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Bone Healing (bone + healing)
Selected AbstractsDo Inhibitors of Cyclooxygenase-2 Impair Bone Healing?JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2002Dr. Thomas A. Einhorn M.D. No abstract is available for this article. [source] Bone healing around implants placed in a jaw defect augmented with Bio-Oss®JOURNAL OF CLINICAL PERIODONTOLOGY, Issue 11 2000An experimental study in dogs Abstract The present experiment was carried out to study some tissue reactions around implants that were placed in an edentulous ridge which had been augmented with deproteinized natural bovine cancellous bone mineral. In 4 male beagle dogs, the premolars in the right side of the mandible were extracted and a large buccal ridge defect was created by mechanical means. The bone plate at the lingual aspect of the defect was left intact. 5 months later, the distal 2/3 of the defect area was augmented with Bio-Oss® (Geistlich Sons Ltd, Wolhusen, Switzerland) mixed with a fibrin sealer (Tisseel®, Immuno AG, Vienna, Austria). After 3 months of healing, 3 fixtures (Astra Tech AB, Mölndal, Sweden; TiO-blast; 8×3.5 mm) were installed in the mandible; 2 were placed in the augmented portion and 1 was placed in the non-augmented portion of the defect. After a healing period of 3 months, abutment connection was performed and a plaque control period initiated. 4 months later, the dogs were sacrificed and each implant region was dissected. The tissue samples were dehydrated, embedded in plastic, sectioned in the bucco-lingual plane and examined in the light microscope. It was observed that osseointegration failed to occur to implant surfaces within an alveolar ridge portion previously augmented with Bio-Oss®. In the augmented portion of the crest, the graft particles were separated from the host tissue as well as from the implant by a well-defined connective tissue capsule. Although the lingual aspect of all fixtures (test and control) was in contact with hard tissue at the time of installation, after 4 months of function, a deep vertical bone defect frequently had formed at the lingual surface of the implants. It was concluded that in this model (i) Bio-Oss® failed to integrate with the host bone tissue and (ii) no osseointegration occurred to the implants within the augmented portion of the crest. [source] Repair of rabbit segmental defects with the thrombin peptide, TP508JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2004Michael R. Sheller Abstract The synthetic peptide, TP508 (Chrysalin®), was delivered to rabbit segmental bone defects in biodegradable controlled-release PLGA microspheres to determine its potential efficacy for enhancing healing of non-critically and critically sized segmental defects. Non-critically sized radial defects were created in the forelimbs of New Zealand White rabbits, which were randomized into three treatment groups receiving 10, 50 and 100 ,g doses of TP508 in the right radius and control microspheres (without TP508) in the left radius. Torsional testing of the radii at six weeks showed a significant increase in ultimate torque, failure torque, ultimate energy, failure energy, and stiffness when treated with TP508 compared to controls (p < 0.01 for all measures). Thus, TP508 appeared to enhance or accelerate bone growth in these defects. In a second set of experiments, critically sized ulnar defects were created in the forelimbs of New Zealand White rabbits, which were randomized into two groups with each rabbit receiving microspheres with 100 or 200 ,g of TP508 into the right ulnar defect and control microspheres (without TP508) alone into the left ulnar defect. Bone healing was evaluated with plain radiographs, synchrotron-based microtomography, and mechanical testing. Radiographs of the rabbit limbs scored by three blinded, independent reviewers demonstrated a significantly higher degree of healing when treated with TP508 than their untreated control limbs (p < 0.05). Three-dimensional synchrotron tomography of a limited number of samples showed that the new bone in TP508-treated samples had a less porous surface appearance and open marrow spaces, suggesting progression of bone remodeling. Torsional testing of the ulnae at nine weeks showed a significant increase in maximum torque and failure energy when treated with TP508 compared to controls (p < 0.01 for both measures). These results suggest that TP508 in a controlled release delivery vehicle has the potential to enhance healing of segmental defects in both critically and non-critically sized defects. © 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source] Bone healing performance of electrophoretically deposited apatite,wollastonite/chitosan coating on titanium implants in rabbit tibiaeJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 7 2009Smriti Sharma Abstract Bone healing of tibial defect in rabbit model was used to evaluate a composite coating of apatite,wollastonite/chitosan on titanium implant. This coating has been developed to overcome the shortcomings, such as implant loosening and lack of adherence, of uncoated titanium implant. An electrophoretic deposition technique was used to coat apatite,wollastonite/chitosan on titanium implants. The present study was designed to evaluate the bone response of coated as compared to uncoated titanium implants in an animal model. After an implantation period of 14 (group A), 21 (group B), 35 (group C) and 42 days (group D), the bone,implant interfaces and defect site healing was evaluated using radiography, scintigraphy, histopathology, fluorescence labeling and haematology. Radiography of defect sites treated with coated implants suggested expedited healing. Scintigraphy of coated implant sites indicated faster bone metabolism than uncoated implant sites. Histopathological examination and fluorescence labeling of bone from coated implant sites revealed higher osteoblastic activity and faster mineralization. Faster bone healing in the case of coated implant sites is attributed to higher cell adhesion on electrostatically charged chitosan surfaces and apatite,wollastonite-assisted mineralization at bone,implant interfaces. Haematological studies showed no significant differences in haemoglobin, total erythrocyte and leukocyte counts, done using one way-ANOVA, during the entire study period. Our results show that AW/chitosan-coated implants have the advantages of faster bone healing, increased mechanical