Cartilage Integration: in Vitro to In Vivo Translation

软骨整合：体外到体内的翻译

• 批准号: 7140680
• 负责人: Robert L Sah
• 金额: $ 17.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140680
• 关键词: articular cartilage; beta aminopropionitrile; biomechanics; biomimetics; biotechnology; cartilage disorder; cartilage transplantation; chondrocytes; collagen; collagenase; disease /disorder model; extracellular matrix; glycoproteins; hyaluronidase; joint prosthesis; knee; medical rehabilitation related tag; musculoskeletal disorder therapy; nonhuman therapy evaluation; proteoglycan; swine; tissue engineering

DESCRIPTION (provided by applicant): A common challenge in tissue engineering is the development of treatments that satisfy the biomechanical requirements of the interfaces between implants and host tissues. In treatments of an articular cartilage defect with a tissue implant, the implant needs to form an adherent and integrated interface with the adjacent host cartilage, but often fails to do so. Conversely, the implant needs to form an articular surface in apposition with host tissue that is a lubricated, low-friction interface, but often fails to do so and instead undergo fibrillation. Nature has achieved integrated and lubricated interfaces thru specific biological processes and molecules. Thus, a biomimetic approach may be useful in achieving the desired interfaces. Our overall hypothesis is that tailoring cartilaginous implants and host tissues to enhance site- specific integration or, alternatively, lubrication can create key localized features that facilitate successful treatment of cartilage defects. The development of human clinical therapies typically involves translation of in vitro investigations through intermediate in vivo studies in animal models. In vitro studies of ours and others have shown that integration of cartilaginous tissue with native cartilage can be accelerated by treatments to stimulate cell- based formation of a collagen network across the interface, whereas lubrication characteristics typical of the articular surface can be achieved by surface localization of cells secreting a lubricant molecule called lubricin (Lub) or Superficial Zone Protein (SZP). To test the utility of these concepts in tissue implants, we established methods, applicable to both in vitro and in vivo studies, (a) for determining the efficacy of integrative cartilage repair, (b) for tracking implanted cells, and (c) for localizing Lub/SZP-secreting cells. Here, we propose to use these methods to address the following translational hypotheses: (1) at the interface region between implant and host cartilage, sufficient cells secreting type II collagen into a receptive matrix facilitates collagen network deposition and successful integration. (2) At the articular surface region of the implant, sufficient cells producing Lub/SZP facilitates maintenance of smooth articulation. Relevance to Public Health. The proposed work will advance research toward clinical treatment of cartilage defects, that otherwise progress to osteoarthritis. If the hypotheses are shown to be correct, the results will (a) extend the concept that the targeted modification of tissue surfaces can be useful for integration or, alternatively, lubrication, (b) delineate the role of implanted versus host cells, and (c) demonstrate how in vitro models of articular defect repair can be translated in vivo.

描述（由申请人提供）：组织工程中的一个常见挑战是开发满足植入物和宿主组织之间界面生物力学要求的治疗方法。在用组织植入物治疗关节软骨缺损时，植入物需要与相邻宿主软骨形成粘附和整合的界面，但通常不能这样做。相反，植入物需要形成与宿主组织并置的关节面，其是润滑的、低摩擦的界面，但通常不能这样做，而是经历纤维化。自然界通过特定的生物过程和分子实现了整合和润滑的界面。因此，仿生方法可用于实现所需的界面。我们的总体假设是，定制软骨植入物和宿主组织以增强位点特异性整合，或者替代地，润滑可以产生促进软骨缺损成功治疗的关键局部特征。 人类临床疗法的开发通常涉及将体外研究转化为动物模型中的中间体内研究。我们和其他人的体外研究表明，软骨组织与天然软骨的整合可以通过刺激跨界面的胶原网络的基于细胞的形成的治疗来加速，而关节表面的典型润滑特性可以通过分泌称为润滑素（Lub）或浅表区蛋白（SZP）的润滑分子的细胞的表面定位来实现。为了测试这些概念在组织植入物中的效用，我们建立了适用于体外和体内研究的方法，（a）用于确定整合软骨修复的功效，（B）用于追踪植入细胞，和（c）用于定位Lu B/SZP分泌细胞。在这里，我们建议使用这些方法来解决以下翻译假设：（1）在植入物和宿主软骨之间的界面区域，足够的细胞分泌II型胶原进入接受基质，促进胶原网络沉积和成功整合。(2)在植入物的关节面区域，产生Lub/SZP的足够细胞有助于保持关节面光滑。 与公共卫生相关。拟议的工作将推进软骨缺损的临床治疗研究，否则将发展为骨关节炎。如果假设被证明是正确的，结果将（a）扩展组织表面的靶向修饰可用于整合或润滑的概念，（B）描述植入细胞与宿主细胞的作用，以及（c）证明关节缺损修复的体外模型如何在体内转化。