Hippo-YAP/TAZ signaling in osteogenesis and macrophage polarization:Therapeutic implications in bone defect repair

Bone defects caused by diseases or surgery are a common clinical problem.Researchers are devoted to finding biological mechanisms that accelerate bone defect repair,which is a complex and continuous process controlled by many factors.As members of transcriptional costimulatory molecules,Yes-associated protein(YAP)and transcriptional co-activator with PDZ-binding motif(TAZ)play an important regulatory role in osteogenesis,and they affect cell function by regulating the expression of osteogenic genes in osteogenesis-related cells.Macrophages are an important group of cells whose function is regulated by YAP/TAZ.Currently,the relationship between YAP/TAZ and macrophage polarization has attracted increasing attention.In bone tissue,YAP/TAZ can realize diverse osteogenic regulation by mediating macrophage polarization.Macrophages polarize into M1 and M2 phenotypes under different stimuli.M1 macrophages dominate the inflammatory response by releasing a number of inflammatory mediators in the early phase of bone defect repair,while massive aggregation of M2 macrophages is beneficial for inflammation resolution and tissue repair,as they secrete many anti-inflammatory and osteogenesis-related cytokines.The mechanism of YAP/TAZ-mediated macrophage polarization during osteogenesis warrants further study and it is likely to be a promising strategy for bone defect repair.In this article,we review the effect of Hippo-YAP/TAZ signaling and macrophage polarization on bone defect repair,and highlight the regulation of macrophage polarization by YAP/TAZ.

Continuously released Zn^(2+)in 3D-printed PLGA/β-TCP/Zn scaffolds for bone defect repair by improving osteoinductive and anti-inflammatory properties

Long-term nonunion of bone defects has always been a major problem in orthopedic treatment.Artificial bone graft materials such as Poly(lactic-co-glycolic acid)/β-tricalcium phosphate(PLGA/β-TCP)scaffolds are expected to solve this problem due to their suitable degradation rate and good osteoconductivity.However,insufficient mechanical properties,lack of osteoinductivity and infections after implanted limit its large-scale clinical application.Hence,we proposed a novel bone repair bioscaffold by adding zinc submicron particles to PLGA/β-TCP using low temperature rapid prototyping 3D printing technology.We first screened the scaffolds with 1 wt%Zn that had good biocompatibility and could stably release a safe dose of zinc ions within 16 weeks to ensure long-term non-toxicity.As designed,the scaffold had a multi-level porous structure of biomimetic cancellous bone,and the Young’s modulus(63.41±1.89 MPa)and compressive strength(2.887±0.025 MPa)of the scaffold were close to those of cancellous bone.In addition,after a series of in vitro and in vivo experiments,the scaffolds proved to have no adverse effects on the viability of BMSCs and promoted their adhesion and osteogenic differentiation,as well as exhibiting higher osteogenic and anti-inflammatory properties than PLGA/β-TCP scaffold without zinc particles.We also found that this osteogenic and anti-inflammatory effect might be related to Wnt/β-catenin,P38 MAPK and NFkB pathways.This study lay a foundation for the follow-up study of bone regeneration mechanism of Zn-containing biomaterials.We envision that this scaffold may become a new strategy for clinical treatment of bone defects.

Biodegradable metals for bone defect repair:A systematic review and meta-analysis based on animal studies

Biodegradable metals are promising candidates for bone defect repair.With an evidence-based approach,this study investigated and analyzed the performance and degradation properties of biodegradable metals in animal models for bone defect repair to explore their potential clinical translation.Animal studies on bone defect repair with biodegradable metals in comparison with other traditional biomaterials were reviewed.Data was carefully collected after identification of population,intervention,comparison,outcome,and study design(PICOS),and following the inclusion criteria of biodegradable metals in animal studies.30 publications on pure Mg,Mg alloys,pure Zn and Zn alloys were finally included after extraction from a collected database of 2543 publications.A qualitative systematic review and a quantitative meta-analysis were performed.Given the heterogeneity in animal model,anatomical site and critical size defect(CSD),biodegradable metals exhibited mixed effects on bone defect repair and degradation in animal studies in comparison with traditional non-degradable metals,biodegradable polymers,bioceramics,and autogenous bone grafts.The results indicated that there were limitations in the experimental design of the included studies,and quality of the evidence presented by the studies was very low.To enhance clinical translation of biodegradable metals,evidence-based research with data validity is needed.Future studies should adopt standardized experimental protocols in investigating the effects of biodegradable metals on bone defect repair with animal models.

