Repair Of Segmental Bone Defects Research Articles

The synergistic effect of bone forming peptide-1 and endothelial progenitor cells to promote vascularization of tissue engineered bone.

Large segmental bone defect repair remains a challenge in orthopedic surgeries. The tissue engineered bone graft will be a promising approach if vascularization of the graft is realized. In this study, beta-tricalcium phosphate (β-TCP) scaffold incorporated with bone forming peptide-1 (BFP-1) was fabricated. Endothelial progenitor cells (EPCs) were introduced as well. We investigated the effect of BFP-1 on the proliferation, differentiation, and angiogenic functions of EPCs. Additionally, segmental femur bone defect was created in rabbits. Prevascularized β-TCP scaffold was constructed and implanted into the bone defect. The vascularization and bone formation were evaluated after 4 and 12 weeks. The results showed that BFP-1 promoted the angiogenesis of EPCs through activating the activin receptor-like kinase-1/Smad pathway. The prevascularized tissue engineered bone graft enhanced capillary vessel in-growth and new bone formation. Significantly higher values of vascularization and radiographic grading scores were observed in groups involving EPCs and BFP-1, compared to β-TCP scaffold alone. In conclusion, the synergy between EPCs and BFP-1 improved the vascularization and new bone regeneration, which has great potentials in clinical applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1008-1021, 2018.

Osteogenesis of dextran sulfate/recombinant human bone morphogenetic protein-2/chitosan nano microspheres combined with coralline hydroxyapatite in repair of large segmental bone defects

Objective To investigate the osteogenic ability of dextran sulfate/recombinant human bone morphogenetic protein-2/chitosan (DS/rhBMP2/CS) nano microspheres combined with coralline hydroxyapatite (CHA) in repair of segmental bone defects. Methods DS/rhBMP2/CS microspheres prepared by ionic crosslinking method were adsorbed into CHA by lyophilization. Seventy-two New Zealand rabbits were randomly divided into 3 equal groups after they had been made into models of bone defect at the right radius. The defects in the 3 groups were implanted respectively with CHA, rhBMP2/CHA and DS/rhBMP2/CS/CHA. Another 18 animals served as a blank control group. Blood and bone samples were obtained at 4, 8 and 12 weeks after implantation. The serum BGP was detected, and the bone grafts were scanned by micro-CT for calculation of volume ratio of the new bone. Hematoxylin and eosin (HE) staining was performed after bonedecalcification. Results All the 72 animals recovered well without any infection or graft exposure. Gross observation at postoperative 12 weeks showed that the DS/rhBMP2/CS/CHA group was the best in the quality, quantity and strength of the new bone, as well as in the healing of bone defects. The serum levels of bone gamma-carboxyglutamic-acid-containing protein at all time points in the DS/rhBMP2/CS/CHA group were significantly higher than those in the CHA and rhBMP2/CHA groups (P<0.05). Micro-CT scanning demonstrated obvious progress in bone formation, cortical bone and marrow cavity at all time points in the DS/rhBMP2/CS/CHA group which showed significantly faster bone reconstruction synchronized with material degradation and significantly higher volume ratio of the new bone than the other 2 groups (P<0.05). Histological examinations showed better morphology of mature cortical bone and new marrow cavity at all time points in the DS/rhBMP2/CS/CHA group than in the other 2 groups. Conclusion Since DS/rhBMP2/CS/CHA possesses a better mechanism of sustained-releasing rhBMP2 to induce bone formation because of its reticular and hole-hole-connected structure, it may perform better in repairing segmental bone defects than simple CHA or rhBMP2/CHA. Key words: Chitosan; Hydroxyapatite; Glucans; Recombinant human morphogenetic protein-2; Bone defect

Composite scaffolds loaded with bone mesenchymal stem cells promote the repair of radial bone defects in rabbit model

