ROLE OF TRANSFORMING GROWTH FACTOR β(TGF-β)IN REPAIRING OF BONE DEFECTS

TGF-β is a multifunctional cytokine that regulates many aspects of cellular function, including periosteal mesenchymal cell proliferation, differentiation. This experiment is to study its effects on bone defect repair. A rabbit radial bone defect model was used to evaluate the effect of TGF-β, which was extracted and purified from bovine blood platelets, on the healing of a large segmental osteoperiosteal defect. A 1. 5-centimeter segmental defect was created in the mid-upper part of the radial shaft of adult rabbits. The defect was filled with implant containing TGF-β that consisted of carrier and bovine TGF-β. Limbs served as controls received carrier alone. The defectswere examined radiographically and histologically at 4, 8,12 , 16 and 20 weeks after implantation. The results showed that in TGF-β implant group . the defect areas at 12 weeks post operation were bridged by uniform new bone and the cut ends of cortex could not be seen;while in control group, the defects remained clear. Only a small amount of new bone formed as a cap on the cut bone ends. In the experimental group, new lamellar and woven bone formed in continuity with the cut ends of the cortex. An early medullar canal appears to be forming and contained normal-appearancing marrow elements; while the control group displayed entirely fibrous tissue within the defect site. Remnants of the cancellous bone carrier were observed in the control specimen. These data demonstrate that exogenous TGF-β initiate osteogenesis and stimulate the bone defects repair in animal model.

Gene expression analysis of cytokines and MMPs in melatonin and rhBMP-2 enhanced bone remodeling

BACKGROUND In the medical and dental fields,there is a need for studies of new therapeutic approaches for the treatment of bone defects that cause extensive bone loss.Melatonin may be an important endogenous biological factor for bone remodeling,and growth factors may enhance the repair process.AIM To evaluate the gene expression of cytokines(IL-1β,IL-6,IL-10 and TNF-α),markers of osteoclastogenesis(RANK,RANKL and OPG)and MMPs(MMP-1,MMP-2,MMP-8 and MMP-13)from the treatment of melatonin associated with an osteogenic membrane and rhBMP-2 on the recovery of a bone injury.METHODS Sixty-four rats were used and divided into 9 experimental groups and were formed according to the treatment carried out in the region of the bone lesion,which varied between the combination of 1,10 and 100μmol/L of melatonin.Gene Expression analysis was performed using real time-PCR by reading the concentration of total RNA and reverse transcription.RESULTS There were differences between groups when compared with clot or scaffold control,and improvement with a higher concentration of melatonin or rhBMP-2.The combination melatonin(1μg)with 5μg of rhBMP-2,using the guided bone regeneration technique,demonstrated some effects,albeit mild,on bone repair of critical bone defects.CONCLUSION This indicates that the approach for administering these substances needs to be reassessed,with the goal of ensuring their direct application to the affected area.Therefore,future research must be carried out,seeking to produce materials with these ideal characteristics.

Skeletal Blood Flow in Bone Repair and Maintenance

Bone is a highly vascularized tissue, although this aspect of bone is often overlooked. In this article, the importance of blood flow in bone repair and regeneration will be reviewed. First, the skeletal vascular anato- my, with an emphasis on long bones, the distinct mechanisms for vascularizing bone tissue, and methods for remodeling existing vasculature are discussed. Next, techniques for quantifying bone blood flow are briefly summarized. Finally, the body of experimental work that demonstrates the role of bone blood flow in fracture healing, distraction osteogenesis, osteoporosis, disuse osteopenia, and bone grafting is examined. These results illustrate that adequate bone blood flow is an important clinical consideration, particularly during bone regeneration and in at-risk patient groups.

Biomass Microcapsules with Stem Cell Encapsulation for Bone Repair

Bone defects caused by trauma,tumor,or osteoarthritis remain challenging due to the lack of effective treatments in clinic.Stem cell transplantation has emerged as an alternative approach for bone repair and attracted widespread attention owing to its excellent biological activities and therapy effect.The attempts to develop this therapeutic approach focus on the generation of effective cell delivery vehicles,since the shortcomings of direct injection of stem cells into target tissues.Here,we developed a novel core-shell microcapsule with a stem cell-laden core and a biomass shell by using all-aqueous phase microfluidic electrospray technology.The designed core-shell microcapsules showed a high cell viability during the culture procedure.In addition,the animal experiments exhibited that stem cell-laden core-shell microcapsules have good biocompatibility and therapeutic effect for bone defects.This study indicated that the core-shell biomass microcapsules generated by microfluidic electrospray have promising potential in tissue engineering and regenerative medicine.

