 3000 times faster than other mapping techniques. Here, we use SRS–XRF combined with microfocus elemental mapping (2–20 µm) to determine the distribution and concentration of trace elements within pathological and normal bone of both extant and extinct archosaurs (Cathartes aura and Allosaurus fragilis). Results reveal discrete chemical inventories within different bone tissue types and preservation modes. Chemical inventories also revealed detail of histological features not observable in thin section, including fine structures within the interface between pathological and normal bone as well as woven texture within pathological tissue. PMID:24806709

  5. Immunohistochemical characterization of wound healing at two different bone graft substitutes.

    PubMed

    Sager, M; Ferrari, D; Wieland, M; Dard, M; Becker, J; Schwarz, F

    2012-05-01

    The immunohistochemical characteristics of wound healing following application of a biphasic calcium phosphate or a collagen coated natural bone combined with a native collagen membrane in a dog model was assessed. Standardized buccal dehiscence-type defects were surgically created following implant bed preparation in 6 dogs. Following implant placement, defects were randomly filled with a collagen coated natural bone mineral (GBO), or a biphasic hydroxyapatite/beta tricalcium phosphate (SBC), and covered with a native collagen membrane. After 1, 4, and 9 weeks' submerged healing, dissected blocks were processed for immunohistochemical (collagen type I (CI), osteocalcin (OC), angiogenesis (TG)) analysis. At 1 week, GBO and SBC granules were homogeneously surrounded by a well vascularized, non-mineralized tissue (NMT). CI and OC antigen reactivity was commonly observed adjacent to both bone graft substitutes. At 4 and 9 weeks, SBC and GBO granules were completely integrated into a secondly formed network of spongiosa. At 9 weeks, dissolution of some granules was observed in the SBC group. Adjacent to these granules, NMT was significantly increased and revealed a pronounced CI, OC and TG antigen reactivity. The initial pattern of bone regeneration and graft integration was comparable in both groups; bone remodelling was more pronounced with SBC.

  6. Synchrotron imaging reveals bone healing and remodelling strategies in extinct and extant vertebrates.

    PubMed

    Anné, Jennifer; Edwards, Nicholas P; Wogelius, Roy A; Tumarkin-Deratzian, Allison R; Sellers, William I; van Veelen, Arjen; Bergmann, Uwe; Sokaras, Dimosthenis; Alonso-Mori, Roberto; Ignatyev, Konstantin; Egerton, Victoria M; Manning, Phillip L

    2014-07-06

    Current understanding of bone healing and remodelling strategies in vertebrates has traditionally relied on morphological observations through the histological analysis of thin sections. However, chemical analysis may also be used in such interpretations, as different elements are known to be absorbed and used by bone for different physiological purposes such as growth and healing. These chemical signatures are beyond the detection limit of most laboratory-based analytical techniques (e.g. scanning electron microscopy). However, synchrotron rapid scanning-X-ray fluorescence (SRS-XRF) is an elemental mapping technique that uniquely combines high sensitivity (ppm), excellent sample resolution (20-100 µm) and the ability to scan large specimens (decimetre scale) approximately 3000 times faster than other mapping techniques. Here, we use SRS-XRF combined with microfocus elemental mapping (2-20 µm) to determine the distribution and concentration of trace elements within pathological and normal bone of both extant and extinct archosaurs (Cathartes aura and Allosaurus fragilis). Results reveal discrete chemical inventories within different bone tissue types and preservation modes. Chemical inventories also revealed detail of histological features not observable in thin section, including fine structures within the interface between pathological and normal bone as well as woven texture within pathological tissue.

  7. Decreased BMP2 signal in GIT1 knockout mice slows bone healing

    PubMed Central

    Fan, Jin; Zhou, Hao; Zuscik, Michael J.; Xie, Chao; Yin, Guoyong; Berk, Bradford C.

    2015-01-01

    Endochondral ossification, an important stage of fracture healing, is regulated by a variety of signaling pathways. Transforming growth factor b (TGFb) superfamily plays important roles and comprises TGFbs, bone morphogenetic proteins (BMPs), and growth differentiation factors. TGFbs primarily regulate cartilage formation and endochondral ossification. BMP2 shows diverse efficacy, from the formation of skeleton and extraskeletal organs to the osteogenesis and remodeling of bone. G-protein-coupled receptor kinase 2-interacting protein-1 (GIT1), a shuttle protein in osteoblasts, facilitates fracture healing by promoting bone formation and increasing the secretion of vascular endothelial growth factor. Our study examined whether GIT1 regulates fracture healing through the BMP2 signaling pathway and/or through the TGFb signaling pathway. GIT1 knockout (KO) mice exhibited delayed fracture healing, chondrocyte accumulation in the fracture area, and reduced staining intensity of phosphorylated Smad1/5/8 (pSmad1/5/8) and Runx2. Endochondral mineralization diminished while the staining intensity of phosphorylated Smad2/3 (pSmad2/3) showed no significant change. Bone marrow mesenchymal stem cells extracted from GIT1 KO mice showed a decline of pSmad1/5/8 levels and of pSmad1/5/8 translocated into the cell nucleus after BMP2 stimulus. We detected no significant change in the pSmad2/3 level after TGFb1 stimulus. Data obtained from reporter gene analysis of C3H10T1/2 cells cultured in vitro confirmed these findings. GIT1-siRNA inhibited transcription in the cell nucleus via pSmad1/5/8 after BMP2 stimulus but had no significant effect on transcription via pSmad2/3 after TGFb1 stimulus. Our results indicate that GIT1 regulates Smad1/5/8 phosphorylation and mediates BMP2 regulation of Runx2 expression, thus affecting endochondral ossification at the fracture site. PMID:25138700

  8. Exogenous PTHrP Repairs the Damaged Fracture Healing of PTHrP+/− Mice and Accelerates Fracture Healing of Wild Mice

    PubMed Central

    Wang, Yinhe; Fang, Xin; Wang, Chun; Ding, Congzhu; Lin, Hua; Liu, Anlong; Wang, Lei; Cao, Yang

    2017-01-01

    Bone fracture healing is a complicated physiological regenerative process initiated in response to injury and is similar to bone development. To demonstrate whether an exogenous supply of parathyroid hormone–related protein (PTHrP) helps in bone fracture healing, closed mid-diaphyseal femur fractures were created and stabilized with intramedullary pins in eight-week-old wild-type (WT) PTHrP+/+ and PTHrP+/− mice. After administering PTHrP for two weeks, callus tissue properties were analyzed at one, two, and four weeks post-fracture (PF) by various methods. Bone formation–related genes and protein expression levels were evaluated by real-time reverse transcriptase–polymerase chain reaction and Western blots. At two weeks PF, mineral density of callus, bony callus areas, mRNA levels of alkaline phosphatase (ALP), type I collagen, Runt-related transcription factor 2 (Runx-2), and protein levels of Runx-2 and insulin-like growth factor-1 decreased in PTHrP+/− mice compared with WT mice. At four weeks PF, total collagen-positive bony callus areas, osteoblast number, ALP-positive areas, and type I collagen-positive areas all decreased in PTHrP+/− mice. At both two and four weeks PF, tartrate-resistant acid phosphatase–positive osteoclast number and surface decreased a little in PTHrP+/− mice. The study indicates that exogenous PTHrP provided by subcutaneous injection could redress impaired bone fracture healing, leading to mutation of activated PTHrP by influencing callus areas, endochondral bone formation, osteoblastic bone formation, and bone turnover. PMID:28178186

  9. Micro-CT Analysis of Bone Healing in Rabbit Calvarial Critical-Sized Defects with Solid Bioactive Glass, Tricalcium Phosphate Granules or Autogenous Bone

    PubMed Central

    Karhula, Sakari S.; Haapea, Marianne; Kauppinen, Sami; Finnilä, Mikko; Saarakkala, Simo; Serlo, Willy; Sándor, George K.

    2016-01-01

    ABSTRACT Objectives The purpose of the present study was to evaluate bone healing in rabbit critical-sized calvarial defects using two different synthetic scaffold materials, solid biodegradable bioactive glass and tricalcium phosphate granules alongside solid and particulated autogenous bone grafts. Material and Methods Bilateral full thickness critical-sized calvarial defects were created in 15 New Zealand white adult male rabbits. Ten defects were filled with solid scaffolds made of bioactive glass or with porous tricalcium phosphate granules. The healing of the biomaterial-filled defects was compared at the 6 week time point to the healing of autologous bone grafted defects filled with a solid cranial bone block in 5 defects and with particulated bone combined with fibrin glue in 10 defects. In 5 animals one defect was left unfilled as a negative control. Micro-computed tomography (micro-CT) was used to analyze healing of the defects. Results Micro-CT analysis revealed that defects filled with tricalcium phosphate granules showed new bone formation in the order of 3.89 (SD 1.17)% whereas defects treated with solid bioactive glass scaffolds showed 0.21 (SD 0.16)%, new bone formation. In the empty negative control defects there was an average new bone formation of 21.8 (SD 23.7)%. Conclusions According to findings in this study, tricalcium phosphate granules have osteogenic potential superior to bioactive glass, though both particulated bone with fibrin glue and solid bone block were superior defect filling materials. PMID:27489608

  10. Orthotopic bone transplantation in mice. III. Methods of reducing the immune response and their effect on healing

    SciTech Connect

    Kliman, M.; Halloran, P.F.; Lee, E.; Esses, S.; Fortner, P.; Langer, F.

    1981-01-01

    Various methods of reducing the immune response to allogeneic bone grafts, either by pretreating the graft or by immunosuppressing the recipient, were compared. Tibial grafts from B10.D2 mice, either untreated or pretreated in various ways, were transplanted into B10 recipients. The antibody response was followed and the extent of bone healing at 4 months was assessed. Pretreatment of the graft by X-irradiation, freezing, or by incubation in alloantisera (either anti-H-2 or anti-Ia) reduced or abolished the immunogenicity of the graft. Immunosuppression of the recipient with methotrexate or antilymphocyte serum (ALS) also greatly depressed the antibody response. But when healing was assessed, none of these treatments except ALS improved the delayed healing of the bone allografts. The reason for this failure was probably that X-irradiation, freezing, alloantiserum pretreatment, and methotrexate all interfered with bone healing directly, whereas ALS did not. We conclude that many methods will reduce the immune response to allogeneic bone, but that only ALS will improve the healing of the allogeneic bone. Furthermore, as a corollary to the observation that pretreatment with anti-Ia serum markedly reduced the immunogenicity of bone allografts, we conclude that much of the immunogenicity of bone allografts is attributable to a population of Ia-positive cells.

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

    PubMed

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

    2006-05-01

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

  12. The effects of physiologic dynamic compression on bone healing under external fixation

    SciTech Connect

    Aro, H.T.; Kelly, P.J.; Lewallen, D.G.; Chao, E.Y. )

    1990-07-01

    The effects of early physiologic dynamic compression on fracture healing were studied in the dog. Transverse midtibial osteotomies were performed bilaterally and stabilized with a relatively rigid external fixation system in a neutralization mode (800 microns) to prevent compression of the osteotomy ends during weight bearing. On the 15th day, one osteotomy in each animal was subjected to dynamic compression through weight bearing by release of the fixator-telescoping mechanism (axial dynamization), while the other side remained unchanged as the control. Analysis of sequential roentgenograms showed that the callus distribution was more symmetric on the dynamic compression side. The two sides showed no significant differences in quantitative technetium-99 bone scans or in osteotomy-site blood flow. There were no statistical differences in new bone formation, bone porosity, or maximum torque between sides. The fixation had maintained the initially created osteotomy gap on the control side and tended to unite through a gap-healing mechanism. The dynamic compression side showed reduction in gap size and union by more of a contact-healing mechanism. There were no statistical differences in the rate of pin loosening, but its distribution according to pin location was significantly different between the two sides.

  13. Biomaterial-Stabilized Soft Tissue Healing for Healing of Critical-Sized Bone Defects: the Masquelet Technique.

    PubMed

    Tarchala, Magdalena; Harvey, Edward J; Barralet, Jake

    2016-03-01

    Critical-sized bone defects present a significant burden to the medical community due to their challenging treatment. However, a successful limb-salvaging technique, the Masquelet Technique (MT), has significantly improved the prognosis of many segmental bone defects in helping to restore form and function. Although the Masquelet Technique has proven to be clinically effective, the physiology of the healing it induces is not well understood. Multiple modifiable factors have been implicated by various surgical and research teams, but no single factor has been proven to be critical to the success of the Masquelet Technique. In this review the most recent clinical and experimental evidence that supports and helps to decipher the traditional Masquelet, as well as the modifiable factors and their effect on the success of the technique are discussed. In addition, future developments for the integration of the traditional Masquelet Technique with the use of alternative biomaterials to increase the effectiveness and expand the clinical applicability of the Masquelet Technique are reviewed.

  14. Soluble VEGFR1 reverses BMP2 inhibition of intramembranous ossification during healing of cortical bone defects.

    PubMed

    Hu, Kai; Besschetnova, Tatiana Y; Olsen, Bjorn R

    2016-09-07

    BMP2 is widely used for promotion of bone repair and regeneration. However, bone formation induced by BMP2 is quite variable. Bone forming progenitor cells in different locations appear to respond to BMP2 in different ways, and repair outcomes can vary as a consequence of modulating effects by other factors. In this study, we have examined the effects of VEGF on BMP2-induced repair of a cortical bone defect, a 1 mm diameter drill hole, in the proximal tibia of mice. Treatment of the defect with either a bolus of PBS or soluble VEGFR1 (sVEGFR1), a decoy receptor for VEGF, had the same effects on bone formation via intramembranous ossification in the defect and cartilage formation and injured periosteum, during the healing process. In contrast, treatment with BMP2 inhibited intramembranous bone formation in the defect while it promoted cartilage and endochondral bone formation in the injured periosteum compared with mice treated with PBS or sVEGFR1. The inhibitory effect of BMP2 on bone formation was unlikely due to increased osteoclast activity and decreased invasion of blood vessels in the defect. Most importantly, co-delivery of BMP2 and sVEGFR1 reversed the inhibition of intramembranous bone formation by BMP2. Furthermore, the decreased accumulation of collagen and production of bone matrix proteins in the defect of groups with BMP2 treatment could also be prevented by co-delivery of BMP2 and sVEGFR1. Our data indicate that introducing a VEGF-binding protein, such as sVEGFR1, to reduce levels of extracellular VEGF, may enhance the effects of BMP2 on intramembranous bone formation. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

  15. Knee loading protects against osteonecrosis of the femoral head by enhancing vessel remodeling and bone healing.

    PubMed

    Liu, Daquan; Li, Xinle; Li, Jie; Yang, Jing; Yokota, Hiroki; Zhang, Ping

    2015-12-01

    Osteonecrosis of the femoral head is a serious orthopedic problem. Moderate loads with knee loading promote bone formation, but their effects on osteonecrosis have not been investigated. Using a rat model, we examined a hypothesis that knee loading enhances vessel remodeling and bone healing through the modulation of the fate of bone marrow-derived cells. In this study, osteonecrosis was induced by transecting the ligamentum teres followed by a tight ligature around the femoral neck. For knee loading, 5 N loads were laterally applied to the knee at 15 Hz for 5 min/day for 5 weeks. Changes in bone mineral density (BMD) and bone mineral content (BMC) of the femur were measured by pDEXA, and ink infusion was performed to evaluate vessel remodeling. Femoral heads were harvested for histomorphometry, and bone marrow-derived cells were isolated to examine osteoclast development and osteoblast differentiation. The results showed that osteonecrosis significantly induced bone loss, and knee loading stimulated both vessel remodeling and bone healing. The osteonecrosis group exhibited the lowest trabecular BV/TV (p b 0.001) in the femoral head, and lowest femoral BMD and BMC (both p b 0.01). However, knee loading increased trabecular BV/TV (p b 0.05) as well as BMD (pb 0.05) and BMC (p b 0.01). Osteonecrosis decreased the vessel volume (pb 0.001), vessel number (pb 0.001) and VEGF expression (p b 0.01), and knee loading increased them (pb 0.001, pb 0.001 and p b 0.01). Osteonecrosis activated osteoclast development, and knee loading reduced its formation, migration, adhesion and the level of “pit” formation (pb 0.001, pb 0.01, pb 0.001 and pb 0.001). Furthermore, knee loading significantly increased osteoblast differentiation and CFU-F (both p b 0.001). A significantly positive correlation was observed between vessel remodeling and bone healing (both p b 0.01). These results indicate that knee loading could be effective in repair osteonecrosis of the femoral head in a rat

  16. Novel locally active estrogens accelerate cutaneous wound healing. A preliminary study.

    PubMed

    Brufani, Mario; Ceccacci, Francesca; Filocamo, Luigi; Garofalo, Barbara; Joudioux, Roberta; La Bella, Angela; Leonelli, Francesca; Migneco, Luisa M; Bettolo, Rinaldo Marini; Farina, Paolo M; Ashcroft, Gillian S; Routley, Claire; Hardman, Matthew; Meda, Clara; Rando, Gianpaolo; Maggi, Adriana

    2009-01-01

    New 17beta-estradiol (E2) derivatives 1-11 were synthesized from an estrone derivative by addition of organometallic reagents prepared from protected alpha,omega-alkynols and further elaboration of the addition products. The estrogenic activity of these novel compounds was determined using in vitro binding competition assay and transactivation analysis. Among the E2 derivatives synthesized, compound 2 showed the highest transactivation potency and was therefore tested for its ability to modulate cutaneous wound healing in vivo. Compound 2's ability to accelerate wound healing in ovariectomized mice and decrease the production of inflammatory molecules was comparable to that of E2. However, the activity of compound 2 was not superimposable to E2 with regard to the cells involved in the wound repairing process. When locally administered, compound 2 did not show any systemic activity on ER. This class of compounds with clear beneficial effects on wound healing and suitable for topical administration may lead to the generation of innovative drugs for an area of unmet clinical need.

  17. 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.

  18. 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.

  19. Microfluidic 3D bone tissue model for high-throughput evaluation of wound-healing and infection-preventing biomaterials.

    PubMed

    Lee, Joung-Hyun; Gu, Yexin; Wang, Hongjun; Lee, Woo Y

    2012-02-01

    We report the use of a microfluidic 3D bone tissue model, as a high-throughput means of evaluating the efficacy of biomaterials aimed at accelerating orthopaedic implant-related wound-healing while preventing bacterial infection. As an example of such biomaterials, inkjet-printed micropatterns were prepared to contain antibiotic and biphasic calcium phosphate (BCP) nanoparticles dispersed in a poly(D,L-lactic-co-glycolic) acid matrix. The micropatterns were integrated with a microfluidic device consisting of eight culture chambers. The micropatterns immediately and completely killed Staphylococcus epidermidis upon inoculation, and enhanced the calcified extracellular matrix production of osteoblasts. Without antibiotic elution, bacteria rapidly proliferated to result in an acidic microenvironment which was detrimental to osteoblasts. These results were used to demonstrate the tissue model's potential in: (i) significantly reducing the number of biomaterial samples and culture experiments required to assess in vitro efficacy for wound-healing and infection prevention and (ii) in situ monitoring of dynamic interactions of biomaterials with bacteria as wells as with tissue cells simultaneously.

  20. Dietary arginine silicate inositol complex increased bone healing: histologic and histomorphometric study

    PubMed Central

    Yaman, Ferhan; Acikan, Izzet; Dundar, Serkan; Simsek, Sercan; Gul, Mehmet; Ozercan, Ibrahim Hanifi; Komorowski, James; Sahin, Kazim

    2016-01-01

    Background Arginine silicate inositol complex (ASI; arginine 49.5%, silicon 8.2%, and inositol 25%) is a novel material that is a bioavailable source of silicon and arginine. ASI offers potential benefits for vascular and bone health. Objective The aim of this study was to evaluate the potential effects of ASI complex on bone healing of critical-sized defects in rats. Methods The rats were randomly assigned to two groups of 21 rats each. The control group was fed a standard diet for 12 weeks; after the first 8 weeks, a calvarial critical-sized defect was created, and the rats were sacrificed 7, 14, and 28 days later. The ASI group was fed a diet containing 1.81 g/kg of ASI for 12 weeks; after the first 8 weeks, a calvarial critical-sized defect was created, and the rats were sacrificed 7, 14, and 28 days later. The calvarial bones of all the rats were then harvested for evaluation. Results Osteoblasts and osteoclasts were detected at higher levels in the ASI group compared with the control group at days 7, 14, and 28 of the calvarial defect (P<0.05). New bone formation was detected at higher levels in the ASI group compared with the controls at day 28 (P<0.05). However, new bone formation was not detected at days 7 and 14 in both the groups (P>0.05). Conclusion ASI supplementation significantly improved bone tissue healing in rats with critical-sized defects. This study demonstrated that ASI can enhance bone repair and has potential as a therapeutic regimen in humans. PMID:27390517

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

    PubMed Central

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

    2015-01-01

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

  2. Accelerated healing of cutaneous leishmaniasis in non-healing BALB/c mice using water soluble amphotericin B-polymethacrylic acid

    PubMed Central

    Corware, Karina; Harris, Debra; Teo, Ian; Rogers, Matthew; Naresh, Kikkeri; Müller, Ingrid; Shaunak, Sunil

    2011-01-01

    Cutaneous leishmaniasis (CL) is a neglected tropical disease that causes prominent skin scaring. No water soluble, non-toxic, short course and low cost treatment exists. We developed a new water soluble amphotericin B-polymethacrylic acid (AmB-PMA) using established and scalable chemistries. AmB-PMA was stable for 9 months during storage. In vitro, it was effective against Leishmania spp. promastigotes and amastigote infected macrophages. It was also less toxic and more effective than deoxycholate-AmB, and similar to liposomal AmB. Its in vivo activity was determined in both early and established CL lesion models of Leishmania major infection in genetically susceptible non-healing BALB/c mice. Intradermal AmB-PMA at a total dose of 18 mg of AmB/kg body weight led to rapid parasite killing and lesion healing. No toxicity was seen. No parasite relapse occurred after 80 days follow-up. Histological studies confirmed rapid parasite clearance from macrophages followed by accelerated fibroblast mediated tissue repair, regeneration and cure of the infection. Quantitative mRNA studies of the CL lesions showed that accelerated healing was associated with increased Tumor Necrosis Factor-α and Interferon-γ, and reduced Interleukin-10. These results suggest that a cost-effective AmB-PMA could be used to pharmacologically treat and immunotherapeutically accelerate the healing of CL lesions. PMID:21807409

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

    PubMed Central

    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

  4. 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

  5. Administration of obestatin accelerates the healing of chronic gastric ulcers in rats

    PubMed Central

    Dembiński, Artur; Warzecha, Zygmunt; Ceranowicz, Piotr; Cieszkowski, Jakub; Dembiński, Marcin; Ptak-Belowska, Agata; Kuwahara, Atsukasu; Kato, Ikuo

    2011-01-01

    Summary Background Previous studies have shown that administration of obestatin exhibits a protective effect in the pancreas, attenuating the development of acute pancreatitis. The aim of the present study was to investigate the influence of obestatin administration on the healing of chronic gastric ulcers. Material/Methods Chronic gastric ulcers were induced in rats by 100% acetic acid applied to the serosal surface of the gastric wall. Obestatin was given twice a day intraperitoneally at the dose of 4, 8 or 16 nmol/kg/dose for 6 days. Six days after induction of ulcers, rats were anesthetized and the stomach was exposed for measurement of gastric blood flow and ulcer area. Biopsy samples from the gastric mucosa were taken for determination of mucosal DNA synthesis and for measurement of gastric expression of mRNA for interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Results Induction of gastric ulcers alone increased mucosal blood flow and tissue expression of mRNA for TNF-α and IL-1β, whereas gastric mucosal DNA synthesis was reduced. In rats with gastric ulcers, administration of obestatin increased gastric mucosal blood flow, accelerated the healing rate of these ulcers and partly reversed the gastric ulcer-induced reduction in gastric mucosal DNA synthesis. These results were associated with a reduction in gastric mucosal expression of pro-inflammatory IL-1β and TNF-α. Conclusions Treatment with obestatin increases gastric mucosal blood flow and cell proliferation, leading to acceleration of healing of gastric ulcers. These effects are associated with a reduction in mucosal expression of pro-inflammatory IL-1β and TNF-α. PMID:21804455

  6. Functional attachment of soft tissues to bone: development, healing, and tissue engineering.

    PubMed

    Lu, Helen H; Thomopoulos, Stavros

    2013-01-01

    Connective tissues such as tendons or ligaments attach to bone across a multitissue interface with spatial gradients in composition, structure, and mechanical properties. These gradients minimize stress concentrations and mediate load transfer between the soft and hard tissues. Given the high incidence of tendon and ligament injuries and the lack of integrative solutions for their repair, interface regeneration remains a significant clinical challenge. This review begins with a description of the developmental processes and the resultant structure-function relationships that translate into the functional grading necessary for stress transfer between soft tissue and bone. It then discusses the interface healing response, with a focus on the influence of mechanical loading and the role of cell-cell interactions. The review continues with a description of current efforts in interface tissue engineering, highlighting key strategies for the regeneration of the soft tissue-to-bone interface, and concludes with a summary of challenges and future directions.