This study aimed to investigate the efficacy of three-dimensional scaffolds of silk fibroin/chitosan/nano-hydroxyapatite (SF/CS/nHA) and bone marrow derived mesenchymal stem cells (BMSCs) on the repair of long segmental bone defects in rabbits. BMSCs were cultured with SF/CS/nHA in vitro, and cell proliferation, alkaline phosphatase activity and Ca2+ content were examined. A 15mm segmental defect in the radius was generated in 12 New Zealand White rabbits, which were divided randomly into three groups (n=4): experimental group with SF/CS/nHA scaffold of induced BMSCs; control group with SF/CS/nHA scaffold; and blank group without any materials. Postoperatively at 12 weeks, osteogenesis effect and the degradation and absorption of SF/CS/nHA were evaluated by X-ray, hematoxylin eosin staining, and scanning electron microscopy. In vitro, SF/CS/nHA scaffolds exhibited good biocompatibility and no toxicity. SF/CS/nHA promoted adhesion, growth, and calcium nodule formation of BMSCs compared to control (P<0.05). In vivo, we observed gradual new bone formation and bone defect gradually recovered at 12 weeks in experimental and control group, but more new bone was formed in experimental group (P<0.05). In blank group, limited bone formation was observed and bone defect was obvious. In conclusion, SF/CS/nHA scaffolds loaded with BMSCs achieve high efficacy to repair segmental defect in the radius.

Repair of segmental bone defects in rabbits' radius with domestic porous tantalum encapsulated with pedicled fascial flap

To investigate the effect of domestic porous tantalum encapsulated with pedicled fascial flap on repairing of segmental bone defect in rabbits' radius. A total of 60 New Zealand white rabbits (aged 6- 8 months and weighing 2.5-3.0 kg) were randomly divided into the experimental group and control group (30 rabbits each group). A 1.5 cm segmental bone defect in right radius was established as the animal model. The porous tantalums encapsulated with pedicled fascial flaps (30 mm×20 mm) were implanted in the created bone defect in the experimental group, and the porous tantalums were only implanted in the control group. X-ray films were observed at the day after operation and at 4, 8, and 16 weeks after operation. Specimens were taken out at 4, 8, and 16 weeks after operation for HE staining and toluidine blue staining observation. The maximum load force and bending strength were detected by three point bending biomechanical test, and the Micro-CT analysis and quantitative analysis of the new bone volume fraction (BV/TV) were performed at 16 weeks after operation to compare the bone defect repair ability in vivo in 2 groups. All incisions healed by first intention without wound infection. At 4, 8, and 16 weeks after operation, the X-ray films showed that the implants were well maintained without apparent displacement. As followed with time, the combination between the implants and host bone became more and more closely, and the fracture line gradually disappeared. HE staining and toluidine blue staining showed that new bone mass and maturity gradually increased at the interface and inside materials in 2 groups, and the new bone gradually growed from the interface to internal pore. At 16 weeks after operation, the three point bending biomechanical test showed that the maximum load force and bending strength in the experimental were (96.54±7.21) N and (91.26±1.76) MPa respectively, showing significant differences when compared with the control group [(82.65±5.65) N and (78.53±1.16) MPa respectively] ( t=3.715, P=0.004; t=14.801, P=0.000). And Micro-CT analysis exhibited that there were a large amount of new bone at the interface and the surface of implant materials and inside the materials. The new bone BV/TV in the experimental group (32.63%±3.56%) was significantly higher than that in control group (25.07%±4.34%) ( t=3.299, P=0.008). Domestic porous tantalum encapsulated with pedicled fascial flap can increase local blood supply, strengthen material bone conduction ability, and promote the segmental bone defect repair.

Repair of Large Segmental Bone Defect using Vascularized Small Corticocancellous Bone in Rabbit Femur.

