Tissue Engineering Strategies to Revitalize Allografts

振兴同种异体移植物的组织工程策略

• 批准号: 10675926
• 负责人: Danielle S. Benoit
• 金额: $ 3.27万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2023-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675926
• 关键词: ANGPT1 gene; Adenoviruses; Adhesions; Adhesives; Allografting; Autologous Transplantation; Biochemical; Biomechanics; Blood Vessels; Bone Regeneration; Bone Transplantation; CXCL12 gene; Caliber; Cell Transplantation; Cells; Chemistry; Clinical; Collagen; Crosslinker; Cues; Data; Defect; Development; Diffuse; Encapsulated; Endothelial Cells; Excision; Failure; Fibronectins; Fibrosis; Fracture; Funding; Gel; Gold; Histology; Hydrogels; Immunohistochemistry; In Vitro; Infection; Infiltration; Laminin; Ligands; MMP2 gene; Matrix Metalloproteinases; Mediating; Mesenchymal Stem Cells; Migration Assay; Morbidity - disease rate; Mus; Natural regeneration; Nerve; Organ Transplantation; Orthopedics; Paracrine Communication; Patients; Peptides; Periosteal Cell; Periosteum; Procedures; Process; Property; Reconstructive Surgical Procedures; Role; Site; Testing; Thinness; Tissue Engineering; Tissues; Torque; Torsion; Transplantation; Trauma; Validation; Vascular Endothelial Growth Factors; Vascularization; Work; allogenic bone transplantation; base; bone; bone reconstruction; cell type; clinical translation; congenital anomaly; contrast imaging; controlled release; crosslink; design; engineering design; ethylene glycol; experimental study; graft healing; healing; implantation; improved; in vivo; in vivo evaluation; innovation; knock-down; mimetics; osteoprogenitor cell; overexpression; paracrine; peptidomimetics; recruit; repaired; response; single-cell RNA sequencing; small hairpin RNA; stem cells; tyrosyl-isoleucyl-glycyl-seryl-arginine

There are limited options for reconstruction of bone defects resulting from congenital anomalies, trauma, infection, and oncologic resection. Over 2 million bone graft procedures are performed annually worldwide, with the clinical ‘gold standard’ being the use of autografts. Autografts fully heal and integrate, mediated by the periosteum, a thin layer of tissue and periosteal cells (PCs) surrounding bone. However, autografts are limited due to tissue availability and donor site morbidity. Thus, decellularized allografts are commonly employed. However, the limited ability of allografts, which lack periosteum, to remodel and integrate with the host tissue directly contributes to ~35% and 60% failure rates within 2 and 10 years of implantation. Periosteal-mediated healing is coordinated by a variety of contextual cues including matrix remodeling and adhesion and temporally defined release of paracrine factors. Our overarching hypothesis is that allograft healing will be dramatically improved by capturing critical healing cues in a tissue engineered periosteum (TEP). In the first funding cycle, we pioneered development of the TEP, which incorporates mesenchymal stem cells (MSCs) and OPs within hydrolytically degradable poly(ethylene glycol)(PEG)-based hydrogels, which are formed around allografts, similar to native periosteum. TEP shows outstanding promise to enhance murine allograft healing, resulting in a 300% increase in maximum fracture torque versus unmodified allografts at 9 weeks post-implantation. However, healing was plagued by fibrotic tissue, which results in the allograft limited to ~50% of autograft maximum torque. Fibrosis is consistent with poorly supported infiltration of TEP by host vessel/tissue, a limitation resulting from bulk hydrolytic TEP degradation which results in structural insufficiencies to support complete host-tissue infiltration. Thus, the focus of this renewal is a cellularly remodeled TEP, which enables localized, cell-demanded degradation while maintaining bulk hydrogel properties to support host-tissue infiltration. Three specific aims are outlined: Specific Aim 1: Tune TEP matrix cues (adhesive peptides and MMP-degradable crosslinks) to coordinate tissue infiltration and improve allograft healing. Specific Aim 2: Characterize TEP-mediated host-tissue recruitment. Specific Aim 3: Exploit the optimized TEP matrix to deliver peptides emulating periosteal paracrine cues as a translatable, acellular TEP. Successful completion of these Aims will significantly advance our understanding of how the periosteum coordinates allograft healing and the design of engineered periosteum to promote these bone regeneration processes. The developed material platforms and general approach are also readily applicable in other tissue engineering applications.

先天异常，创伤，创伤，重建骨缺损的选择有限 感染和肿瘤切除术。全世界每年进行超过200万个骨移植手术 临床“黄金标准”是使用自体移植。自体移植完全治愈和整合，由 骨膜，骨骼和骨膜细胞（PC）的一层薄层。但是，自身移植受到限制 由于组织可用性和供体部位发病率。那是通常雇用脱细胞的分支机构。 但是，缺乏骨膜的异源能力有限，与宿主组织进行重塑和整合 直接在植入2年和10年内直接导致约35％和60％的失败率。骨膜介导 康复是通过各种情境线索协调的，包括基质重塑和粘合剂以及临时 旁分泌因子的定义释放。我们的总体假设是同种异体移植愈合将是巨大的 通过在组织工程骨膜（TEP）中捕获临界愈合线索来改善。在第一个资金周期中， 我们开发了TEP的发展，该TEP结合了间充质干细胞（MSC）和OPS 基于水解的聚乙二醇（PEG）的水凝胶，围绕分布形成， 类似于天然骨膜。 TEP显示出增强鼠同种异体愈合的良好承诺，从而 植入后9周时，最大断裂扭矩与未修饰的同种异体移植物增加了300％。 但是，愈合受到纤维化组织的困扰，这导致同种异体移植限制为〜50％的自体移植 最大扭矩。纤维化与宿主血管/组织TEP浸润的纤维化一致，A 大量水解TEP降解产生的限制，导致结构性不足以支持 完整的主机组织渗透。这是此更新的重点是一个细胞重塑的TEP，它可以 局部，细胞调整的降解，同时维持散装水凝胶特性以支持宿主组织 浸润。概述了三个具体目的：特定目标1：调整TEP矩阵提示（粘合肽和 MMP降解交联）以协调组织浸润并改善同种异体移植愈合。具体目标2： TEP介导的主机组织招募表征。特定目标3：利用优化的TEP矩阵传递 肽将骨膜旁线提示作为可翻译的大量TEP。这些成功完成 目标将大大提高我们对骨膜如何坐标的理解 设计骨膜的设计以促进这些骨再生过程。发达的材料 平台和通用方法也很容易适用于其他组织工程应用。