Image-Based Modeling for Improved Functionality in Tissue Engineered Constructs

描述(申请人提供)：组织工程学在改善健康和生活质量方面具有巨大的潜力，但要生产具有机械功能的组织，需要精确了解组织的微观结构与其整体机械性能之间的相互作用。由于天然组织的复杂性，我们必须从一种简单的测试系统开始--胶原凝胶--它具有天然组织的一些特性，并为逐步添加其他基质成分提供“主干”。此外，我们需要一个同时提供力学测试和成像能力的实验系统，并能够跟踪局部凝胶网络排列随载荷的演变。最后，需要一个多尺度计算模型形式的理论框架，将每个尺度联系起来，并将微观结构与宏观功能联系起来。我们的基本假设是，工程化组织的机械性能由微结构决定，这可以用现代成像技术来阐明。为了验证这一假设，我们需要评估实验和计算模型在组织和网络尺度上的一致性。一个成功的模型必须做三件事：预测的宏观力学响应必须与凝胶的宏观力学响应相匹配；预测的局部基质重排和应变必须与凝胶的相匹配；模型中的局部矩阵表示必须反映凝胶中各组分的排列和组成。我们建议首先生产、成像和机械测试不同纤维排列的胶原凝胶。我们将同时通过双轴测试获得胶原凝胶的力学数据，通过偏振光显微镜获得局部排列，并通过相位相关获得应变图。高分辨率 扫描电子显微镜图像将提供补充的微观结构信息。其次，我们将基于凝胶的局部纤维微结构生成多尺度模型，并将其与实验数据进行比较。实验的边界条件、加载方案和初始对齐图将作为多尺度模型的输入。将对宏观力学行为和网络取向、排列和应变的局部演化进行比较。最后，我们将对有限压缩下的凝胶重复这一过程，并逐步添加其他基质成分，首先是核心蛋白聚糖，这是一种已知的影响细胞行为和凝胶机械性能的蛋白多糖。如果成功，该项目将为更合理的工程组织设计和未来对天然组织结构-功能关系的分析奠定基础。修复或替换病变和受损组织的方法将对患者的健康和生活质量具有巨大的价值。

DESCRIPTION (provided by applicant): Tissue engineering has tremendous potential to improve health and quality of life, but to produce a mechanically functional tissue requires precise understanding of the interplay between a tissue's microstructure and its overall mechanical properties. Because of the complexity of native tissues, we must begin with a simple test system - a collagen gel - that shares some properties of native tissue and provides a "backbone" for the step-wise addition of other matrix components. In addition, we require an experimental system that simultaneously provides mechanical testing and imaging capabilities, and can track the evolution of local gel network arrangement with load. Finally, a theoretical framework, in the form of a multiscale computational model, is needed to connect each scale and relate microscopic structure to macroscopic function. Our essential hypothesis is that the mechanical properties of an engineered tissue are determined by the microstructure, which can be elucidated with modern imaging techniques. In order to test the hypothesis, we need to assess agreement between experiments and computational models at both the tissue and the network scale. A successful model must do three things: the predicted macroscopic mechanical response must match the gel's; the predicted local matrix rearrangements and strains must match the gel's; and the local matrix representation in the model must reflect the arrangement and composition of components in the gel. We propose first to produce, to image, and to test mechanically collagen gels that differ in fiber alignment. We will simultaneously acquire collagen gel mechanical data via biaxial testing, local alignment via polarized light microscopy, and strain maps via phase correlation. High resolution SEM images will provide supplemental microstructural information. Second, we will generate a multi-scale model based of the gel's local fiber microstructure and compare it to experimental data. The experiment's boundary conditions, loading protocol, and initial alignment map will serve as inputs for the multi-scale model. Comparisons between macroscopic mechanical behavior and local evolution of network orientation, alignment, and strain will be made. Finally, we will repeat this process for gels under confined compression and with the step-wise addition of other matrix components, starting with decorin, a proteoglycan known to effect cell behavior and gel mechanical properties. If successful, this project will lay the groundwork for more rational design of engineered tissues and for future analysis of structure-function relationships in native tissues. A means of repairing or replacing diseased and damaged tissues would be of enormous value to the health and quality of life of a patient