Background Although free-vascularized long-bone transfer is useful for reconstruction of a large segmental bone defect, it is limited by availability of transplantable bone, meticulous microsurgical technique, and donor-site morbidities. Hence, easier, readily available, and safer surgical procedures are warranted. This study evaluated the effects of vascularized small corticocancellous bone grafting for reconstruction of a large segmental rabbit femur defect. Methods A 1.5 cm defect was created in the femurs of 40 New Zealand white rabbits and divided into a control group (n = 10, bone defect without graft), group A (n = 10, bone defect filled with morselized autogenous bone), group B (n = 10, bone defect grafted with a vascularized small corticocancellous bone and morselized autogenous bone), and group C (n = 10, bone defect grafted with a vascularized small corticocancellous bone). Simple radiographs were taken postoperatively, and bone healing ability was scored using Taira's radiologic scale. Histologic examinations were scored using Emery's histologic scale. The expression of osteogenesis-related growth factors (BMP-2, -4, and -7, VEGF, and RANKL) was analyzed. Results Radiologically, group B showed superior biological efficacy in bone formation and consolidation over the other groups. Histologically, the defect in group B was filled with more abundant mature bone than the other groups. Group B showed higher gene expression of BMP-2, -4, and -7, and VEGF. Conclusions The grafting of the morselized autogenous bone (MSB) combined with the vascularized small corticocancellous bone is more effective than that of the MSB alone for repairing a large segmental bone defect.

Abstract P29: Self Contained Bioreactor For Bone Regeneration

PURPOSE: The current gold standard for the repair of segmental bone defects is autologous bone grafts or flaps, however these are limited by donor site morbidity, limited graft tissue availability, and potential for complications at the harvest site. ASCs (adipose derived stem cells) have potential to aid bone regeneration due to their ability to differentiate into osteoblasts. BMP-2 (bone morphogenetic protein) has been shown to induce osteogenic differentiation of ASCs and enhance bone growth. We present a bioreactor for bone regeneration consisting of three main components: (i) a biodegradable PLLA scaffold seeded with ASCs, (ii) a drug reservoir made of PLLA and (iii) a controlled drug diffusion system for sustained release of BMP-2 to repair segmental bone defects. The drug reservoir is attached to the porous polymer scaffold seeded with ASCs and is capable of delivering growth factors for prolonged periods. METHODS: The components for the drug delivering setup were made from poly-lactic-acid (Purac Biomaterials) using solvent casting method. The device consists of two concentric tubes and a reservoir in between the tubes that stores BMP-2. Six 180 μm diffusion holes were drilled into the inner tube by pulsing a laser cutter. In vitro release tests were performed over a 30-day period. The concentration of BMP-2 released from devices was determined with an enzyme linked immunosorbent assay (R&D systems). The PLLA scaffolds were manufactured by a salt leaching method. ASC seeded scaffolds were inserted in the inner tube. We first evaluated the dosage(s) of BMP-2 that allows for the differentiation of ASCs into osteogenic cells using RT-PCR. ASC seeded devices were then loaded with BMP-2 and in vitro osteogenic differentiation of the ASCs was evaluated by direct delivery of BMP-2 from the drug reservoir to the seeded scaffold. RESULTS: The RT-PCR data showed increased expression of osteogenic markers such as ALK and Runx-2 in ASCs treated with 100ng/ml BMP-2 compared to no BMP-2 (p<0.05). Alizarin Red staining results showed that we were able to achieve osteogenic differentiation of ASCs with 100ng/ml BMP-2/day and the percentage of mineralization was greater in the PLLA scaffold compared to ‘no scaffold’ (p<0.05). The results for drug release kinetics showed that the drug delivery setup test was effective in achieving controlled local release of BMP-2 for 30 days. The results of the sealed (no hole) devices (n=2) validated sealing techniques for the drug-release reservoirs. The diffusion tests (n=6) indicated that 6x180 μm holes allowed for a sustainable and controlled BMP-2 release in the range of 50–100 ng/ml/day for 30 days. CONCLUSION: The bone bioreactor was able to release BMP-2 for 30 days in a controlled manner. The ASC seeded PLLA scaffold exposed to 50-100ng/m/day of BMP-2 produced significantly higher mineralization as compared to no scaffold. Further in vivo testing will be done to demonstrate that directly delivering BMP-2 from our reservoir to the ASC seeded scaffold enhances bone regeneration.

Enhanced repair of segmental bone defects in rabbit radius by porous tantalum scaffolds modified with the RGD peptide.