Large-sized bone defect repair by combining a decalcified bone matrix framework and bone regeneration units based on photo-crosslinkable osteogenic microgels

Physiological repair of large-sized bone defects is great challenging in clinic due to a lack of ideal grafts suitable for bone regeneration.Decalcified bone matrix(DBM)is considered as an ideal bone regeneration scaffold,but low cell seeding efficiency and a poor osteoinductive microenvironment greatly restrict its application in large-sized bone regeneration.To address these problems,we proposed a novel strategy of bone regeneration units(BRUs)based on microgels produced by photo-crosslinkable and microfluidic techniques,containing both the osteogenic ingredient DBM and vascular endothelial growth factor(VEGF)for accurate biomimic of an osteoinductive microenvironment.The physicochemical properties of microgels could be precisely controlled and the microgels effectively promoted adhesion,proliferation,and osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)in vitro.BRUs were successfully constructed by seeding BMSCs onto microgels,which achieved reliable bone regeneration in vivo.Finally,by integrating the advantages of BRUs in bone regeneration and the advantages of DBM scaffolds in 3D morphology and mechanical strength,a BRU-loaded DBM framework successfully regenerated bone tissue with the desired 3D morphology and effectively repaired a large-sized bone defect of rabbit tibia.The current study developed an ideal bone biomimetic microcarrier and provided a novel strategy for bone regeneration and large-sized bone defect repair.

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

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Bone Regeneration Enhanced by Antigen-Extracted Xenogeneic Cancellous Bone Graft with rhBMP-2 in Rabbits Mandibular Defect Repair

The effects of large piece xenogeneic bone which was separated from healthy pigs as a scaffold on repair of mandibular defect was investigated and the applicability of antigen-extracted xenogeneic cancellous bone (AXCB) soaked with rhBMP-2 in bone defect repair was assessed. Mandibular defects were created in 48 New Zealand Rabbits, and then randomly divided into 4 groups, which was grafted in the mandibular defects with AXCB, AXCB soaked with rhBMP-2, autograft bone, or blank. Equal number of animals from each group was classified into three time points (4, 8, and 12 weeks) after operation for gross pathological observation, hematoxylin and eosin (H & E) staining, radiographic examination, and bone density measurement. H & E staining revealed that the area percentage of bone regeneration in the group of AXCB/rhBMP-2 graft was 27.72 ± 4.68, 53.90 ± 21.92, and 77.35 ± 9.83 when at 4, 8, and 12 weeks, which was better than that of auto bone graft, prompting that the group of AXCB/rhBMP-2 graft had commendable osteogenic effect. And comparing with the AXCB without rhBMP-2, of which the area percentage of bone regeneration was only 14.03 ± 5.02, 28.49 ± 11.35, and 53.90 ± 21.92, the osteogenic effect of AXCB/rhBMP-2 graft was demonstrated to be much better. In the group of AXCB/rhBMP-2 graft, the area percentage of bone regeneration increased, and the implanted materials were gradually degraded and replaced by autogenous bone regeneration over time. We concluded that antigen-extracted xenogeneic cancellous bone (AXCB) graft soaked with rhBMP-2 had shown excellent osteogenic effect in repair of bone defects, with good biocompability.

