Image-Based Modeling for Improved Functionality in Tissue Engineered Constructs

描述（由申请人提供）：组织工程在改善健康和生活质量方面具有巨大的潜力，但要产生具有机械功能的组织，需要精确理解组织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，我们必须从一个简单的测试系统开始——胶原蛋白凝胶——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，我们需要一个实验系统，同时提供机械测试和成像能力，并可以跟踪局部凝胶网络排列随负载的演变。最后，需要一个理论框架，以多尺度计算模型的形式，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，工程组织的机械性能是由微观结构决定的，这可以用现代成像技术来阐明。为了验证这一假设，我们需要在组织和网络尺度上评估实验和计算模型之间的一致性。一个成功的模型必须做到三件事：预测的宏观力学响应必须与凝胶相匹配；预测的局部基质重排和应变必须与凝胶相匹配；模型中的局部矩阵表示必须反映凝胶中组分的排列和组成。我们建议首先生产、成像和机械测试纤维排列不同的胶原蛋白凝胶。我们将同时通过双轴测试获得胶原凝胶力学数据，通过偏振光显微镜获得局部校准数据，通过相位相关获得应变图。高分辨率

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