Fast and stable repair of segmental bone defects remains a challenge for clinical orthopedic surgery. In recent years, porous tantalum has been widely applied in clinical orthopedics for low modulus of elasticity, with three-dimensional microstructures similar to cancellous bone and excellent biocompatibility. To further improve bone the repairing ability of porous tantalum, the cyclo(-RGDfK-) peptide was coated on the surface of porous tantalum scaffolds. A model of 15 mm segmental defect was made at the midshaft of right radius in New Zealand White rabbits. In the experimental group, defects were implanted (press-fit) using porous tantalum scaffolds modified with cyclo(-RGDfK-) peptide. Control animals were implanted with non-modified porous tantalum scaffolds or xenogeneic cancellous bone scaffolds, respectively. No implant was provided for the blank group. Bone repair was assessed by X-ray and histological observations at 4, 8, and 16 weeks post-operation, with biomechanical tests and micro-computed tomography performed at 16 weeks post-surgery. The results showed that bone formation was increased at the interface and inside the inner pores of modified porous tantalum scaffolds than those of non-modified porous tantalum scaffolds; biomechanical properties in the modified porous tantalum group were superior to those of the non-modified porous tantalum and xenogeneic cancellous bone groups, while new bone volume fractions using micro-computed tomography analysis were similar between the modified porous tantalum and xenogeneic cancellous bone groups. Our findings suggested that modified porous tantalum scaffolds had enhanced repairing ability in segmental bone defect in rabbit radius, and may serve as a potential material for repairing large bone defects.

Delayed Endothelial Progenitor Cell Therapy Promotes Bone Defect Repair in a Clinically Relevant Rat Model.

The repair of segmental bone defects remains a significant challenge for orthopaedic surgeons. Endothelial progenitor cells (EPCs) have successfully promoted the repair of acute defects in animal models; however, the ability of EPCs to induce the repair of chronic nonhealing defects, such as those often encountered clinically, has not been investigated. Therefore, the purpose of this study was to investigate the ability of EPCs delivered in delayed fashion to induce the repair of nonhealing defects in a clinically relevant model. In order to simulate delayed treatment, 5 mm segmental defects in Fischer 344 rat femora were treated with bone marrow-derived EPCs on a Gelfoam scaffold at 3 weeks post creation of the defect. At ten weeks posttreatment, 100% of EPC-treated defects achieved union, whereas complete union was only achieved in 37.5% of defects treated with Gelfoam alone. Furthermore, significant increases in ultimate torque (p = 0.022) and torsional stiffness (p = 0.003) were found in EPC-treated defects compared to controls. Critically, no differences in outcomes were observed between acute and delayed EPC treatments. These results suggest that EPCs can enhance bone healing when applied in an acute or delayed fashion and that their use may represent a clinically translatable therapy for bone healing in humans.

Repair of large segmental bone defects with fascial flap-wrapped allogeneic bone.

BackgroundThe objective of this study was to investigate the therapeutic effects of the application of fascial flap-wrapped allogeneic bone for repair of large segmental tibial defects in rabbits and provide a theoretical basis for treatment of large segmental defects in weight-bearing bones.MethodsForty-eight healthy adult New Zealand White (NZW) rabbits were randomized into two groups to establish 15-mm bone defects in the proximal tibia. Bone defects in test and control groups were repaired using allogeneic bone with and without a vascularized fascial flap from the rabbit proximal tibia, respectively. The differences in repair of bone defects between the two groups were assessed with postoperative X-ray examination, new bone quantity assessment, serum bone Gla protein (BGP) level, and biomechanical testing.ResultsThe therapeutic effect in the test group was superior to that in the control group.ConclusionsFascial flap-wrapped allogeneic bone is superior to allogeneic bone alone, and is ideal for the treatment of large segmental bone defects.

A Study of BMP-2-Loaded Bipotential Electrolytic Complex around a Biphasic Calcium Phosphate-Derived (BCP) Scaffold for Repair of Large Segmental Bone Defect.

