Biomimetic Tissue-engineered Articular Cartilage Repair

仿生组织工程化关节软骨修复 关节软骨损伤不能自我修复，如果无人照料，将导致骨性关节炎(OA)的 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，但 导致功能性和耐久性软骨修复的治疗策略尚未实现。对大多数人来说 组织工程修复骨软骨缺损，这是一种单相材料，通常是可变形和机械的 结构上的一致性也得到了测试，但同样没有获得一致的成功。其中一个主要原因是 软骨修复失败的原因是修复组织与周围软骨不整合。有限 元素计算机模拟表明，修复组织的过度变形导致相当大的 种植体-宿主界面的应力，这会导致修复组织的失效。关节软骨是一种 结构复杂的组织，其功能部分依赖于完整的软骨下骨的支持。我们假设 一种双相复合研磨系统，该系统在 骨软骨缺损的底部和促进关节软骨修复的另一个是必不可少的 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。 并提供良好的机械环境，以降低植入物的应力水平- 宿主界面，有利于宿主-修复组织整合，促进功能修复。DBM有机械 完整性，并含有多种内在的生长因子，体积至少大20倍 浓度高于血清中的浓度。这些生长因子能够促进骨愈合并调节骨软骨的形成。 并可能通过以下途径促进骨组织的持续重塑 破骨和成骨活动。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陷时的因素。软骨组织可以在体外用任何一种材料进行工程化 骨髓间充质干细胞(MSCs)或明胶培养扩增软骨细胞 海绵或透明质酸(HA)载体基质。特别关注了集成的优化 通过使用HA-寡聚体来促进新生组织与宿主的组织的这种整合，在本提案中，一种新的 DBM与体外组织工程前软骨复合移植的实验研究 将被测试以修复骨软骨缺陷。目的是重新评估这种机械设备的使用情况 因子与合适的胶原蛋白输送载体，用于骨软骨缺损的细胞治疗。这 这一目标将通过以下具体目标来实现： 特异性目的1.优化MSCs或软骨细胞体外工程化软骨组织的条件 结合成明胶或透明质酸基质。其目标是准备一种可植入的软骨组织，用于 软骨缺损处的表面修复。 特定目的2.在兔模型上测试双相复合材料移植物，并评估其机制和顺序 骨软骨缺损修复过程中发生的事件。 特定目标3.将这些小动物的结果从特定目标1和2转化为更大的、临床相关的结果 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.