strength and good bone,implant bonding. Copyright © 2009 John Wiley & Sons, Ltd. [source] Transplantation of a vascularized rabbit femoral diaphyseal segment: Mechanical and histologic properties of a new living bone transplantation modelMICROSURGERY, Issue 4 2008Goetz A. Giessler M.D. A new vascularized bone transplantation model is described, including the anatomy and surgical technique of isolating a rabbit femoral diaphyseal segment on its nutrient vascular pedicle. The histologic and biomechanical parameters of pedicled vascularized femoral autotransplants were studied following orthotopic reimplantation in the resulting mid-diaphyseal defect. Vascularized femur segments were isolated in 10 rabbits on their nutrient pedicle, and then replaced orthotopically with appropriate internal fixation. Postoperative weightbearing and mobility were unrestricted, and the contralateral femora served as no-treatment controls. After 16 weeks, the bone flaps were evaluated by x-ray (bone healing), mechanical testing (material properties), microangiography (quantification of intraosseous vasculature), histology (bone viability), and histomorphometry (bone remodeling). Bone healing occurred by 2 weeks, with further callus remodeling throughout the survival period. Eight transplants healed completely, while two had a distal pseudarthrosis. Microangiography demonstrated patent pedicles in all transplants. Intraosseous vessel densities were comparable to nonoperated (control) femora. We found ultimate strength and elastic modulus to be significantly reduced when compared to normal controls. Viable bone, increased mineral apposition rate, and bone turnover were demonstrated in all transplants. The method described, and the data provided will be of value for the further study of isolated segments of living bone, and in particular, for investigations of reconstruction of segmental bone loss in weight-bearing animal models. This study also provides important normative data on living autologous bone flap material properties, vascularity, and bone remodeling. We intend to use this method and data for comparison in subsequent studies of large bone vascularized allotransplantation. © 2008 Wiley-Liss, Inc. Microsurgery, 2008. [source] Bone healing with electric current: a histological assessmentORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 3 2000Hui-Ling Chen Skeletal relapse is a major concern after correction of retrognathism with surgical mandibular advancement. It was hypothesized that the stimulation from a direct electric current can accelerate the osseous repair through the enhancement of the maturation of fibrocartilage. Furthermore, this stimulation may enhance the mechanical properties of the facial osteotomy site and reduce the skeletal relapse. The purpose of the present study was to examine the osteotomy site histologically and determine the effect of post-surgical electrical stimulation on the healing of a facial osteotomy site in a rat model. Three groups of adult male Sprague,Dawley rats, 15 in each group (direct electric current, electric sham, and control), were used to generate data. Electrodes were placed in both the direct electric current and the electric sham groups. A 20-,A direct current was delivered to the osteotomy site only in the direct electric current group. Histological slides of the osteotomy site for each animal were prepared and interpreted to characterize the healing process of the osteotomy site for each animal. The results showed no statistically significant difference among the three groups of animals (p>0.005). An examination with histology earlier in the healing process and the utilization of an experimental animal with a larger jaw are suggested for any further investigation that involves electrical stimulation and osseous healing in a facial osteotomy site. [source] Bone healing and graft resorption of autograft, anorganic bovine bone and ,-tricalcium phosphate.CLINICAL ORAL IMPLANTS RESEARCH, Issue 3 2006A histologic, histomorphometric study in the mandibles of minipigs Abstract Objective: The purpose was to qualitatively and quantitatively compare the bone formation and graft resorption of two different bone substitutes used in both orthopedic and oral surgery, with autogenous bone as a positive control. Materials and methods: Three standardized bone defects were prepared in both mandibular angles of 12 adult minipigs. The defects were grafted with either autograft, anorganic bovine bone (ABB), or synthetic ,-tricalcium phosphate (,-TCP). Sacrifice was performed after 1, 2, 4, and 8 weeks for histologic and histomorphometric analysis. Results: At 2 weeks, more new bone formation was seen in defects filled with autograft than with ABB (P,0.0005) and ,-TCP (P,0.002). After 4 weeks, there was no significant difference between ,-TCP and the two other materials. Defects grafted with ABB still exhibited less bone formation as compared with autograft (P,0.004). At 8 weeks, more bone formation was observed in defects grafted with autograft (P,0.003) and ,-TCP (P,0.00004) than with ABB. No difference could be demonstrated between ,-TCP and autograft. ,-TCP resorbed almost completely over 8 weeks, whereas ABB remained stable. Conclusion: Both bone substitutes seemed to decelerate bone regeneration in the early healing phase as compared with autograft. All defects ultimately regenerated with newly formed bone and a developing bone marrow. The grafting materials showed complete osseous integration. Both bone substitutes may have a place in reconstructive surgery where different clinical indications require differences in biodegradability. [source] Different Calcium Phosphate Granules for 3-D Printing of Bone Tissue Engineering Scaffolds,ADVANCED ENGINEERING MATERIALS, Issue 5 2009Hermann Seitz The 3-D printing technique was used for the fabrication of HA, TCP and BCP ceramics and the influence of the granulate composition on the 3-D printed scaffolds was investigated. An optimal composition for 3-D printing granulates was found. Thus, individual implants can be manufactured via 3-D printing from different CaP phase compositions to tailor their degradation behavior and osteoconductivity for enhanced bone healing. [source] Bioceramic Bone Graft Substitutes: Influence of Porosity and ChemistryINTERNATIONAL JOURNAL OF APPLIED CERAMIC TECHNOLOGY, Issue 3 2005Karin A. Hing Bioceramics have been considered for use as synthetic bone graft substitutes (BGSs) for