  7. The influence of root surface distance to alveolar bone and periodontal ligament on periodontal wound healing

    PubMed Central

    2016-01-01

    Purpose The purpose of this animal study was to perform a 3-dimensional micro-computed tomography (micro-CT) analysis in order to investigate the influence of root surface distance to the alveolar bone and the periodontal ligament on periodontal wound healing after a guided tissue regeneration (GTR) procedure. Methods Three adult Sus scrofa domesticus specimens were used. The study sample included 6 teeth, corresponding to 2 third mandibular incisors from each animal. After coronectomy, a circumferential bone defect was created in each tooth by means of calibrated piezoelectric inserts. The experimental defects had depths of 3 mm, 5 mm, 7 mm, 9 mm, and 11 mm, with a constant width of 2 mm. One tooth with no defect was used as a control. The defects were covered with a bioresorbable membrane and protected with a flap. After 6 months, the animals were euthanised and tissue blocks were harvested and preserved for micro-CT analysis. Results New alveolar bone was consistently present in all experimental defects. Signs of root resorption were observed in all samples, with the extent of resorption directly correlated to the vertical extent of the defect; the medial third of the root was the most commonly affected area. Signs of ankylosis were recorded in the defects that were 3 mm and 7 mm in depth. Density and other indicators of bone quality decreased with increasing defect depth. Conclusions After a GTR procedure, the periodontal ligament and the alveolar bone appeared to compete in periodontal wound healing. Moreover, the observed decrease in bone quality indicators suggests that intrabony defects beyond a critical size cannot be regenerated. This finding may be relevant for the clinical application of periodontal regeneration, since it implies that GTR has a dimensional limit. PMID:27800213

  8. N-Acetylated Proline-Glycine-Proline Accelerates Cutaneous Wound Healing and Neovascularization by Human Endothelial Progenitor Cells

    PubMed Central

    Kwon, Yang Woo; Heo, Soon Chul; Lee, Tae Wook; Park, Gyu Tae; Yoon, Jung Won; Jang, Il Ho; Kim, Seung-Chul; Ko, Hyun-Chang; Ryu, Youngjae; Kang, Hyeona; Ha, Chang Man; Lee, Sang Chul; Kim, Jae Ho

    2017-01-01

    Human endothelial progenitor cells (hEPCs) are promising therapeutic resources for wound repair through stimulating neovascularization. However, the hEPCs-based cell therapy has been hampered by poor engraftment of transplanted cells. In this study, we explored the effects of N-acetylated Proline-Glycine-Proline (Ac-PGP), a degradation product of collagen, on hEPC-mediated cutaneous wound healing and neovascularization. Treatment of hEPCs with Ac-PGP increased migration, proliferation, and tube-forming activity of hEPCs in vitro. Knockdown of CXCR2 expression in hEPCs abrogated the stimulatory effects of Ac-PGP on migration and tube formation. In a cutaneous wound healing model of rats and mice, topical application of Ac-PGP accelerated cutaneous wound healing with promotion of neovascularization. The positive effects of Ac-PGP on wound healing and neovascularization were blocked in CXCR2 knockout mice. In nude mice, the individual application of Ac-PGP treatment or hEPC injection accelerated wound healing by increasing neovascularization. Moreover, the combination of Ac-PGP treatment and hEPC injection further stimulated wound healing and neovascularization. Topical administration of Ac-PGP onto wound bed stimulated migration and engraftment of transplanted hEPCs into cutaneous dermal wounds. Therefore, these results suggest novel applications of Ac-PGP in promoting wound healing and augmenting the therapeutic efficacy of hEPCs. PMID:28230162

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

    PubMed Central

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

    2015-01-01

    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 3d (Ptch1, Gli1 expression), and was markedly inhibited by GDC-0449 at 1d and 3d in the loaded and non-loaded ulnae. GDC-0449 did not affect Hh ligand expression (Shh, Ihh, Dhh) at 1d, but decreased Shh expression by 37% at 3d. GDC-0449 decreased woven bone volume (−37%) and mineral density (−17%) at 7d. Dynamic histomorphometry revealed that the 7d 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 3d), osteoblastic differentiation (Osx expression at 1d and 3d), chondrogenic gene expression (Acan, Sox9, and Col2α1 expression at 1d and 3d), or bone resorption metrics (callus TRAP staining at 3d, Rankl and Opg expression at 1d and 3d). To evaluate angiogenesis, vWF immunohistochemistry showed that GDC-0449 reduced fracture callus blood vessel density by 55% at 3d, 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 to the woven bone callus) showed that GDC-0449

  10. 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

  11. Bone healing induced by local delivery of an engineered parathyroid hormone prodrug.

    PubMed

    Arrighi, Isabelle; Mark, Silke; Alvisi, Monica; von Rechenberg, Brigitte; Hubbell, Jeffrey A; Schense, Jason C

    2009-03-01

    Regenerative medicine requires innovative therapeutic designs to accommodate high morphogen concentrations in local depots, provide their sustained presence, and enhance cellular invasion and directed differentiation. Here we present an example for inducing local bone regeneration with a matrix-bound engineered active fragment of human parathyroid hormone (PTH(1-34)), linked to a transglutaminase substrate for binding to fibrin as a delivery and cell-invasion matrix with an intervening plasmin-sensitive link (TGplPTH(1-34)). The precursor form displays very little activity and signaling to osteoblasts, whereas the plasmin cleavage product, as it would be induced under the enzymatic influence of cells remodeling the matrix, was highly active. In vivo animal bone-defect experiments showed dose-dependent bone formation using the PTH-fibrin matrix, with evidence of both osteoconductive and osteoinductive bone-healing mechanisms. Results showed that this PTH-derivatized matrix may have potential utility in humans as a replacement for bone grafts or to repair bone defects.

  12. COX-2 FROM THE INJURY MILIEU IS CRITICAL FOR THE INITIATION OF PERIOSTEAL PROGENITOR CELL MEDIATED BONE HEALING

    PubMed Central

    Xie, Chao; Ming, Xue; Wang, Qun; Schwarz, Edward M.; Guldberg, Robert E.; O’Keefe, Regis J.; Zhang, Xinping

    2009-01-01

    Although a critical role of COX-2 in bone repair has been established, the mechanism involved remains unclear. During early inflammatory phase of bone healing, COX-2 is produced by the surrounding inflammatory cells as well as bone/cartilage progenitors. Based on the temporal and spatial expression of COX-2 during the early phase of fracture healing, we hypothesize that COX-2 from both sources is critical for progenitor cell activation, proliferation and differentiation. To directly test this we utilized a murine femoral grafting model, in which live segmental grafts from the same strains were transplanted and donor versus host cell involvement in healing was assessed. Specifically, fresh femur cortical bone grafts of 4-mm in length from COX-2-/- (KO) mice were transplanted into wild type (WT) mice with the same sized segmental defect in femurs. Similarly, grafts from WT were transplanted into the defects in KO mice. As controls, transplantations between wild types, and transplantations between KO were also performed. Histologic analyses showed that WT-to-WT transplantation resulted in normal endochondral bone healing as evidenced by markedly induction of neovascularization and periosteal bone formation on donor graft. In contrast, transplantation of KO graft into KO host led to 96 % reduction of bone formation and near elimination of donor cell-initiated periosteal bone formation. Similarly, transplantation of WT graft into a KO host resulted in 87% reduction of bone formation (n=8, p>0.05), indicating that KO host impaired WT donor progenitor cell expansion and differentiation. When a KO graft was transplanted into WT host, KO donor periosteal cell-initiated endochondral bone formation was restored. Histomorphometric analyses demonstrated 10-fold increase in bone formation and 3-fold increase in cartilage formation compared to KO-to-KO transplantation (n=8, p<0.05), suggesting that COX-2 deficient donor cells were capable to differentiate and form bone when

  13. Micro-CT analysis with multiple thresholds allows detection of bone formation and resorption during ultrasound-treated fracture healing.

    PubMed

    Freeman, Theresa A; Patel, Payal; Parvizi, Javad; Antoci, Valentin; Shapiro, Irving M

    2009-05-01

    Multiple threshold algorithms applied to microcomputed tomography analysis were used to probe the effects of low-intensity pulsed ultrasound on fracture healing. Rat femurs were fractured in accordance with IACUC guidelines. Ultrasound treatment was administered daily to one femur; the contralateral bone was treated with a sham transducer. Each week for 3 weeks healing fractures were harvested and scanned by micro-CT. Remodeling activity was confirmed by evaluation of TRAP activity. Using thresholds of 331-700 and 225-330, area of cortical bone, and new bone formation, respectively, were identified, and by inference, regions of bone resorption. The increased sensitivity of this multithresholding procedure revealed that ultrasound treatment significantly increased the rate of fracture healing in vivo by activating both new bone formation and by increasing the removal of cortical bone in a time- and site-specific manner. At week 1, compared to the proximal side, there was a significant increase in new bone formation distal to the fracture site. Removal of the existing cortical bone followed the same pattern at week 2. Results of the study indicate that at sites of bone turnover, this multithresholding analytical technique can be used to provide quantitative information on bone formation, as well as resorption.

  14. Chitosan nanofiber scaffold improves bone healing via stimulating trabecular bone production due to upregulation of the Runx2/osteocalcin/alkaline phosphatase signaling pathway.

    PubMed

    Ho, Ming-Hua; Yao, Chih-Jung; Liao, Mei-Hsiu; Lin, Pei-I; Liu, Shing-Hwa; Chen, Ruei-Ming

    2015-01-01

    Osteoblasts play critical roles in bone formation. Our previous study showed that chitosan nanofibers can stimulate osteoblast proliferation and maturation. This translational study used an animal model of bone defects to evaluate the effects of chitosan nanofiber scaffolds on bone healing and the possible mechanisms. In this study, we produced uniform chitosan nanofibers with fiber diameters of approximately 200 nm. A bone defect was surgically created in the proximal femurs of male C57LB/6 mice, and then the left femur was implanted with chitosan nanofiber scaffolds for 21 days and compared with the right femur, which served as a control. Histological analyses revealed that implantation of chitosan nanofiber scaffolds did not lead to hepatotoxicity or nephrotoxicity. Instead, imaging analyses by X-ray transmission and microcomputed tomography showed that implantation of chitosan nanofiber scaffolds improved bone healing compared with the control group. In parallel, microcomputed tomography and bone histomorphometric assays further demonstrated augmentation of the production of new trabecular bone in the chitosan nanofiber-treated group. Furthermore, implantation of chitosan nanofiber scaffolds led to a significant increase in the trabecular bone thickness but a reduction in the trabecular parameter factor. As to the mechanisms, analysis by confocal microscopy showed that implantation of chitosan nanofiber scaffolds increased levels of Runt-related transcription factor 2 (Runx2), a key transcription factor that regulates osteogenesis, in the bone defect sites. Successively, amounts of alkaline phosphatase and osteocalcin, two typical biomarkers that can simulate bone maturation, were augmented following implantation of chitosan nanofiber scaffolds. Taken together, this translational study showed a beneficial effect of chitosan nanofiber scaffolds on bone healing through stimulating trabecular bone production due to upregulation of Runx2-mediated alkaline

  15. Chitosan nanofiber scaffold improves bone healing via stimulating trabecular bone production due to upregulation of the Runx2/osteocalcin/alkaline phosphatase signaling pathway

    PubMed Central

    Ho, Ming-Hua; Yao, Chih-Jung; Liao, Mei-Hsiu; Lin, Pei-I; Liu, Shing-Hwa; Chen, Ruei-Ming

    2015-01-01

    Osteoblasts play critical roles in bone formation. Our previous study showed that chitosan nanofibers can stimulate osteoblast proliferation and maturation. This translational study used an animal model of bone defects to evaluate the effects of chitosan nanofiber scaffolds on bone healing and the possible mechanisms. In this study, we produced uniform chitosan nanofibers with fiber diameters of approximately 200 nm. A bone defect was surgically created in the proximal femurs of male C57LB/6 mice, and then the left femur was implanted with chitosan nanofiber scaffolds for 21 days and compared with the right femur, which served as a control. Histological analyses revealed that implantation of chitosan nanofiber scaffolds did not lead to hepatotoxicity or nephrotoxicity. Instead, imaging analyses by X-ray transmission and microcomputed tomography showed that implantation of chitosan nanofiber scaffolds improved bone healing compared with the control group. In parallel, microcomputed tomography and bone histomorphometric assays further demonstrated augmentation of the production of new trabecular bone in the chitosan nanofiber-treated group. Furthermore, implantation of chitosan nanofiber scaffolds led to a significant increase in the trabecular bone thickness but a reduction in the trabecular parameter factor. As to the mechanisms, analysis by confocal microscopy showed that implantation of chitosan nanofiber scaffolds increased levels of Runt-related transcription factor 2 (Runx2), a key transcription factor that regulates osteogenesis, in the bone defect sites. Successively, amounts of alkaline phosphatase and osteocalcin, two typical biomarkers that can simulate bone maturation, were augmented following implantation of chitosan nanofiber scaffolds. Taken together, this translational study showed a beneficial effect of chitosan nanofiber scaffolds on bone healing through stimulating trabecular bone production due to upregulation of Runx2-mediated alkaline

  16. 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.

  17. Modulation of fixation stiffness from flexible to stiff in a rat model of bone healing

    PubMed Central

    Bartnikowski, Nicole; Claes, Lutz E; Koval, Lidia; Glatt, Vaida; Bindl, Ronny; Steck, Roland; Ignatius, Anita; Schuetz, Michael A; Epari, Devakara R

    2017-01-01

    Background and purpose Constant fixator stiffness for the duration of healing may not provide suitable mechanical conditions for all stages of bone repair. We therefore investigated the influence of stiffening fixation on callus stiffness and morphology in a rat diaphyseal osteotomy model to determine whether healing time was shortened and callus stiffness increased through modulation of fixation from flexible to stiff. Material and methods An external unilateral fixator was applied to the osteotomized femur and stiffened by decreasing the offset of the inner fixator bar at 3, 7, 14, and 21 days after operation. After 5 weeks, the rats were killed and healing was evaluated with mechanical, histological, and microcomputed tomography methods. Constant fixation stiffness control groups with either stiff or flexible fixation were included for comparison. Results The callus stiffness of the stiff group and all 4 experimental groups was greater than in the flexible group. The callus of the flexible group was larger but contained a higher proportion of unmineralized tissue and cartilage. The stiff and modulated groups (3, 7, 14, and 21 days) all showed bony bridging at 5 weeks, as well as signs of callus remodeling. Stiffening fixation at 7 and 14 days after osteotomy produced the highest degree of callus bridging. Bone mineral density in the fracture gap was highest in animals in which the fixation was stiffened after 14 days. Interpretation The predicted benefit of a large robust callus formed through early flexible fixation could not be shown, but the benefits of stabilizing a flexible construct to achieve timely healing were demonstrated at all time points. PMID:27841708

  18. Modulation of fixation stiffness from flexible to stiff in a rat model of bone healing.

    PubMed

    Bartnikowski, Nicole; Claes, Lutz E; Koval, Lidia; Glatt, Vaida; Bindl, Ronny; Steck, Roland; Ignatius, Anita; Schuetz, Michael A; Epari, Devakara R

    2016-11-14

    Background and purpose - Constant fixator stiffness for the duration of healing may not provide suitable mechanical conditions for all stages of bone repair. We therefore investigated the influence of stiffening fixation on callus stiffness and morphology in a rat diaphyseal osteotomy model to determine whether healing time was shortened and callus stiffness increased through modulation of fixation from flexible to stiff. Material and methods - An external unilateral fixator was applied to the osteotomized femur and stiffened by decreasing the offset of the inner fixator bar at 3, 7, 14, and 21 days after operation. After 5 weeks, the rats were killed and healing was evaluated with mechanical, histological, and microcomputed tomography methods. Constant fixation stiffness control groups with either stiff or flexible fixation were included for comparison. Results - The callus stiffness of the stiff group and all 4 experimental groups was greater than in the flexible group. The callus of the flexible group was larger but contained a higher proportion of unmineralized tissue and cartilage. The stiff and modulated groups (3, 7, 14, and 21 days) all showed bony bridging at 5 weeks, as well as signs of callus remodeling. Stiffening fixation at 7 and 14 days after osteotomy produced the highest degree of callus bridging. Bone mineral density in the fracture gap was highest in animals in which the fixation was stiffened after 14 days. Interpretation - The predicted benefit of a large robust callus formed through early flexible fixation could not be shown, but the benefits of stabilizing a flexible construct to achieve timely healing were demonstrated at all time points.

  19. Bone-defects healing by high-molecular hyaluronic acid: preliminary results

    PubMed Central

    Baldini, Alberto; Zaffe, Davide; Nicolini, Gabriella

    2010-01-01

    Summary Aim. The aim of this study is to evaluate the capability of Hyaloss™ matrix (Fab – Fidia Advanced Biopolymers – Pd – Italy), a biomaterial based on hyaluronic acid, used as organic scaffold in bone repair in post-extractive defects. Materials and methods: 20 post-extractive sockets were selected, with similar size defects in the same patient and in the same hemiarch. Hyaluronic acid with high molecular weight (Hyaloss™ matrix, Fab – Pd – Italy) was mixed with autologous bone obtained using Safescraper® curve (Meta – Re – Italy) to repair post-extractive sites. Safescraper® is a cutting edge system that allows to the collection of autologous bone without using traditional, incision-based collection techniques, which could cause discomfort to the patient. Results: Clinical and hystological evaluations were performed, four months after grafting, in the maxilla and in the mandible. From a clinical point of view Hyaloss™ matrix mixed with autologous bone and patient’s blood becomes a substance similar to gel, which is easy to insert in to the defect. From a hystological point of view, in the treated site there is the presence of an erosive activity, with accelerated angiogenetic and bone remodelling activities. Conclusions: The preliminary results show an acceleration of the bone deposit process and of its remodelling due to the presence of Hyaloss™ matrix, which, from a clinical point of view, improves the handling and application of the bone matrix inside the defects and, from a hystologic point of view makes it possible to obtain bone regeneration in less time when it is used with autologous bone. PMID:22238698

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

    PubMed

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

    2009-10-01

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

  1. Protein growth factors loaded highly porous chitosan scaffold: a comparison of bone healing properties.

    PubMed

    Nandi, Samit K; Kundu, Biswanath; Basu, Debabrata

    2013-04-01

    Present study aimed to investigate and compare effectiveness of porous chitosan alone and in combination with insulin like growth factor-1 (IGF-1) and bone morphogenetic protein-2 (BMP-2) in bone healing. Highly porous (85±2%) with wide distribution of macroporous (70-900 μm) chitosan scaffolds were fabricated as bone substitutes by employing a simple liquid hardening method using 2% (w/v) chitosan suspension. IGF-1 and BMP-2 were infiltrated using vacuum infiltration with freeze drying method. Adsorption efficiency was found to be 87±2 and 90±2% for BMP-2 and IGF-1 respectively. After thorough material characterization (pore details, FTIR and SEM), samples were used for subsequent in vivo animal trial. Eighteen rabbit models were used to evaluate and compare control (chitosan) (group A), chitosan with IGF-1 (group B) and chitosan with BMP-2 (group C) in the repair of critical size bone defect in tibia. Radiologically, there was evidence of radiodensity in defect area from 60th day (initiated on 30th day) in groups B and C as compared to group A and attaining nearly bony density in most of the part at day 90. Histological results depicted well developed osteoblastic proliferation around haversian canal along with proliferating fibroblast, vascularization and reticular network which was more pronounced in group B followed by groups C and A. Fluorochrome labeling and SEM studies in all groups showed similar outcome. Hence, porous chitosan alone and in combination with growth factors (GFs) can be successfully used for bone defect healing with slight advantage of IGF-1 in chitosan samples.

  2. Wound healing after irradiation of bone tissues by Er:YAG laser

    NASA Astrophysics Data System (ADS)

    Watanabe, Hisashi; Yoshino, Toshiaki; Aoki, Akira; Ishikawa, Isao

    1997-05-01

    Clinical applications of Er:YAG laser are now developing in periodontics and restorative dentistry. To date, there have been few studies indicating safety criteria for intraoral usage of the Er:YAG laser. The present study examined the effects of the Er:YAG laser on bone tissues, supposing mis- irradiation in the oral cavity during dental application, especially periodontal surgery. The experiments were performed using the newly-developed Er:YAG laser apparatus equipped with a contact probe. In experiment 1, 10 pulses of laser irradiation were administered to the parietal bone of a rat at 50, 150 and 300 mJ/pulse with and without water irrigation, changing the irradiation distance to 0, 5, 10 and 20 mm, respectively. As a control, electric knife was employed. Macroscopic and SEM observations of the wound surface were performed. In experiment 2, laser irradiation in a straight line was performed at 150 mJ/pulse, 1- pps and 0,5, 10 mm irradiation distance without water irrigation. Wound healing was observed histologically at 0, 3, 7, 14 and 28 days after laser irradiation and compared with that of the control. Non-contact irradiation by Er:YAG laser did not cause severe damage to the parietal bone tissue under water irrigation. Contact irradiation induced a limited wound, however, new bone formation was observed 28 days after laser irradiation, while osseous defect with thermal degenerative tissue remained at the control site. In conclusion, irradiation with an Er:YAG laser would not cause severe damage to surrounding bone tissues in the oral cavity when used within the usual power settings for dental treatment. Furthermore, this laser may be applicable for osseous surgery because of its high ablation efficiency and good wound healing after irradiation.

  3. 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.

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

    PubMed

    Perdikouri, Christina; Tägil, Magnus; Isaksson, Hanna

    2015-01-01

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

  5. Effects of laser and ozone therapies on bone healing in the calvarial defects.

    PubMed

    Kazancioglu, Hakki Oguz; Ezirganli, Seref; Aydin, Mehmet Serif

    2013-11-01

    This study aims to analyze the effect of the low-level laser therapy (LLLT) and ozone therapy on the bone healing of critical size defect (CSD) in rat calvaria. A total of 30 Wistar male rats were used. A 5-mm-diameter trephine bur was used to create CSD on the right side of the parietal bone of each rat calvarium. Once the bone was excised, a synthetic biphasic calcium phosphate graft material was implanted to all the bone defect sites. The animals were randomly divided into 3 groups as follows: the control group (n = 10), which received no LLLT or ozone therapy; the LLLT group (n = 10), which received only LLLT (120 seconds, 3 times a week for 2 weeks); and the ozone therapy group (n = 10) (120 seconds, 3 times a week for 2 weeks). After 1 month, all the rats were killed, and the sections were examined to evaluate the presence of inflammatory infiltrate, connective tissue, and new bone formation areas. Histomorphometric analyses showed that in the LLLT and ozone groups, the new bone areas were significantly higher than in the control group (P < 0.05). In the LLLT group, higher new bone areas were found than in the ozone group (P < 0.05). This study demonstrated that both ozone and laser therapies had a positive effect on bone formation in rat calvarial defect, compared with the control group; however, ozone therapy was more effective than LLLT (808 nm; 0.1 W; 4 J/cm(2); 0.028 cm(2), continuous wave mode).

  6. Effects of low-intensity pulsed ultrasound on new trabecular bone during bone-tendon junction healing in a rabbit model: a synchrotron radiation micro-CT study.

    PubMed

    Lu, Hongbin; Zheng, Cheng; Wang, Zhanwen; Chen, Can; Chen, Huabin; Hu, Jianzhong

    2015-01-01

    This study was designed to evaluate the effects of low-intensity pulsed ultrasound on bone regeneration during the bone-tendon junction healing process and to explore the application of synchrotron radiation micro computed tomography in three dimensional visualization of the bone-tendon junction to evaluate the microarchitecture of new trabecular bone. Twenty four mature New Zealand rabbits underwent partial patellectomy to establish a bone-tendon junction injury model at the patella-patellar tendon complex. Animals were then divided into low-intensity pulsed ultrasound treatment (20 min/day, 7 times/week) and placebo control groups, and were euthanized at week 8 and 16 postoperatively (n = 6 for each group and time point). The patella-patellar tendon specimens were harvested for radiographic, histological and synchrotron radiation micro computed tomography detection. The area of the newly formed bone in the ultrasound group was significantly greater than that of control group at postoperative week 8 and 16. The high resolution three dimensional visualization images of the bone-tendon junction were acquired by synchrotron radiation micro computed tomography. Low-intensity pulsed ultrasound treatment promoted dense and irregular woven bone formation at week 8 with greater bone volume fraction, number and thickness of new trabecular bone but with lower separation. At week 16, ultrasound group specimens contained mature lamellar bone with higher bone volume fraction and thicker trabeculae than that of control group; however, there was no significant difference in separation and number of the new trabecular bone. This study confirms that low-intensity pulsed ultrasound treatment is able to promote bone formation and remodeling of new trabecular bone during the bone-tendon junction healing process in a rabbit model, and the synchrotron radiation micro computed tomography could be applied for three dimensional visualization to quantitatively evaluate the

  7. Treatment with Carnitine Enhances Bone Fracture Healing under Osteoporotic and/or Inflammatory Conditions.

    PubMed

    Aydin, Ali; Halici, Zekai; Albayrak, Abdulmecit; Polat, Beyzagul; Karakus, Emre; Yildirim, Omer Selim; Bayir, Yasin; Cadirci, Elif; Ayan, Arif Kursad; Aksakal, Ahmet Murat

    2015-09-01

    The aim of this study was to examine the effects of carnitine on bone healing in ovariectomy (OVX) and inflammation (INF)-induced osteoporotic rats. The rats were randomly divided into nine groups (n = 8 animals per group): sham-operated (Group 1: SHAM); sham + magnesium silicate (Mg-silicate) (Group 2: SHAM + INF); ovariectomy (Group 3: OVX); ovariectomy + femoral fracture (Group 4: OVX + FRC); ovariectomy + femoral fracture + Mg-silicate (Group 5: OVX + FRC + INF); ovariectomy + femoral fracture + carnitine 50 mg/kg (Group 6: OVX + FRC + CAR50); ovariectomy + femoral fracture + carnitine 100 mg/kg (Group 7: OVX + FRC + CAR100); ovariectomy + femoral fracture + Mg-silicate + carnitine 50 mg/kg (Group 8: OVX + FRC + INF + CAR50); and ovariectomy + femoral fracture + Mg-silicate + carnitine 100 mg/kg (Group 9: OVX + FRC + INF + CAR100). Eight weeks after OVX, which allowed for osteoporosis to develop, INF was induced with subcutaneous Mg-silicate. On day 80, all of the rats in groups 4-9 underwent fracture operation on the right femur. Bone mineral density (BMD) showed statistically significant improvements in the treatment groups. The serum markers of bone turnover (osteocalcin and osteopontin) and pro-inflammatory cytokines (tumour necrosis factor α, interleukin 1β and interleukin 6) were decreased in the treatment group. The X-ray images showed significantly increased callus formation and fracture healing in the groups treated with carnitine. The present results show that in a rat model with osteoporosis induced by ovariectomy and Mg-silicate, treatment with carnitine improves the healing of femur fractures.