A bipotential polyelectrolyte complex with biphasic calcium phosphate (BCP) powder dispersion provides an excellent option for protein adsorption and cell attachment and can facilitate enhanced bone regeneration. Application of the bipotential polyelectrolyte complex embedded in a spongy scaffold for faster healing of large segmental bone defects (LSBD) can be a promising endeavor in tissue engineering application. In the present study, a hollow scaffold suitable for segmental long bone replacement was fabricated by the sponge replica method applying the microwave sintering process. The fabricated scaffold was coated with calcium alginate at the shell surface, and genipin-crosslinked chitosan with biphasic calcium phosphate (BCP) dispersion was loaded at the central hollow core. The chitosan core was subsequently loaded with BMP-2. The electrolytic complex was characterized using SEM, porosity measurement, FTIR spectroscopy and BMP-2 release for 30 days. In vitro studies such as MTT, live/dead, cell proliferation and cell differentiation were performed. The scaffold was implanted into a 12 mm critical size defect of a rabbit radius. The efficacy of this complex is evaluated through an in vivo study, one and two month post implantation. BV/TV ratio for BMP-2 loaded sample was (42±1.76) higher compared with hollow BCP scaffold (32±0.225).

Oxygen Tension-Controlled Matrices with Osteogenic and Vasculogenic Cells for Vascularized Bone Regeneration In Vivo.

Despite recent progress, segmental bone defect repair is still a significant challenge in orthopedic surgery. While bone tissue engineering approaches using biodegradable matrices along with bone/blood vessel forming cells offered improved possibilities, current regenerative strategies lack the ability to achieve vascularized bone regeneration in critical-sized/segmental bone defects. In this study, we introduced and evaluated a two-pronged approach for vascularized bone regeneration in vivo. The goal was to demonstrate vascularized bone formation using oxygen tension-controlled (OTC) matrices seeded with bone and blood vessel forming cells. OTC matrices were coimplanted with rabbit mesenchymal stem cells (MSCs) and peripheral blood-derived endothelial progenitor cells (PB-EPCs) to demonstrate the osteogenic and vasculogenic differentiation of these cells, postseeding on a matrix, especially deep inside the matrix pore structure. Matrices coimplanted with varied rabbit MSC and PB-EPC ratios (1:4, 1:1, and 4:1) were assessed in a nude mouse subcutaneous implantation model to determine a coimplantation ratio with superior osteogenic as well as vasculogenic properties. The implants were analyzed, at week 8, for endothelial (CD31 and Von Willebrand factor [vWF]) and osteogenic marker (RunX2 and Col I) staining qualitatively and collagen deposition and number of vessel formation quantitatively. Results from these experiments established MSC-to-PB-EPC ratio 1:1 as the best coimplantation ratio. OTC matrix with 1:1 coimplantation ratio was assessed for segmental bone defect repair in a rabbit critical-sized bone defect model. The group under investigation was OTC matrix, and the matrix was seeded with MSCs, EPCs, or MSCs:EPCs in a 1:1 ratio. Explants at week 12 were evaluated for bone defect repair via micro-CT and histology. Results from rabbit in vivo experiments show enhanced mineralization and vascularization for the 1:1 coimplantation group. Overall, the study establishes a two-pronged approach involving OTC matrix and effective progenitors for large-area and vascularized bone regeneration.

Ultrahigh strength of three-dimensional printed diluted magnesium doping wollastonite porous scaffolds

Abstract

Bioactive borate glass promotes the repair of radius segmental bone defects by enhancing the osteogenic differentiation of BMSCs

Bioactive borate glass (BG) has emerged as a promising alternative for bone regeneration due to its high osteoinductivity, osteoconductivity, compressive strength, and biocompatibility. However, the role of BG in large segmental bone repair is unclear and little is known about the underlying mechanism of BG’s osteoinductivity. In this study, we demonstrated that BG possessed pro-osteogenic effects in an experimental model of critical-sized radius defects. Transplanting BG to radius defects resulted in better repair of bone defects as compared to widely used β-TCP. Histological and morphological analysis indicated that BG significantly enhanced new bone formation. Furthermore, the degradation rate of the BG was faster than that of β-TCP, which matched the higher bone regeneration rate. In addition, ions from BG enhanced cell viability, ALP activity, and osteogenic-related genes expression. Mechanistically, the critical genes Smad1/5 and Dlx5 in the BMP pathway and p-Smad1/5 proteins were significantly elevated after BG transplantation, and these effects could be blocked by the BMP/Smad specific inhibitor. Taken together, our findings suggest that BG could repair large segmental bone defects through activating the BMP/Smad pathway and osteogenic differentiation in BMSCs.

