Biomechanical Regulation of Architecture of Engineered Cartilage

9987353：需要扩大合成关节软骨组织用于治疗关节炎的科学基础。目前的方法已经不能产生具有正常关节软骨的功能结构和生物力学特性的组织。这种组织对于修复大的关节缺陷或替换受损的关节表面是必要的。以前，我们和其他人已经发现，使用当前的组织工程学方法形成的软骨结构可以包含正常软骨的主要成分；然而，这种结构的整体基质密度和机械性能明显低于正常软骨。最近，我们在短期实验中发现，某些应变和流体流动刺激调节了此类结构中基质成分的合成和损失。我们的其他研究已经对正常关节软骨的深度变化生物力学特性进行了实验测量和理论分析。基于这些结果，我们假设，在生长软骨结构中应用某些动态机械刺激将诱导形成在组成、结构和功能上与正常关节软骨相似的组织。此外，我们假设这一机制将是通过以空间变化的方式调节特定组织成分的合成和丢失。拟议研究的具体目标将在工程化软骨组织上进行。我们将确定(1)种子细胞的密度如何影响组织厚度、机械功能和组成，(2)长期动态加载方案是如何调节整体和深度变化的组织功能和组成的，以及(3)这种变化是否可以通过特定组织成分的合成和丢失的整体和深度变化的调节来解释。在研究过程中，将通过两名研究生的培训来开发组织工程的人力资源。

9987353SahThere is a need to extend the scientific basis for synthesizing articular cartilage tissue for treating arthritic joints. Current approaches have been unable to produce tissue with the functional architecture and biomechanical properties of normal articular cartilage. Such tissue is necessary for the repair of large articular defects or replacement of damaged joint surfaces. Previously, we and others have found that cartilaginous constructs, formed using current tissue- engineering approaches, can contain the major components of normal cartilage; however, the overall matrix density and mechanical properties of such constructs are markedly inferior to those of normal cartilage. Recently we found in short-term experiments that certain strain and fluid-flow stimuli regulate the synthesis and loss of matrix components from such constructs. Our other studies have experimentally measured and theoretically analyzed the depth-varying biomechanical properties of normal articular cartilage. Based on these results, we hypothesize that application of certain dynamic mechanical stimuli to growing cartilage constructs will induce formation of a tissue that resembles normal articular cartilage in composition, structure, and function. Further, we hypothesize that the mechanism of this will be through modulation of the synthesis and loss of specific tissue components in a spatially-varying manner. The specific aims of the proposed study will be conducted on engineered cartilage tissue. We will determine (1) how the density of seeded cells affects tissue thickness, mechanical function, and composition, (2) how long-term dynamic loading protocols, chosen to induce specific strain and fluid flow profiles, modulate the evolution of overall and depth-varying tissue function and composition, and (3) if this evolution can be explained by overall and depth-varying regulation of synthesis and loss of specific tissue components.The proposed work will emphasize quantitative experiments and analysis in the context of practical models for cartilage tissue engineering. During the course of the study, human resources will be developed for tissue engineering through the training of two graduate students.