  8. 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.

  9. Decreased BMP2 signal in GIT1 knockout mice slows bone healing.

    PubMed

    Sheu, T J; Zhou, Wei; Fan, Jin; Zhou, Hao; Zuscik, Michael J; Xie, Chao; Yin, Guoyong; Berk, Bradford C

    2014-12-01

    Endochondral ossification, an important stage of fracture healing, is regulated by a variety of signaling pathways. Transforming growth factor β (TGFβ) superfamily plays important roles and comprises TGFβs, bone morphogenetic proteins (BMPs), and growth differentiation factors. TGFβs primarily regulate cartilage formation and endochondral ossification. BMP2 shows diverse efficacy, from the formation of skeleton and extraskeletal organs to the osteogenesis and remodeling of bone. G-protein-coupled receptor kinase 2-interacting protein-1 (GIT1), a shuttle protein in osteoblasts, facilitates fracture healing by promoting bone formation and increasing the secretion of vascular endothelial growth factor. Our study examined whether GIT1 regulates fracture healing through the BMP2 signaling pathway and/or through the TGFβ signaling pathway. GIT1 knockout (KO) mice exhibited delayed fracture healing, chondrocyte accumulation in the fracture area, and reduced staining intensity of phosphorylated Smad1/5/8 (pSmad1/5/8) and Runx2. Endochondral mineralization diminished while the staining intensity of phosphorylated Smad2/3 (pSmad2/3) showed no significant change. Bone marrow mesenchymal stem cells extracted from GIT1 KO mice showed a decline of pSmad1/5/8 levels and of pSmad1/5/8 translocated into the cell nucleus after BMP2 stimulus. We detected no significant change in the pSmad2/3 level after TGFβ1 stimulus. Data obtained from reporter gene analysis of C3H10T1/2 cells cultured in vitro confirmed these findings. GIT1-siRNA inhibited transcription in the cell nucleus via pSmad1/5/8 after BMP2 stimulus but had no significant effect on transcription via pSmad2/3 after TGFβ1 stimulus. Our results indicate that GIT1 regulates Smad1/5/8 phosphorylation and mediates BMP2 regulation of Runx2 expression, thus affecting endochondral ossification at the fracture site.

  10. Enhanced growth of endothelial precursor cells on PCG-matrix facilitates accelerated, fibrosis-free, wound healing: a diabetic mouse model.

    PubMed

    Kanitkar, Meghana; Jaiswal, Amit; Deshpande, Rucha; Bellare, Jayesh; Kale, Vaijayanti P

    2013-01-01

    Diabetes mellitus (DM)-induced endothelial progenitor cell (EPC) dysfunction causes impaired wound healing, which can be rescued by delivery of large numbers of 'normal' EPCs onto such wounds. The principal challenges herein are (a) the high number of EPCs required and (b) their sustained delivery onto the wounds. Most of the currently available scaffolds either serve as passive devices for cellular delivery or allow adherence and proliferation, but not both. This clearly indicates that matrices possessing both attributes are 'the need of the day' for efficient healing of diabetic wounds. Therefore, we developed a system that not only allows selective enrichment and expansion of EPCs, but also efficiently delivers them onto the wounds. Murine bone marrow-derived mononuclear cells (MNCs) were seeded onto a PolyCaprolactone-Gelatin (PCG) nano-fiber matrix that offers a combined advantage of strength, biocompatibility wettability; and cultured them in EGM2 to allow EPC growth. The efficacy of the PCG matrix in supporting the EPC growth and delivery was assessed by various in vitro parameters. Its efficacy in diabetic wound healing was assessed by a topical application of the PCG-EPCs onto diabetic wounds. The PCG matrix promoted a high-level attachment of EPCs and enhanced their growth, colony formation, and proliferation without compromising their viability as compared to Poly L-lactic acid (PLLA) and Vitronectin (VN), the matrix and non-matrix controls respectively. The PCG-matrix also allowed a sustained chemotactic migration of EPCs in vitro. The matrix-effected sustained delivery of EPCs onto the diabetic wounds resulted in an enhanced fibrosis-free wound healing as compared to the controls. Our data, thus, highlight the novel therapeutic potential of PCG-EPCs as a combined 'growth and delivery system' to achieve an accelerated fibrosis-free healing of dermal lesions, including diabetic wounds.

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

    PubMed Central

    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. PMID:26798415

  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.

  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. PDGF-B gene therapy accelerates bone engineering and oral implant osseointegration.

    PubMed

    Chang, P-C; Seol, Y-J; Cirelli, J A; Pellegrini, G; Jin, Q; Franco, L M; Goldstein, S A; Chandler, L A; Sosnowski, B; Giannobile, W V

    2010-01-01

    Platelet-derived growth factor-BB (PDGF-BB) stimulates repair of healing-impaired chronic wounds such as diabetic ulcers and periodontal lesions. However, limitations in predictability of tissue regeneration occur due, in part, to transient growth factor bioavailability in vivo. Here, we report that gene delivery of PDGF-B stimulates repair of oral implant extraction socket defects. Alveolar ridge defects were created in rats and were treated at the time of titanium implant installation with a collagen matrix containing an adenoviral (Ad) vector encoding PDGF-B (5.5 x 10(8) or 5.5 x 10(9) pfu ml(-1)), Ad encoding luciferase (Ad-Luc; 5.5 x 10(9) pfu ml(-1); control) or recombinant human PDGF-BB protein (rhPDGF-BB, 0.3 mg ml(-1)). Bone repair and osseointegration were measured through backscattered scanning electron microscopy, histomorphometry, micro-computed tomography and biomechanical assessments. Furthermore, a panel of local and systemic safety assessments was performed. Results indicated that bone repair was accelerated by Ad-PDGF-B and rhPDGF-BB delivery compared with Ad-Luc, with the high dose of Ad-PDGF-B more effective than the low dose. No significant dissemination of the vector construct or alteration of systemic parameters was noted. In summary, gene delivery of Ad-PDGF-B shows regenerative and safety capabilities for bone tissue engineering and osseointegration in alveolar bone defects comparable with rhPDGF-BB protein delivery in vivo.

  16. Fragmented Adipose Tissue Graft for Bone Healing: Histological and Histometric Study in Rabbits’ Calvaria

    PubMed Central

    Oliveira, Lidiane C.; Giovanini, Allan F.; Abuabara, Allan; Klug, Luiz G.; Gonzaga, Carla C.; Zielak, João C.; Urban, Cícero A.

    2013-01-01

    Objective The adipose tissue represents an important reservoir of stem cells. There are few studies in the literature with which to histologically evaluate whether or not the adipose tissue graft is really a safe option to achieve bone repair. This study histologically analyzed the effect of fragmented autogenous adipose tissue grafts on bone healing in surgically created, critical-size defects (CSD) in a rabbit’s calvaria. Study design Forty-two New Zealand rabbits were used in this study. CSD that were 15 mm in diameter were created in the calvarium of each animal. The defects were randomly divided into two groups: in Group C (control), the defect was filled only by a blood clot and, in Group FAT (i.e., fragmented adipose tissue), the defect was filled with fragmented autogenous adipose tissue grafts. The groups were divided into subgroups (n = 7) for euthanasia at 7, 15, and 40 days after the procedure had been conducted. Histologic and histometric analyses were performed. Data were statistically analysed with ANOVA and Tukey’s tests (p < 0.05). Results The amount of bone formation did not show statistically significant differences seven days after the operation, which indicates that the groups had similar amounts of mineral deposition in the earlier period of the repair. Conversely, a significant of amount of bone matrix deposition was identified in the FAT group at 15 and 40 days following the operation, both on the border and in the body of the defect. Such an outcome was not found in the control group. Conclusion In this study, an autologous adipose tissue graft may be considered as likely biomaterial for bone regeneration, since it positively affected the amount of bone formation in surgically created CSD in the rabbits’ calvaria 40 days after the procedure had been performed. Further investigations with a longer time evaluation are warranted to determine the effectiveness of autologous adipose tissue graft in the bone healing. Key words

  17. Exposure to omega-3 fatty acids at early age accelerate bone growth and improve bone quality.

    PubMed

    Koren, Netta; Simsa-Maziel, Stav; Shahar, Ron; Schwartz, Betty; Monsonego-Ornan, Efrat

    2014-06-01

    Omega-3 fatty acids (FAs) are essential nutritional components that must be obtained from foods. Increasing evidence validate that omega-3 FAs are beneficial for bone health, and several mechanisms have been suggested to mediate their effects on bone, including alterations in calcium absorption and urinary calcium loss, prostaglandin synthesis, lipid oxidation, osteoblast formation and inhibition of osteoclastogenesis. However, to date, there is scant information regarding the effect of omega-3 FAs on the developing skeleton during the rapid growth phase. In this study we aim to evaluate the effect of exposure to high levels of omega-3 FAs on bone development and quality during prenatal and early postnatal period. For this purpose, we used the fat-1 transgenic mice that have the ability to convert omega-6 to omega-3 fatty acids and the ATDC5 chondrogenic cell line as models. We show that exposure to high concentrations of omega-3 FAs at a young age accelerates bone growth through alterations of the growth plate, associated with increased chondrocyte proliferation and differentiation. We further propose that those effects are mediated by the receptors G-protein coupled receptor 120 (GPR120) and hepatic nuclear factor 4α, which are expressed by chondrocytes in culture. Additionally, using a combined study on the structural and mechanical bone parameters, we show that high omega-3 levels contribute to superior trabecular and cortical structure, as well as to stiffer bones and improved bone quality. Most interestingly, the fat-1 model allowed us to demonstrate the role of maternal high omega-3 concentration on bone growth during the gestation and postnatal period.

  18. The regeneration and augmentation of bone with injectable osteogenic cell sheet in a rat critical fracture healing model.

    PubMed

    Shimizu, Takamasa; Akahane, Manabu; Morita, Yusuke; Omokawa, Shohei; Nakano, Kenichi; Kira, Tsutomu; Onishi, Tadanobu; Inagaki, Yusuke; Okuda, Akinori; Kawate, Kenji; Tanaka, Yasuhito

    2015-08-01

    Limitations in the current treatment strategies make cases with compromised bone healing challenging clinical problems. Osteogenic cell sheets (OCSs), fabricated from rat bone marrow stromal cells (BMSCs), contain enriched osteoblasts and extracellular matrix. Here, we evaluated whether the minimally invasive percutaneous injection of OCSs without a scaffold could be used as a treatment to increase bone regeneration in a critical fracture healing model. Critical fracture healing model was created in the femora of 60 male Fischer 344 inbred rats using marrow ablation and periosteal removal. The rats were then randomly divided into two groups. Six hours after fracture, one group received an injection of OCSs (OCS group), while the second group was injected with phosphate-buffered saline (PBS) (control group). Fracture healing was evaluated using radiological, histological, micro-computed tomography (CT) and biomechanical analyses. The radiological and histological evaluations demonstrated enhanced bone regeneration in the OCS group compared with that in the control group. By 12 weeks, the hard callus had been remodelled via recorticalization in the OCS group. By contrast, no fracture union was found in the rats in the control group. Biomechanical testing revealed a significantly higher maximum bending load in the OCS group compared with that in the control group. The results of the present study demonstrate that the injection of entire OCSs can enhance bone regeneration and lead to bony union in a critical fracture healing model. Therefore, this procedure offers a minimally invasive technique to promote hard tissue reconstruction and, in particular, bone repair strategies for cases with compromised bone healing.

  19. Bioactive cell-derived matrices combined with polymer mesh scaffold for osteogenesis and bone healing.

    PubMed

    Kim, In Gul; Hwang, Mintai P; Du, Ping; Ko, Jaehoon; Ha, Chul-won; Do, Sun Hee; Park, Kwideok

    2015-05-01

    Successful bone tissue engineering generally requires an osteoconductive scaffold that consists of extracellular matrix (ECM) to mimic the natural environment. In this study, we developed a PLGA/PLA-based mesh scaffold coated with cell-derived extracellular matrix (CDM) for the delivery of bone morphogenic protein (BMP-2), and assessed the capacity of this system to provide an osteogenic microenvironment. Decellularized ECM from human lung fibroblasts (hFDM) was coated onto the surface of the polymer mesh scaffolds, upon which heparin was then conjugated onto hFDM via EDC chemistry. BMP-2 was subsequently immobilized onto the mesh scaffolds via heparin, and released at a controlled rate. Human placenta-derived mesenchymal stem cells (hPMSCs) were cultured in such scaffolds and subjected to osteogenic differentiation for 28 days in vitro. The results showed that alkaline phosphatase (ALP) activity, mineralization, and osteogenic marker expression were significantly improved with hPMSCs cultured in the hFDM-coated mesh scaffolds compared to the control and fibronectin-coated ones. In addition, a mouse ectopic and rat calvarial bone defect model was used to examine the feasibility of current platform to induce osteogenesis as well as bone regeneration. All hFDM-coated mesh groups exhibited a significant increase of newly formed bone and in particular, hFDM-coated mesh scaffold loaded with a high dose of BMP-2 exhibited a nearly complete bone defect healing as confirmed via micro-CT and histological observation. This work proposes a great potency of using hFDM (biophysical) coupled with BMP-2 (biochemical) as a promising osteogenic microenvironment for bone tissue engineering applications.

  20. The Effect of Bone Marrow-Derived Mesenchymal Stem Cells and Their Conditioned Media Topically Delivered in Fibrin Glue on Chronic Wound Healing in Rats.

    PubMed

    Mehanna, Radwa A; Nabil, Iman; Attia, Noha; Bary, Amany A; Razek, Khalid A; Ahmed, Tamer A E; Elsayed, Fatma

    2015-01-01

    Bone marrow-derived mesenchymal stem cells (BM-MSCs) represent a modern approach for management of chronic skin injuries. In this work, we describe BM-MSCs application versus their conditioned media (CM) when delivered topically admixed with fibrin glue to enhance the healing of chronic excisional wounds in rats. Fifty-two adult male rats were classified into four groups after induction of large-sized full-thickness skin wound: control group (CG), fibrin only group (FG), fibrin + MSCs group (FG + SCs), and fibrin + CM group (FG + CM). Healing wounds were evaluated functionally and microscopically. Eight days after injury, number of CD68+ macrophages infiltrating granulation tissue was considerably higher in the latter two groups. Although--later--none of the groups depicted a substantially different healing rate, the quality of regenerated skin was significantly boosted by the application of either BM-MSCs or their CM both (1) structurally as demonstrated by the obviously increased mean area percent of collagen fibers in Masson's trichrome-stained skin biopsies and (2) functionally as supported by the interestingly improved epidermal barrier as well as dermal tensile strength. Thus, we conclude that topically applied BM-MSCs and their CM-via fibrin vehicle--could effectively improve the quality of healed skin in chronic excisional wounds in rats, albeit without true acceleration of wound closure.

  1. The Effect of Bone Marrow-Derived Mesenchymal Stem Cells and Their Conditioned Media Topically Delivered in Fibrin Glue on Chronic Wound Healing in Rats

    PubMed Central

    Mehanna, Radwa A.; Nabil, Iman; Attia, Noha; Bary, Amany A.; Razek, Khalid A.; Ahmed, Tamer A. E.; Elsayed, Fatma

    2015-01-01

    Bone marrow-derived mesenchymal stem cells (BM-MSCs) represent a modern approach for management of chronic skin injuries. In this work, we describe BM-MSCs application versus their conditioned media (CM) when delivered topically admixed with fibrin glue to enhance the healing of chronic excisional wounds in rats. Fifty-two adult male rats were classified into four groups after induction of large-sized full-thickness skin wound: control group (CG), fibrin only group (FG), fibrin + MSCs group (FG + SCs), and fibrin + CM group (FG + CM). Healing wounds were evaluated functionally and microscopically. Eight days after injury, number of CD68+ macrophages infiltrating granulation tissue was considerably higher in the latter two groups. Although—later—none of the groups depicted a substantially different healing rate, the quality of regenerated skin was significantly boosted by the application of either BM-MSCs or their CM both (1) structurally as demonstrated by the obviously increased mean area percent of collagen fibers in Masson's trichrome-stained skin biopsies and (2) functionally as supported by the interestingly improved epidermal barrier as well as dermal tensile strength. Thus, we conclude that topically applied BM-MSCs and their CM—via fibrin vehicle—could effectively improve the quality of healed skin in chronic excisional wounds in rats, albeit without true acceleration of wound closure. PMID:26236740

  2. 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

  3. 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

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

    PubMed

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

    2013-01-10

    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.

  5. [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.

  6. [Semax and some glyproline peptides accelerate the healing of acetic ulcers in rats].

    PubMed

    Zhuĭkova, S E; Badmaeva, K E; Samonina, G E; Plesskaia, L G

    2003-01-01

    Previously we showed that peptides PGP, PG, GP and semax have protective anti-ulcer properties using different models of ulcerogenesis. Semax (MEHFPGP) is a nootropic analogue of adrenocorticotropin 4-7 stabilized by PGP in the C-terminal region. In this study we examined the impact of these peptides on the development and healing of acetic ulcers in rats. The histomorphological and dynamical characteristics of acetic ulcers are most similar to human chronic ulcers. All the peptides were shown to accelerate the process of ulcer cicatrisation in a varying degree (GP semax PG PGP). The dynamics of structural changes in the place of ulcer formation investigated with the use of cytohistological control demonstrated that their anti-ulcer effects can be related to their ability to accelerate ulcer clarification from necrotic tissues and to activate the process of cicatrisation and epithelization. PGP and GP were also shown to reduce the inflammation in the ulcer zone on the fifth day after acetic acid application.

  7. Impacts of bone marrow aspirate and peripheral blood derived platelet-rich plasma on the wound healing in chronic ischaemic limb.

    PubMed

    Nishimoto, Soh; Kawai, Kenichiro; Tsumano, Tomoko; Fukuda, Kenji; Fujiwara, Toshihiro; Kakibuchi, Masao

    2013-06-01

    Platelet rich plasma (PRP) has attracted attention as a safe and cost-effective source of growth factors that stimulate cells to regenerate tissue. Bone marrow cells are also estimated as an effective material for treating chronic ulcers. With the same technique to concentrate PRP from peripheral blood, bone marrow aspirate was processed and marrow cells were concentrated as well as platelets. Impact of PRP derived from bone marrow aspirate (bm-PRP) and that from peripheral blood (pb-PRP) on wound healing of persistent ischaemic rabbits' limbs were observed. Full thickness skin defects were made on the thighs, which had been treated to be persistent ischaemic status 3 weeks previously. Saline, pb-PRP, and bm-PRP were injected into the wound floor, respectively. Skin defected areas on ischaemic limbs were significantly wider than those on non-ischaemic limbs. bm-PRP injected wounds showed a significantly smaller skin defect area compared with pb-PRP and ischaemic-saline wounds at all time points. Fluorescently dyed cells of bm-PRP, injected into the wounds, could be traced 4 weeks after, whereas those of pb-PRP could be traced no more than 2 weeks. Wound healing on an ischaemic limb was accelerated with bm-PRP, whereas pb-PRP could not show any significance from saline. This difference can be attributed to the kind of cells contained in the PRPs. Injection of bm-PRP is a good candidate for treating wounds on ischaemic limbs.

  8. The mobilization and effect of endogenous bone marrow progenitor cells in diabetic wound healing.

    PubMed

    Fiorina, Paolo; Pietramaggiori, Giorgio; Scherer, Saja S; Jurewicz, Mollie; Mathews, Jasmine C; Vergani, Andrea; Thomas, Gebhard; Orsenigo, Elena; Staudacher, Carlo; La Rosa, Stefano; Capella, Carlo; Carothers, Adelaide; Zerwes, Hans-Gunter; Luzi, Livio; Abdi, Reza; Orgill, Dennis P

    2010-01-01

    Diabetic patients suffer from impaired wound healing, characterized by only modest angiogenesis and cell proliferation. Stem cells may stimulate healing, but little is known about the kinetics of mobilization and function of bone marrow progenitor cells (BM-PCs) during diabetic wound repair. The objective of this study was to investigate the kinetics of BM-PC mobilization and their role during early diabetic wound repair in diabetic db/db mice. After wounding, circulating hematopoietic stem cells (Lin(-)c-Kit(+)Sca-1(+)) stably increased in the periphery and lymphoid tissue of db/db mice compared to unwounded controls. Peripheral endothelial progenitor cells (CD34(+)VEGFR(+)) were 2.5- and 3.5-fold increased on days 6 and 10 after wounding, respectively. Targeting the CXCR4-CXCL12 axis induced an increased release and engraftment of endogenous BM-PCs that was paralleled by an increased expression of CXCL12/SDF-1α in the wounds. Increased levels of peripheral and engrafted BM-PCs corresponded to stimulated angiogenesis and cell proliferation, while the addition of an agonist (GM-CSF) or an antagonist (ACK2) did not further modulate wound healing. Macroscopic histological correlations showed that increased levels of stem cells corresponded to higher levels of wound reepithelialization. After wounding, a natural release of endogenous BM-PCs was shown in diabetic mice, but only low levels of these cells homed in the healing tissue. Higher levels of CXCL12/SDF-1α and circulating stem cells were required to enhance their engraftment and biological effects. Despite controversial data about the functional impairment of diabetic BM-PCs, in this model our data showed a residual capacity of these cells to trigger angiogenesis and cell proliferation.

  9. Evaluation of bone-tendon junction healing using water jet ultrasound indentation method.

    PubMed

    Lu, Min-Hua; Zheng, Yong-Ping; Lu, Hong-Bin; Huang, Qing-Hua; Qin, Ling

    2009-11-01

    The re-establishment of bone-tendon junction (BTJ) tissues with the junction, characterized as a unique transitional fibrocartilage zone, is involved in many trauma and reconstructive surgeries. Experimental and clinical findings have shown that a direct BTJ repair requires a long period of immobilization, which may be associated with a postoperative weak knee. Therefore, it is necessary to evaluate the morphologic and mechanical properties of BTJ tissues in situ to better understand the healing process for the purpose of reducing the adverse effects of immobilization. We previously reported a noncontact ultrasound water jet indentation system for measuring and mapping tissue mechanical properties. The key idea was to utilize a water jet as an indenter as well as the coupling medium for high-frequency ultrasound. In this article, we used ultrasound water jet indentation to evaluate the BTJ healing process. The system's capability of measuring the material elastic modulus was first validated using tissue-mimicking phantoms. Then it was employed to assess the healing of the BTJ tissues after partial patellectomy over time on twelve 18-week-old female New Zealand White rabbits. It was found that in comparison with the normal control samples, the elastic modulus of the fibrocartilage of the postoperative samples was significantly smaller, while its thickness increased significantly. Among the postoperative sample groups, the elastic modulus of the fibrocartilage of the samples harvested at week 18 was significantly higher than those harvested at week 6 and week 12, which was even comparable with the value of the control samples at the same sacrifice time. The results suggested that the noncontact ultrasound water jet indentation system provided a nondestructive way to evaluate the material properties of small animal tissues in situ and thus had the ability to evaluate the healing process of BTJ.

  10. Surface Modification of Biomedical and Dental Implants and the Processes of Inflammation, Wound Healing and Bone Formation

    PubMed Central

    Stanford, Clark M.

    2010-01-01

    Bone adaptation or integration of an implant is characterized by a series of biological reactions that start with bone turnover at the interface (a process of localized necrosis), followed by rapid repair. The wound healing response is guided by a complex activation of macrophages leading to tissue turnover and new osteoblast differentiation on the implant surface. The complex role of implant surface topography and impact on healing response plays a role in biological criteria that can guide the design and development of future tissue-implant surface interfaces. PMID:20162020

  11. The effect of bone growth factor in the tendon to bone healing in anterior cruciate ligament reconstruction: An experimental study in rabbits

    PubMed Central

    Al-Bluwi, Mohammed T; Azam, Md Q; Sadat-Ali, Mir

    2016-01-01

    Background: Reconstruction of the anterior cruciate ligament (ACL) involves use of semintendinosis and gracilis tendons graft that is transplanted into bone tunnels at the femoral and tibial insertion sites and the sites and the bone tendon interface is a weak link in the early healing period due to slow rate of healing. We hypothesized that an addition of bone growth factor like Sadat-Habdan mesenchymal stimulating peptide (SHMSP) could enhance bone tendon healing rate so that re-rupture of the tendon does not take place. Methodology: Twenty skeletally mature rabbits underwent ACL reconstruction of the right knee. In 10 of the rabbits at the site of the tendon-graft 5 mg/kg body weight of SHMSP was put in the bone tunnel. In 10 other animals, nothing was added. At eight and 12 weeks 5 animals from each group were sacrificed. The tendon-graft site was harvested and sent for histopathological examination to assess the healing at the tendon-bone graft to the tibial tunnel. Results: There were no deaths in both the groups. One rabbit of the control group developed an infection. In all the animals of the study group from 4 weeks onward showed bone formation, wherein the control group only granulation tissue was observed. By 8 weeks in the study group, the canal was totally obliterated with the new bone formation which extended onto the periosteal area. In the control, there was minimal change in the formation of the new bone formation. Conclusion: Addition of a growth factor like SHMSP would enhance the osteo-integration of the tendon-graft in the bony tunnel after ACL reconstruction in vivo. PMID:26958518

  12. Cbfa1/Runx2-deficiency delays bone wound healing and locally delivered Cbfa1/Runx2 promotes bone repair in animal models.