One-Stage Repair and Reconstruction of Craniomaxillofacial Bone Defects

Objective: Severe craniomaxillofacial injuries and craniomaxillofacial tumors can lead to craniomaxillofacial bone defects and deformities. Seriously affect the patients’ appearance and quality of life. So one-stage repair and reconstruction of craniomaxillofacial bone defects is of great significance. The current study summarizes the clinical experience of one-stage repair and reconstruction of craniomaxillofacial bone defects. Material and Methods: Data in one-stage repair and reconstruction of?craniomaxillofacial bone defects performed on 13 patients were retrospectively analyzed out of 34 patients with?craniomaxillofacial injuries or tumors who received treatment at the outpatient department between January 2002 and March 2011. Surgical indications and approaches were explored after two typical cases were detected. Results: One-stage repair and reconstruction of bone defects was suitable for patients with craniomaxillofacial injuries and excised craniomaxillofacial benign tumors. Adjacent autogenous bones and artificial materials (such as titanium plates, titanium mesh, and so on) work well for the repair of the craniomaxillofacial bone frame and restoration of facial features. Conclusions: Surgical indications should be strictly selected in one-stage repair and reconstruction of craniomaxillofacial bone defects and deformities. Furthermore, the adoption of autogenous bones and artificial materials is a good choice in restoring the craniofacial features.

Role of transforming growth factor P and bone morphogenetic protein composite on repair of bone defects

Objective: To study the effect of transforming growth factor β/bone morphogenetic protein (TGFβ/BMP) composite on healing of large segmental bone defects and the interaction between TGF-β and BMP.Methods: A 1. 5-centimeter segmental defect was created in the mid-upper part of the radial shaft of adultrabbit. The defects were filled with implant of TGF-β/carrier, BMP/carrier and TGF-a/BMP/carrier, respectively. Purified bovine TGF-β 120 μg and BMP 12 mg were used in the composite. The defects were examined radiographically and histologically at 4, 8. 12 and 16 weeks post-operation (PO). Results: In groupof TGF-β/carrier, the defect areas were bridged at 4 weeks PO, with material of uniform radiodensity. Conices of the cut ends were obscured by the new bone. By 16 weeks PO, the defects were bridged by uniformnew bone and the cut ends of cortex could not be seen in all groups. In group of BMP/carrier, the defectswere filled with more irregular woven callus in comparison with the other two groups. The TGF-β/BMP--implanted defect sites in animals killed at 16 weeks PO showed histologically new larnellar and woven bone,formed in continuity with the cut ends of the cortex. The medullar cavity was recanalized and contained marrow elements with normal appearance. ConClUsion: These data demonstrate the synergistic action betweenTGF-β and BMP in the process of bone healing, and the better effect of TGF-β/BMP composite than that ofsingle TGF-β or BMP on bone repair.

Effect of low intensity pulsed ultrasound on repairing the periodontal bone of Beagle canines

Objective:To investigate the repairing effect of low intensity pulsed ultrasound(LIPUS)on the Beagle canines periodontal bone defect.Methods:A total of 12 Beagle dogs with periodontal bone defect model were randomly divided into control group,LIPUS group,guided tissue regeneration(GTR)group and LIPUS+GTR group,with three in each.After completion of the models,no other proceeding was performed in control group;LIPUS group adopt direct exposure to radiation line LIPUS processing 1 week after modeling;GTR group adopted treatment with GTR,following the CTR standard operation reference;LIPUS+GTR group was treated with LIPUS joint GTR.Temperature change before treatment and histopathological change of periodontal tissue after repair was observed.Results:There was no significant difference in temperature changes of periodontal tissue between groups(P>0.05).The amount and maturity of LIPUS+GTR group were superior to other groups;new cementum,dental periodontal bones of GTR group were superior to the control group but less than LIPUS group;new collagen and maturity of the control group is not high relatively.Conclusions:LIPUS can accelerate the calcium salt deposition and new bone maturation,thus it can serve as promoting periodontal tissue repair,and shortening the periodontal tissue repair time.