Recent advances in nano scaffolds for bone repair

Biomedical applications of nanomaterials are exponentially increasing every year due to analogy to various cell receptors, ligands, structural proteins, and genetic materials(that is, DNA). In bone tissue, nanoscale materials can provide scaffold for excellent tissue repair via mechanical stimulation, releasing of various loaded drugs and mediators, 3D scaffold for cell growth and differentiation of bone marrow stem cells to osteocytes. This review will therefore highlight recent advancements on tissue and nanoscale materials interaction.

Antler stem cells and their potential in wound healing and bone regeneration

Compared to other vertebrates,the regenerative capacity of appendages in mammals is very limited.Deer antlers are an exception and can fully regenerate annually in postnatal mammals.This process is initiated by the antler stem cells(AnSCs).AnSCs can be divided into three types:(1)Antlerogenic periosteum cells(for initial pedicle and first antler formation);(2)Pedicle periosteum cells(for annual antler regeneration);and(3)Reserve mesenchyme cells(RMCs)(for rapid antler growth).Previous studies have demonstrated that AnSCs express both classic mesenchymal stem cells(MSCs)and embryonic stem cells(ESCs),and are able to differentiate into multiple cell types in vitro.Thus,AnSCs were defined as MSCs,but with partial ESC attributes.Near-perfect generative wound healing can naturally occur in deer,and wound healing can be achieved by the direct injection of AnSCs or topical application of conditioned medium of AnSCs in rats.In addition,in rabbits,the use of both implants with AnSCs and cell-free preparations derived from AnSCs can stimulate osteogenesis and repair defects of bone.A more comprehensive understanding of AnSCs will lay the foundation for developing an effective clinical therapy for wound healing and bone repair.

BMP-IHH-mediated interplay between mesenchymal stem cells and osteoclasts supports calvarial bone homeostasis and repair

Calvarial bones are connected by fibrous sutures. These sutures provide a niche environment that includes mesenchymal stem cells(MSCs), osteoblasts, and osteoclasts, which help maintain calvarial bone homeostasis and repair. Abnormal function of osteogenic cells or diminished MSCs within the cranial suture can lead to skull defects, such as craniosynostosis. Despite the important function of each of these cell types within the cranial suture, we have limited knowledge about the role that crosstalk between them may play in regulating calvarial bone homeostasis and injury repair. Here we show that suture MSCs give rise to osteoprogenitors that show active bone morphogenetic protein(BMP) signalling and depend on BMP-mediated Indian hedgehog(IHH) signalling to balance osteogenesis and osteoclastogenesis activity. IHH signalling and receptor activator of nuclear factor kappa-Β ligand(RANKL) may function synergistically to promote the differentiation and resorption activity of osteoclasts. Loss of Bmpr1a in MSCs leads to downregulation of hedgehog(Hh) signalling and diminished cranial sutures. Significantly, activation of Hh signalling partially restores suture morphology in Bmpr1a mutant mice, suggesting the functional importance of BMP-mediated Hh signalling in regulating suture tissue homeostasis. Furthermore, there is an increased number of CD200+ cells in Bmpr1a mutant mice, which may also contribute to the inhibited osteoclast activity in the sutures of mutant mice. Finally, suture MSCs require BMPmediated Hh signalling during the repair of calvarial bone defects after injury. Collectively, our studies reveal the molecular and cellular mechanisms governing cell–cell interactions within the cranial suture that regulate calvarial bone homeostasis and repair.