    PubMed

    Tu, Qisheng; Zhang, Jin; James, Laji; Dickson, Julia; Tang, Jean; Yang, Pishan; Chen, Jake

    2007-01-01

    Core binding factor 1 (Cbfa1)/runt-related transcription factor 2 (Runx2) has been identified as a "master gene" in osteoblastic differentiation. In this two-part study, part I of the study was undertaken to test the hypothesis that bone regeneration is compromised in Cbfa1+/- mice. Compared with wild-type mice, wound healing was dramatically delayed in Cbfa1+/- mice characterized by the presence of a small amount of bone near the base of the wounds. The bone defects were largely filled with fibrous connective tissues 3 weeks after surgery. Part II was performed to determine the effects of Cbfa1 in enhancing bone wound healing using a gene-activated matrix (GAM) method. Cbfa1 cDNA was mixed with a biodegradable bovine type I collagen sponge and was inserted into the periodontal window wounds of mice. Control sponges were collagen matrix without Cbfa1 cDNA. Histological analysis and immunohistochemical staining demonstrated that compared with controls, there was increased new bone formation that almost filled the wound defects 14 days after surgery in the Cbfa1-GAM group. The collagen sponge matrix did not seem to elicit significant foreign body reaction in either group. In conclusion, the reduced expression of Cbfa1 interferes with the process of bone wound healing, and local application of Cbfa1 cDNA incorporated into a collagen matrix promotes bone tissue regeneration.

  13. Histological analysis of the effects of a static magnetic field on bone healing process in rat femurs

    PubMed Central

    Puricelli, Edela; Ulbrich, Lucienne M; Ponzoni, Deise; Filho, João Julio da Cunha

    2006-01-01

    Background The aim of this study was to investigate, in vivo, the quality of bone healing under the effect of a static magnetic field, arranged inside the body. Methods A metallic device was developed, consisting of two stainless steel washers attached to the bone structure with titanium screws. Twenty-one Wistar rats (Rattus novergicus albinus) were used in this randomized experimental study. Each experimental group had five rats, and two animals were included as control for each of the groups. A pair of metal device was attached to the left femur of each animal, lightly touching a surgically created bone cavity. In the experimental groups, washers were placed in that way that they allowed mutual attraction forces. In the control group, surgery was performed but washers, screws or instruments were not magnetized. The animals were sacrificed 15, 45 and 60 days later, and the samples were submitted to histological analysis. Results On days 15 and 45 after the surgical procedure, bone healing was more effective in the experimental group as compared to control animals. Sixty days after the surgical procedure, marked bone neoformation was observed in the test group, suggesting the existence of continued magnetic stimulation during the experiment. Conclusion The magnetic stainless steel device, buried in the bone, in vivo, resulted in increased efficiency of the experimental bone healing process. PMID:17125508

  14. Extended fatigue life of a catalyst-free self-healing acrylic bone cement using microencapsulated 2-octyl cyanoacrylate

    PubMed Central

    Brochu, Alice B.W.; Matthys, Oriane B.; Craig, Stephen L.; Reichert, William M.

    2014-01-01

    The tissue adhesive 2-octyl cyanoacrylate (OCA) was encapsulated in polyurethane microshells and incorporated into bone cement to form a catalyst free, self-healing bone cement comprised of all clinically approved components. The bending strength, modulus, and fatigue lifetime were investigated in accordance with ASTM and ISO standards for the testing of PMMA bone cement. The bending strength of bone cement specimens decreased with increasing wt% capsules content for capsules without or with OCA, with specimens of < 5 wt% capsule content showing minimal effect. In contrast, bone cement bending modulus was insensitive to capsule content. Load controlled fatigue testing was performed in air at room temperature on capsule free bone cement (0 wt%), bone cement with 5 wt% OCA-free capsules (5 wt% No OCA), and 5 wt% OCA-containing capsules (5 wt% OCA). Specimens were tested at a frequency of 5 Hz at maximum stresses of 90%, 80%, 70% and 50% of each specimen's bending strength until failure. The 5 wt% OCA exhibited significant self-healing at 70% and 50% of its reference strength (p < 0.05). Fatigue testing of all three specimen types in air at 22 MPa (50% of reference strength of the 5 wt% OCA specimens) showed that the cycles to failure of OCA-containing specimens was increased by two-fold compared to the OCA-free and capsule-free specimens. This study represents the first demonstration of dynamic, catalyst-free self-healing in a biomaterial formulation. PMID:24825796

  15. Bioelectric modulation of wound healing in a 3D in vitro model of tissue-engineered bone

    PubMed Central

    Sundelacruz, Sarah; Li, Chunmei; Choi, Young Jun; Levin, Michael; Kaplan, David L.

    2013-01-01

    Long-standing interest in bioelectric regulation of bone fracture healing has primarily focused on exogenous stimulation of bone using applied electromagnetic fields. Endogenous electric signals, such as spatial gradients of resting potential among non-excitable cells in vivo, have also been shown to be important in cell proliferation, differentiation, migration, and tissue regeneration, and may therefore have as-yet unexplored therapeutic potential for regulating wound healing in bone tissue. To study this form of bioelectric regulation, there is a need for three-dimensional (3D) in vitro wound tissue models that can overcome limitations of current in vivo models. We present a 3D wound healing model in engineered bone tissue that serves as a pre-clinical experimental platform for studying electrophysiological regulation of wound healing. Using this system, we identified two electrophysiology-modulating compounds, glibenclamide and monensin, that augmented osteoblast mineralization. Of particular interest, these compounds displayed differential effects in the wound area compared to the surrounding tissue. Several hypotheses are proposed to account for these observations, including the existence of heterogeneous subpopulations of osteoblasts that respond differently to bioelectric signals, or the capacity of the wound-specific biochemical and biomechanical environment to alter cell responses to electrophysiological treatments. These data indicate that a comprehensive characterization of the cellular, biochemical, biomechanical, and bioelectrical components of in vitro wound models is needed to develop bioelectric strategies to control cell functions for improved bone regeneration. PMID:23764116

  16. Low intensity pulsed ultrasound increases the mechanical properties of the healing tissues at bone-tendon junction.

    PubMed

    Lu, Min-Hua; Zheng, Yong-Ping; Huang, Qing-Hua; Lu, Hong-Bin; Qin, Ling

    2009-01-01

    The re-establishment of bone-tendon junction (BTJ) tissues is involved in many trauma and reconstructive surgeries. A direct BTJ repair requires a long period of immobilization which may be associated with a postoperative weak knee. In this study, we investigated if low-intensity pulsed ultrasound treatment increases the material properties of healing tissues at bone-tendon junction (BTJ) after partial patellectomy using rabbit models. Standard partial patellectomy was conducted on one knee of twenty four rabbits which were randomly divided into an ultrasound group and a control group. The bony changes of BTJ complexes around the BTJ healing interface were measured by anteroposterior x-ray radiographs; then the volumetric bone-mineral density (BMD) of the new bone was assessed using a peripheral computed tomography scanner (pQCT). The stiffness of patellar cartilage, fibrocartilage at the healing interface and the tendon were measured in situ using a novel noncontact ultrasound water jet indentation system. Not only significantly more newly formed bone at the BTJ healing interface but also increased stiffness of the junction tissues were found in the ultrasound group compared with the controls at week 18. In addition, the ultrasound group also showed significantly 44% higher BMD at week 6 than controls.

  17. Bioelectric modulation of wound healing in a 3D in vitro model of tissue-engineered bone.

    PubMed

    Sundelacruz, Sarah; Li, Chunmei; Choi, Young Jun; Levin, Michael; Kaplan, David L

    2013-09-01

    Long-standing interest in bioelectric regulation of bone fracture healing has primarily focused on exogenous stimulation of bone using applied electromagnetic fields. Endogenous electric signals, such as spatial gradients of resting potential among non-excitable cells in vivo, have also been shown to be important in cell proliferation, differentiation, migration, and tissue regeneration, and may therefore have as-yet unexplored therapeutic potential for regulating wound healing in bone tissue. To study this form of bioelectric regulation, there is a need for three-dimensional (3D) in vitro wound tissue models that can overcome limitations of current in vivo models. We present a 3D wound healing model in engineered bone tissue that serves as a pre-clinical experimental platform for studying electrophysiological regulation of wound healing. Using this system, we identified two electrophysiology-modulating compounds, glibenclamide and monensin, that augmented osteoblast mineralization. Of particular interest, these compounds displayed differential effects in the wound area compared to the surrounding tissue. Several hypotheses are proposed to account for these observations, including the existence of heterogeneous subpopulations of osteoblasts that respond differently to bioelectric signals, or the capacity of the wound-specific biochemical and biomechanical environment to alter cell responses to electrophysiological treatments. These data indicate that a comprehensive characterization of the cellular, biochemical, biomechanical, and bioelectrical components of in vitro wound models is needed to develop bioelectric strategies to control cell functions for improved bone regeneration.

  18. Autologous bone marrow-derived cells for healing excisional dermal wounds of rabbits.

    PubMed

    Borena, B M; Pawde, A M; Amarpal; Aithal, H P; Kinjavdekar, P; Singh, R; Kumar, D

    2009-11-07

    The wound-healing potential of autologous bone marrow-derived nucleated cells was evaluated in full-thickness skin wounds in the thoracolumbar region of 20 clinically healthy rabbits. Three wounds of 2 x 2 cm, one on the left side and two right of the midline, were created on the dorsal lumbar region of each rabbit under xylazine-ketamine anaesthesia. The wounds of each animal were randomly assigned to one of three treatments: injection of autologous bone marrow-derived cells into wound margins (BI), topical application of bone marrow-derived cells over the wound surface (BT) or 5 per cent povidone iodine solution (PI) (control). Wounds were observed for 28 days for granulation tissue formation, wound contraction, histomorphological and histochemical evaluation, and time to complete healing. The mean (se) time to appearance of granulation tissue was significantly less in BI-treated wounds (3.22 [0.22] days) than the BT-treated (3.89 [0.40] days) and PI-treated (4.89 [0.47] days) groups. On days 14 and 21 after surgery, wound contraction was significantly (P<0.05) higher in BI-treated wounds (73.00 and 97.35 per cent) than in those treated with BT (58.75 and 84.87 per cent) and PI (54.84 and 84.60 per cent). Histomorphological findings showed an earlier disappearance of inflammatory reaction, better epithelialisation, significantly more neovascularisation, more fibroplasia and collagenation, and earlier histological maturation in BI- and BT-treated wounds than in control wounds.

  19. Antioxidant potential of bilirubin-accelerated wound healing in streptozotocin-induced diabetic rats.

    PubMed

    Ram, Mahendra; Singh, Vishakha; Kumar, Dhirendra; Kumawat, Sanjay; Gopalakrishnan, Anu; Lingaraju, Madhu C; Gupta, Priyanka; Tandan, Surendra Kumar; Kumar, Dinesh

    2014-10-01

    Oxidative injury is markedly responsible for wound complications in diabetes mellitus. The biological actions of bilirubin may be relevant to prevent oxidant-mediated cell death, as bilirubin application at a low concentration scavenges reactive oxygen species. Hence, we hypothesized that topical bilirubin application might improve wound healing in diabetic rats. Diabetes was induced in adult male Wistar rats, which were divided into two groups, i.e., diabetic control and diabetic treated. Non-diabetic healthy rats were also taken as healthy control group. Wound area was measured on days 3, 7, 14, and 19 post-wounding. The levels of malondialdehyde (MDA) and reduced glutathione (GSH) and the activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were estimated in the granulation tissue. There was a significant increase in percent wound closure in healthy control and diabetic treated rats on days 7, 14, and 19, as compared to diabetic control rats on days 7, 14, and 19. There was significant decrease in MDA levels on days 7, 14, and 19 in diabetic treated rats, as compared to diabetic control rats. Levels of GSH were significantly increased on days 3, 7, 14, and 19 in diabetic treated rats, as compared to diabetic control rats. GPx, SOD, and CAT activities were significantly higher on days 3, 7, and 14 in diabetic treated rats, as compared to diabetic control rats. The findings indicate that bilirubin is effective in reducing the oxidant status in wounds of diabetic rats which might have accelerated wound healing in these rats.

  20. 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.

  1. Knockdown of SVCT2 impairs in-vitro cell attachment, migration and wound healing in bone marrow stromal cells.

    PubMed

    Sangani, Rajnikumar; Pandya, Chirayu D; Bhattacharyya, Maryka H; Periyasamy-Thandavan, Sudharsan; Chutkan, Norman; Markand, Shanu; Hill, William D; Hamrick, Mark; Isales, Carlos; Fulzele, Sadanand

    2014-03-01

    Bone marrow stromal cell (BMSC) adhesion and migration are fundamental to a number of pathophysiologic processes, including fracture and wound healing. Vitamin C is beneficial for bone formation, fracture repair and wound healing. However, the role of the vitamin C transporter in BMSC adhesion, migration and wound healing is not known. In this study, we knocked-down the sodium-dependent vitamin C transporter, SVCT2, the only known transporter of vitamin C in BMSCs, and performed cell adhesion, migration, in-vitro scratch wound healing and F-actin re-arrangement studies. We also investigated the role of oxidative stress on the above processes. Our results demonstrate that both oxidative stress and down-regulation of SVCT2 decreased cell attachment and spreading. A trans-well cell migration assay showed that vitamin C helped in BMSC migration and that knockdown of SVCT2 decreased cell migration. In the in-vitro scratch wound healing studies, we established that oxidative stress dose-dependently impairs wound healing. Furthermore, the supplementation of vitamin C significantly rescued the BMSCs from oxidative stress and increased wound closing. The knockdown of SVCT2 in BMSCs strikingly decreased wound healing, and supplementing with vitamin C failed to rescue cells efficiently. The knockdown of SVCT2 and induction of oxidative stress in cells produced an alteration in cytoskeletal dynamics. Signaling studies showed that oxidative stress phosphorylated members of the MAP kinase family (p38) and that vitamin C inhibited their phosphorylation. Taken together, these results indicate that both the SVCT2 transporter and oxidative stress play a vital role in BMSC attachment, migration and cytoskeletal re-arrangement. BMSC-based cell therapy and modulation of SVCT2 could lead to a novel therapeutic approach that enhances bone remodeling, fracture repair and wound healing in chronic disease conditions.

  2. 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

  3. Healing of onlay mandibular bone grafts covered with collagen membrane or bovine bone substitutes: a microscopical and immunohistochemical study in the sheep.

    PubMed

    Adeyemo, W L; Reuther, T; Bloch, W; Korkmaz, Y; Fischer, J H; Zöller, J E; Kuebler, A C

    2008-07-01

    The objective of this study was to evaluate the role of collagen membrane and Bio-Oss coverage in healing of an onlay graft to the mandible. Twelve adult sheep each received an onlay bone graft (experiment 1), bone graft+Bio-Gide (experiment 2), and bone graft+Bio-Oss/Bio-Gide (experiment 3) on the lateral surface of the mandible. The animals were euthanized at 4, 8, 12 or 16 weeks after surgery, and findings were analysed by routine microscopy and immunohistochemistry for proliferation (Ki67) and apoptotic (Caspase-3) markers. Grafts were fully incorporated in all specimens. Pronounced resorption was observed in experiment 1. Minimal loss of graft volume was seen in experiment 2 specimens without membrane displacement. A remarkable increase in the augmented region of the mandible was observed in experiment 3. A high number of osteoclasts were expressed within the grafts during the early healing period, and thereafter declined markedly. Osteoblasts within the grafts expressed a moderate level of Ki67 at 8 weeks, which thereafter declined markedly. The strongest expression of Caspase-3 on the bone surface was observed after 16 weeks. In conclusion, the effect of collagen membrane coverage on bone graft volume maintenance was dependent on membrane stability during healing. An autogenous bone graft covered with Bio-Oss particles resulted in a remarkable increase in augmented lateral surface of the mandible. The late stage of bone graft healing was associated with a high apoptotic induction pathway of osteoblasts lining the surfaces of the new bone, demonstrated by strong positive Caspase-3 immunoreactivity.

  4. Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing

    PubMed Central

    Fröbel, J.; Prodinger, P. M.; Mrotzek, S. J.; Fischer, J. C.; Zilkens, C.; Bittersohl, B.; Krauspe, R.

    2016-01-01

    Objectives Venous thromboembolism (VTE) is a major potential complication following orthopaedic surgery. Subcutaneously administered enoxaparin has been used as the benchmark to reduce the incidence of VTE. However, concerns have been raised regarding the long-term administration of enoxaparin and its possible negative effects on bone healing and bone density with an increase of the risk of osteoporotic fractures. New oral anticoagulants such as rivaroxaban have recently been introduced, however, there is a lack of information regarding how these drugs affect bone metabolism and post-operative bone healing. Methods We measured the migration and proliferation capacity of mesenchymal stem cells (MSCs) under enoxaparin or rivaroxaban treatment for three consecutive weeks, and evaluated effects on MSC mRNA expression of markers for stress and osteogenic differentiation. Results We demonstrate that enoxaparin, but not rivaroxaban, increases the migration potential of MSCs and increases their cell count in line with elevated mRNA expression of C-X-C chemokine receptor type 4 (CXCR4), tumor necrosis factor alpha (TNFα), and alpha-B-crystallin (CryaB). However, a decrease in early osteogenic markers (insulin-like growth factors 1 and 2 (IGF1, IGF2), bone morphogenetic protein2 (BMP2)) indicated inhibitory effects on MSC differentiation into osteoblasts caused by enoxaparin, but not by rivaroxaban. Conclusions Our findings may explain the adverse effects of enoxaparin treatment on bone healing. Rivaroxaban has no significant impact on MSC metabolism or capacity for osteogenic differentiation in vitro. Cite this article: Dr H. Pilge. Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing. Bone Joint Res 2016;5:95–100. DOI: 10.1302/2046-3758.53.2000595. PMID:26989119

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

    PubMed

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

    2015-01-01

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

  6. 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.

  7. Efficacy of Electrical Stimulators for Bone Healing: A Meta-Analysis of Randomized Sham-Controlled Trials

    PubMed Central

    Aleem, Ilyas S.; Aleem, Idris; Evaniew, Nathan; Busse, Jason W.; Yaszemski, Michael; Agarwal, Arnav; Einhorn, Thomas; Bhandari, Mohit

    2016-01-01

    Electrical stimulation is a common adjunct used to promote bone healing; its efficacy, however, remains uncertain. We conducted a meta-analysis of randomized sham-controlled trials to establish the efficacy of electrical stimulation for bone healing. We identified all trials randomizing patients to electrical or sham stimulation for bone healing. Outcomes were pain relief, functional improvement, and radiographic nonunion. Two reviewers assessed eligibility and risk of bias, performed data extraction, and rated the quality of the evidence. Fifteen trials met our inclusion criteria. Moderate quality evidence from 4 trials found that stimulation produced a significant improvement in pain (mean difference (MD) on 100-millimeter visual analogue scale = −7.7 mm; 95% CI −13.92 to −1.43; p = 0.02). Two trials found no difference in functional outcome (MD = −0.88; 95% CI −6.63 to 4.87; p = 0.76). Moderate quality evidence from 15 trials found that stimulation reduced radiographic nonunion rates by 35% (95% CI 19% to 47%; number needed to treat = 7; p < 0.01). Patients treated with electrical stimulation as an adjunct for bone healing have less pain and are at reduced risk for radiographic nonunion; functional outcome data are limited and requires increased focus in future trials. PMID:27539550

  8. Enhancement of tendon–bone healing via the combination of biodegradable collagen-loaded nanofibrous membranes and a three-dimensional printed bone-anchoring bolt

    PubMed Central

    Chou, Ying-Chao; Yeh, Wen-Lin; Chao, Chien-Lin; Hsu, Yung-Heng; Yu, Yi-Hsun; Chen, Jan-Kan; Liu, Shih-Jung

    2016-01-01

    A composite biodegradable polymeric model was developed to enhance tendon graft healing. This model included a biodegradable polylactide (PLA) bolt as the bone anchor and a poly(D,L-lactide-co-glycolide) (PLGA) nanofibrous membrane embedded with collagen as a biomimic patch to promote tendon–bone interface integration. Degradation rate and compressive strength of the PLA bolt were measured after immersion in a buffer solution for 3 months. In vitro biochemical characteristics and the nanofibrous matrix were assessed using a water contact angle analyzer, pH meter, and tetrazolium reduction assay. In vivo efficacies of PLGA/collagen nanofibers and PLA bolts for tendon–bone healing were investigated on a rabbit bone tunnel model with histological and tendon pullout tests. The PLGA/collagen-blended nanofibrous membrane was a hydrophilic, stable, and biocompatible scaffold. The PLA bolt was durable for tendon–bone anchoring. Histology showed adequate biocompatibility of the PLA bolt on a medial cortex with progressive bone ingrowth and without tissue overreaction. PLGA nanofibers within the bone tunnel also decreased the tunnel enlargement phenomenon and enhanced tendon–bone integration. Composite polymers of the PLA bolt and PLGA/collagen nanofibrous membrane can effectively promote outcomes of tendon reconstruction in a rabbit model. The composite biodegradable polymeric system may be useful in humans for tendon reconstruction. PMID:27601901

  9. The use of low output laser therapy to accelerate healing of diabetic foot ulcers: a randomized prospective controlled trial

    NASA Astrophysics Data System (ADS)

    Naidu, S. V. L. G.; Subapriya, S.; Yeoh, C. N.; Soosai, S.; Shalini, V.; Harwant, S.

    2005-11-01

    The aim of this study was to assess the effects of low output laser therapy as an adjuvant treatment in grade 1 diabetic foot ulcers. Methods: Sixteen patients were randomly divided equally into two groups. Group A had daily dressing only, while group B had low output laser therapy instituted five days a week in addition to daily dressing. Serial measurement of the ulcer was done weekly using digital photography and analyzed. Results: The rate of healing in group A was 10.42 mm2/week, and in group B was 66.14mm2/week. The difference in the rate of healing was statistically significant, p<0.05. Conclusion: Laser therapy as an adjuvant treatment accelerates diabetic ulcer healing by six times in a six week period.

  10. [Influence of honey, royal jelly and propolis on accelerating acetate healing of experimental gastric ulcers in rats].

    PubMed

    Belostotskiĭ, N I; Kas'ianenko, V I; Dubtsova, E A; Lazebnik, L B

    2009-01-01

    This study examines gastric acetic ulcer healing in the rat after administration of honey, royal jelly and propolis into the stomach. Chronic gastric ulcers were induced in male Wistar rats by the application of 100% acetic acid to the serosal surface of the stomach on 60 sec. Bee-keeping products were administrated into the stomach from 2nd to 7th day after acetic ulcer induction. On 7th day animals were killed, and ulcer area was measured in mm2. In gastric juice pH and activity of pepsin were measured. The healing of acetic ulcers is accelerated with the administration of honey, royal jelly or propolis during six days. The largest healing effect was demonstrated with propolis and royal jelly, smaller one with the honey. It was revealed decrease of stomach acid secretion in the rats, which have received bee-keeping products versus the rats of control group.

  11. Effect of Mesenchymal Stem Cells and Platelet-Rich Plasma on the Bone Healing of Ovariectomized Rats

    PubMed Central

    Wei, Bo; Quan, Juanhua

    2016-01-01

    We evaluated the efficacy of platelet-rich plasma (PRP) in combination with allogeneic bone marrow mesenchymal stem cells (BMSCs) for the treatment of osteoporotic bone defects in an ovariectomized rat model. By day 42 after injury, in vivo microcomputed tomography (micro-CT) imaging revealed that bone defects of control rats and ovariectomized rats treated with PRP and BMSCs were completely repaired, whereas those of ovariectomized rats treated with PRP or BMSCs alone exhibited slower healing. Histological data were consistent with these results. We also assessed changes to bone trabeculae in the proximal tibial growth plate. In ovariectomized rats treated with PRP or with a combination of PRP and BMSCs, the trabecular connectivity densities (Conn.D), bone volume ratios (BV/TV), and numbers (Tb.N) in the defect areas increased significantly from day 7 to day 42. These results indicate that PRP treatment enhances bone microarchitecture in osteoporosis. Moreover, expression levels of osteogenesis-specific marker genes including RUNX2, OSX, and OPN were significantly upregulated in rats treated with PRP and BMSCs compared to those of other groups. Thus, we conclude that treatment with PRP combined with BMSCs significantly promotes healing of osteoporotic bone defects. This study provides an alternative strategy for the treatment of osteoporotic bone loss. PMID:27994625

  12. Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing.

    PubMed

    Rabbani, Piul S; Zhou, Anna; Borab, Zachary M; Frezzo, Joseph A; Srivastava, Nikita; More, Haresh T; Rifkin, William J; David, Joshua A; Berens, Samuel J; Chen, Raymond; Hameedi, Sophia; Junejo, Muhammad H; Kim, Camille; Sartor, Rita A; Liu, Che F; Saadeh, Pierre B; Montclare, Jin K; Ceradini, Daniel J

    2017-04-03

    Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.

  13. 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.

  14. Healing of bone in the rat following surgery with the erbium-YAG laser

    NASA Astrophysics Data System (ADS)

    Dickinson, Mark R.; Devlin, Hugh; El Montaser, Monsour A.; Sloan, Philip

    1996-12-01

    Background and objectives: the aim of this study was to examine the pattern of healing in rat calvarial defects prepared with the erbium-YAG laser, using the 'guided tissue regeneration' technique. Materials and method: PTFE membranes were placed over lased skull defects, and the skin wounds sutured. Rats were killed humanely at intervals after surgery, and the skulls processed for paraffin wax histology. A further group of mature rats were also killed humanely and the calvariae removed. Slots were prepared using the erbium-YAG laser and immediately examined under the environmental scanning electron microscope (ESEM) in hydrated conditions, which avoided drying artifacts. Results: An amorphous, mineral-rich carbon layer surrounds the lased bone defect, which in the in vivo experiments was seen as a basophilic zone which was resistant to resorption.