over 30 years, throughout which there have been two primary areas of research: (i) optimization of the physical pore structure and (ii) formulation of an appropriate bioceramic chemistry. While it is well recognized that both the rate of integration and the final volume of regenerated bone are primarily dependent on the macroporosity, there still seems to be some dispute regarding the optimum "type" of porosity. The rate and quality of bone integration have, in turn, been related to a dependence on pore size, porosity volume fraction, and interconnection size and interconnection density, both as a function of structural permeability and mechano-transduction. Moreover, the role of strut microstructure and pore geometry have been considered with respect to their influence on entrapment and recruitment of growth factors (GFs) in addition to its influence on scaffold mechanics. Deconvoluting the relative affects of these parameters is complicated by the use of both resorbable and nonresorbable bioactive bioceramics, which are believed to mediate bioactivity in the osseous environment through two principal mechanisms: (i) directly through dissolution and release of ionic products in vivo, elevating local concentrations of soluble species that interact directly with local cells or influence cell behavior by their effect on local pH, (ii) indirectly through the influence that surface chemistry will have on protein adsorption, GF entrapment, and subsequent cell attachment and function. This article aims to review some of the recent developments in bioceramic BGSs, with a view to understanding how the various physiochemical parameters may be optimized to promote bone healing. [source] Bone repair in mandibular body osteotomy after using 2.0 miniplate system , histological and histometric analysis in dogsINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 2 2008Cássio Edvard Sverzut Summary The objective of this study was to evaluate the bone repair along a mandibular body osteotomy after using a 2.0 miniplate system. Nine adult mongrel dogs were subjected to unilateral continuous defect through an osteotomy between the mandibular 3rd and 4th premolars. Two four-hole miniplates were placed in accordance with the Arbeitgeimeinschaft für Osteosynthesefragen Manual. Miniplates adapted to the alveolar processes were fixed monocortically with 6.0-mm-length titanium alloy self-tapping screws, whereas miniplates placed near the mandible bases were fixed bicortically. At 2, 6 and 12 weeks, three dogs were sacrificed per period, and the osteotomy sites were removed, divided into three thirds (Tension Third, TT; Intermediary Third, IT; Compression Third, CT) and prepared for conventional and polarized light microscopy. At 6 weeks, while the CT repaired faster and showed bone union by woven bone formation, the TT and IT exhibited a ligament-like fibrous connective tissue inserted in, and connecting, newly formed woven bone overlying the parent lamellar bone edges. At 12 weeks, bone repair took place at all thirds. Histometrically, proportions of newly formed bone did not alter at TT, IT and CT, whereas significantly enhanced bone formation was observed for the 12-week group, irrespective of the third. The results demonstrated that although the method used to stabilize the mandibular osteotomy allowed bone repair to occur, differences in the dynamics of bone healing may take place along the osteotomy site, depending on the action of tension and compression forces generated by masticatory muscles. [source] A composite polymer/tricalcium phosphate membrane for guided bone regeneration in maxillofacial surgeryJOURNAL OF BIOMEDICAL MATERIALS RESEARCH, Issue 5 2001Anita A. Ignatius Abstract The aim of the study was the development of a resorbable membrane for guided bone regeneration (GBR) with improved biocompatibility, which should be stiff enough to avoid membrane collapse during bone healing. Combining a bioactive ceramic with a resorbable polymer may improve the biocompatibility and osteoconductivity of resorbable devices. The present article describes the preparation, the mechanical properties, and the in vitro degradation characteristic of a composite membrane made of poly(L, DL-lactide) and ,-tricalcium phosphate in comparison to a membrane made of pure poly(L, DL-lactide). The tensile strength and the elastic modulus as well as the molecular weight of the membranes were measured after in vitro degradation in buffer at 37 °C up to 28 weeks. The initial tensile strength of the composite and the polymer membrane was 37.3 ± 2.4 MPa and 27.7 ± 2.3 MPa and the elastic modulus 3106 ± 108 MPa and 3101 ± 104 MPa, respectively. The mechanical properties remained constant up to 8 weeks and then decreased slowly until week 28. The molecular weight of both membranes decreased steadily from 170,000 D to 30,000 D. It was concluded that the mechanical requirements for a membrane for GBR were fulfilled by the composite membrane. © 2001 John Wiley & Sons, Inc. J Biomed Mater Res (Appl Biomater) 58: 564,569, 2001 [source] Noggin Inhibits Postoperative Resynostosis in Craniosynostotic Rabbits,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2007Gregory M Cooper PhD Abstract Inhibition of bone formation after surgery to correct craniosynostosis would alleviate the need for secondary surgeries and decrease morbidity and mortality. This study used a single dose of Noggin protein to prevent resynostosis and improve postoperative outcomes in a rabbit model of craniosynostosis. Introduction: Craniosynostosis is defined as the premature fusion of one or more of the cranial sutures, which causes secondary deformations of the cranial vault, cranial base, and brain. Current surgical intervention involves extirpation of the fused suture to allow unrestricted brain growth. However, resynostosis of the extirpated regions often occurs. Several bone morphogenetic proteins (BMPs), well-described inducers of ossification, are involved in bone healing. This study tested the hypothesis that a postoperative treatment with Noggin, an extracellular BMP inhibitor, can inhibit resynostosis in a rabbit model of human familial nonsyndromic craniosynostosis. Materials and Methods: Thirty-one New Zealand white rabbits with bilateral coronal suture synostosis were divided into three groups: (1) suturectomy controls (n = 13); (2) suturectomy with BSA in a slow-resorbing collagen vehicle, (n = 8); and (3) suturectomy with Noggin in a slow-resorbing collagen vehicle (n = 10). At 10 days of age, a 3 × 15-mm coronal suturectomy was performed. The sites in groups 2 and 3 were immediately filled with BSA-loaded gel or Noggin-loaded gel, respectively. Serial 3D-CT scan reconstructions of the defects and standard radiographs were obtained at 10, 25, 42, and 84 days of age, and the sutures were harvested for histological analysis. Results: Radiographic analysis revealed that Noggin-treated animals had significantly greater coronal suture marker separation by 25 days and significantly greater craniofacial length at 84 days of age compared with controls. 