Phosphate Glass Fibre Composites for Bone Repair

We investigate high-modulus degradable materials intended to replace metals in biomedical applications.These are typically composites comprising a polylactide(PLA)matrix reinforced with phosphate glass fibres,which provide reinforcement similar to E-glass but are entirely degradable in water to produce,principally,calcium phosphate.We have made composites using a variety of fibre architectures,from non-woven random mats to unidirectional fibre tapes.Flexural properties in the region of 30 GPa modulus and 350 MPa strength have been achieved-directly comparable to quoted values for human cortical bone.In collaboration with other groups we have begun to consider the development of foamed systems with structures mimicking cancellous bone and this has shown significant promise.The fibres in these foamed structures provide improved creep resistance and reinforcement of the pore walls.To date the materials have exhibited excellent cellular responses in vitro and further studies are due to include consideration of the surface character of the materials and the influence of this on cell interaction, both with the composites and the glass fibres themselves,which show promise as a standalone porous scaffold.

Doxycycline induces bone repair and changes in Wnt signalling

Doxycycline （DOX） exhibits anti-inflammatory and MMP inhibitory properties. The objectives of this study were to evaluate the effects of DOX on alveolar bone repair. Controls （CTL） and DOX-treated （10 and 25 mg. kg- 1） molars were extracted, and rats were killed 7 or 14 days later. The maxillae were processed and subjected to histological and immunohistochemical assays. Hematoxylin-eosin staining （7th day） revealed inflammation in the CTL group that was partly reversed after DOX treatment. On the 14th day, the CTL group exhibited bone neoformation, conjunctive tissue, re-epithelization and the absence of inflammatory infiltrate. DOX-treated groups exhibited complete re-epithelization, tissue remodelling and almost no inflammation. Picrosirius red staining in the DOXlO group （7th and 14th days） revealed an increased percentage of type I and III collagen fibres compared with the CTL and DOX25 groups. The DOXlO and DOX25 groups exhibited increases in osteoblasts on the 7th and 14th days. However, there were fewer osteoclasts in the DOXlO and DOX25 groups on the 7th and 14th days. Wnt-lOb- immunopositive cells increased by 130% and 150% on the 7th and 14th days, respectively, in DOX-treated groups compared with the CTL group. On the 7th day, Dickkopf （Dkk）-I immunostaining was decreased by 63% and 46% in the DOXlO and DOX25 groups, respectively. On the 14th day, 69% and 42% decreases in immunopositive cells were observed in the DOXlO and DOX25 groups, respectively, compared with the CTL group. By increasing osteoblasts, decreasing osteoclasts, activating Wnt lOb and neutralising Dkk, DOX is a potential candidate for bone repair in periodontal diseases.

Biodegradable materials for bone defect repair

Compared with non-degradable materials,biodegradable biomaterials play an increasingly important role in the repairing of severe bone defects,and have attracted extensive attention from researchers.In the treatment of bone defects,scaffolds made of biodegradable materials can provide a crawling bridge for new bone tissue in the gap and a platform for cells and growth factors to play a physiological role,which will eventually be degraded and absorbed in the body and be replaced by the new bone tissue.Traditional biodegradable materials include polymers,ceramics and metals,which have been used in bone defect repairing for many years.Although these materials have more or fewer shortcomings,they are still the cornerstone of our development of a new generation of degradable materials.With the rapid development of modern science and technology,in the 21 st century,more and more kinds of new biodegradable materials emerge in endlessly,such as new intelligent micro-nano materials and cell-based products.At the same time,there are many new fabrication technologies of improving biodegradable materials,such as modular fabrication,3 D and 4 D printing,interface reinforcement and nanotechnology.This review will introduce various kinds of biodegradable materials commonly used in bone defect repairing,especially the newly emerging materials and their fabrication technology in recent years,and look forward to the future research direction,hoping to provide researchers in the field with some inspiration and reference.

The Clinical Application of Human Bone Matrix Gelatin

This paper reports the results of 24 cases of bone defect resulting from bone tumor or tumor condition excision, and of posterior spinal fusion, treated by human bone matrix gelatin. The success rate of bone defect repair and spinal fusion is 91. 67 %. The results suggest that human bone matrix gelatin has. excellent osteoinductive effect and is ideal substitute for bone autografts.

Development of Nano-biomaterials for Bone Repair

A new kind of nano-biomaterials of nano apatite （ NA ） and polyamide8063 （ PA ） composite was prepared by direct using NA slurry. The experimental results showed that the NA content in the composite was similar to that of natural bone. Interfrace chemical bonding was formed between NA and PA. The NA keeps the original morphological structure with a crystal size of 10- 30 nm in width by 50- 90 nm in length with a ratio of - 2.5 and distributed uniformly in thepolymer. The synthetic nano-biomaterials could be one of the best bioactive materials for load-bearing bone repair or substitution materials.