  15. Acceleration of diabetic-wound healing with PEGylated rhaFGF in healing-impaired streptozocin diabetic rats.

    PubMed

    Huang, Zhifeng; Lu, Meifei; Zhu, Guanghui; Gao, Hongchang; Xie, Liyun; Zhang, Xiaoqin; Ye, Chaohui; Wang, Yan; Sun, Chuanchuan; Li, Xiaokun

    2011-01-01

    Molecular modification with polyethylene glycol (PEGylation) is an effective approach to improve protein biostability, in vivo lifetime and therapeutic potency. In the present study, the recombinant human acid fibroblast growth factor (rhaFGF) was site-selectively PEGylated with 20 kDa mPEG-butyraldehyde. Mono-PEGylated rhaFGF was purified to near homogeneity by Sephadex G 25-gel filtration followed by a Heparin Sepharose TM CL-6B affinity chromatography. PEGylated rhaFGF has less effect than the native rhaFGF on the stimulation of 3T3 cell proliferation in vitro; however, its relative thermal stability at normal physiological temperature and structural stability were significantly enhanced, and its half-life time in vivo was significantly extended. Then, the physiological function of PEGylated rhaFGF on diabetic-wound healing was evaluated in type 1 diabetic Sprague Dawley rats. The results showed that, compared with the group of animal treated with native rhaFGF, the group treated with PEGylated rhaFGF exhibited better therapeutic efficacy with shorter healing time, quicker tissue collagen generation, earlier and higher transforming growth factor (TGF)-β expression, and dermal cell proliferation. In addition, in vivo analysis showed that both native and PEGylated rhaFGF were more effective in the wound healing in the diabetic group compared with the nondiabetic one. Taken together, these results suggest that PEGylation of rhaFGF could be a more effective approach to the pharmacological and therapeutic application of native rhaFGF.

  16. The influence of low-level laser therapy with alendronate irrigation on healing of bone defects in rats.

    PubMed

    Akyol, Utkan Kamil; Sipal, Sare; Demirci, Elif; Gungormus, Metin

    2015-04-01

    The aim of this study was to investigate the effects of alendronate (Aln) irrigation with low-level laser therapy (LLLT) on the healing of bone defects in rats. Sixty Wistar rats weighing 250 to 300 g were randomly divided into three groups of 20 animals each: (1) control group, (2) Aln group, and (3) Aln with LLLT group. The distal epiphysis of all rats was perforated with a surgical bone drill. Twenty rats served as control. The bone defects of 40 rats received local alendronate sodium trihydrate irrigation (1 mg/ml) at the time of surgery. LLLT was applied to the bone defects of 20 rats immediately after Aln irrigation, and repeated on days 2, 4, 6, and 8 with a total dose of 10 J/cm(2) (2 J/cm(2) × 5). Continuous wave of GaAlAs laser (808 nm) was used with a power density of 0.1 W/cm(2). Laser energy was applied for 20 s (0.1 W × 20 s/1 cm(2)) per session. Control group, Aln group, and Aln with LLLT group rats were sacrificed at days 10 and 20 to compare the bone healing of each group histologically. There were significant differences between the three groups regarding union, substantia spongiosa, cortex formation, and in sum of histologic scores on days 10 and 20 (P < 0.0001). Our findings demonstrated that Aln has a more positive effect with LLLT on bone healing in rats. It was concluded that combining LLLT (808 nm laser at 10 J/cm(2)) with Aln irrigation has a beneficial effect in bone repair. It was demonstrated experimentally that Aln irrigation during the surgery had a significant effect to enhance bone formation, and LLLT significantly potentiated the osseous healing effects of Aln on bone defects. This administration method is able to minimize the dose of Aln in order to avoid both systemic and local adverse effects as well as the local injection times during the bone healing process.

  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. 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

  19. Accelerated healing of skin burns by anti-Gal/alpha-gal liposomes interaction.

    PubMed

    Galili, Uri; Wigglesworth, Kim; Abdel-Motal, Ussama M

    2010-03-01

    Topical application of alpha-gal liposomes on burns results in rapid local recruitment of neutrophils and macrophages. Recruited macrophages are pivotal for healing of burns because they secrete cytokines/growth factors that induce epidermis regeneration and tissue repair. alpha-Gal liposomes have glycolipids with alpha-gal epitopes (Galalpha1-3Galbeta1-4GlcNAc-R) which bind anti-Gal, the most abundant natural antibody in humans constituting approximately 1% of immunoglobulins. Interaction of alpha-gal liposomes with anti-Gal within the fluid film formed on burns, activates complement and generates chemotactic complement cleavage peptides which effectively recruit neutrophils and macrophages. Anti-Gal IgG coating alpha-gal liposomes further binds to Fcgamma receptors on macrophages and activates them to secrete cytokines/growth factors. Efficacy of alpha-gal liposomes treatment in accelerating burn healing is demonstrated in the experimental model of alpha1,3galactosyltransferase knockout mice. These mice are the only available nonprimate mammals that can produce anti-Gal in titers similar to those in humans. Pairs of burns in mice were covered either with a spot bandage coated with 10mg alpha-gal liposomes, or with a control spot bandage coated with saline. On Day 3 post-treatment, the alpha-gal liposomes treated burns contained approximately 5-fold as many neutrophils as control burns, whereas macrophages were found only in alpha-gal liposomes treated burns. On Day 6, 50-100% of the surface area of alpha-gal liposomes treated burns were covered with regenerating epidermis (re-epithelialization), whereas almost no epidermis was found in control burns. The extensive recruitment of macrophages by anti-Gal/alpha-gal liposomes interaction was further demonstrated in vivo with polyvinyl alcohol (PVA) sponge discs containing alpha-gal liposomes, implanted subcutaneously. Since anti-Gal is abundant in all humans, it is suggested that treatment with alpha-gal liposomes

  20. Use of radiography to identify keel bone fractures in laying hens and assess healing in live birds.

    PubMed

    Richards, G J; Nasr, M A; Brown, S N; Szamocki, E M G; Murrell, J; Barr, F; Wilkins, L J

    2011-09-10

    The aim of this study was to use radiography to assess and characterise naturally occurring keel bone fractures in laying hens and monitor live birds over several weeks to examine the healing process. Twenty-four Lohmann brown commercial laying hens with varying degrees of keel bone fracture were used in the study. Birds were radiographed regularly over six weeks and the radiographic features and changing appearance of keel bone fractures were evaluated. The radiographic characteristics of old and new fractures were categorised and indicated that 80 per cent of birds entering the study with new fractures had healed after 35 days and five birds had incurred new fractures irrespective of their original fracture status.

  1. Microencapsulation of 2-octylcyanoacrylate tissue adhesive for self-healing acrylic bone cement

    PubMed Central

    Brochu, Alice B. W.; Chyan, William J.; Reichert, William M.

    2014-01-01

    Here, we report the first phase of developing self-healing acrylic bone cement: the preparation and characterization of polyurethane (PUR) microcapsules containing a medical cyanoacrylate tissue adhesive. Capsules were prepared by interfacial polymerization of a toluene-2,4-diisocyanate-based polyurethane prepolymer with 1,4-butanediol to encapsulate 2-octylcyanoacrylate (OCA). Various capsule characteristics, including: resultant morphology, average size and size distribution, shell thickness, content and reactivity of encapsulated agent, and shelf life are investigated and their reliance on solvent type and amount, surfactant type and amount, temperature, pH, agitation rate, reaction time, and mode of addition of the oil phase to the aqueous phase are presented. Capsules had average diameters ranging from 74 to 222 μm and average shell thicknesses ranging from 1.5 to 6 μm. The capsule content was determined via thermogravimetric analysis and subsequent analysis of the capsules following up to 8 weeks storage revealed minimal loss of core contents. Mechanical testing of OCA-containing capsules showed individual capsules withstood compressive forces up to a few tenths of Newtons, and the contents released from crushed capsules generated tensile adhesive forces of a few Newtons. Capsules were successfully mixed into the poly(- methyl methacrylate) bone cement, surviving the mixing process, exposure to methyl methacrylate monomer, and the resulting exothermic matrix curing. PMID:22807313

  2. [Healing of osseous defects by guided bone regeneration using ribose cross linked collagen membranes].

    PubMed

    Tal, H

    2004-07-01

    The ultimate goal of periodontal therapy has long been the complete regeneration of the periodontal attachment apparatus. Guided Tissue Regeneration (GTR) and Guided Bone Regeneration (GBR) are two regenerative procedures which converted this goal from a dream to reality. In search of a biocompatible resorbable tissue barrier, collagen, being a natural protein and a weak antigen, has attracted much interest and became the focus of much intention during the 80's and the 90's. The understanding that cross linking of collagen with aldehyde sugars, especially ribose, produces collagen which is highly resistant to resorption in vivo led to the development of a "natural" Crossed-Linked Collagen Barrier (CB-SX). Animal and Human studies have shown that the newly developed membrane is biocompatible, remains intact in the tissues 6 months and more, and results in impressive guided tissue/bone regeneration. Spontaneous early exposure of the membrane is common but the healing potential of the resulted tissue dehiscence is favorable with no tendency for bacterial infection. The commercial version of the CB-SX is especially suitable for GBR procedures; it is highly recommended that the gingival flaps involved will properly be released, will lack tension, and be thoroughly sutured.

  3. Bioprinted Amniotic Fluid-Derived Stem Cells Accelerate Healing of Large Skin Wounds

    PubMed Central

    Skardal, Aleksander; Mack, David; Kapetanovic, Edi; Atala, Anthony; Jackson, John D.; Yoo, James

    2012-01-01

    Stem cells obtained from amniotic fluid show high proliferative capacity in culture and multilineage differentiation potential. Because of the lack of significant immunogenicity and the ability of the amniotic fluid-derived stem (AFS) cells to modulate the inflammatory response, we investigated whether they could augment wound healing in a mouse model of skin regeneration. We used bioprinting technology to treat full-thickness skin wounds in nu/nu mice. AFS cells and bone marrow-derived mesenchymal stem cells (MSCs) were resuspended in fibrin-collagen gel and “printed” over the wound site. At days 0, 7, and 14, AFS cell- and MSC-driven wound closure and re-epithelialization were significantly greater than closure and re-epithelialization in wounds treated by fibrin-collagen gel only. Histological examination showed increased microvessel density and capillary diameters in the AFS cell-treated wounds compared with the MSC-treated wounds, whereas the skin treated only with gel showed the lowest amount of microvessels. However, tracking of fluorescently labeled AFS cells and MSCs revealed that the cells remained transiently and did not permanently integrate in the tissue. These observations suggest that the increased wound closure rates and angiogenesis may be due to delivery of secreted trophic factors, rather than direct cell-cell interactions. Accordingly, we performed proteomic analysis, which showed that AFS cells secreted a number of growth factors at concentrations higher than those of MSCs. In parallel, we showed that AFS cell-conditioned media induced endothelial cell migration in vitro. Taken together, our results indicate that bioprinting AFS cells could be an effective treatment for large-scale wounds and burns. PMID:23197691

  4. Effect of Immediate and Delayed High-Strain Loading on Tendon-to-Bone Healing After Anterior Cruciate Ligament Reconstruction

    PubMed Central

    Packer, Jonathan D.; Bedi, Asheesh; Fox, Alice J.; Gasinu, Selom; Imhauser, Carl W.; Stasiak, Mark; Deng, Xiang-Hua; Rodeo, Scott A.

    2014-01-01

    Background: We previously demonstrated, in a rat anterior cruciate ligament (ACL) graft reconstruction model, that the delayed application of low-magnitude-strain loading resulted in improved tendon-to-bone healing compared with that observed after immediate loading and after prolonged immobilization. The purpose of this study was to determine the effect of higher levels of strain loading on tendon-to-bone healing. Methods: ACL reconstruction was carried out in a rat model in three randomly assigned groups: high-strain daily loading beginning on either (1) postoperative day one (immediate-loading group; n = 7) or (2) postoperative day four (delayed-loading group; n = 11) or (3) after prolonged immobilization (immobilized group; n = 8). Animals were killed two weeks after surgery and micro-computed tomography (micro-CT) and biomechanical testing of the bone-tendon-bone complex were carried out. Results: The delayed-loading group had greater tissue mineral density than either the immediate-loading or immobilized group (mean [and standard deviation], 813.0 ± 24.9 mg/mL compared with 778.4 ± 32.6 mg/mL and 784.9 ± 26.4 mg/mL, respectively; p < 0.05). There was a trend toward greater bone volume per total volume fraction in both the immobilized and the delayed-loading group compared with the immediate-loading group (0.24 ± 0.03 and 0.23 ± 0.06 compared with 0.20 ± 0.05; p = 0.06). Trabecular thickness was greater in the immobilized group compared with the immediate-loading group (106.5 ± 23.0 μm compared with 72.6 ± 10.6 μm; p < 0.01). There were no significant differences in failure load or stiffness between the immobilized group and either high-strain cyclic-loading group. Conclusions: Immediate application of high-strain loading appears to have a detrimental effect on healing in this rat model. Any beneficial effects of delayed loading on the healing tendon-bone interface (after a brief period of immobilization) may be offset by the detrimental effects of

  5. [Effect of combined therapeutic methods on healing of periodontal vertical bone defects in regenerative surgery].

    PubMed

    Dori, Ferenc

    2009-03-15

    Several methods are available to enhance the healing and regeneration of periodontal tissues after surgical therapy of intrabony defects. The main indications for the use of combined regenerative procedures are the extent and morphology of the osseous lesions. The six studies of the present dissertation focused on the clinical effect of different barrier techniques, bone substitutes, enamel matrix derivatives and a growth factors containing adjuvant used in various combinations on the healing of severe periodontal intrabony impairments. Synthetic, xenogenetic and autologous materials were used in these randomized clinical studies. Mechanical barriers (polytetrafluoroethylene and collagen membranes) for GTR, biological barriers/enamel matrix proteins (EMD), synthetic (beta-TCP) and xenogeneic (NBM) bone grafts and autologous platelet-rich plasma (PRP) were combined in the test and control groups of the trials. The main clinical variable was the clinical attachment level (CAL) and the subsidiary one was the probing pocket depth (PPD), estimated at baseline and after one year. The summation of the results after the statistical analysis takes cognizance of the followings: a) Each of the eleven regenerative methods evaluated (ten combined procedures) leads to significant CAL gain and PPD decrease. b) Using beta-TCP or NBM with EMD or with PRP+GTR and GTR's, the difference between the parameters of the test and control groups were not statistically significant. c) It was confirmed in four studies that the addition of PRP to graft materials has not increased significantly the positive outcomes independent of the type of barrier or graft. d) Adding platelet-rich plasma to natural bone mineral, no benefit was observed from the point of view of the clinical variables. e) The polypeptide proteins of the platelet-rich plasma do not enhance the clinical regenerative effect of enamel matrix proteins. In conclusion, the option of the periodontal surgeons between these methods

  6. Evaluation of autologous bone marrow in wound healing in animal model: a possible application of autologous stem cells.

    PubMed

    Akela, Ashok; Nandi, Samit Kumar; Banerjee, Dibyajyoti; Das, Partha; Roy, Subhasis; Joardar, Siddhartha Narayan; Mandal, Mohan; Das, Pradip Kumar; Pradhan, Nisith Ranjan

    2012-10-01

    A study was conducted to evaluate the potential of autologous bone marrow-derived cells in comparison with buffy coat of autologous blood for rapid cutaneous wound healing in rabbit model. Three square full-thickness skin excisional wounds were created in 15 selected experimental animals (rabbit) divided randomly into three groups. The wound was treated with autologous bone marrow cells in plasma (group 1), buffy coat of blood in plasma (group 2) and autologous plasma as control (group 3). Wounds were observed for 30 days for granulation tissue formation, biochemical, histomorphological and histochemical evaluation. In this study, granulation tissue appeared significantly lesser in wounds of group 3 animals followed by group 2 and 1 animals. Neovascularisation, granulation tissue formation, denser, thicker and better arranged collagen fibres, reticulin fibres and elastin fibres formation was more in group 1 as compared with other groups. It was concluded that the application of bone marrow-derived nucleated cells into the wound margins resulted in early and significantly faster rate of complete healing as compared with buffy coat of autologous blood and autologous plasma (control). This approach may be beneficial in various surface wounds that heal at a slower rate and recommended for healing of various complicated wound in future.

  7. Comparison of the Effects of Low-Level Laser Therapy and Ozone Therapy on Bone Healing.

    PubMed

    Alan, Hilal; Vardi, Nigar; Özgür, Cem; Acar, Ahmet Hüseyin; Hüseyin, Ahmet; Yolcu, Ümit; Doğan, Derya Ozdemir

    2015-07-01

    This study aims to compare the effect of low-level laser therapy (LLLT) and ozone therapy on the bone healing. Thirty-six adult male Wistar albino rats were used for this study. Monocortical defects were shaped in right femur of all rats. Defects were filled with nano-hydroxyapatite graft. The animals were divided into 3 groups and each group was than divided into 2 subgroups. Then, LLLT with a diode laser was applied to the first group (G1), ozone therapy was applied to the second group (G2), and no treatment was applied to the third group as a control group (G3). Animals were sacrificed after 4th and 8th weeks and the sections were examined to evaluate the density of the inflammation, the formation of connective tissue, the osteogenic potential, and osteocalcin activity. As a result, there were no significant differences among the groups of 4 weeks in terms of new bone formation. In the immunohistochemical assessment, the number of osteocalcin-positive cells was higher in the laser group compared to the other group of 4 weeks; this difference was statistically significant in the LLLT and ozone groups (P < 0.05). Histomorphometric assessment showed that the new bone areas were higher in the LLLT and ozone groups; furthermore, there was a statistically significant difference in the LLLT in comparison with the control group at 8th week (P < 0.05). At the same time immunohistochemical assessment showed that osteocalcin-positive cells were considerably higher in G2 than G1 at 8th week (P < 0.05). The findings of this study may be the result of differences in the number of treatment sessions. Further studies are therefore needed to determine the optimal treatment modality.

  8. The accelerating effect of chitosan-silica hybrid dressing materials on the early phase of wound healing.

    PubMed

    Park, Ji-Ung; Jung, Hyun-Do; Song, Eun-Ho; Choi, Tae-Hyun; Kim, Hyoun-Ee; Song, Juha; Kim, Sukwha

    2016-05-24

    Commercialized dressing materials with or without silver have played a passive role in early-phase wound healing, protecting the skin defects from infections, absorbing exudate, and preventing dehydration. Chitosan (CTS)-based sponges have been developed in pure or hybrid forms for accelerating wound healing, but their wound-healing capabilities have not been extensively compared with widely used commercial dressing materials, providing limited information in a practical aspect. In this study, we have developed CTS-silica (CTS-Si) hybrid sponges with water absorption, flexibility, and mechanical behavior similar to those of CTS sponges. In vitro and in vivo tests were performed to compare the CTS-Si sponges with three commercial dressing materials [gauze, polyurethane (PU), and silver-containing hydrofiber (HF-Ag)] in addition to CTS sponges. Both in vitro and in vivo tests showed that CTS-Si sponges promoted fibroblast proliferation, leading to accelerated collagen synthesis, whereas the CTS sponges did not exhibit significant differences in fibroblast proliferation and collagen synthesis from gauze, PU, and HF-Ag sponges. In case of CTS-Si, the inflammatory cells were actively recruited to the wound by the influence of the released silicon ions from CTS-Si sponges, which, in return, led to an enhanced secretion of growth factors, particularly TGF-β during the early stage. The higher level of TGF-β likely improved the proliferation of fibroblasts, and as a result, collagen synthesis by fibroblasts became remarkably productive, thereby increasing collagen density at the wound site. Therefore, the CTS-Si hybrid sponges have considerable potential as a wound-dressing material for accelerating wound healing. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2016.

  9. Accelerated wound healing in a diabetic rat model using decellularized dermal matrix and human umbilical cord perivascular cells.

    PubMed

    Milan, P Brouki; Lotfibakhshaiesh, N; Joghataie, M T; Ai, J; Pazouki, A; Kaplan, D L; Kargozar, S; Amini, N; Hamblin, M R; Mozafari, M; Samadikuchaksaraei, A

    2016-11-01

    There is an unmet clinical need for novel wound healing strategies to treat full thickness skin defects, especially in diabetic patients. We hypothesized that a scaffold could perform dual roles of a biomechanical support and a favorable biochemical environment for stem cells. Human umbilical cord perivascular cells (HUCPVCs) have been recently reported as a type of mesenchymal stem cell that can accelerate early wound healing in skin defects. However, there are only a limited number of studies that have incorporated these cells into natural scaffolds for dermal tissue engineering. The aim of the present study was to promote angiogenesis and accelerate wound healing by using HUCPVCs and decellularized dermal matrix (DDM) in a rat model of diabetic wounds. The DDM scaffolds were prepared from harvested human skin samples and histological, ultrastructural, molecular and mechanical assessments were carried out. In comparison with the control (without any treatment) and DDM alone group, full thickness excisional wounds treated with HUCPVCs-loaded DDM scaffolds demonstrated an accelerated wound closure rate, faster re-epithelization, more granulation tissue formation and decreased collagen deposition. Furthermore, immunofluorescence analysis showed that the VEGFR-2 expression and vascular density in the HUCPVCs-loaded DDM scaffold treated group were also significantly higher than the other groups at 7days post implantation. Since the rates of angiogenesis, re-epithelization and formation of granulation tissue are directly correlated with full thickness wound healing in patients, the proposed HUCPVCs-loaded DDM scaffolds may fulfil a role neglected by current treatment strategies. This pre-clinical proof-of-concept study warrants further clinical evaluation.

  10. 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

  11. Rapid recruitment and activation of macrophages by anti-Gal/α-Gal liposome interaction accelerates wound healing.

    PubMed

    Wigglesworth, Kim M; Racki, Waldemar J; Mishra, Rabinarayan; Szomolanyi-Tsuda, Eva; Greiner, Dale L; Galili, Uri

    2011-04-01

    Macrophages are pivotal in promoting wound healing. We hypothesized that topical application of liposomes with glycolipids that carry Galα1-3Galβ1-4GlcNAc-R epitopes (α-gal liposomes) on wounds may accelerate the healing process by rapid recruitment and activation of macrophages in wounds. Immune complexes of the natural anti-Gal Ab (constituting ∼1% of Ig in humans) bound to its ligand, the α-gal epitope on α-gal liposomes would induce local activation of complement and generation of complement chemotactic factors that rapidly recruit macrophages. Subsequent binding of the Fc portion of anti-Gal coating α-gal liposomes to FcγRs on recruited macrophages may activate macrophage genes encoding cytokines that mediate wound healing. We documented the efficacy of this treatment in α1,3galactosyltrasferase knockout mice. In contrast to wild-type mice, these knockout mice lack α-gal epitopes and can produce the anti-Gal Ab. The healing time of excisional skin wounds treated with α-gal liposomes in these mice is twice as fast as that of control wounds. Moreover, scar formation in α-gal liposome-treated wounds is much lower than in physiologic healing. Additional sonication of α-gal liposomes resulted in their conversion into submicroscopic α-gal nanoparticles. These α-gal nanoparticles diffused more efficiently in wounds and further increased the efficacy of the treatment, resulting in 95-100% regeneration of the epidermis in wounds within 6 d. The study suggests that α-gal liposome and α-gal nanoparticle treatment may enhance wound healing in the clinic because of the presence of high complement activity and high anti-Gal Ab titers in humans.

  12. An activin A/BMP2 chimera, AB204, displays bone-healing properties superior to those of BMP2.

    PubMed

    Yoon, Byung-Hak; Esquivies, Luis; Ahn, Chihoon; Gray, Peter C; Ye, Sang-Kyu; Kwiatkowski, Witek; Choe, Senyon

    2014-09-01

    Recombinant bone morphogenetic protein 2 (rhBMP2) has been used clinically to treat bone fractures in human patients. However, the high doses of rhBMP2 required for a therapeutic response can cause undesirable side effects. Here, we demonstrate that a novel Activin A/BMP2 (AB2) chimera, AB204, promotes osteogenesis and bone healing much more potently and effectively than rhBMP2. Remarkably, 1 month of AB204 treatment completely heals tibial and calvarial defects of critical size in mice at a concentration 10-fold lower than a dose of rhBMP2 that only partially heals the defect. We determine the structure of AB204 to 2.3 Å that reveals a distinct BMP2-like fold in which the Activin A sequence segments confer insensitivity to the BMP2 antagonist Noggin and an affinity for the Activin/BMP type II receptor ActRII that is 100-fold greater than that of BMP2. The structure also led to our identification of a single Activin A-derived amino acid residue, which, when mutated to the corresponding BMP2 residue, resulted in a significant increase in the affinity of AB204 for its type I receptor BMPRIa and a further enhancement in AB204's osteogenic potency. Together, these findings demonstrate that rationally designed AB2 chimeras can provide BMP2 substitutes with enhanced potency for treating non-union bone fractures.

  13. Evaluation of an injectable bioactive borate glass cement to heal bone defects in a rabbit femoral condyle model.

    PubMed

    Cui, Xu; Huang, Wenhai; Zhang, Yadong; Huang, Chengcheng; Yu, Zunxiong; Wang, Lei; Liu, Wenlong; Wang, Ting; Zhou, Jie; Wang, Hui; Zhou, Nai; Wang, Deping; Pan, Haobo; Rahaman, Mohamed N

    2017-04-01

    There is a need for synthetic biomaterials to heal bone defects using minimal invasive surgery. In the present study, an injectable cement composed of bioactive borate glass particles and a chitosan bonding solution was developed and evaluated for its capacity to heal bone defects in a rabbit femoral condyle model. The injectability and setting time of the cement in vitro decreased but the compressive strength increased (8±2MPa to 31±2MPa) as the ratio of glass particles to chitosan solution increased (from 1.0gml(-1) to 2.5gml(-1)). Upon immersing the cement in phosphate-buffered saline, the glass particles reacted and converted to hydroxyapatite, imparting bioactivity to the cement. Osteoblastic MC3T3-E1 cells showed enhanced proliferation and alkaline phosphatase activity when incubated in media containing the soluble ionic product of the cement. The bioactive glass cement showed a better capacity to stimulate bone formation in rabbit femoral condyle defects at 12weeks postimplantation when compared to a commercial calcium sulfate cement. The injectable bioactive borate glass cement developed in this study could provide a promising biomaterial to heal bone defects by minimal invasive surgery.

