Cartilage Integration: in Vitro to In Vivo Translation

描述(申请人提供)：组织工程学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的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，植入物需要与邻近的宿主软骨形成粘连和完整的界面，但往往无法做到这一点。相反，植入物需要形成与宿主组织相对的关节表面，这是一个润滑的、低摩擦的界面，但通常无法做到这一点，而是经历纤颤。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，仿生方法在实现所需界面方面可能是有用的。我们的总体假设是，定制软骨植入物和宿主组织以增强特定部位的整合，或者，替代地，润滑可以创造关键的局部特征，从而促进成功地治疗软骨缺陷。 人类临床治疗的发展通常包括通过动物模型的中间体内研究来转换体外研究。我们和其他人的体外研究表明，通过刺激界面上基于细胞的胶原网络的形成，可以加速软骨组织与天然软骨的整合，而关节表面典型的润滑特性可以通过分泌一种名为润滑素(Lub)或表面带蛋白(SZP)的润滑剂分子的细胞表面定位来实现。为了测试这些概念在组织植入中的实用性，我们建立了适用于体外和体内研究的方法，(A)确定一体化软骨修复的有效性，(B)跟踪植入的细胞，(C)定位Lub/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)在种植体和宿主软骨的交界处，足够的细胞将II型胶原分泌到可接受的基质中，促进胶原网络的沉积和成功整合。(2)在种植体的关节面区，足够的细胞产生Lub/SZP有助于保持关节的顺畅。 与公共卫生的相关性。这项拟议的工作将推进软骨缺陷的临床治疗研究，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改可以用于整合或润滑的概念，(B)描述植入细胞对宿主细胞的作用，以及(C)展示关节缺陷修复的体外模型如何在体内翻译。

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.