MSM: Multiscale Mechanics of Bioengineered Tissues

描述（由申请人提供）：我们建议继续对生物工程组织进行多尺度力学分析。在上一个资助期，我们使用了双尺度模型，微观尺度通过离散网络表示胶原纤维，宏观尺度通过连续有限元表示整个组织;这两个尺度完全耦合，我们已经将该模型应用于各种系统。主要进展包括（1）基于图像的模型生成方案，（2）双相分析，包括网络-流体和网络-固体系统，（3）动态修改单个纤维以表示酶降解或损伤，以及（4）纯凝胶（胶原）和共凝胶（胶原-琼脂糖和胶原-纤维蛋白）的实验研究。目前的模型已经非常成功，但在工程组织的适当材料科学可以说存在之前，还有更多的工作要做。在这次更新中，我们提出了三个主要进展，将创建下一代生物工程组织的理论描述：（1）我们将通过第三个尺度将细胞力学添加到模型中。这三个尺度代表组织，细胞-基质复合物 和纤维基质。这个模型将是一个显着的进步，现有的模型的细胞-凝胶复合材料，它将提供一种机制，以捕捉矩阵的内部力学，并探讨了广泛的细胞力学模型。 (2)我们将扩展我们的初始模型的纤维故障到一个模型，可以捕获渐进的纤维损伤和损伤的纤维间材料，后者可能是重要的，因为高强度的胶原蛋白相对于许多其他ECM成分。 (3)我们将补充我们现有的模型与粘弹性条款，由于纤维网络，原纤维间的材料，和他的细胞，以及添加额外的水相的模型，以考虑通过原纤维间的材料的间隙流的影响（扩展我们早期的两相模型）。第一个PDRC将解决组织复杂性，但仍然是故障前和准静态的。第二个将允许研究失败或损坏的系统，第三个将捕获动态组织行为。所有三个提出的理论进步将与实验相结合，以指定和测试模型。组织工程是一个重要的领域，特别是对于动脉、心脏瓣膜和皮肤等机械组织，为受损或患病的组织创造替代物。阻碍组织工程进步的一个主要障碍，特别是创造和使用完全生物工程化的组织，是我们无法像设计其他工程产品那样设计组织。该项目直接关系到公共卫生，因为它将提供工具，以帮助创造下一代替代组织。

DESCRIPTION (provided by applicant): We propose to continue our multiscale mechanical analysis of bioengineered tissues. In the previous grant period, we used a two-scale model, with the microscopic scale representing collagen fibers via a discrete network and the macroscopic scale representing tissue as a whole via continuous finite elements; the two scales are fully coupled, and we have applied the model to a variety of systems. Major advances include (1) An image-based model generation scheme, (2) Biphasic analysis, including both network-fluid and network-solid systems, (3) Dynamic modification of individual fibers to represent enzymatic degradation or damage, and (4) Experimental studies of pure gels (collagen) and co-gels (collagen-agarose and collagen-fibrin). The current model has been extremely successful, but there is still more work to be done before a proper materials science of engineered tissues can be said to exist. In this renewal, we propose three major advances that will create the next generation theoretical description of a bioengineered tissue: (1) We will add cell mechanics to the model via a third scale. The three scales will represent the tissue, the cell-matrix composite with discrete cells, and the fiber matrix. This model will be a significant advance over existing models of cell-gel composites in that it will provide a mechanism to capture the internal mechanics of the matrix and to explore a wide range of cytomechanical models. (2) We will extend our initial model of fiber failure into a model that can capture progressive damage to the fibers and damage to the interfibrillar material, the latter potentially important because of the high strength of collagen relative to many other ECM components. (3) We will supplement our existing model with viscoelastic terms due to the fiber network, the interfibrillar material, and he cells, as well as add an extra water phase to the model to account for the effect of interstitial flow through the interfibrillar materials (extending our earlier biphasic models). The first advanc will address tissue complexity but remains prefailure and quasistatic. The second will allow the study of failing or damaged systems, and the third will capture dynamic tissue behavior. All three proposed theoretical advances will be combined with experiments to specify and test the models. Tissue engineering, the creation of replacements for damaged or diseased tissues, is an important area, especially for mechanical tissues such as artery, heart valve, and skin. A major impediment to advances in tissue engineering, especially to the creation and use of wholly bioengineered tissues, is our inability to design tissues as we design other engineered products. This project relates directly to public health because it will provide tools to help creae the next generation of replacement tissues.