Structural bone allografts with intramedullary vascularized fibular autografts for the treatment of massive bone defects in extremities

Objective:To report the clinical outcome of repairing massive bone defects biologically in limbs by homeochronous using structural bone allografts with intramedullary vascularized fibular autografts. Methods: From January 2001 to December 2005, large bone defects in 19 patients (11 men and 8 women, aged 6 to 35 years) were repaired by structural bone allografts with intramedullary vascularized fibular autografts in the homeochronous period. The range of the length of bone defects was 11 to 25 cm (mean 17.6 cm), length of vascularized free fibular was 15 to 29 cm (mean 19.2 cm), length of massive bone allografts was 11 to 24 cm (mean 17.1 cm). Location of massive bone defects was in humerus(n=1), in femur(n=9) and in tibia(n=9), respectively. Results: After 9 to 69 months (mean 38.2 months) follow-up, wounds of donor and recipient sites were healed inⅠstage, monitoring-flaps were alive, eject reaction of massive bone allografts were slight, no complications in donor limbs. Fifteen patients had the evidence of radiographic union 3 to 6 months after surgery, 3 cases united 8 months later, and the remained one case of malignant synovioma in distal femur recurred and amputated the leg 2.5 months, postoperatively. Five patients had been removed internal fixation, complete bone unions were found one year postoperatively. None of massive bone allografts were absorbed or collapsed at last follow-up. Conclusion: The homeochronous usage of structural bone allograft with an intramedullary vascularized fibular autograft can biologically obtain a structure with the immediate mechanical strength of the allograft, a potential result of revascularization through the vascularized fibula, and accelerate bone union not only between fibular autograft and the host but also between massive bone allograft and the host.

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.

Remote control of the recruitment and capture of endogenous stem cells by ultrasound for in situ repair of bone defects

Stem cell-based tissue engineering has provided a promising platform for repairing of bone defects.However,the use of exogenous bone marrow mesenchymal stem cells(BMSCs)still faces many challenges such as limited sources and potential risks.It is important to develop new approach to effectively recruit endogenous BMSCs and capture them for in situ bone regeneration.Here,we designed an acoustically responsive scaffold(ARS)and embedded it into SDF-1/BMP-2 loaded hydrogel to obtain biomimetic hydrogel scaffold complexes(BSC).The SDF-1/BMP-2 cytokines can be released on demand from the BSC implanted into the defected bone via pulsed ultrasound(p-US)irradiation at optimized acoustic parameters,recruiting the endogenous BMSCs to the bone defected or BSC site.Accompanied by the daily p-US irradiation for 14 days,the alginate hydrogel was degraded,resulting in the exposure of ARS to these recruited host stem cells.Then another set of sinusoidal continuous wave ultrasound(s-US)irradiation was applied to excite the ARS intrinsic resonance,forming highly localized acoustic field around its surface and generating enhanced acoustic trapping force,by which these recruited endogenous stem cells would be captured on the scaffold,greatly promoting them to adhesively grow for in situ bone tissue regeneration.Our study provides a novel and effective strategy for in situ bone defect repairing through acoustically manipulating endogenous BMSCs.

骨组织工程中研究水凝胶微球的特征

背景:水凝胶微球由于其多孔性和可注射性等在递送细胞和生物活性因子/药物、构建组织修复支架等生物医学领域展现独特优势,具有广阔的应用前景。目的:综述基于水凝胶微球的骨组织工程最新研究进展,讨论基于水凝胶微球的骨组织工程研究面临的关键问题和挑战。方法:应用计算机检索PubMed和中国知网数据库收录的相关文献。英文检索词为“hydrogels,microparticles,microspheres,microcarriers,bone,bone defect,bone repair,bone healing,bone tissue engineering”,中文检索词为“水凝胶,微球,微粒,骨组织工程,骨缺损,骨修复,骨再生”。检索文献时限为2002-2022年,最终纳入127篇文献进行综述。结果与结论:①目前,不同的水凝胶微球材料已被开发用于骨组织工程策略并取得了较好的效果,如搭载细胞或生物活性因子/药物的水凝胶微球、作为生物支架的水凝胶微球、刺激响应性水凝胶微球、生物矿化水凝胶微球、与其他生物材料结合的水凝胶微球等。②基于水凝胶微球的骨组织工程修复策略主要通过促进干细胞的招募与成骨分化、调节损伤局部炎症微环境以及促进损伤部位血管生成等机制来调控骨修复。但目前的研究没有深入探索基于水凝胶微球的骨组织工程诱导内源性干细胞招募与分化,以及水凝胶微球的理化性质对炎症微环境的调控,且水凝胶微球的体内长期不良反应尚未探明,批量生产存在困难,因此,未来的研究需要在机制探索和技术路线上加强深入,从而为开发能够用于临床转化的水凝胶微球材料提供合理参考。

