Biomimetic Tissue-engineered Articular Cartilage Repair

仿生组织工程关节软骨修复 关节软骨损伤不能自我修复，如果不加注意，将导致骨关节炎（OA）。 受影响的关节已经开发了许多不同的程序来修复受损的软骨， 导致功能性和持久的软骨修复的治疗策略尚未实现。对于大多数 骨软骨缺损的组织工程修复，一种单相材料，通常是可变形的， 并且结构上均匀已经过测试，同样没有均匀的成功。的主要原因之一 软骨修复失败的原因是修复组织和周围软骨之间的不整合。有限 元素计算机建模表明，修复组织的过度变形会导致相当大的 植入物-宿主界面处的应力，这有助于修复组织的失效。关节软骨是 结构复杂的组织，其功能部分取决于完整的软骨下骨的支撑。我们假设 一种双相复合材料支撑系统，一种在所述支撑系统处提供功能性机械支撑的双相复合材料支撑系统， 骨软骨缺损的基底和另一个促进关节软骨修复的基底对于 软骨修复成功这种双相复合移植物模拟了骨软骨的生理结构 界面，并提供有利的机械环境，降低植入物处的应力水平。 宿主界面，有利于宿主修复组织整合和促进功能修复。DBM具有机械 完整性，并含有各种内在生长因子，其体积至少是20倍 浓度高于血清。这些生长因子能够促进骨愈合和调节骨软骨形成 祖细胞，并可能有助于骨组织的不断重塑， 成骨细胞和成骨细胞活性。DBM作为天然平衡的多种生物活性物质的储存库， 当它被用来修复骨或软骨缺损时，软骨组织可以在体外工程化， 明胶中的骨髓来源的间充质干细胞（MSC）或培养扩增的软骨细胞 海绵或透明质酸（HA）载体基质。特别注意的是提供的集成优化 通过使用HA-寡聚体促进这种整合，将新组织与宿主的新组织结合。 DBM与体外组织工程化前软骨（MSCs或软骨细胞）组成的双相复合移植物 将被用来修复骨软骨缺损目的是重新评估这种机械的使用 因子与合适的胶原递送载体用于骨软骨缺损的基于细胞的治疗。这 将通过以下具体目标实现这一目标： 具体目标1.优化骨髓间充质干细胞和软骨细胞体外构建软骨组织的条件 结合到明胶或HA基质中。目标是准备一种可植入的软骨组织， 修复软骨缺损 具体目标2.在兔模型中测试双相复合移植物，并评估其机制和顺序 骨软骨缺损修复期间的事件。 具体目标3.为了将特定目标1和2中的这些小动物结果转化为更大的临床相关结果， 动物模型（山羊），以开发修复软骨缺损的治疗策略。

Biomimetic tissue-engineered articular cartilage repair Articular cartilage injuries cannot self-repair and if left unattended, will lead to osteoarthritis (OA) of the affected joints. A number of different procedures have been developed to repair damaged cartilage, yet a therapeutic strategy that results in a functional and durable cartilage repair has not been achieved. For most tissue engineering repair of osteochondral defects, a single-phase material that is usually deformable and mechanically and structurally uniform has been tested, again without uniform success. One of the major causes for failure of cartilage repair is non-integration between the repair tissue and the surrounding cartilage. Finite element computer modeling indicates that excessive deformation of the repair tissue causes considerable stress at the implant-host interface, which contributes to the failure of the repair tissue. Articular cartilage is a structurally complex tissue, whose function partly depends on the support of intact subchondral bone. We hypothesize that a biphasic composite gran system, one that provides the functional mechanical support at the base of the osteochondral defect and the other that facilitates the repair of articular cartilage, is essential for successful cartilage repair. This biphasic composite graft mimics the physiological structure of the osteochondral interface and provides a favorable mechanical environment that reduces the stress level at the implant- host interface, favoring host-repair tissue integration and facilitating functional repair. DBM has mechanical integrity and contains a variety of intrinsic growth factors that are, at least, 20 times greater in volume concentration than in serum. These growth factors are able to enhance bone healing and modulate the osteochondrogenesis of progenitor cells and may contribute to the constant remodeling of bone tissue through osteoclastic and osteoblastic activities. DBM functions as a reservoir of naturally balanced multiple bioactive factors when it is used to repair bone or cartilage defects. Cartilage tissue can be engineered in vitro with either bone marrow-derived Mesenchymal Stem Cells (MSCs) or culture-expanded chondrocytes in a gelatin sponge or hyaluronan (HA) carrier matrix. Special attention is provided to the optimization of the integration of neo- tissue with that of the host by using HA-oligomers to facilitate such integration In this proposal, a novel dual-phase composite graft composed of DBM and in vitro tissue engineered precartilage (MSCs or chondrocytes) will be tested to repair an osteochondral defect. The objective is to re-evaluate the use of this mechanical factor with a suitable collagenous delivery vehicle for the cell-based therapy of osteochondral defects. This objective will be addressed by the following Specific Aims: SPECIFIC AIM 1. To optimize the conditions for in vitro engineering of cartilage tissue with MSCs or chondrocytes combined into the gelatin or HA matrix. The goal is to prepare an implantable cartilage tissue for resurfacing of the cartilage defect. SPECIFIC AIM 2. To test a biphasic composite graft in a rabbit model and assess the mechanism and sequential events during the repair of osteochondral defects. SPECIFIC AIM 3. To translate these small animal results from Specific Aims 1 and 2 to a larger, clinically relevant animal model (goats) to develop a therapeutic strategy for repair of cartilage defects.