Preparation and characterization of hemihydrate calcium sulfate-calcium hydroxide composite bone repair materials

Objective:To prepare a bone repair material with certain mechanical strength and biological activity,this paper used calcium sulfate hemihydrate(CSH)powder compounded with calcium hydroxide(Ca(OH)2)powder to prepare a bone repair scaffold material for physicochemical property characterization and testing.Methods:The physical and chemical properties and characterization of the dried and cured bone repair materials were determined by Fourier infrared spectroscopy(FT-IR),X-ray diffraction(XRD),and scanning electron microscopy;Universal material testing machine to determine the mechanical and mechanical strength of composite materials.Results:XRD showed that the structure of the composite material phase at 5%concentration was calcium sulfate hemihydrate and calcium hydroxide after hydration.The FT-IR and XRD analyses were consistent.Scanning electron microscopy(SEM)results showed that calcium hydroxide was uniformly dispersed in the hemihydrate calcium sulfate material.0%,1%,5%,and 10%specimen groups had compressive strengths of 3.86±3.1,5.27±1.28,8.22±0.96,and 14.4±3.28 MPa.10%addition of calcium hydroxide significantly improved the mechanical strength of the composites,but also reduced the the porosity of the material.Conclusion:With the addition of calcium hydroxide,the CSH-Ca(OH)2 composite was improved in terms of mechanical material and is expected to be a new type of bone repair material.

Construction of Customized Bio Incubator and Designing of Tailored Scaffolds for Bone Tissue Engineering from Laboratory Scale Up to Clinical Scale

In order to obtain larger,clinical-scale and practical-scale bone grafts,we have designed both tailored scaffolds and tailored bio incubator with optimal bio-production characteristics.Using DIC files to Simpleware Scan-IP(Simple-ware-exeter United Kingdom),we have digitally reconstructed segmental additive bone-tissue in order to perform images processing.Both hydroxyapatite and tannin composites have been used in order to get the final bone modules combined for retexturing of segmental bone defect.We have found that sectioning of bone segment deficiency reorganizations into well disk-shaped design permits one to standardize the cell culture and seeding protocol,to get better products.The present study concludes that some techniques with cultured cell in segmental bone grafts in the laboratory can be transferred and clinically used.

The influence of yttrium and manganese additions on the degradation and biocompatibility of magnesium-zinc-based alloys:In vitro and in vivo studies

The repair and regeneration of bone defects are highly challenging orthopedic problems.Recently,Mg-based implants have gained popularity due to their unique biodegradation and elastic modulus similar to that of human bone.The aim of our study is to develop a magnesium alloy with a controllable degradation that can closely match bone tissue to help injuries heal in vivo and avoid cytotoxicity caused by a sudden increase in ion concentration.In this study,we prepared and modified Mg-3Zn,Mg-3Zn-1Y,and Mg-2Zn-1Mn by hot extrusion,and used Mg-2.5Y-2.5Nd was as a control.We then investigated the effect of additions of Y and Mn on alloys'properties.Our results show that Mn and Y can improve not only compression strength but also corrosion resistance.The alloy Mg-2Zn-1Mn demonstrated good cytocompatibility in vitro,and for this reason we selected it for implantation in vivo.The degraded Mg-2Zn-1Mn implanted a bone defect area did not cause obvious rejection and inflammatory reaction,and the degradation products left no signs of damage to the heart,liver,kidney,or brain.Furthermore,we find that Mg-2Zn-1Mn can promote an osteoinductive response in vivo and the formation of bone regeneration.

Self-reinforced Calcium Phosphate Cement Inspired by Sea Cucumber Dermis

A composite bone cement based onα-TCP with self-reinforcing characteristics is prepared by compounding cellulose whiskers and polyvinyl alcohol in different proportions.In this system,we are inspired by the sea cucumber,which can alter the stiffness of their inner dermis reversibly.Through the formation of hydrogen bonds between the hydroxyl groups on the cellulose whiskers and PVA,the bone cement matrix can be strengthened during the curing process of cement.In the process of bone cement blending,there is more water,the hydrogen bond connection is destroyed,so the slurry has better fluidity at this time.As the hydration of the bone cement progresses,the reduction of the water phase leads to the formation of a permeable network structure of hydrogen bond connections between the whiskers.The dual-phase action of PVA and whiskers greatly increases the mechanical strength of the bone cement system(5.5 to 23.8 MPa),while the presence of polyvinyl alcohol improves the toughness of the bone cement system.This work was supposed to explore whether the chemoresponsive materials can be adapted to biomedical materials,for example,bone repair.