Bioactive Glass for Large Bone Repair.

There has been an ongoing quest for new biomedical materials for the repair and regeneration of large segmental bone defects caused by disease or trauma. Autologous bone graft (ABG) remains the gold standard for bone repair despite their limited supply and donor-site morbidity. The current tissue engineering approach with synthetically derived bone grafts requires a bioactive ceramic or polymeric scaffold loaded with growth factors for osteoinduction and angiogenesis, and bone marrow stromal cells (BMSCs) for osteogenic properties. Unfortunately, this approach has serious drawbacks: the low mechanical strength of scaffolds, the high cost of growth factors, and a lack of optimal strategies for growth-factor delivery. Here, it is shown that, for the first time, a synthetic material alone can repair large bone defects as efficiently as the gold standard ABG. Through the use of strong and resorbable bioactive glass scaffolds, complete bone healing, and defect bridging can be achieved in a rabbit femur segmental defect model without growth factors or BMSCs. New bone and blood vessel formation, in both inner and peripheral scaffolds, demonstrates the excellent osteoinductive and osteogenic properties of these scaffolds similar as ABG.

The effect of BMP-7 gene activated muscle tissue implants on the repair of large segmental bone defects.

This study was conducted in order to investigate the effect of Bone Morphogenetic Protein-7 (BMP-7) transduced muscle cells on bone formation and to further develop an innovative abbreviated ex vivo gene therapy for bone repair. As conventional ex vivo gene therapy methods require an elaborative and time-consuming extraction and expansion of cells we evaluated an expedited approach. Fragments of muscle tissue were directly activated by BMP-7 cDNA and implanted into bone defects. 25 male, syngeneic Fischer 344 rats were used in the present study. Muscle tissue was harvested from two donor rats and either transduced with an adenovirus carrying the BMP-7 cDNA or remained unmodified. 5mm osseous defects in the right femora of 23 rats were treated with either unmodified muscle tissue (control group) or BMP-7 activated muscle tissue (treatment group). Six weeks after surgery, rat femora were evaluated by radiographs, micro-computed tomography (μCT) and histology. Implantation of BMP-7 activated muscle grafts led to bony bridging in 5 out of 12 defects (41.7%) and to bone formation without bridging in 2 out of 12 defects. In 2 femoral defects of this group radiographs, μCT-imaging and histology did not reveal significant mineralization. Three animals of the BMP-7 treatment group had to be euthanized due to serious wound infection. The bone volume of the treatment group was significantly (p=0.007) higher compared to the control group. This study shows that BMP-7 gene activated muscle fragments have the potential to regenerate critical-size segmental bone defects in rats. However, further development of this promising expedited treatment modality is required to improve the healing rate and to investigate if the high infection rate is related to treatment with BMP-7 activated muscle grafts.

Simultaneous mechanical property and biodegradation improvement of wollastonite bioceramic through magnesium dilute doping

The large-area bone defects in head (including calvarial, orbital, and maxillofacial bone) and segmental bone are attracting increased attention in a wide range of clinical departments. A key requirement for the clinical success of the bioactive ceramics is the match of the mechanical behavior of the implants with the specific bone tissue to be filled. This raises the question as to what design strategy might be the best indicators for the balance between mechanical properties and biological performances. Here we go beyond the traditional approaches that use phase conversion or biphasic hybrid; instead, we achieved a simultaneous enhancement of several mechanical parameters and optimalization of biodegradability by using a dilute doping of Mg in a single-phase wollastonite bioceramic. We show that the wollastonite ceramic can be rationally tuned in phase (α or β), mechanical strength (in compression and bending mode), elastic modulus (18–23GPa), and fracture toughness (>3.2MPam1/2) through the usage of Mg dopant introduced at precisely defined dilute concentrations (Mg/Ca molar ratio: 1.2–2.1%). Meanwhile, the dilute Mg-doped wollastonite ceramics are shown to exhibit good bioactivity in vitro in SBF but biodegradation in Tris is inversely proportional to Mg content. Consequently, such new highly bioactive ceramics with appreciable strength and toughness are promising for making specific porous scaffolds for enhancing large segmental bone defect and thin-wall bone defect repair.