  14. An Activin A/BMP2 chimera displays bone healing properties superior to those of BMP2

    PubMed Central

    Yoon, Byung-Hak; Esquivies, Luis; Ahn, Chihoon; Gray, Peter C.; Ye, Sang-kyu; Kwiatkowski, Witek; Choe, Senyon

    2014-01-01

    Recombinant Bone Morphogenetic Protein 2 (rhBMP2) has been used clinically to treat bone fractures in human patients. However, the high doses of rhBMP2 required for a therapeutic response can cause undesirable side effects. Here, we demonstrate that a novel Activin A/BMP2 (AB2) chimera, AB204, promotes osteogenesis and bone healing much more potently and effectively than rhBMP2. Remarkably, 1 month of AB204 treatment completely heals tibial and calvarial defects of critical size in mice at a concentration 10-fold lower than a dose of rhBMP2 that only partially heals the defect. We determine the structure of AB204 to 2.3 Å that reveals a distinct BMP2-like fold in which the Activin A sequence segments confer insensitivity to the BMP2 antagonist Noggin and an affinity for the Activin/BMP type II receptor ActRII that is 100-fold greater than that of BMP2. The structure also led to our identification of a single Activin A-derived amino acid residue which when mutated to the corresponding BMP2 residue resulted in a significant increase in the affinity of AB204 for its type I receptor BMPRIa and a further enhancement in AB204's osteogenic potency. Together, these findings demonstrate that rationally designed AB2 chimeras can provide BMP2 substitutes with enhanced potency for treating non-union bone fractures. PMID:24692083

  15. Anabolic potential of bone mineral in human periosteal fibroblasts using steroid markers of healing.

    PubMed

    Suchak, A; Soory, M

    2013-05-01

    A deproteinized natural cancellous bone mineral (B) was studied in a cell culture model for its anabolic potential using two radiolabelled steroid substrates, 14C-testosterone (14C-T) and 14C-4-androstenedione (14C-4-A) independently; in the presence or absence of the anti-androgen finasteride (F) and minocycline (M). Culture medium was assayed for the biologically active metabolite 5 alpha-dihydrotestosterone (DHT) a marker of regenerative potential and wound healing. Confluent monolayer cultures of human periosteal fibroblasts were incubated in Eagle's minimum essential medium with each of the substrates 14C-T and 14C-4-A. Incubations were performed with previously established optimal concentrations of B5 (milligrams/ml), M25 (μg/ml) and F5 (μg/ml) alone and in combination (n=6) for 24h. The eluent was solvent extracted with ethyl acetate (2 ml x 2) and subjected to TLC in a benzene/acetone solvent system (4:1 v/v) for separation of metabolites; they were quantified using a radioisotope scanner. The yield of DHT was increased over controls in response to B and M with both substrates 14C-T and 14C-4-A by 1.7, 1.8-fold and 1.7, 1.6-fold respectively (n=6; p<0.001; one way ANOVA). Combined incubations of B and M resulted in similar yields. F inhibited DHT yields with both radiolabelled substrates by 2-3-fold (n=6; p<0.001) which was overcome by a combined incubation of F+B to values similar to those of controls (p<0.01). Documented pro-anabolic effects of minocycline were applicable as a standard for confirmation of responses to B. Significant increases in yields of DHT in response to B and M with both substrates indicate their anabolic potential in periosteal fibroblasts with implications for wound healing.

  16. Bone Healing Improvements Using Hyaluronic Acid and Hydroxyapatite/Beta-Tricalcium Phosphate in Combination: An Animal Study

    PubMed Central

    Chang, Yen-Lan; Lo, Yi-June; Huang, Yu-Chih; Tsai, Hsin-Yuan; Lin, Che-Tong; Fan, Kan-Hsin

    2016-01-01

    The purpose of this study was to investigate whether the use of HLA as an aqueous binder of hydroxyapatite/beta-tricalcium phosphate (HA-βTCP) particles can reduce the amount of bone graft needed and increase ease of handling in clinical situations. In this study, HA/βTCP was loaded in commercially available crosslinking HLA to form a novel HLA/HA-βTCP composite. Six New Zealand White rabbits (3.0–3.6 kg) were used as test subjects. Four 6 mm defects were prepared in the parietal bone. The defects were filled with the HLA/HA-βTCP composite as well as HA-βTCP particle alone. New bone formation was analyzed by micro-CT and histomorphometry. Our results indicated that even when the HA-βTCP particle numbers were reduced, the regenerative effect on bone remained when the HLA existed. The bone volume density (BV/TV ratio) of HLA/HA-βTCP samples was 1.7 times larger than that of the control sample at week 2. The new bone increasing ratio (NBIR) of HLA/HA-βTCP samples was 1.78 times higher than the control group at week 2. In conclusion, HA-βTCP powder with HLA contributed to bone healing in rabbit calvarial bone defects. The addition of HLA to bone grafts not only promoted osteoconduction but also improved handling characteristics in clinical situations. PMID:28070520

  17. 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

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

    PubMed

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

    2015-05-01

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

  19. 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.

  20. Efficacy of nano-hydroxyapatite prepared by an aqueous solution combustion technique in healing bone defects of goat.

    PubMed

    Nandi, Samit Kumar; Kundu, Biswanath; Ghosh, Samir Kumar; De, Dipak Kumar; Basu, Debabrata

    2008-06-01

    The present study was undertaken to evaluate porous hydroxyapatite (HAp), the powder of which was prepared by a novel aqueous solution combustion technique, as a bone substitute in healing bone defects in vivo, as assessed by radiologic and histopathologic methods, oxytetracycline labeling, and angiogenic features in Bengal goat. Bone defects were created in the diaphysis of the radius and either not filled (group I) or filled with a HAp strut (group II). The radiologic study in group II showed the presence of unabsorbed implants which acted as a scaffold for new bone growth across the defect, and the quality of healing of the bone defect was almost indistinguishable from the control group, in which the defect was more or less similar, although the newly formed bony tissue was more organized when HAp was used. Histologic methods showed complete normal ossification with development of Haversian canals and well-defined osteoblasts at the periphery in group II, whereas the control group had moderate fibro-collagenization and an adequate amount of marrow material, fat cells, and blood vessels. An oxytetracycline labeling study showed moderate activity of new bone formation with crossing-over of new bone trabeculae along with the presence of resorption cavities in group II, whereas in the control group, the process of new bone formation was active from both ends and the defect site appeared as a homogenous non-fluoroscent area. Angiograms of the animals in the control group showed uniform angiogenesis in the defect site with establishment of trans-transplant angiogenesis, whereas in group II there was complete trans-transplant shunting of blood vessel communication. Porous HAp ceramic prepared by an aqueous combustion technique promoted bone formation over the defect, confirming their biologic osteoconductive property.

  1. Bacterial cellulose/acrylic acid hydrogel synthesized via electron beam irradiation: accelerated burn wound healing in an animal model.

    PubMed

    Mohamad, Najwa; Mohd Amin, Mohd Cairul Iqbal; Pandey, Manisha; Ahmad, Naveed; Rajab, Nor Fadilah

    2014-12-19

    Natural polymer-based hydrogels are of interest to health care professionals as wound dressings owing to their ability to absorb exudates and provide hydration for healing. The aims of this study were to develop and characterize bacterial cellulose/acrylic acid (BC/AA) hydrogels synthesized by electron beam irradiation and investigate its wound healing potential in an animal model. The BC/AA hydrogels were characterized by SEM, tensile strength, water absorptivity, and water vapor transmission rate (WVTR). The cytotoxicity of the hydrogels was investigated in L929 cells. Skin irritation and wound healing properties were evaluated in Sprague-Dawley rats. BC/AA hydrogels had a macroporous network structure, high swelling ratio (4000-6000% at 24h), and high WVTR (2175-2280 g/m(2)/day). The hydrogels were non-toxic in the cell viability assay. In vivo experiments indicated that hydrogels promoted faster wound-healing, enhanced epithelialization, and accelerated fibroblast proliferation compared to that in the control group. These results suggest that BC/AA hydrogels are promising materials for burn dressings.

  2. A cold plasma jet accelerates wound healing in a murine model of full-thickness skin wounds.

    PubMed

    Schmidt, Anke; Bekeschus, Sander; Wende, Kristian; Vollmar, Brigitte; von Woedtke, Thomas

    2017-02-01

    Cold plasma has been successfully applied in several fields of medicine that require, for example, pathogen inactivation, implant functionalization or alteration of cellular activity. Previous studies have provided evidence that plasma supports the healing of wounds owing to its beneficial mixtures of reactive species and modulation of inflammation in cells and tissues. To investigate the wound healing activity of an atmospheric pressure plasma jet in vivo, we examined the cold plasma's efficacy on dermal regeneration in a murine model of dermal full-thickness ear wound. Over 14 days, female mice received daily plasma treatment. Quantitative analysis by transmitted light microscopy demonstrated a significantly accelerated wound re-epithelialization at days 3-9 in comparison with untreated controls. In vitro, cold plasma altered keratinocyte and fibroblast migration, while both cell types showed significant stimulation resulting in accelerated closure of gaps in scratch assays. This plasma effect correlated with the downregulation of the gap junctional protein connexin 43 which is thought to be important in the regulation of wound healing. In addition, plasma induced profound changes in adherence junctions and cytoskeletal dynamics as shown by downregulation of E-cadherin and several integrins as well as actin reorganization. Our results theorize cold plasma to be a beneficial treatment option supplementing existing wound therapies.

  3. [Present status of research in bone marrow-derived mesenchymal stem cells for promoting the healing of diabetic ulcer].

    PubMed

    Zheng, Shu-Juan; Jia, Chi-Yu

    2012-08-01

    The delayed healing of diabetic ulcer has been haunting the surgeons and researchers for a long time. Although we have been researching and exploring the effective therapies for many years, the progress has been limited. Bone marrow-derived mesenchymal stem cells (BMSCs) have gradually won worldwide attention for their characteristics of differentiating into tissue repair cells and secreting multiple cytokines as well as growth factors. In recent years, the role of BMSCs in the treatment of diabetic ulcer has been drawing more and more attention. This article reviewed the advancement in the research of BMSCs in promoting the healing of diabetic ulcer. Through a discussion of the treatment of diabetic ulcer, the related research in BMSCs, as well as its role in diabetic ulcer treatment, the mechanism of BMSCs in promoting healing of diabetic ulcers is discussed. We expect through further research, unified criteria for the quality of BMSCs, application approach and dosage of BMSCs could be established.

  4. VEGF and BFGF Expression and Histological Characteristics of the Bone-Tendon Junction during Acute Injury Healing

    PubMed Central

    Wang, Lin; Gao, Weiwei; Xiong, Kaiyu; Hu, Kuan; Liu, Xincun; He, Hui

    2014-01-01

    Bone-tendon junction (BTJ) injuries are common and may be caused by acute trauma and delayed healing during exercise or work. To understand the nature of the healing process of BTJ injuries would help to prevent injuries and improve treatment. Thirty-three mature female rabbit hindlimbs were assigned to normal control (CON, n = 7) and injury groups (n = 26). The acute injury was established by administering one 7 plum-blossom needle puncture. Specimens were harvested post injury at 1, 2, 4, and 8 weeks (ND1W, n = 6; ND2W, n = 6; ND4W, n = 7; and ND8W, n = 7). The injury existed in all of the injury groups. Compared with the CON group, all of the animals in the injury group showed poor cell profiles, an unclear or undetectable tide mark, a proteoglycan area and profile changes; the BTJ cell density diminished significantly in the ND1W (p < 0.01), ND2W (p < 0.05), ND4W (p < 0.01), and ND8W groups (p < 0.01); the fibrocartilage zone thickness in all injury groups was significantly thicker than in the CON group (p < 0.05), but no significant difference was found among the injury groups (p>0.05). The basic fibroblast growth factor (bFGF) expression in the CON group was significantly less than in the ND1W group (p<0.01), but no significant difference was found when compared with the ND2W, ND4W, and ND8W groups. The bFGF expression in the ND1W group was higher than that of the ND4W (p < 0.05) and ND8W groups (p < 0.01). The vascular endothelial growth factor (VEGF) levels were not significantly different among the groups (p > 0.05). The bFGF and VEGF expression levels indicated that the healing process stopped at 8 weeks post injury or was not activated, although the injury had not healed by histological examination. A repeatable animal model of BTJ acute injury was established in this study, and the results described the BTJ acute injury healing difficult concerned with the repairing stop. Key Points This study described the bone-tendon junction acute injury nature

  5. The transcriptome of fracture healing defines mechanisms of coordination of skeletal and vascular development during endochondral bone formation.

    PubMed

    Grimes, Rachel; Jepsen, Karl J; Fitch, Jennifer L; Einhorn, Thomas A; Gerstenfeld, Louis C

    2011-11-01

    Fractures initiate one round of endochondral bone formation in which callus cells differentiate in a synchronous manner that temporally phenocopies the spatial variation of endochondral development of a growth plate. During fracture healing C57BL/6J (B6) mice initiate chondrogenesis earlier and develop more cartilage than bone, whereas C3H/HeJ (C3H) mice initiate osteogenesis earlier and develop more bone than cartilage. Comparison of the transcriptomes of fracture healing in these strains of mice identified the genes that showed differences in timing and quantitative expression and encode for the variations in endochondral bone development of the two mouse strains. The complement of strain-dependent differences in gene expression was specifically associated with ontologies related to both skeletal and vascular formation. Moreover, the differences in gene expression associated with vascular tissue formation during fracture healing were correlated with the underlying differences in development and function of the cardiovascular systems of these two strains of mice. Significant differences in gene expression associated with bone morphogenetic protein/transforming growth factor β (BMP/TGF-β) signal-transduction pathways were identified between the two strains, and a network of differentially expressed genes specific to the MAP kinase cascade was further defined as a subset of the genes of the BMP/TGF-β pathways. Other signal-transduction pathways that showed significant strain-specific differences in gene expression included the RXR/PPAR and G protein-related pathways. These data identify how bone and vascular regeneration are coordinated through expression of common sets of transcription and morphogenetic factors and suggest that there is heritable linkage between vascular and skeletal tissue development during postnatal regeneration.

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

    PubMed Central

    2011-01-01

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

  7. 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.

  8. Dynamics of bone healing after osteotomy with piezosurgery or conventional drilling – histomorphometrical, immunohistochemical, and molecular analysis

    PubMed Central

    2013-01-01

    Background Piezosurgery is an osteotomy system used in medical and dental surgery. Many studies have proven clinical advantages of piezosurgery in terms of quality of cut, maneuverability, ease of use, and safety. However, few investigations have tested its superiority over the traditional osteotomy systems in terms of dynamics of bone healing. Therefore, the aim of this study was to evaluate the dynamics of bone healing after osteotomies with piezosurgery and to compare them with those associated to traditional bone drilling. Methods One hundred and ten rats were divided into two groups with 55 animals each. The animals were anesthetized and the tibiae were surgically exposed to create defects 2 mm in diameter by using piezosurgery (Piezo group) and conventional drilling (Drill group). Animals were sacrificed at 3, 7, 14, 30 and 60 days post-surgery. Bone samples were collected and processed for histological, histomorphometrical, immunohistochemical, and molecular analysis. The histological analysis was performed at all time points (n = 8) whereas the histomorphometrical analysis was performed at 7, 14, 30 and 60 days post-surgery (n = 8). The immunolabeling was performed to detect Vascular Endothelial Growth Factor (VEGF), Caspase-3 (CAS-3), Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor kappa-B Ligand (RANKL), and Osteocalcin (OC) at 3, 7, and 14 days (n = 3). For the molecular analysis, animals were sacrificed at 3, 7 and 14 days, total RNA was collected, and quantification of the expression of 21 genes related to BMP signaling, Wnt signaling, inflammation, osteogenenic and apoptotic pathways was performed by qRT-PCR (n = 5). Results Histologically and histomorphometrically, bone healing was similar in both groups with the exception of a slightly higher amount of newly formed bone observed at 30 days after piezosurgery (p < 0.05). Immunohistochemical and qRT-PCR analyses didn’t detect significant differences in

  9. Monitoring the Changes of Material Properties at Bone-Implant Interface during the Healing Process In Vivo: A Viscoelastic Investigation

    PubMed Central

    Chen, Hsiang-Ho; Lai, Wei-Yi; Chee, Tze-Jian

    2017-01-01

    The aim of this study was to monitor the changes of viscoelastic properties at bone-implant interface via resonance frequency analysis (RFA) and the Periotest device during the healing process in an experimental rabbit model. Twenty-four dental implants were inserted into the femoral condyles of rabbits. The animals were sacrificed immediately after implant installation or on day 14, 28, or 56 after surgery. Viscoelastic properties at bone-implant interface were evaluated by measuring the implant stability quotient (ISQ) using RFA and by measuring the Periotest values (PTVs) using the Periotest device. The bone/implant specimens were evaluated histopathologically and histomorphometrically to determine the degree of osseointegration (BIC%). The BIC% values at different time points were then compared with the corresponding ISQ values and PTVs. The mean ISQ value increased gradually and reached 81 ± 1.7 on day 56, whereas the mean PTV decreased over time, finally reaching −0.7 ± 0.5 on day 56. Significant correlations were found between ISQ and BIC% (r = 0.701, p < 0.001), PTV and BIC% (r = −0.637, p < 0.05), and ISQ and PTV (r = −0.68, p < 0.05). These results show that there is a positive correlation between implant stability parameters and peri-implant-bone healing, indicating that the RFA and Periotest are useful for measuring changes of viscoelastic properties at bone-implant interface and are reliable for indirectly predicting the degree of osseointegration. PMID:28373978

  10. Fibrin biomatrix-conjugated platelet-derived growth factor AB accelerates wound healing in severe thermal injury.

    PubMed

    Mittermayr, Rainer; Branski, Ludwik; Moritz, Martina; Jeschke, Marc G; Herndon, David N; Traber, Daniel; Schense, Jason; Gampfer, Jörg; Goppelt, Andreas; Redl, Heinz

    2016-05-01

    Controlled delivery of growth factors from biodegradable biomatrices could accelerate and improve impaired wound healing. The study aim was to determine whether platelet-derived growth factor AB (PDGF.AB) with a transglutaminase (TG) crosslinking substrate site released from a fibrin biomatrix improves wound healing in severe thermal injury. The binding and release kinetics of TG-PDGF.AB were determined in vitro. Third-degree contact burns (dorsum of Yorkshire pigs) underwent epifascial necrosectomy 24 h post-burn. Wound sites were covered with autologous meshed (3:1) split-thickness skin autografts and either secured with staples or attached with sprayed fibrin sealant (FS; n = 8/group). TG-PDGF.AB binds to the fibrin biomatrix using the TG activity of factor XIIIa, and is subsequently released through enzymatic cleavage. Three doses of TG-PDGF.AB in FS (100 ng, 1 µg and 11 µg/ml FS) were tested. TG-PDGF.AB was bound to the fibrin biomatrix as evidenced by western blot analysis and subsequently released by enzymatic cleavage. A significantly accelerated and improved wound healing was achieved using sprayed FS containing TG-PDGF.AB compared to staples alone. Low concentrations (100 ng-1 µg TG-PDGF.AB/ml final FS clot) demonstrated to be sufficient to attain a nearly complete closure of mesh interstices 14 days after grafting. TG-PDGF.AB incorporated in FS via a specific binding technology was shown to be effective in grafted third-degree burn wounds. The adhesive properties of the fibrin matrix in conjunction with the prolonged growth factor stimulus enabled by this binding technology could be favourable in many pathological situations associated with wound-healing disturbances. Copyright © 2013 John Wiley & Sons, Ltd.

  11. Treatment with paracetamol, ketorolac or etoricoxib did not hinder alveolar bone healing: a histometric study in rats

    PubMed Central

    FRACON, Ricardo Nogueira; TEÓFILO, Juliana Mazzonetto; MORIS, Izabela Cristina; LAMANO, Teresa

    2010-01-01

    Prostaglandins control osteoblastic and osteoclastic function under physiological or pathological conditions and are important modulators of the bone healing process. The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and consequently prostaglandins synthesis. Experimental and clinical evidence has indicated a risk for reparative bone formation related to the use of non-selective (COX-1 and COX-2) and COX-2 selective NSAIDs. Ketorolac is a non-selective NSAID which, at low doses, has a preferential COX-1 inhibitory effect and etoricoxib is a new selective COX-2 inhibitor. Although literature data have suggested that ketorolac can interfere negatively with long bone fracture healing, there seems to be no study associating etoricoxib with reparative bone formation. Paracetamol/acetaminophen, one of the first choices for pain control in clinical dentistry, has been considered a weak anti-inflammatory drug, although supposedly capable of inhibiting COX-2 activity in inflammatory sites. Objective The purpose of the present study was to investigate whether paracetamol, ketorolac and etoricoxib can hinder alveolar bone formation, taking the filling of rat extraction socket with newly formed bone as experimental model. Material and methods The degree of new bone formation inside the alveolar socket was estimated two weeks after tooth extraction by a differential point-counting method, using an optical microscopy with a digital camera for image capture and histometry software. Differences between groups were analyzed by ANOVA after confirming a normal distribution of sample data. Results and conclusions Histometric results confirmed that none of the tested drugs had a detrimental effect in the volume fraction of bone trabeculae formed inside the alveolar socket. PMID:21308296

  12. The Influence of Root-End Filling Materials on Bone Healing – An Experimental Study

    PubMed Central

    KUI, ANDREEA GULIE; BERAR, ANTONELA; LASCU, LIANA; BOLFA, POMPEI; BOSCA, BIANCA; MIHU, CARMEN; BACIUT, MIHAELA; AVRAM, RAMONA; BADEA, MÂNDRA

    2014-01-01

    Aims. The aim of this experimental study is to assess the bone healing phenomenon produced in the presence of several dental materials: a polycarboxylate cement, a glass-ionomer cement, a composite resin and MTA (mineral trioxide aggregate) based cement. Methods. The biocompatibility of four root-end fillings materials, used in periapical surgery was investigated after intra-osseous implantation of the materials in rats’ calvaria. Tissue reaction was studied at 2, 4, 6, 8, 10 and 12 weeks after implantation. We took into consideration the presence of inflammatory cells (polymorphonuclear leukocytes, macrophages, plasma cells, lymphocytes and giant cells) and classified the aspects of the histological samples according to the following scale: 0 - no inflammation, 1 – mild, isolated inflammation, 2 - moderate, localized inflammatory reaction, 3 - severe, diffuse and intense inflammatory reaction. Results. The inflammatory reaction was present at the six intervals for all the tested materials, but at 12 week interval, the reaction was minimal in all cases. Also, a dissolution reaction was observed for all the materials, less intense for glass-ionomer cement and polycarboxilate cement. Conclusions. At the end of the experimental period, glass-ionomer cement and polycarboxilate cement suffered a lesser dissolution reaction as compared to the second group of tested materials. PMID:26528034

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

    PubMed Central

    Haffner‐Luntzer, Melanie; Heilmann, Aline; Heidler, Verena; Liedert, Astrid; Schinke, Thorsten; Amling, Michael; Yorgan, Timur Alexander; vom Scheidt, Annika

    2016-01-01

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

  14. 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.

  15. Accelerated Ulcer Healing and Resistance to Ulcer Recurrence with Gastroprotectants in Rat Model of Acetic Acid-induced Gastric Ulcer

    PubMed Central

    Young Oh, Tae; Ok Ahn, Byung; Jung Jang, Eun; Sang Park, Joo; Jong Park, Sang; Wook Baik, Hyun; Hahm, Ki-Baik

    2008-01-01

    Quality of ulcer healing (QOUH) is defined as ideal ulcer healing featuring with the fine granular ulcer scar, high functional restoration and the resistance to recurrence. This study was designed to compare the rates of QOUH achievement in rat gastric ulcer model between acid suppressant treated group and gastroprotectant treated group accompanied with elucidations of molecular mechanisms. Serosal injection of acetic acids for generating gastric ulcer and intraperitoneal (ip) injection of recombinant interleukin 1-beta (IL-1β) for recurring healed ulcer was done in SD rats. The 72 rats were divided into three groups according to treatment as follows; Group I, no further treatment, Group II, 8 weeks treatment of omeprazole, and Group III, 8 weeks of gastroprotectant treatment. IL-1β was administered for ulcer recurrence after 28 weeks of acetic acid injection. At four weeks after gastric ulcerogenesis, 58.3% (7/12) of active gastric ulcer were converted to healing stage in Group III, but 16.7% (2/12) in Group II and none in Group I, for which significant levels of epidermal growth factor, mucin, and pS2/trefoil peptide1 were contributive to these accelerated healings of Group III. ip injections of rIL-1β (200 µg/kg) at 28 weeks after acetic acid injection led to 100% of ulcer recurrence in Group I and 75.0% in Group II, but only 16.7% of Group III rats showed ulcer recurrence. Significantly attenuated levels of inflammatory cytokines including IL-2, transforming growth factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), nitrotyrosine were responsible for the resistance to ulcer recurrence in Group III. Conclusively, gastroprotectant might be prerequisite in order to achieve ideal QOUH through significant inductions of remodeling. PMID:18545642

  16. A deficiency in cold-inducible RNA-binding protein accelerates the inflammation phase and improves wound healing.

    PubMed

    Idrovo, Juan Pablo; Jacob, Asha; Yang, Weng Lang; Wang, Zhimin; Yen, Hao Ting; Nicastro, Jeffrey; Coppa, Gene F; Wang, Ping

    2016-02-01

    Chronic or non-healing wounds are a major concern in clinical practice and these wounds are mostly associated with diabetes, and venous and pressure ulcers. Wound healing is a complex process involving overlapping phases and the primary phase in this complex cascade is the inflammatory state. While inflammation is necessary for wound healing, a prolonged inflammatory phase leads to impaired healing. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that are expressed in high levels under stress conditions. Recently, we demonstrated that a deficiency in CIRP led to decreased inflammation and mortality in an experimental model of hemorrhagic shock. Thus, we hypothesized that a deficiency in CIRP would accelerate the inflammatory phase and lead to an improvement in cutaneous wound healing. In this study, to examine this hypothesis, a full-thickness wound was created on the dorsum of wild-type (WT) and CIRP-/- mice. The wound size was measured every other day for 14 days. The wound area was significantly decreased in the CIRP-/- mice by day 9 and continued to decrease until day 14 compared to the WT mice. In a separate cohort, mice were sacrificed on days 3 and 7 after wounding and the skin tissues were harvested for histological analysis and RNA measurements. On day 3, the mRNA expression of tumor necrossis factor (TNF)-α in the skin tissues was increased by 16-fold in the WT mice, whereas these levels were increased by 65-fold in the CIRP-/- mice. Of note on day 7, while the levels of TNF-α remained high in the WT mice, these levels were significantly decreased in the CIRP-/- mice. The histological analysis of the wounded skin tissue indicated an improvement as early as day 3 in the CIRP-/- mice, whereas in the WT mice, infiltrated immune cells were still present on day 7. On day 7 in the CIRP-/- mice, Gr-1 expression was low and CD31 expression was high, whereas in the WT mice, Gr-1 expression was high and CD31 expression was low

  17. Histologic and biomechanical evaluation of the effects of implant insertion torque on peri-implant bone healing.

    PubMed

    Consolo, Ugo; Travaglini, Domenico; Todisco, Marzio; Trisi, Paolo; Galli, Silvia

    2013-05-01

    The aim of this study was to evaluate histologically and biomechanically the peri-implant bone healing around implants placed with high torque after a follow-up of 8 and 12 weeks. A total of 12 implants were placed in the lower edge of the mandible of 2 sheep. In each sheep, 3 implants were placed with a low torque (<25 N · cm, LT group) as a control, and 3 implants were placed with a high insertion torque (maximum torque, HT group). The sheep were killed after 8 and 12 weeks of healing, and the implants were examined for removal torque, resonance frequency analysis, and histologic analysis.The mean insertion torque in the LT group was 24 N · cm, whereas it was 105.6 N · cm in HT. All the implants osseointegrated and histologic analysis showed similar aspects of the peri-implant bone tissue for both groups and both healing times. Mean removal torque values for LT implants were 159.5 and 131.5 N · cm after 8 and 12 weeks, respectively, whereas those for the HT were 140 and 120 N · cm at 8 and 12 weeks, respectively. Implant stability quotient values were 26.6 and 76 for the LT group and 74 and 76 for the HT group at 8 and 12 weeks, respectively.It could be concluded that high implant insertion torque does not induce adverse reaction in cortical bone and does not lead to implant failure.