金属离子在骨组织工程中的应用

背景:金属离子在人体中发挥着重要的作用,随着材料合成和加工技术的进步,目前多种可应用于骨组织工程中的金属离子已被开发,如镁(Mg2+)、锌(Zn2+)、锰(Mn2+)、锶(Sr2+)、铜(Cu2+)等。目的:总结各金属离子在骨组织工程中的研究进展和发展方向。方法:检索2014-2022年期间中国知网数据库、PubMed数据库、万方数据库收录的文献,中文检索词为“金属离子,骨组织工程,成骨活性,镁离子,锌离子,锰离子,锶离子,铜离子,钙离子,锂离子,钴离子”,英文检索词为“metal ions,bone tissue engineering,osteogenic activity,magnesium ions,zinc ions,manganese ions,strontium ions,copper ions,calcium ions,lithium ions,cobalt ions”。结果与结论:不同金属离子随材料植入体内后会发生不同程度的释放,可改变组织微环境,从而改善材料成血管、成骨的能力。与生长因子相比,金属离子更易控制释放速率,且成本更低,还能够改善植入材料力学性能。金属离子在骨组织工程中的应用充满前景,虽然部分金属离子已经可以用于治疗骨缺损,但许多金属离子在人体内的作用机制尚未完全明确、应用效果缺少临床试验验证,投入临床应用前还需进一步探索。

高模量高强度丝素蛋白GBR膜的制备及性能评估

目的拟制备一种高模量和高强度的可降解丝素蛋白引导骨再生(GBR)膜,以解决骨缺损修复成骨空间维持问题。方法提纯丝素蛋白后利用蒸发-热压法制备膜材,使用拉伸测试、体外模拟、细胞共培养等方法评估其理化性质与生物性能。结果制得丝素蛋白GBR膜,体外模拟12 h降解率为35.3%,湿态弹性模量达45 MPa,拉伸强度达8.39 MPa,7 d细胞生存率近100%。结论所制得可降解GBR膜具有高模量和高强度,以及优异的生物相容性,有望为解决骨缺损修复成骨空间维持问题提供材料基础。

生物电效应材料在骨组织工程支架设计中的应用

背景:骨具有生物电效应,然而骨缺损的发生会导致骨骼内源性生物电的缺失。具有生物电效应的骨组织工程支架植入骨缺损处会补足缺失的电信号,加速骨缺损的修复。目的:文章介绍了骨组织的生物电效应,阐述了电刺激对骨缺损的修复作用,总结了生物电效应应用于骨组织工程的研究进展,以期为骨组织工程的研究提供新的思路。方法:以“bioelectrical effect,bioelectrical materials,electrical stimulation,bone tissue engineering,bone scaffold,bone defect,bone repair,osteogenesis”为英文检索词,以“生物电效应,生物电支架,电刺激,骨组织工程,骨支架,骨缺损,骨修复,骨再生”为中文检索词,在中国知网、万方、PubMed、Web of Science和ScienceDirect数据库检索与生物电效应骨组织工程支架相关的文献,最终纳入87篇进行系统归纳、总结和分析。结果与结论:①生物电效应结合体外电刺激设计骨组织工程支架是一种理想可行的方法,主要涉及的材料包括金属材料、石墨烯材料、天然生物衍生材料以及人工合成生物材料;目前运用最广泛的导电材料是石墨烯材料,得益于自身的超强导电性能、大比表面积、同细胞及骨骼的良好生物相容性以及优异的力学性能。②石墨烯材料主要是作为修饰材料引入支架以增强整体支架的电导率,同时其大表面积和丰富的官能团能够促进生物活性物质的装载和释放。③然而生物电效应的骨组织工程支架尚存一些重大挑战需要克服:满足导电性能的同时还需考虑支架的综合性能;缺乏统一、标准化的生物电效应骨组织工程支架的制备方式;体外电刺激干预系统尚不够成熟;缺乏个体化指导支架的选择以实现针对不同病理情况的患者选择并设计最适宜的支架。④研究者们在设计导电支架时,要深入考虑支架的综合效应,譬如生物相容性、力学性能以及生物降解性能等,而此种综合性能可以通过多种材料的复合来实现。⑤除此之外,临床转化应该是导电支架设计的最终考量,在评估出电刺激作用于人体且有利于骨缺损修复的安全电流阈值的基础之上,设计动物实验以及基础实验,然后应用于临床,从而在未来实现生物电效应骨组织工程支架应用于临床的终极目标。