Biological aspects of segmental bone defects management.

Segmental bone defect management is among the most demanding issues in orthopaedics and there is a great medical need for establishing an appropriate treatment option. Tissue transfer, including bone autografts or free flaps, depending on the size of the bone deficiency, is currently the "gold standard" for treatment of such defects. Osteogenic cells in combination with adequate growth factors and a suitable scaffold, from the aspect of osteoinductivity, osteoconductivity and mechanical stability, are mandatory to successfully restore a bone defect as determined in the "diamond concept". Our current knowledge on this topic is limited and mostly based on retrospective studies, case reports and a few small randomised clinical trials due to the lack of large and accurately designed randomised clinical trials using novel approaches to regenerative orthopaedics. However, preclinical research on different animal models for critical size defects is abundant, showing emerging candidate cells and cytokines for defect rebridgement. In this article we provide an overview on existing clinical studies and promising preclinical experiments that utilised osteogenic cells, growth factors and biomaterials, as well as their combination for repair of segmental bone defects.

Repair of segmental bone defects in the maxilla by transport disc distraction osteogenesis: Clinical experience with a new device.

The bones of the maxillary complex are vital for normal oro-nasal function and facial cosmetics. Maxillary tumor excision results in large defects that commonly include segments of the alveolar and palatine processes, compromising eating, speech and facial appearance. Unlike the conventional approach to maxillary defect repair by vascularized bone grafting, transport disc distraction osteogenesis (TDDO) stimulates new bone by separating the healing callus, and stimulates growth of surrounding soft tissues as well. Bone formed in this way closely mimics the parent bone in form and internal structure, producing a superior anatomical, functional and cosmetic result. Historically, TDDO has been successfully used to close small horizontal cleft defects in the maxilla, not exceeding 25 mm. Fujioka et al. reported in 2012 that “no bone transporter corresponding to the (large) size of the oro-antral fistula is marketed. The authors report the successful treatment of 4 cases involving alveolar defects of between 25 mm and 80 mm in length.

Repair of large segmental bone defects in rabbits using BMP and FGF composite xenogeneic bone.

The objective of this study was to determine the ability of bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) to repair large segmental radial bone defects in rabbits. We treated calf cancellous bones with 3 mg/L BMP (Group A), 5 μg/L FGF (Group B), or 3 mg/L BMP plus 5 μg/L FGF (Group C). A bone damage model was established using healthy radii from rabbits. The complexes were implanted in the areas of the bone defects in the radii. After successful transplantation, the rabbits underwent radiographic imaging, and bone graft specimens were detected by histopathology methods. Biomechanical indexes were also assessed in order to observe the healing status of the bone defects. Our results indicated that the repair of bone defects was significantly better in Group C compared to the other 2 groups. Therefore, we concluded that combining BMP and FGF significantly promoted bone defect repair and achieved effects that were superior to the use of BMP alone.

A potential translational approach for bone tissue engineering through endochondral ossification.

Bone defect repair is a significant clinical challenge in orthopedic surgery. Despite tremendous efforts, the majority of the current bone tissue engineering strategies depend on bone formation via intramembranous ossification (IO), which often results in poor vascularization and limited-area bone regeneration. Recently, there has been increasing interest in exploring bone regeneration through a cartilage-mediated process similar to endochondral ossification (EO). This method is advantageous because long bones are originally developed through EO and moreover, vascularization is an inherent step of this process. Therefore, it may be possible to effectively employ the EO method for the repair and regeneration of large and segmental bone defects. Although a number of studies have demonstrated engineered bone formation through EO, there are no approaches aiming for their clinical translation. In this study, we propose a strategy modeled after the U.S. Food and Drug Administration (FDA) approved autologus chondrocyte implantation (ACI) procedure. In its implementation, we concentrated human bone marrow aspirate via a minimally manipulated process and demonstrated the potential of human bone marrow derived cells for in vitro pre-cartilage template formation and bone regeneration in vivo.