  18. Exosomes derived from human amniotic epithelial cells accelerate wound healing and inhibit scar formation.

    PubMed

    Zhao, Bin; Zhang, Yijie; Han, Shichao; Zhang, Wei; Zhou, Qin; Guan, Hao; Liu, Jiaqi; Shi, Jihong; Su, Linlin; Hu, Dahai

    2017-04-01

    Wound healing is a highly orchestrated physiological process consisting of a complex events, and scarless wound healing is highly desired for the development and application in clinical medicine. Recently, we have demonstrated that human amniotic epithelial cells (hAECs) promoted wound healing and inhibited scar formation through a paracrine mechanism. However, exosomes (Exo) are one of the most important paracrine factors. Whether exosomes derived from human amniotic epithelial cells (hAECs-Exo) have positive effects on scarless wound healing have not been reported yet. In this study, we examined the role of hAECs-Exo on wound healing in a rat model. We found that hAECs, which exhibit characteristics of both embryonic and mesenchymal stem cells, have the potential to differentiate into all three germ layers. hAECs-Exo ranged from 50 to 150 nm in diameter, and positive for exosomal markers CD9, CD63, CD81, Alix, TSG101 and HLA-G. Internalization of hAECs-Exo promoted the migration and proliferation of fibroblasts. Moreover, the deposition of extracellular matrix (ECM) were partly abolished by the treatment of high concentration of hAECs-Exo (100 μg/mL), which may be through stimulating the expression of matrix metalloproteinase-1 (MMP-1). In vivo animal experiments showed that hAECs-Exo improved the skin wound healing with well-organized collagen fibers. Taken together, These findings represent that hAECs-Exo can be used as a novel hope in cell-free therapy for scarless wound healing.

  19. Deletion of the α2A/α2C-adrenoceptors accelerates cutaneous wound healing in mice

    PubMed Central

    Romana-Souza, Bruna; Nascimento, Adriana P; Brum, Patricia C; Monte-Alto-Costa, Andréa

    2014-01-01

    The α2-adrenoceptors regulate the sympathetic nervous system, controlling presynaptic catecholamine release. However, the role of the α2-adrenoceptors in cutaneous wound healing is poorly understood. Mice lacking both the α2A/α2C-adrenoceptors were used to evaluate the participation of the α2-adrenoceptor during cutaneous wound healing. A full-thickness excisional lesion was performed on the dorsal skin of the α2A/α2C-adrenoceptor knockout and wild-type mice. Seven or fourteen days later, the animals were euthanized and the lesions were formalin-fixed and paraffin-embedded or frozen. Murine skin fibroblasts were also isolated from α2A/α2C-adrenoceptor knockout and wild-type mice, and fibroblast activity was evaluated. The in vivo study demonstrated that α2A/α2C-adrenoceptor depletion accelerated wound contraction and re-epithelialization. A reduction in the number of neutrophils and macrophages was observed in the α2A/α2C-adrenoceptor knockout mice compared with wild-type mice. In addition, α2A/α2C-adrenoceptor depletion enhanced the levels of nitrite and hydroxyproline, and the protein expression of transforming growth factor-β and vascular endothelial growth factor. Furthermore, α2A/α2C-adrenoceptor depletion accelerated blood vessel formation and myofibroblast differentiation. The in vitro study demonstrated that skin fibroblasts isolated from α2A/α2C-adrenoceptor knockout mice exhibited enhanced cell migration, α-smooth muscle actin _protein expression and collagen deposition compared with wild-type skin fibroblasts. In conclusion, α2A/α2C-adrenoceptor deletion accelerates cutaneous wound healing in mice. PMID:25186490

  20. Deletion of the α2A/α2C-adrenoceptors accelerates cutaneous wound healing in mice.

    PubMed

    Romana-Souza, Bruna; Nascimento, Adriana P; Brum, Patricia C; Monte-Alto-Costa, Andréa

    2014-10-01

    The α2-adrenoceptors regulate the sympathetic nervous system, controlling presynaptic catecholamine release. However, the role of the α2-adrenoceptors in cutaneous wound healing is poorly understood. Mice lacking both the α2A/α2C-adrenoceptors were used to evaluate the participation of the α2-adrenoceptor during cutaneous wound healing. A full-thickness excisional lesion was performed on the dorsal skin of the α2A/α2C-adrenoceptor knockout and wild-type mice. Seven or fourteen days later, the animals were euthanized and the lesions were formalin-fixed and paraffin-embedded or frozen. Murine skin fibroblasts were also isolated from α2A/α2C-adrenoceptor knockout and wild-type mice, and fibroblast activity was evaluated. The in vivo study demonstrated that α2A/α2C-adrenoceptor depletion accelerated wound contraction and re-epithelialization. A reduction in the number of neutrophils and macrophages was observed in the α2A/α2C-adrenoceptor knockout mice compared with wild-type mice. In addition, α2A/α2C-adrenoceptor depletion enhanced the levels of nitrite and hydroxyproline, and the protein expression of transforming growth factor-β and vascular endothelial growth factor. Furthermore, α2A/α2C-adrenoceptor depletion accelerated blood vessel formation and myofibroblast differentiation. The in vitro study demonstrated that skin fibroblasts isolated from α2A/α2C-adrenoceptor knockout mice exhibited enhanced cell migration, α-smooth muscle actin _protein expression and collagen deposition compared with wild-type skin fibroblasts. In conclusion, α2A/α2C-adrenoceptor deletion accelerates cutaneous wound healing in mice.

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

    PubMed Central

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

    2014-01-01

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

  2. Enhancement of Bone-Marrow-Derived Mesenchymal Stem Cell Angiogenic Capacity by NPWT for a Combinatorial Therapy to Promote Wound Healing with Large Defect

    PubMed Central

    Ma, Zhanjun

    2017-01-01

    Poor viability of engrafted bone marrow mesenchymal stem cells (BMSCs) often hinders their application for wound healing, and the strategy of how to take full advantage of their angiogenic capacity within wounds still remains unclear. Negative pressure wound therapy (NPWT) has been demonstrated to be effective for enhancing wound healing, especially for the promotion of angiogenesis within wounds. Here we utilized combinatory strategy using the transplantation of BMSCs and NPWT to investigate whether this combinatory therapy could accelerate angiogenesis in wounds. In vitro, after 9-day culture, BMSCs proliferation significantly increased in NPWT group. Furthermore, NPWT induced their differentiation into the angiogenic related cells, which are indispensable for wound angiogenesis. In vivo, rat full-thickness cutaneous wounds treated with BMSCs combined with NPWT exhibited better viability of the cells and enhanced angiogenesis and maturation of functional blood vessels than did local BMSC injection or NPWT alone. Expression of angiogenesis markers (NG2, VEGF, CD31, and α-SMA) was upregulated in wounds treated with combined BMSCs with NPWT. Our data suggest that NPWT may act as an inductive role to enhance BMSCs angiogenic capacity and this combinatorial therapy may serve as a simple but efficient clinical solution for complex wounds with large defects. PMID:28243602

  3. Platelet-rich plasma (PRP) in dental and oral surgery: from the wound healing to bone regeneration

    PubMed Central

    2013-01-01

    Platelet-rich plasma (PRP) is a new approach to tissue regeneration and it is becoming a valuable adjunct to promote healing in many procedures in dental and oral surgery, especially in aging patients. PRP derives from the centrifugation of the patient's own blood and it contains growth factors that influence wound healing, thereby playing an important role in tissue repairing mechanisms. The use of PRP in surgical practice could have beneficial outcomes, reducing bleeding and enhancing soft tissue healing and bone regeneration. Studies conducted on humans have yielded promising results regarding the application of PRP to many dental and oral surgical procedures (i.e. tooth extractions, periodontal surgery, implant surgery). The use of PRP has also been proposed in the management of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with the aim of enhancing wound healing and bone maturation. The aims of this narrative review are: i) to describe the different uses of PRP in dental surgery (tooth extractions and periodontal surgery) and oral surgery (soft tissues and bone tissue surgery, implant surgery and BRONJ surgery); and ii) to discuss its efficacy, efficiency and risk/benefit ratio. This review suggests that the use of PRP in the alveolar socket after tooth extractions is certainly capable of improving soft tissue healing and positively influencing bone regeneration but the latter effect seems to decrease a few days after the extraction. PRP has produced better results in periodontal therapy in association with other materials than when it is used alone. Promising results have also been obtained in implant surgery, when PRP was used in isolation as a coating material. The combination of necrotic bone curettage and PRP application seem to be encouraging for the treatment of refractory BRONJ, as it has proven successful outcomes with minimal invasivity. Since PRP is free from potential risks for patients, not difficult to obtain and use, it can be employed

  4. Salmon DNA Accelerates Bone Regeneration by Inducing Osteoblast Migration

    PubMed Central

    Sato, Ayako; Kajiya, Hiroshi; Mori, Nana; Sato, Hironobu; Fukushima, Tadao; Kido, Hirofumi

    2017-01-01

    The initial step of bone regeneration requires the migration of osteogenic cells to defective sites. Our previous studies suggest that a salmon DNA-based scaffold can promote the bone regeneration of calvarial defects in rats. We speculate that the salmon DNA may possess osteoinductive properties, including the homing of migrating osteogenic cells. In the present study, we investigated the influence of the salmon DNA on osteoblastic differentiation and induction of osteoblast migration using MG63 cells (human preosteoblasts) in vitro. Moreover, we analyzed the bone regeneration of a critical-sized in vivo calvarial bone defect (CSD) model in rats. The salmon DNA enhanced both mRNA and protein expression of the osteogenesis-related factors, runt-related transcription factor 2 (Runx2), alkaline phosphatase, and osterix (OSX) in the MG63 cells, compared with the cultivation using osteogenic induction medium alone. From the histochemical and immunohistochemical assays using frozen sections of the bone defects from animals that were implanted with DNA disks, many cells were found to express aldehyde dehydrogenase 1, one of the markers for mesenchymal stem cells. In addition, OSX was observed in the replaced connective tissue of the bone defects. These findings indicate that the DNA induced the migration and accumulation of osteogenic cells to the regenerative tissue. Furthermore, an in vitro transwell migration assay showed that the addition of DNA enhanced an induction of osteoblast migration, compared with the medium alone. The implantation of the DNA disks promoted bone regeneration in the CSD of rats, compared with that of collagen disks. These results indicate that the salmon DNA enhanced osteoblastic differentiation and induction of migration, resulting in the facilitation of bone regeneration. PMID:28060874

  5. Carbon nanotubes functionalized with fibroblast growth factor accelerate proliferation of bone marrow-derived stromal cells and bone formation

    NASA Astrophysics Data System (ADS)

    Hirata, Eri; Ménard-Moyon, Cécilia; Venturelli, Enrica; Takita, Hiroko; Watari, Fumio; Bianco, Alberto; Yokoyama, Atsuro

    2013-11-01

    Multi-walled carbon nanotubes (MWCNTs) were functionalized with fibroblast growth factor (FGF) and the advantages of their use as scaffolds for bone augmentation were evaluated in vitro and in vivo. The activity of FGF was assessed by measuring the effect on the proliferation of rat bone marrow stromal cells (RBMSCs). The presence of FGF enhanced the proliferation of RBMSCs and the FGF covalently conjugated to the nanotubes (FGF-CNT) showed the same effect as FGF alone. In addition, FGF-CNT coated sponges were implanted between the parietal bone and the periosteum of rats and the formation of new bone was investigated. At day 14 after implantation, a larger amount of newly formed bone was clearly observed in most pores of FGF-CNT coated sponges. These findings indicated that MWCNTs accelerated new bone formation in response to FGF, as well as the integration of particles into new bone during its formation. Scaffolds coated with FGF-CNT could be considered as promising novel substituting materials for bone regeneration in future tissue engineering applications.

  6. [Plea for accelerated rehabilitation after ligament plasty of the knee by a bone-patellar tendon-bone graft].

    PubMed

    Boileau, P; Rémi, M; Lemaire, M; Rousseau, P; Desnuelle, C; Argenson, C

    1999-09-01

    Knee rehabilitation after ACL repair with bone-tendon-bone graft is still controversial. While there was a tendency to protect the graft and the donor site in the eighties, actual tendency is to propose more aggressive, so called accelerated rehabilitation protocol. An extensive analysis of the literature shows that this accelerated rehabilitation is justified because of histologic, biomechanic, surgical and clinical arguments. This accelerated rehabilitation is based on seven reasons, at least: 1) the necrosis of the graft, initially observed in animals, does not seem to be as important in humans as demonstrated by histological studies after in vivo biopsies; 2) the use of solid bone-tendon-bone graft, whose resistance is maximum in the early post-operative period and is superior to the resistance of the ACL; 3) the more precise positioning (more "isometric") because of optic magnification allowed by arthroscopy; 4) the absence of graft impingement, routinely controlled, because of a more posterior tibial placement of the graft and the eventual notch-plasty; 5) the solid and confident fixation of the graft because of interference screws; 6) anterior knee pain are less important when early constraints are applied on the knee; 7) finally, undisciplined and demanding patients who refuse all protection for the graft and the donor site, have good and stable results regarding stability of the knees. Early constraints on the knee after bone-tendon-bone graft and interference fixation give better tolerance on the extension mechanism without compromising integrity of the graft and knee stability. Appropriate level of constraints on the ACL graft and the donor site guides the collagenic reorganisation process. Early restoration of normal hyperextension, decreased knee pain and maintenance of muscular trophicity, allowing patients to go back to sport at 4 months, are the most evident benefits of this accelerated rehabilitation. These considerations cannot be applied to the

  7. Parathyroid Hormone (1-34) Might Not Improve Early Bone Healing after Sinus Augmentation in Healthy Rabbits

    PubMed Central

    Huh, Jisun; Park, Kyeong-Mee; Kim, Hyun Sil; Kim, Kee-Deog

    2017-01-01

    Purpose. This study evaluated the effect of administering intermittent parathyroid hormone [PTH (1-34), henceforth PTH] on the early-stage bone healing of maxillary sinus augmentation in healthy rabbits. Materials and Methods. Bovine bone mineral was grafted on the sinuses of 20 female New Zealand white rabbits. The animals were randomly divided into two groups, PTH (n = 10) or saline (n = 10), in which either PTH or saline was injected subcutaneously 5 days a week for 2 weeks. Half of the animals in each group were killed at 2 weeks postoperatively and the other half were killed at 4 weeks postoperatively. The dosage of PTH was 10 μg/kg/day. Radiographic and histomorphometric analyses were performed. Result. The new bone area (NBA) did not differ significantly between the PTH and saline groups. The NBA in the PTH group in the total augmented area and in the demarcated window, center, and Schneiderian membrane regions increased significantly from 2 to 4 weeks. The number of osteoclasts decreased significantly from 2 to 4 weeks in both groups, with no difference between the two groups. Conclusion. Intermittent PTH might not stimulate new bone formation in healthy rabbits during the first 4 weeks of healing. PMID:28280735

  8. The efficacy of low-level 940 nm laser therapy with different energy intensities on bone healing.

    PubMed

    Atasoy, Kerem Turgut; Korkmaz, Yavuz Tolga; Odaci, Ersan; Hanci, Hatice

    2017-01-05

    The aim of this study was to evaluate the efficacy of low-level 940 nm laser therapy with energy intensities of 5, 10 and 20 J/cm2 on bone healing in an animal model. A total of 48 female adult Wistar rats underwent surgery to create bone defects in the right tibias. Low-level laser therapy (LLLT) was applied immediately after surgery and on post-operative days 2, 4, 6, 8, 10 and 12 in three study groups with energy intensities of 5 J/cm2, 10 J/cm2 and 20 J/cm2 using a 940 nm Gallium-Aluminium-Arsenide (Ga-Al-As) laser, while one control group underwent only the tibia defect surgery. All animals were sacrificed 4 or 8 weeks post-surgery. Fibroblasts, osteoblasts, osteocytes, osteoclasts and newly formed vessels were evaluated by a histological examination. No significant change was observed in the number of osteocytes, osteoblasts, osteoclasts and newly formed vessels at either time period across all laser groups. Although LLLT with the 10 J/cm2 energy density increased fibroblast activity at the 4th week in comparison with the 5 and 20 J/cm2 groups, no significant change was observed between the laser groups and the control group. These results indicate that low-level 940 nm laser with different energy intensities may not have marked effects on the bone healing process in both phases of bone formation.

  9. Calcium phosphate-hybridized tendon graft to enhance tendon-bone healing two years after ACL reconstruction in goats

    PubMed Central

    2011-01-01

    Background We developed a novel technique to improve tendon-bone attachment by hybridizing calcium phosphate (CaP) with a tendon graft using an alternate soaking process. However, the long-term result with regard to the interface between the tendon graft and the bone is unclear. Methods We analyzed bone tunnel enlargement by computed tomography and histological observation of the interface and the tendon graft with and without the CaP hybridization 2 years after anterior cruciate ligament (ACL) reconstruction in goats using EndoButton and the postscrew technique (CaP, n = 4; control, n = 4). Results The tibial bone tunnel enlargement rates in the CaP group were lower than those in the control group (p < 0.05). In the CaP group, in the femoral and tibial bone tunnels at the anterior and posterior of the joint aperture site, direct insertion-like formation that contained a cartilage layer without tidemarks was more observed at the tendon-bone interface than in the control group (p < 0.05). Moreover, the gap area between the tendon graft and the bone was more observed at the femoral bone tunnel of the joint aperture site in the control group than in the CaP group (p < 0.05). The maturation of the tendon grafts determined using the ligament tissue maturation index was similar in both groups. Conclusions The CaP-hybridized tendon graft enhanced the tendon-bone healing 2 years after ACL reconstruction in goats. The use of CaP-hybridized tendon grafts can reduce the bone tunnel enlargement and gap area associated with the direct insertion-like formation in the interface near the joint. PMID:22166674

  10. Novel Anti-Microbial Peptide SR-0379 Accelerates Wound Healing via the PI3 Kinase/Akt/mTOR Pathway

    PubMed Central

    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

  11. 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

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

    NASA Astrophysics Data System (ADS)

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

    2016-09-01

    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.

  13. Skin-derived precursors possess the ability of differentiation into the epidermal progeny and accelerate burn wound healing.

    PubMed

    Bayati, Vahid; Abbaspour, Mohammad Reza; Neisi, Niloofar; Hashemitabar, Mahmoud

    2017-02-01

    Skin-derived precursors (SKPs) are remnants of the embryonic neural crest stem cells that reside in the dermis until adulthood. Although they possess a wide range of differentiation potentials, their differentiation into keratinocyte-like cells and their roles in skin wound healing are obscure. The present study aimed to investigate the differentiation of SKPs into keratinocyte-like cells and evaluate their role in healing of third degree burn wounds. To this aim, SKPs were differentiated into keratinocyte-like cells on tissue culture plate and collagen-chitosan scaffold prepared by freeze-drying. Their differentiation capability was detected by real-time RT-PCR and immunofluorescence. Thereafter, they were cultured on scaffold and implanted in a rat model of burn wound. Histopathological and immunohistochemical analyses were employed to examine the reconstituted skin. The research findings revealed that SKPs were able to differentiate along the epidermal lineage and this ability can be enhanced on a suitable scaffold. Additionally, the results indicated that SKPs apparently promoted wound healing process and accelerate its transition from proliferating stage to maturational phase, especially if they were differentiated into keratinocyte-like cells. Regarding the results, it is concluded that SKPs are able to differentiate into keratinocyte-like cells, particularly when they are cultured on collagen-chitosan scaffold. Moreover, they can regenerate epidermal and dermal layers including thick collagen bundles, possibly through differentiation into keratinocyte-like cells.

  14. Early stages of bone fracture healing: formation of a fibrin-collagen scaffold in the fracture hematoma.

    PubMed

    Echeverri, L F; Herrero, M A; Lopez, J M; Oleaga, G

    2015-01-01

    This work is concerned with the sequence of events taking place during the first stages of bone fracture healing, from bone breakup until the formation of early fibrous callus (EFC). The latter provides a scaffold over which subsequent remodeling processes will eventually result in successful bone repair. Specifically, some mathematical models are proposed to estimate the time required for (1) the formation immediately after fracture of a fibrin clot, described in terms of a phase transition in a polymerization process, and (2) the onset of EFC which is produced when fibroblasts arising from differentiation of chemotactically recruited mesenchymal stem cells remodel a previous fibrin clot by releasing a collagen matrix over it. An attempt has been made to keep models as simple as possible, so that a explicit dependence of the estimates obtained on relevant biochemical parameters involved is obtained.

  15. The Probiotic Mixture VSL#3 Accelerates Gastric Ulcer Healing by Stimulating Vascular Endothelial Growth Factor

    PubMed Central

    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 (6×109 bacteria) or high (1.2×1010 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

  16. Acarbose Accelerates Wound Healing via Akt/eNOS Signaling in db/db Mice

    PubMed Central

    Yu, Jiawen; Sun, Yuannan; Ren, Guofei; Zhu, Jianjun

    2017-01-01

    Refractory wound is a dreaded complication of diabetes and is highly correlated with EPC dysfunction caused by hyperglycemia. Acarbose is a widely used oral glucose-lowering drug exclusively for T2DM. Previous studies have suggested the beneficial effect of acarbose on improving endothelial dysfunction in patients with T2DM. However, no data have been reported on the beneficial efficacy of acarbose in wound healing impairment caused by diabetes. We herein investigated whether acarbose could improve wound healing in T2DM db/db mice and the possible mechanisms involved. Acarbose hastened wound healing and enhanced angiogenesis, accompanied by increased circulating EPC number in db/db mice. In vitro, a reversed BM-EPC dysfunction was observed after the administration of acarbose in db/db mice, as reflected by tube formation assay. In addition, a significantly increased NO production was also witnessed in BM-EPCs from acarbose treated db/db mice, with decreased O2 levels. Akt inhibitor could abolish the beneficial effect of acarbose on high glucose induced EPC dysfunction in vitro, accompanied by reduced eNOS activation. Acarbose displayed potential effect in promoting wound healing and improving angiogenesis in T2DM mice, which was possibly related to the Akt/eNOS signaling pathway. PMID:28373902

  17. Accelerated features of age-related bone loss in zmpste24 metalloproteinase-deficient mice.

    PubMed

    Rivas, Daniel; Li, Wei; Akter, Rahima; Henderson, Janet E; Duque, Gustavo

    2009-10-01

    Age-related bone loss is associated with changes in bone cellularity, which include marrow fat infiltration and decreasing levels of osteoblastogenesis. The mechanisms that explain these changes remain unclear. Although nuclear lamina alterations occur in premature aging syndromes that include changes in body fat and severe osteoporosis, the role of proteins of the nuclear lamina in age-related bone loss remains unknown. Using the Zmpste24-null progeroid mice (Zmpste24(-/-)), which exhibit nuclear lamina defects and accumulate unprocessed prelamin A, we identified several alterations in bone cellularity in vivo. We found that defective prelamin A processing induced accelerated features of age-related bone loss including lower osteoblast and osteocyte numbers and higher levels of marrow adipogenesis. In summary, processing of prelamin A could become a new approach to regulate osteoblastogenesis and bone turnover and thus for the prevention and treatment of senile osteoporosis.