Nanobioceramics for Tissue Engineering Application

Nanobiomaterials demonstrate great potential in bone and dental tissue regeneration.These materials mimic the natural extracellular matrix in the human body,promoting the controlled release of growth factors and other bioactive molecules to enhance tissue regeneration and integration.Nanobioceramics mimic the structure and composition of natural bone.A major challenge in hard tissue healing is creating scaffolds that incorporate stem cells for bone tissue engineering.Scaffolds and implants for regenerative medicine should be designed using computer-aided design(CAD)and three-dimensional(3D)printing to replicate the tissue's anatomical structure.Future studies should examine the relationship between the size of bioceramics and biological reactions.The more interacting nature of nanoceramics better triggers the cellular processes,facilitating the regeneration of calcified tissue.Osteoblasts and osteoclasts are crucial in the development and maintenance of calcified tissue in vivo,and nanoceramics enhance the functionality of orthopedic and dental implants.

Evaluation on the corrosion resistance, antibacterial property and osteogenic activity of biodegradable Mg-Ca and Mg-Ca-Zn-Ag alloys

The rapid degradation of magnesium(Mg)-based implants in physiological environment limits its clinical applications, and alloying treatment is an effective way to regulate the degradation rate of Mg-based materials. In the present study, three Mg alloys, including Mg-0.8Ca(denoted as ZQ), Mg-0.8Ca-5Zn-1.5Ag(denoted as ZQ71) and Mg-0.8Ca-5Zn-2.5Ag(denoted as ZQ63), were fabricated by alloying with calcium(Ca), zinc(Zn) and silver(Ag). The results obtained from electrochemical corrosion tests and in vitro degradation evaluation demonstrated that the three Mg alloys exhibited distinct corrosion resistance, and ZQ71 exhibited the lowest degradation rate in vitro among them. After addition of Zn and Ag, the antibacterial potential of Mg alloys was also enhanced. The in vitro cell experiments showed that all the three Mg alloys had good biocompatibility. After implantation in a rat femoral defect, ZQ71 showed significantly higher osteogenic activity and bone substitution rate than ZQ63 and ZQ, due to its higher corrosion resistance as well as the stimulatory effects of the released metallic ions. In addition, the average daily degradation rate of each Mg alloy in vivo was significantly higher than that in vitro, as could be due to the implantation site located in the highly vascularized trabecular region. Importantly, the correlations between the in vitro and in vivo degradation parameters of the Mg alloys were systematically analyzed to find out the potential predictors of the in vivo degradation performance of the materials. The current work not only evaluated the clinical potential of the three biodegradable Mg alloys as bone grafts but also provided a feasible approach for predicting the in vivo degradation behavior of biodegradable materials.

Repair of Rat Segmental Defects with Mineralized Collagen Grafts Combined with or without Mesenchymal Stem Cells and BMP-2

The aim of the present study was to investigate and compare the bone formation capacity with three different grafts. Four millimeter segmental defects were created in adult rat tibias and were either left empty （control defects） or implanted with （1） nano-hydroxyapatite/collagen/PIA （nHAC/PIA） composite, （2） nHAC/ PIA composite added with bone marrow mesenchymal tem cells （ BMSCs ）, （ 3 ） nHAC/ PIA composite added with bone morphogenetic protein 2 （ BMP- 2）. Radiographs of the defects were taken weekly post-surgery. After 1 or 2 months, the rats were eathaaized. Histologic analyses were performed on the harvested tissue. nHAC/ PIA composite could enhance the repair of rat tibia segmental defects. Addition of BMSCs or BMP- 2 to nHAC/ PIA led to an increase in osteogenesis, nHAC/ PIA composite could be an Meal alternative bone-grafi material and it could also be used as an Meal carrier of BMSCs or BMP- 2.