3D-CT analysis revealed that Noggin treatment led to significantly greater defect areas through 84 days and to increased intracranial volumes at 84 days of age compared with other groups. Histological analysis supported CT data, showing that the untreated and BSA-treated groups had significant healing of the suturectomy site, whereas the Noggin-treated group had incomplete wound healing. Conclusions: These data support our hypothesis that inhibition of BMP activity using Noggin may prevent postoperative resynostosis in this rabbit model. These findings also suggest that Noggin therapy may have potential clinical use to prevent postoperative resynostosis in infants with craniosynostosis. [source] Application of Histomorphometric Methods to the Study of Bone Repair,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2005Louis C Gerstenfeld Abstract ABSTRACT: Standardized methods for the histomorphometric assessment of bone are essential features of most studies of metabolic bone diseases and their treatments. These methodologies were developed to assess coupled remodeling, focusing primarily on osteoblasts and osteoclasts, the anabolic and catabolic rates of these cells, and structural features of mature bone. Research studies on bone healing and the development of new therapeutic approaches for the enhancement of bone repair also require a comprehensive understanding of the basic cellular and tissue level mechanisms that underlie these processes. However, the histological methods developed for metabolic bone disease studies are not completely suitable for studies of bone repair because they are based on assumptions that there is little variation in tissue composition within a sample of bone and not generally designed to quantify other types of tissues, such as cartilage, that contribute to bone healing. These techniques also do not provide tissue-based structural measurements that are relatable to the specific types of biomechanical and radiographic structural assessments that are used to determine rates of bone healing. These deficiencies in current histological approaches therefore point to the need to establish standardized criteria for the histomorphometric assessments that are specifically adapted for the study of bone repair in models of fracture healing and bone regeneration. In this Perspective, we outline what we believe to be the specific structural, tissue. and cellular aspects that need to be addressed to establish these standardized criteria for the histomorphometric assessment of bone repair. We present the specific technical considerations that need to be addressed to appropriately sample repair tissues to obtain statistically meaningful results and suggest specific procedures and definitions of nomenclatures for the application of this technology to bone repair. Finally, we present how aspects of histomorphometric measurements of bone repair can be related to biomechanical and radiographic imaging properties that functionally define rates of bone healing, and thus, how these tools can be used to provide corroborating data. [source] Shock Wave Application Enhances Pertussis Toxin Protein-Sensitive Bone Formation of Segmental Femoral Defect in Rats,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2003Yeung-Jen Chen Abstract Extracorporeal shock waves (ESWs) elicit a dose-dependent effect on the healing of segmental femoral defects in rats. After ESW treatment, the segmental defect underwent progressive mesenchymal aggregation, endochondral ossification, and hard callus formation. Along with the intensive bone formation, there was a persistent increase in TGF-,1 and BMP-2 expression. Pretreatment with pertussis toxin reduced ESW-promoted callus formation and gap healing, which presumably suggests that Gi proteins mediate osteogenic signaling. Introduction: Extracorporeal shock waves (ESWs) have previously been used to promote bone repair. In our previous report, we found that ESWs promoted osteogenic differentiation of mesenchymal cells through membrane perturbation and activation of Ras protein. In this report, we show that ESWs elicit a dose-dependent effect on the healing of segmental defects and that Gi proteins play an important role in mediating ESW stimulation. Materials and Methods: Rats with segmental femoral defects were subjected to ESW treatment at different energy flux densities (EFD) and impulses. Bone mass (mineral density and calcium content), osteogenic activities (bone alkaline phosphatase activity and osteocalcin content), and immunohistochemistry were assessed. Results: An optimal ESW energy (500 impulses at 0.16 mJ/mm2 EFD) stimulated complete bone healing without complications. ESW-augmented healing was characterized by significant increases (p < 0.01) in callus size, bone mineral density, and bone tissue formation. With exposure to ESW, alkaline phosphatase activity and osteocalcin production in calluses were found to be significantly enhanced (p < 0.05). After ESW treatment, the histological changes we noted included progressive mesenchymal aggregation, endochondral ossification, and hard callus formation. Intensive bone formation was associated with a persistent increase in transforming growth factor-beta 1 (TGF-,1) and bone morphogenetic protein-2 (BMP-2) expression, suggesting both growth factors were active in ESW-promoted bone formation. We also found that pertussis toxin, an inhibitor of membrane-bound Gi proteins, significantly reduced (p < 0.01) ESW promotion of callus formation and fracture healing. Conclusion: ESW treatments enhanced bone formation and the healing of segmental femoral defects in rats. It also seems likely that TGF-,1 and BMP-2 are important osteogenic factors for ESW promotion of fracture healing, presumably through Gi protein-mediated osteogenic signaling. [source] Immediate implants at fresh extraction