  18. Effect of Magnetic Field on Bone Healing around Endosseous Implants – An In-vivo Study

    PubMed Central

    Anam, Chandrasekar; Mamidi, Praveen; Chiluka, Radha; Kumar, A. Gautam; Bibinagar, Ragini

    2016-01-01

    Introduction After implant placement, a stress-free healing period of 3-6 months is a pre-requisite to achieve good osseointegration. If this duration could be reduced, the patients would feel happier. Eventhough, immediate loading of implants is a clinically feasible concept; it is not possible in certain situations. Few studies have shown that Static magnetic field is useful to promote bone formation faster after the bone is wounded. Aim This pilot study was intended to evaluate the tissue response after implant placement under the influence of magnetic field. Materials and Methods Twenty Tidal Spiral implants were used for this study. Two implants were placed in each patient in the anterior mandible corresponding to the B and D regions and the implant on the D region was exposed to magnetic field using safer magnet (Neodymium Boron Iron) and the implant on the B region served as a control. Both the implants were compared for stability using Resonance Frequency Analyzer (RFA) at Days 0, 30, 60 and 90. Mean Implant Stability Quotient (ISQ) values were compared on both sides using student’s paired t-test and repeated measures ANOVA (analysis of variance). There was a significant difference in the mean ISQ values, hence, a post-hoc test was done to evaluate whether there is any difference between the follow-ups. Results The average ISQ value for implants at 0 day in the B and D regions was 68.6 and 68.7 respectively. The average ISQ value at 30th day, 60th day and 90th day was 73.25, 76.05 and 78.95 respectively on the magnetic side (D region). Whereas on the non-magnetic side (B region) at 30th day, 60th day and 90th day was 68.45, 72.05 and 74.45 respectively. Conclusion The implant stability quotient values obtained on the magnetic side were significantly greater than on the non-magnetic side. Positive correlation exists between the magnetic field and osseointegration. PMID:27891492

  19. Transplantation of endothelial progenitor cells accelerates dermal wound healing with increased recruitment of monocytes/macrophages and neovascularization.

    PubMed

    Suh, Wonhee; Kim, Koung Li; Kim, Jeong-Min; Shin, In-Soon; Lee, Young-Sam; Lee, Jae-Young; Jang, Hyung-Suk; Lee, Jung-Sun; Byun, Jonghoe; Choi, Jin-Ho; Jeon, Eun-Seok; Kim, Duk-Kyung

    2005-01-01

    Endothelial progenitor cells (EPCs) act as endothelial precursors that promote new blood vessel formation and increase angiogenesis by secreting growth factors and cytokines in ischemic tissues. These facts prompt the hypothesis that EPC transplantation should accelerate the wound-repair process by facilitating neovascularization and the production of various molecules related to wound healing. In a murine dermal excisional wound model, EPC transplantation accelerated wound re-epithelialization compared with the transplantation of mature endothelial cells (ECs) in control mice. When the wounds were analyzed immunohistochemically, the EPC-transplanted group exhibited significantly more monocytes/macrophages in the wound at day 5 after injury than did the EC-transplanted group. This observation is consistent with enzyme-linked immunosorbent assay results showing that EPCs produced in abundance several chemoattractants of monocytes and macrophages that are known to play a pivotal role in the early phase of wound healing. At day 14 after injury, the EPC-transplanted group showed a statistically significant increase in vascular density in the granulation tissue relative to that of the EC-transplanted group. Fluorescence microscopy revealed that EPCs preferentially moved into the wound and were directly incorporated into newly formed capillaries in the granulation tissue. These results suggest that EPC transplantation will be useful in dermal wound repair and skin regeneration, because EPCs both promote the recruitment of monocytes/macrophages into the wound and increase neovascularization.

  20. 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

  1. The effects of supplemental melatonin administration on the healing of bone defects in streptozotocin-induced diabetic rats

    PubMed Central

    YILDIRIMTURK, Senem; BATU, Sule; ALATLI, Canan; OLGAC, Vakur; FIRAT, Deniz; SIRIN, Yigit

    2016-01-01

    ABSTRACT Diabetes mellitus (DM) causes an increased production of free radicals that can impair bone healing. Melatonin is a hormone secreted mainly by the pineal gland, which participates in the neutralization process of free radicals. Objective The aim of this study was to investigate histologic and biochemical effects of supplemental melatonin administration on bone healing and antioxidant defense mechanism in diabetic rats. Material and Methods Eighty-six Sprague-Dawley male rats were used in this study. Diabetes mellitus was induced by intraperitoneal (i.p.) administration of 65 mg/kg streptozotocin (STZ). Surgical bone defects were prepared in the tibia of each animal. Diabetic animals and those in control groups were treated either with daily melatonin (250 μg/animal/day/i.p.) diluted in ethanol, only ethanol, or sterile saline solution. Rats were humanely killed at the 10th and 30th postoperative days. Plasma levels of Advanced Oxidation Protein Products (AOPP), Malondialdehyde (MDA), and Superoxide Dismutase (SOD) were measured. The number of osteoblasts, blood vessels and the area of new mineralized tissue formation were calculated in histologic sections. Results At the 10th day, DM+MEL (rats receiving both STZ and melatonin) group had significantly higher number of osteoblasts and blood vessels as well as larger new mineralized tissue surfaces (p<0.05 for each) when compared with DM group. At the 30th day, DM group treated with melatonin had significantly lower levels of AOPP and MDA than those of DM group (p<0.05). Conclusion Melatonin administration in STZ induced diabetic rats reduced oxidative stress related biomarkers and showed beneficial effects on bone healing at short term. PMID:27383705

  2. Assessment of bone healing ability of calcium phosphate cements loaded with platelet lysate in rat calvarial defects.

    PubMed

    Babo, Pedro S; Carvalho, Pedro P; Santo, Vítor E; Faria, Susana; Gomes, Manuela E; Reis, Rui L

    2016-11-01

    Injectable calcium phosphate cements have been used as a valid alternative to autologous bone grafts for bone augmentation with the additional advantage of enabling minimally invasive implantation procedures and for perfectly fitting the tissue defect. Nevertheless, they have low biodegradability and lack adequate biochemical signaling to promote bone healing and remodeling. In previous in vitro studies, we observed that the incorporation of platelet lysate directly into the cement paste or loaded in hyaluronic acid microspheres allowed to modulate the cement degradation and the in vitro expression of osteogenic markers in seeded human adipose derived stem cells. The present study aimed at investigating the possible effect of this system in new bone formation when implanted in calvarial bilateral defects in rats. Different formulations were assessed, namely plain calcium phosphate cements, calcium phosphate cements loaded with human platelet lysate, hybrid injectable formulations composed of the calcium phosphate cement incorporating hyaluronin acid non-loaded microparticles (20% hyaluronin acid) or with particles loaded with platelet lysate. The degradability and new bone regrowth were evaluated in terms of mineral volume in the defect, measured by micro-computed tomography and histomorphometric analysis upon 4, 8 and 12 weeks of implantation. We observed that the incorporation of hyaluronin acid microspheres induced an overly rapid cement degradation, impairing the osteoconductive properties of the cement composites. Moreover, the incorporation of platelet lysate induced higher bone healing than the materials without platelet lysate, up to four weeks after surgery. Nevertheless, this effect was not found to be significant when compared to the one observed in the sham-treated group.

  3. Topical Estrogen Accelerates Cutaneous Wound Healing in Aged Humans Associated with an Altered Inflammatory Response

    PubMed Central

    Ashcroft, Gillian S.; Greenwell-Wild, Teresa; Horan, Michael A.; Wahl, Sharon M.; Ferguson, Mark W. J.

    1999-01-01

    The effects of intrinsic aging on the cutaneous wound healing process are profound, and the resulting acute and chronic wound morbidity imposes a substantial burden on health services. We have investigated the effects of topical estrogen on cutaneous wound healing in healthy elderly men and women, and related these effects to the inflammatory response and local elastase levels, an enzyme known to be up-regulated in impaired wound healing states. Eighteen health status-defined females (mean age, 74.4 years) and eighteen males (mean age, 70.7 years) were randomized in a double-blind study to either active estrogen patch or identical placebo patch attached for 24 hours to the upper inner arm, through which two 4-mm punch biopsies were made. The wounds were excised at either day 7 or day 80 post-wounding. Compared to placebo, estrogen treatment increased the extent of wound healing in both males and females with a decrease in wound size at day 7, increased collagen levels at both days 7 and 80, and increased day 7 fibronectin levels. In addition, estrogen enhanced the strength of day 80 wounds. Estrogen treatment was associated with a decrease in wound elastase levels secondary to reduced neutrophil numbers, and decreased fibronectin degradation. In vitro studies using isolated human neutrophils indicate that one mechanism underlying the altered inflammatory response involves both a direct inhibition of neutrophil chemotaxis by estrogen and an altered expression of neutrophil adhesion molecules. These data demonstrate that delays in wound healing in the elderly can be significantly diminished by topical estrogen in both male and female subjects. PMID:10514397

  4. Experimental bone defect healing with xenogenic demineralized bone matrix and bovine fetal growth plate as a new xenograft: radiological, histopathological and biomechanical evaluation.

    PubMed

    Bigham, A S; Dehghani, S N; Shafiei, Z; Nezhad, S Torabi

    2009-02-01

    The following study was designed to evaluate xenogenic bovine demineralized bone matrix (DBM) and new xenograft (Bovine fetal growth plate) effects on bone healing process. Twenty male White New Zealand rabbits were used in this study. In group I (n = 10) the defect was filled by xenogenic DBM and in group II (n = 10) the defect was filled by a segment of bovine fetal growth plate and was fixed by cercelage wire. Radiological, histopathological, and biomechanical evaluations were performed blindly and results scored and analyzed statistically. Statistical tests did not support significant differences between two groups radiographically (P > 0.05). There was a significant difference for union at the 28th postoperative radiologically (P < 0.05). Xenograft was superior to DBM group at the 28th postoperative day for radiological union (P < 0.03). Histopathological and biomechanical evaluation revealed no significant differences between two groups. In conclusion, the results of this study indicate that satisfactory healing occurred in rabbit radius defect filled with xenogenic bovine DBM and xenogenic bovine fetal growth plate. Complications were not identified and healing was faster in two grafting groups.

  5. Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation.

    PubMed

    Fernández, Tulio; Olave, Gilberto; Valencia, Carlos H; Arce, Sandra; Quinn, Julian M W; Thouas, George A; Chen, Qi-Zhi

    2014-07-01

    Vascularization of an artificial graft represents one of the most significant challenges facing the field of bone tissue engineering. Over the past decade, strategies to vascularize artificial scaffolds have been intensively evaluated using osteoinductive calcium phosphate (CaP) biomaterials in animal models. In this work, we observed that CaP-based biomaterials implanted into rat calvarial defects showed remarkably accelerated formation and mineralization of new woven bone in defects in the initial stages, at a rate of ∼60 μm/day (0.8 mg/day), which was considerably higher than normal bone growth rates (several μm/day, 0.1 mg/day) in implant-free controls of the same age. Surprisingly, we also observed histological evidence of primary osteon formation, indicated by blood vessels in early-region fibrous tissue, which was encapsulated by lamellar osteocyte structures. These were later fully replaced by compact bone, indicating complete regeneration of calvarial bone. Thus, the CaP biomaterial used here is not only osteoinductive, but vasculogenic, and it may have contributed to the bone regeneration, despite an absence of osteons in normal rat calvaria. Further investigation will involve how this strategy can regulate formation of vascularized cortical bone such as by control of degradation rate, and use of models of long, dense bones, to more closely approximate repair of human cortical bone.

  6. Tooth loss early in life accelerates age-related bone deterioration in mice.

    PubMed

    Kurahashi, Minori; Kondo, Hiroko; Iinuma, Mitsuo; Tamura, Yasuo; Chen, Huayue; Kubo, Kin-ya

    2015-01-01

    Both osteoporosis and tooth loss are health concerns that affect many older people. Osteoporosis is a common skeletal disease of the elderly, characterized by low bone mass and microstructural deterioration of bone tissue. Chronic mild stress is a risk factor for osteoporosis. Many studies showed that tooth loss induced neurological alterations through activation of a stress hormone, corticosterone, in mice. In this study, we tested the hypothesis that tooth loss early in life may accelerate age-related bone deterioration using a mouse model. Male senescence-accelerated mouse strain P8 (SAMP8) mice were randomly divided into control and toothless groups. Removal of the upper molar teeth was performed at one month of age. Bone response was evaluated at 2, 5 and 9 months of age. Tooth loss early in life caused a significant increase in circulating corticosterone level with age. Osteoblast bone formation was suppressed and osteoclast bone resorption was activated in the toothless mice. Trabecular bone volume fraction of the vertebra and femur was decreased in the toothless mice with age. The bone quality was reduced in the toothless mice at 5 and 9 months of age, compared with the age-matched control mice. These findings indicate that tooth loss early in life impairs the dynamic homeostasis of the bone formation and bone resorption, leading to reduced bone strength with age. Long-term tooth loss may have a cumulative detrimental effect on bone health. It is important to take appropriate measures to treat tooth loss in older people for preventing and/or treating senile osteoporosis.

  7. An Innovative Approach for Enhancing Bone Defect Healing Using PLGA Scaffolds Seeded with Extracorporeal-shock-wave-treated Bone Marrow Mesenchymal Stem Cells (BMSCs)

    PubMed Central

    Chen, Youbin; Xu, Jiankun; Huang, Zhonglian; Yu, Menglei; Zhang, Yuantao; Chen, Hongjiang; Ma, Zebin; Liao, Haojie; Hu, Jun

    2017-01-01

    Although great efforts are being made using growth factors and gene therapy, the repair of bone defects remains a major challenge in modern medicine that has resulted in an increased burden on both healthcare and the economy. Emerging tissue engineering techniques that use of combination of biodegradable poly-lactic-co-glycolic acid (PLGA) and mesenchymal stem cells have shed light on improving bone defect healing; however, additional growth factors are also required with these methods. Therefore, the development of novel and cost-effective approaches is of great importance. Our in vitro results demonstrated that ESW treatment (10 kV, 500 pulses) has a stimulatory effect on the proliferation and osteogenic differentiation of bone marrow-derived MSCs (BMSCs). Histological and micro-CT results showed that PLGA scaffolds seeded with ESW-treated BMSCs produced more bone-like tissue with commitment to the osteogenic lineage when subcutaneously implanted in vivo, as compared to control group. Significantly greater bone formation with a faster mineral apposition rate inside the defect site was observed in the ESW group compared to control group. Biomechanical parameters, including ultimate load and stress at failure, improved over time and were superior to those of the control group. Taken together, this innovative approach shows significant potential in bone tissue regeneration. PMID:28272494

  8. 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.

  9. SDF-1/CXCR4 axis in Tie2-lineage cells including endothelial progenitor cells contributes to bone fracture healing.

    PubMed

    Kawakami, Yohei; Ii, Masaaki; Matsumoto, Tomoyuki; Kuroda, Ryosuke; Kuroda, Tomoya; Kwon, Sang-Mo; Kawamoto, Atsuhiko; Akimaru, Hiroshi; Mifune, Yutaka; Shoji, Taro; Fukui, Tomoaki; Kurosaka, Masahiro; Asahara, Takayuki

    2015-01-01

    CXC chemokine receptor 4 (CXCR4) is a specific receptor for stromal-derived-factor 1 (SDF-1). SDF-1/CXCR4 interaction is reported to play an important role in vascular development. On the other hand, the therapeutic potential of endothelial progenitor cells (EPCs) in fracture healing has been demonstrated with mechanistic insight of vasculogenesis/angiogenesis and osteogenesis enhancement at sites of fracture. The purpose of this study was to investigate the influence of the SDF-1/CXCR4 pathway in Tie2-lineage cells (including EPCs) in bone formation. We created CXCR4 gene conditional knockout mice using the Cre/loxP system and set two groups of mice: Tie2-Cre(ER) CXCR4 knockout mice (CXCR4(-/-) ) and wild-type mice (WT). We report here that in vitro, EPCs derived from of CXCR4(-/-) mouse bone marrow demonstrated severe reduction of migration activity and EPC colony-forming activity when compared with those derived from WT mouse bone marrow. In vivo, radiological and morphological examinations showed fracture healing delayed in the CXCR4(-/-) group and the relative callus area at weeks 2 and 3 was significantly smaller in CXCR4(-/-) group mice. Quantitative analysis of capillary density at perifracture sites also showed a significant decrease in the CXCR4(-/-) group. Especially, CXCR4(-/-) group mice demonstrated significant early reduction of blood flow recovery at fracture sites compared with the WT group in laser Doppler perfusion imaging analysis. Real-time RT-PCR analysis showed that the gene expressions of angiogenic markers (CD31, VE-cadherin, vascular endothelial growth factor [VEGF]) and osteogenic markers (osteocalcin, collagen 1A1, bone morphogenetic protein 2 [BMP2]) were lower in the CXCR4(-/-) group. In the gain-of-function study, the fracture in the SDF-1 intraperitoneally injected WT group healed significantly faster with enough callus formation compared with the SDF-1 injected CXCR4(-/-) group. We demonstrated that an EPC SDF-1/CXCR4 axis plays an

  10. Enhancement of tendon-bone healing for anterior cruciate ligament (ACL) reconstruction using bone marrow-derived mesenchymal stem cells infected with BMP-2.

    PubMed

    Dong, Yu; Zhang, Qingguo; Li, Yunxia; Jiang, Jia; Chen, Shiyi

    2012-10-22

    At present, due to the growing attention focused on the issue of tendon-bone healing, we carried out an animal study of the use of genetic intervention combined with cell transplantation for the promotion of this process. Here, the efficacy of bone marrow stromal cells infected with bone morphogenetic protein-2 (BMP-2) on tendon-bone healing was determined. A eukaryotic expression vector containing the BMP-2 gene was constructed and bone marrow-derived mesenchymal stem cells (bMSCs) were infected with a lentivirus. Next, we examined the viability of the infected cells and the mRNA and protein levels of BMP-2-infected bMSCs. Gastrocnemius tendons, gastrocnemius tendons wrapped by bMSCs infected with the control virus (bMSCs+Lv-Control), and gastrocnemius tendons wrapped by bMSCs infected with the recombinant BMP-2 virus (bMSCs+Lv-BMP-2) were used to reconstruct the anterior cruciate ligament (ACL) in New Zealand white rabbits. Specimens from each group were harvested four and eight weeks postoperatively and evaluated using biomechanical and histological methods. The bMSCs were infected with the lentivirus at an efficiency close to 100%. The BMP-2 mRNA and protein levels in bMSCs were significantly increased after lentiviral infection. The bMSCs and BMP-2-infected bMSCs on the gastrocnemius tendon improved the biomechanical properties of the graft in the bone tunnel; specifically, bMSCs infected with BMP-2 had a positive effect on tendon-bone healing. In the four-week and eight-week groups, bMSCs+Lv-BMP-2 group exhibited significantly higher maximum loads of 29.3 ± 7.4 N and 45.5 ± 11.9 N, respectively, compared with the control group (19.9 ± 6.4 N and 21.9 ± 4.9 N) (P = 0.041 and P = 0.001, respectively). In the eight-week groups, the stiffness of the bMSCs+Lv-BMP-2 group (32.5 ± 7.3) was significantly higher than that of the bMSCs+Lv-Control group (22.8 ± 7.4) or control groups (12.4 ± 6.0) (p = 0.036 and 0.001, respectively). Based on the histological

  11. 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.

  12. Evaluation of an Oxygen-Diffusion Dressing for Accelerated Healing of Donor-Site Wounds

    DTIC Science & Technology

    2014-06-01

    of their wounds, compared with a similar occlusive dressing without oxygen.7 Hyperbaric oxy- gen therapy is thought to improve healing of chronic...wounds in humans,8 but requires visits to facilities with trained personnel and is limited by oxygen toxicity issues. Compared with hyperbaric oxygen...3rd, Fife CE, Gesell LB, Bennett M. Undersea Hyperbaric Medicine Society (UHMS) position statement: topical oxygen for chronic wounds. Undersea

  13. Icariin Promotes Tendon-Bone Healing during Repair of Rotator Cuff Tears: A Biomechanical and Histological Study

    PubMed Central

    Ye, Chenyi; Zhang, Wei; Wang, Shengdong; Jiang, Shuai; Yu, Yuanbin; Chen, Erman; Xue, Deting; Chen, Jianzhong; He, Rongxin

    2016-01-01

    To investigate whether the systematic administration of icariin (ICA) promotes tendon-bone healing after rotator cuff reconstruction in vivo, a total of 64 male Sprague Dawley rats were used in a rotator cuff injury model and underwent rotator cuff reconstruction (bone tunnel suture fixation). Rats from the ICA group (n = 32) were gavage-fed daily with ICA at 0.125 mg/g, while rats in the control group (n = 32) received saline only. Micro-computed tomography, biomechanical tests, serum ELISA (calcium; Ca, alkaline phosphatase; AP, osteocalcin; OCN) and histological examinations (Safranin O and Fast Green staining, type I, II and III collagen (Col1, Col2, and Col3), CD31, and vascular endothelial growth factor (VEGF)) were analyzed two and four weeks after surgery. In the ICA group, the serum levels of AP and OCN were higher than in the control group. More Col1-, Col2-, CD31-, and VEGF-positive cells, together with a greater degree of osteogenesis, were detected in the ICA group compared with the control group. During mechanical testing, the ICA group showed a significantly higher ultimate failure load than the control group at both two and four weeks. Our results indicate that the systematic administration of ICA could promote angiogenesis and tendon-bone healing after rotator cuff reconstruction, with superior mechanical strength compared with the controls. Treatment for rotator cuff injury using systematically-administered ICA could be a promising strategy. PMID:27792147

  14. Icariin Promotes Tendon-Bone Healing during Repair of Rotator Cuff Tears: A Biomechanical and Histological Study.

    PubMed

    Ye, Chenyi; Zhang, Wei; Wang, Shengdong; Jiang, Shuai; Yu, Yuanbin; Chen, Erman; Xue, Deting; Chen, Jianzhong; He, Rongxin

    2016-10-25

    To investigate whether the systematic administration of icariin (ICA) promotes tendon-bone healing after rotator cuff reconstruction in vivo, a total of 64 male Sprague Dawley rats were used in a rotator cuff injury model and underwent rotator cuff reconstruction (bone tunnel suture fixation). Rats from the ICA group (n = 32) were gavage-fed daily with ICA at 0.125 mg/g, while rats in the control group (n = 32) received saline only. Micro-computed tomography, biomechanical tests, serum ELISA (calcium; Ca, alkaline phosphatase; AP, osteocalcin; OCN) and histological examinations (Safranin O and Fast Green staining, type I, II and III collagen (Col1, Col2, and Col3), CD31, and vascular endothelial growth factor (VEGF)) were analyzed two and four weeks after surgery. In the ICA group, the serum levels of AP and OCN were higher than in the control group. More Col1-, Col2-, CD31-, and VEGF-positive cells, together with a greater degree of osteogenesis, were detected in the ICA group compared with the control group. During mechanical testing, the ICA group showed a significantly higher ultimate failure load than the control group at both two and four weeks. Our results indicate that the systematic administration of ICA could promote angiogenesis and tendon-bone healing after rotator cuff reconstruction, with superior mechanical strength compared with the controls. Treatment for rotator cuff injury using systematically-administered ICA could be a promising strategy.

  15. Proangiogenic activity of plant extracts in accelerating wound healing - a new face of old phytomedicines.

    PubMed

    Majewska, Iwona; Gendaszewska-Darmach, Edyta

    2011-01-01

    Angiogenesis, the formation of new capillaries from pre-existing vascular network, plays an important role in physiological and pathological processes such as embryonic development, wound healing, and development of atherosclerosis. Extension of the circulatory network is also considered to be one the most important factors during cancerogenesis. Inhibition of angiogenesis may lead to inhibition of tumor growth whereas stimulation may improve wound healing. Research achievements suggest the use of plants and their extracts as potential therapeutic agents with pro- or antiangiogenic activity. Since the anticancer and antiangiogenic properties of many phytomedicines have been amply reviewed elsewhere this paper will focus on the treatment of vascular insufficiency in wound healing. Globally accepted herbal drugs are thought to be safe and effective, however, there is a need for more evidence-based confirmation in controlled and validated trials. Among the most frequently studied proangiogenic phytochemicals are ginsenosides from Panax ginseng, beta-sitosterol from Aloe vera, calycosin from Radix Astragali, and extracts from Hippophae rhamnoides L. and Angelica sinensis.

  16. 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.

  17. Design and fabrication of a flexible large area fabric transducer for bone healing application

    NASA Astrophysics Data System (ADS)

    Jadidian, Bahram

    The electromechanical transducers have found applications in their either passive or active modes. These applications include hydrophone, medical imaging, nondestructive evaluation, motors, sensors, actuators, civil and aerospace engineering. Other medical applications for ultrasonic transducers include therapeutics, osteosynthesis, lithotripsy, thrombolysis, and transdermal drug administration. During the past few decades, lead zirconate titanate (PZT), has been utilized in transducer applications in the form of a bulk piezoelectric ceramic and/or ceramic-polymer composites because of its high piezoelectric charge coefficient d33. The usage of piezoelectric ceramic/polymer composites allows designers to overcome some of the problems dealing with either monolithic piezoceramics or piezopolymers in transducer applications. In this work, a variety of composites with different connectivity patterns were formed. Composites with 1-3 connectivity were fabricated using bundling and collimating methods. Sized and unsized fibers were woven to form fabric. The fabric was used to form 3-3 composites and spiral structures. Square sheets of the fabric were laminated on top of each other, heat treated, and embedded in different types of polymer. The effect of applied pressure on the stack during heat treatment was studied. Plane fabric was formed in the spiral manner and used to construct piezocomposites. A piezoelectric transducer with high thickness coupling coefficient and its matching layer were exploited for bone healing application. One of the structures with the highest electromechanical properties, developed in this work, was chosen for the array fabrication. The spiral composite elements, with the best properties, were arranged in a 3 x 4 format embedded in a flexible polymer. The mechanical endurance of the elements and the array was studied. A large area flexible matching layer with low attenuation was developed. An extensive study was performed to determine the

  18. 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.

  19. G-CSF Administration after the Intraosseous Infusion of Hypertonic Hydroxyethyl Starche