免疫细胞对骨髓间充质干细胞成骨分化作用及机制的研究进展

骨髓间充质干细胞(bone marrow mesenchymal stem cells,BMSCs)在骨缺损修复和骨再生中的作用得到了广泛研究。许多证据表明,有效的内源性骨再生需要免疫系统的协调。在骨缺损愈合中,免疫细胞和BMSCs的相互作用是促进骨形成的关键。近年来的研究发现,多种免疫细胞通过释放的细胞因子和信号促进BMSCs的成骨向分化,从而利于骨缺损修复和骨再生,成为新的骨缺损修复治疗靶点。因此,本文就免疫细胞对BMSCs成骨作用及其相关机制的研究现状进行综述。

氧化石墨烯材料在骨缺损修复中的作用研究进展

外伤、感染、肿瘤等导致的骨缺损是临床治疗难点,而目前自体或异体骨移植的治疗方法应用受限,使得骨缺损临床疗效不佳,寻找新的治疗方法迫在眉睫。氧化石墨烯是一种导电性能良好、高比表面积、力学性能优异、材料稳定,以及具有良好生物相容性和低毒性的新型材料,将其与天然材料如明胶、丝素蛋白、胶原蛋白等或者人工合成材料如聚乳酸、聚醚醚酮、生物玻璃等结合形成性能独特的骨缺损修复材料,将会为骨缺损患者带来福音。

羟基磷灰石/聚合物骨修复材料的特性及问题

背景:羟基磷灰石是骨组织的主要无机成分,聚合物可仿生细胞外基质的结构和功能,两者的复合材料得到了广泛研究。目的:总结羟基磷灰石复合聚合物材料用于骨组织修复的研究现状。方法:检索2010年1月至2023年4月PubMed、Web of Science、中国知网及万方数据库收录的相关文献,中文检索词为“羟基磷灰石,聚合物,复合材料,可降解性,骨缺损,骨修复”,英文检索词:“hydroxyapatite,polymer,composites,degradability,bone defect,bone repair”,最终纳入75篇文献进行综述分析。结果与结论:常与羟基磷灰石复合用于骨组织修复的聚合物包括天然聚合物(胶原、壳聚糖、海藻酸盐、丝素蛋白、纤维素、透明质酸、聚羟基丁酸酯等)和合成聚合物(聚乳酸、聚乳酸-羟基乙酸共聚物、聚己内酯、聚氨基酸、聚乙烯醇等)。羟基磷灰石/聚合物复合材料较纯羟基磷灰石的机械性能、骨诱导性得到了提高,羟基磷灰石与聚合物复合可制成多孔支架、水凝胶、涂层等用于骨修复。羟基磷灰石/聚合物复合材料因其仿生细胞外基质结构和功能可缓释负载的药物和细胞因子,加速骨重建。基于骨缺损原因的多样性以及骨修复为多种生物因子和蛋白共同参与的复杂连续过程,机械性能与骨组织匹配、降解过程与骨修复同步、高效成骨成血管的修复材料有待进一步研究。