sockets: bone healing in four different implant systemsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 8 2009Massimo De Sanctis Abstract Objectives: To describe the differences in bone healing, when placing four different implant systems in fresh extraction sockets. Material and Methods: Eight beagle dogs received implants randomly installed into the distal socket of three P3 and four P4. Four-implant systems were evaluated. Each animal provided four test implant sites. All animals were sacrificed at 6 weeks after implant placement, providing specimens for histo-morphometric analysis of bone to implant contact (BIC), bone area, new bone formation, as well as histometric measurements of the ridge alterations. Results: No statistically significant difference was observed among the four-implant systems. The mean BIC % ranged between 58.5% and 72.1%. Bone modelling of the buccal plate was marked and amounted approximately to 2.5 mm, independently of the system used. Conclusion: This study failed to demonstrate differences in the healing pattern after 6 weeks when placing four different implant systems in fresh extraction sockets. In spite of achieving predictable osteointegration with the four implants studied, the occurrence of buccal bone resorption may limit the use of this surgical approach. [source] Early healing of implants placed into fresh extraction sockets: an experimental study in the beagle dog.JOURNAL OF CLINICAL PERIODONTOLOGY, Issue 3 2009De novo bone formation Abstract Objectives: Describe the early phases of tissue integration in implants placed into fresh extraction sockets and test whether a new implant surface nano-topography (DCD nano-particles, NanotiteÔ) promotes early osseointegration when compared with minimally rough surface implants (DAE, Osseotite®). Material and Methods: Sixteen beagle dogs received 64 test and control implants randomly installed into the distal socket of 3P3 and 4P4. Histomorphometric analysis of bone to implant contact (BIC) and bone area was performed at 4 h, 1, 2, 4 and 8 weeks. Results: Wound healing initiated with a coagulum that was substituted by a provisional matrix at 1 week. Bone formation started concomitant to a marked bone resorption. At 2 weeks, woven bone formation was evident and gradually remodelled into lamellar bone at 4 and 8 weeks. BIC increased similarly throughout the study in both groups with a tendency to higher percentages for the test devices at 2 and 4 weeks. The influence of the DCD nano-particles was more evident at the fourth premolar site. Conclusion: Osseointegration occurred similarly at both implant groups, although the socket dimension appeared to influence bone healing. It is suggested that the enhanced nano-topography has a limited effect in the immediate implant surgical protocol. [source] Differential regulation of blood vessel formation between standard and delayed bone healingJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 9 2009Jasmin Lienau Abstract 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. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] FGF23 is a putative marker for bone healing and regenerationJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 9 2009Sascha Goebel Abstract Besides numerous other factors, fibroblast growth factor receptor (FGFR) signaling is involved in fracture healing and bone remodeling. FGF23 is a phosphatonin produced by osteoblastic cells, which signals via FGFR1, thereby exerting effects in bone and kidney. We analyzed if serum FGF23 levels might be an indicator to predict fracture healing and union. FGF23 (C-Term) was elevated on day 3 postoperatively in 55 patients sustaining an exchange of total hip implants due to aseptic loosening. A prospective study of 40 patients undergoing primary hip arthroplasty also showed elevated FGF23 (C-Term) but no change in FGF23 (intact) levels on days 1, 4, and 10 postoperatively. Serum phosphate and phosphate clearance stayed within normal ranges. FGF23 mRNA expression in ovine callus was compared between a standard and delayed course of osteotomy healing. In the standard model, a marked increase in FGF23 mRNA expression compared to the delayed healing situation was observed. Immunohistochemical analysis showed FGF23 production of osteoblasts and granulation tissue in the fracture callus during bone healing. In conclusion, FGF23 is involved in bone healing, can be measured by a sensitive assay in peripheral blood, and is a promising candidate as an indicator for healing processes prone to reunion versus nonunion. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] Stem cell-mediated accelerated bone healing observed with in vivo molecular and small animal imaging technologies in a model of skeletal injuryJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 3 2009Sheen-Woo Lee Abstract Adult stem cells are promising therapeutic reagents for skeletal regeneration. We hope to validate by molecular imaging technologies the in vivo life cycle of adipose-derived multipotent cells (ADMCs) in an animal model of skeletal injury. Primary ADMCs were lentivirally transfected with a fusion reporter gene and injected intravenously into mice with bone injury or sham operation. Bioluminescence imaging (BLI), [18F]FHBG (9-(fluoro-hydroxy-methyl-butyl-guanine)-micro-PET, [18F]Fluoride ion micro-PET and micro-CT were performed to monitor stem cells and their effect. Bioluminescence microscopy and immunohistochemistry were done for histological confirmation. BLI showed ADMC's traffic from the lungs then to the injury site. BLI microscopy and immunohistochemistry confirmed the ADMCs in the bone defect. Micro-CT measurements showed increased bone healing in the cell-injected group compared to the noninjected group at postoperative day 7 (p,<,0.05). Systemically administered ADMC's traffic to the site of skeletal injury and facilitate bone healing, as demonstrated by molecular and small animal imaging. Molecular imaging technologies can validate the usage of adult adipose tissue-derived multipotent cells to promote fracture healing. Imaging can in the future help establish therapeutic strategies including dosage and administration route. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:295,302, 2009 [source] Models of tibial fracture healing in normal and Nf1-deficient miceJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 8 2008Aaron Schindeler Abstract Delayed union and nonunion are common complications associated with tibial fractures, particularly in the distal tibia. Existing mouse tibial fracture models are typically closed and middiaphyseal, and thus poorly recapitulate the prevailing conditions following surgery on a human open distal tibial fracture. This report describes our development of two open tibial fracture models in the mouse, where the bone is broken either in the tibial midshaft (mid-diaphysis) or in the distal tibia. Fractures in the distal tibial model showed delayed repair compared to fractures in the tibial midshaft. These tibial fracture models were applied to both wild-type and Nf1-deficient (Nf1+/,) mice. Bone repair has been reported to be exceptionally problematic in human NF1 patients, and these patients can also spontaneously develop tibial nonunions (known as congenital pseudarthrosis of the tibia), which are recalcitrant to even vigorous intervention. pQCT analysis confirmed no fundamental differences in cortical or cancellous bone in Nf1 -deficient mouse tibiae compared to wild-type mice. Although no difference in bone healing was seen in the tibial midshaft fracture model, the healing of distal tibial fractures was found to be impaired in Nf1+/, mice. The histological features associated with nonunited Nf1+/, fractures were variable, but included delayed cartilage removal, disproportionate fibrous invasion, insufficient new bone anabolism, and excessive catabolism. These findings imply that the pathology of tibial pseudarthrosis in human NF1 is complex and likely to be multifactorial. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1053,1060, 2008 [source] The effects of RANKL inhibition on fracture healing and bone strength in a mouse model of osteogenesis imperfectaJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 2 2008Demetris Delos Abstract Currently, the standard treatment for osteogenesis imperfecta (OI) is bisphosphonate therapy. Recent studies, however, have shown delayed healing of osteotomies in a subset of OI patients treated with such agents. The current study sought to determine the effects of another therapy, RANKL inhibition, on bone healing and bone strength in the growing oim/oim mouse, a model of moderate to severe OI. Mice [73 oim/oim and 69 wild-type (WT)] were injected twice weekly with either soluble murine RANK (RANK-Fc) (1.5 mg/kg) or saline beginning at 6 weeks of age. At 8 weeks of age, the animals underwent transverse mid-diaphyseal osteotomies of the right femur. Therapy was continued until sacrifice at 2, 3, 4, or 6 weeks postfracture. At 6 weeks post-fracture, greater callus area (6.59,±,3.78 mm2 vs. 2.67,±,2.05 mm2, p,=,0.003) and increased radiographic intensity (mineral density) (0.48,±,0.14 vs. 0.30,±,0.80, p,=,0.005) were found in the RANK-Fc versus saline oim/oim group, indicating a delay in callus remodeling. Despite this delay, mechanical tests at 6 weeks postfracture revealed no significant differences in whole bone properties of stiffness and failure moment. Further, RANKL inhibition resulted in a greater failure moment and greater work to failure for the nonfractured contralateral WT bones compared to the nonfractured saline WT bones. Together, these results demonstrate that RANKL inhibition does not adversely affect the mechanical properties of healing bone in the oim/oim mice, and is associated with increased strength in intact bone in the WT mice. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:153,164, 2008 [source] Accelerated repair of cortical bone defects using a synthetic extracellular matrix to deliver human demineralized bone matrixJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 7 2006Yanchun Liu Abstract Injectable hydrogel and porous sponge formulations of CarbylanÔ-GSX, a crosslinked synthetic extracellular matrix (ECM), were used to deliver human demineralized bone matrix (DBM) in a rat femoral defect model. A cortical, full-thickness 5-mm defect was created in two femurs of each rat. Six rats were assigned to each of five experimental groups (thus, 12 defects per group). The defects were either untreated or filled with CarbylanÔ-GSX hydrogel or sponges with or without 20% (w/v) DBM. Radiographs were obtained on day 1 and at weeks 2, 4, 6, and 8 postsurgery of each femur. Animals were sacrificed at week 8 postsurgery and each femur was fixed, embedded, sectioned, and processed for Masson's Trichrome staining. The bone defects were measured from radiographs and the fraction of bone healing was calculated. The average fractions of bone healing for each group were statistically different among all groups, and all treatment groups were significantly better than the control group. The CarbylanÔ-GSX sponge with DBM was superior to the sponge without DBM and to the hydrogel with DBM. Histology showed that defects treated with the CarbylanÔ-GSX sponge plus DBM were completely filled with newly generated bone tissue with a thickness comparable to native bone. CarbylanÔ-GSX sponge was an optimal delivery vehicle for human DBM to accelerate bone healing. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1454,1462, 2006 [source] Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fracturesJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 7 2006Takahiro Niikura Abstract Nonunion is a challenging problem that may occur following certain bone fractures. However, there has been little investigation of the molecular basis of nonunions. Bone morphogenetic proteins (BMPs) play a significant role in osteogenesis. However, little is known about the expression patterns of BMPs in abnormal bone healing that results in nonunion formation. These facts prompted us to investigate and compare the gene expression patterns of BMPs and their antagonists in standard healing fractures and nonunions using rat experimental models. Standard closed healing fractures and experimental atrophic nonunions produced by periosteal cauterization at the fracture site were created in rat femurs. At postfracture days 3, 7, 10, 14, 21, and 28, total RNA was extracted from the callus of standard healing fracture and fibrous tissue of nonunion (n,=,4 per each time point and each group). Gene expression of BMPs, BMP antagonists, and other regulatory molecules were studied by methods including Genechip® microarray and real-time quantitative RT-PCR. Gene expression of BMP-2, 3, 3B, 4, 6, 7, GDF-5, 7, and BMP antagonists noggin, drm, screlostin, and BAMBI were significantly lower in nonunions compared to standard healing fractures at several time points. Downregulation in expression of osteogenic BMPs may account for the nonunions of fracture. The balance between BMPs and their endogenous antagonists is critical for optimal fracture healing. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1463,1471, 2006 [source] In vivo study on the healing of bone defects treated with bone marrow stromal cells, platelet-rich plasma, and freeze-dried bone allografts, alone and in combinationJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2006D. Dallari Abstract The repair of confined trabecular bone defects in rabbits treated by autologous bone marrow stromal cells (BMSC), platelet-rich plasma (PRP), freeze-dried bone allografts (FDBA) alone and in combination (BMSC,+,PRP; FDBA,+,BMSC; FDBA,+,PRP; FDBA,+,PRP,+,BMSC) was compared. A critical size defect was created in the distal part of the femurs of 48 adult rabbits. Histology and histomorphometry were used in the evaluation of healing at 2, 4, and 12 weeks after surgery. The healing rate (%) was calculated by measuring the residual bone defect area. Architecture of the newly formed bone was compared with that of bone at the same distal femur area of healthy rabbits. The defect healing rate was higher in PRP,+,BMSC, FDBA,+,PRP, FDBA,+,BMSC, and FDBA,+,PRP,+,BMSC treatments, while lower values were achieved with PRP treatment at all experimental times. The highest bone-healing rate at 2 weeks was achieved with FDBA,+,PRP,+,BMSC treatment, which resulted significantly different from PRP (p,<,0.05) and BMSC (p,<,0.05) treatments. At 4 weeks, the bone-healing rate increased except for PRP treatment. Finally, the bone-healing rate of FDBA,+,PRP, FDBA,+,BMSC, and FDBA,+,PRP,+,BMSC was significantly higher than that of PRP at 12 weeks (p,<,0.05). At 12 weeks, significant differences still existed between PRP, BMSC, and FDBA groups and normal bone (p,<,0.05). These results showed that the combination of FDBA, BMSC and PRP permitted an acceleration in bone healing and bone remodeling processes. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] CYR61 (CCN1) Protein Expression during Fracture Healing in an Ovine Tibial Model and Its Relation to the Mechanical Fixation StabilityJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 2 2006Jasmin Lienau Abstract The formation of new blood vessels is a prerequisite for bone healing. CYR61 (CCN1), an extracellular matrix-associated signaling protein, is a potent stimulator of angiogenesis and mesenchymal stem cell expansion and differentiation. A recent study showed that CYR61 is expressed during fracture healing and suggested that CYR61 plays a significant role in cartilage and bone formation. The hypothesis of the present study was that decreased fixation stability, which leads to a delay in healing, would lead to reduced CYR61 protein expression in fracture callus. The aim of the study was to quantitatively analyze CYR61 protein expression, vascularization, and tissue differentiation in the osteotomy gap and relate to the mechanical fixation stability during the course of healing. A mid-shaft osteotomy of the tibia was performed in two groups of sheep and stabilized with either a rigid or semirigid external fixator, each allowing different amounts of interfragmentary movement. The sheep were sacrificed at 2, 3, 6, and 9 weeks postoperatively. The tibiae were tested biomechanically and histological sections from the callus were analyzed immunohistochemically with regard to CYR61 protein expression and vascularization. Expression of CYR61 protein was upregulated at the early phase of fracture healing (2 weeks), decreasing over the healing time. Decreased fixation stability was associated with a reduced upregulation of the CYR61 protein expression and a reduced vascularization at 2 weeks leading to a slower healing. The maximum cartilage callus fraction in both groups was reached at 3 weeks. However, the semirigid fixator group showed a significantly lower CYR61 immunoreactivity in cartilage than the rigid fixator group at this time point. The fraction of cartilage in the semirigid fixator group was not replaced by bone as quickly as in the rigid fixator group leading to an inferior histological and mechanical callus quality at 6 weeks and therefore to a slower healing. The results supply further evidence that CYR61 may serve as an important regulator of bone healing. © 2005 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] In vivo assessment of regenerate axial stiffness in distraction osteogenesisJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 2 2005Gudrun Trøite Aarnes Abstract This paper presents an in vivo test for assessment of regenerate axial stiffness after the distraction phase of lengthening therapy. The test result supplements radiography in evaluating bone healing and assists in determining when the regenerate stiffness is sufficient for removal of the external fixator. The test is non-invasive and does not require fixator removal. The theoretical basis for the method is that an externally applied load is shared between the fixator and the regenerating bone. The amount of load carried by the regenerate depends on its axial stiffness, which increases with advanced mineralization. By measuring the force in the fixator while applying a known external load to the limb, the load-share ratio between fixator and limb can be assessed. A load-share ratio of 100% indicates that the entire load is carried by the fixator. The ratio decreases as the regenerate structure gradually stiffens. In a clinical trial of 22 individuals with tibial lengthening, the fixator was removed when the load-share ratio dropped below 10%. None of the patients experienced fracture after removal of the fixator. © 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source] Enhancement of bone healing using non-glycosylated rhBMP-2 released from a fibrin matrix in dogs and catsJOURNAL OF SMALL ANIMAL PRACTICE, Issue 1 2005H. G. Schmoekel Objectives: To test a non-glycosylated recombinant human bone morphogenetic protein-2 (ngly-rhBMP-2)/fibrin composite, which has been shown experimentally to enhance healing of bone defects in rodents, in a clinical case series of dogs and cats undergoing treatment for fracture non-unions and arthrodesis. Methods: A ngly-rhBMP-2/fibrin composite was applied in 41 sites in 38 dogs and cats for which a cancellous bone autograft was indicated, replacing the graft. Results: Bridging of the bone defect with functional bone healing was achieved in 90 per cent of the arthrodesis and fracture nonunions treated in this manner. Clinical Significance: This prospective clinical study demonstrates the beneficial effects of ngly-rhBMP-2 in a specially designed fibrin matrix on the treatment of bone defects, and validates the use of this composite as an alternative to bone autografts in dogs and cats. [source] Bone healing performance of electrophoretically deposited apatite,wollastonite/chitosan coating on titanium implants in rabbit tibiaeJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 7 2009Smriti Sharma Abstract Bone healing of tibial defect in rabbit model was used to evaluate a composite coating of apatite,wollastonite/chitosan on titanium implant. This coating has been developed to overcome the shortcomings, such as implant loosening and lack of adherence, of uncoated titanium implant. An electrophoretic deposition technique was used to coat apatite,wollastonite/chitosan on titanium implants. The present study was designed to evaluate the bone response of coated as compared to uncoated titanium implants in an animal model. After an implantation period of 14 (group A), 21 (group B), 35 (group C) and 42 days (group D), the bone,implant interfaces and defect site healing was evaluated using radiography, scintigraphy, histopathology, fluorescence labeling and haematology. Radiography of defect sites treated with coated implants suggested expedited healing. Scintigraphy of coated implant sites indicated faster bone metabolism than uncoated implant sites. Histopathological examination and fluorescence labeling of bone from coated implant sites revealed higher osteoblastic activity and faster mineralization. Faster bone healing in the case of coated implant sites is attributed to higher cell adhesion on electrostatically charged chitosan surfaces and apatite,wollastonite-assisted mineralization at bone,implant interfaces. Haematological studies showed no significant differences in haemoglobin, total erythrocyte and leukocyte counts, done using one way-ANOVA, during the entire study period. Our results show that AW/chitosan-coated implants have the advantages of faster bone healing, increased mechanical strength and good bone,implant bonding. Copyright © 2009 John Wiley & Sons, Ltd. [source] Transplantation of a vascularized rabbit femoral diaphyseal segment: Mechanical and histologic properties of a new living bone transplantation modelMICROSURGERY, Issue 4 2008Goetz A. Giessler M.D. A new vascularized bone transplantation model is described, including the anatomy and surgical technique of isolating a rabbit femoral diaphyseal segment on its nutrient vascular pedicle. The histologic and biomechanical parameters of pedicled vascularized femoral autotransplants were studied following orthotopic reimplantation in the resulting mid-diaphyseal defect. Vascularized femur segments were isolated in 10 rabbits on their nutrient pedicle, and then replaced orthotopically with appropriate internal fixation. Postoperative weightbearing and mobility were unrestricted, and the contralateral femora served as no-treatment controls. After 16 weeks, the bone flaps were evaluated by x-ray (bone healing), mechanical testing (material properties), microangiography (quantification of intraosseous vasculature), histology (bone viability), and histomorphometry (bone remodeling). Bone healing occurred by 2 weeks, with further callus remodeling throughout the survival period. Eight transplants healed completely, while two had a distal pseudarthrosis. Microangiography demonstrated patent pedicles in all transplants. Intraosseous vessel densities were comparable to nonoperated (control) femora. We found ultimate strength and elastic modulus to be significantly reduced when compared to normal controls. Viable bone, increased mineral apposition rate, and bone turnover were demonstrated in all transplants. The method described, and the data provided will be of value for the further study of isolated segments of living bone, and in particular, for investigations of reconstruction of segmental bone loss in weight-bearing animal models. This study also provides important normative data on living autologous bone flap material properties, vascularity, and bone remodeling. We intend to use this method and data for comparison in subsequent studies of large bone vascularized allotransplantation. © 2008 Wiley-Liss, Inc. Microsurgery, 2008. [source] Stromal cell,derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse modelARTHRITIS & RHEUMATISM, Issue 3 2009Toshiyuki Kitaori Objective Stromal cell,derived factor 1 (SDF-1; CXCL12/pre,B cell growth-stimulating factor) is a dominant chemokine in bone marrow and is known to be involved in inflammatory diseases, including rheumatoid arthritis. However, its role in bone repair remains unknown. The purpose of this study was to investigate the role of SDF-1 and its receptor, CXCR4, in bone healing. Methods The expression of SDF-1 during the repair of a murine structural femoral bone graft was examined by real-time polymerase chain reaction and immunohistochemical analysis. The bone graft model was treated with anti,SDF-1 neutralizing antibody or TF14016, an antagonist for CXCR4, and evaluated by histomorphometry. The functional effect of SDF-1 on primary mesenchymal stem cells was determined by in vitro and in vivo migration assays. New bone formation in an exchanging-graft model was compared with that in the autograft models, using mice partially lacking SDF-1 (SDF-1+/,) or CXCR4 (CXCR4+/,). Results The expression of SDF1 messenger RNA was increased during the healing of live bone grafts but was not increased in dead grafts. High expression of SDF-1 protein was observed in the periosteum of the live graft. New bone formation was inhibited by the administration of anti,SDF-1 antibody or TF14016. SDF-1 increased mesenchymal stem cell chemotaxis in vitro in a dose-dependent manner. The in vivo migration study demonstrated that mesenchymal stem cells recruited by SDF-1 participate in endochondral bone repair. Bone formation was decreased in SDF-1+/, and CXCR4+/, mice and was restored by the graft bones from CXCR4+/, mice transplanted into the SDF-1+/, femur, but not vice versa. Conclusion SDF-1 is induced in the periosteum of injured bone and promotes endochondral bone repair by recruiting mesenchymal stem cells to the site of injury. [source] | ||||||||||||||||