Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, 14853, NY, USA.
Institutes of Mechanical Engineering and Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Biomech Model Mechanobiol. 2024 Dec;23(6):1815-1835. doi: 10.1007/s10237-024-01870-2. Epub 2024 Jul 7.
Cellular contractility, migration, and extracellular matrix (ECM) mechanics are critical for a wide range of biological processes including embryonic development, wound healing, tissue morphogenesis, and regeneration. Even though the distinct response of cells near the tissue periphery has been previously observed in cell-laden microtissues, including faster kinetics and more prominent cell-ECM interactions, there are currently no models that can fully combine coupled surface and bulk mechanics and kinetics to recapitulate the morphogenic response of these constructs. Mailand et al. (Biophys J 117(5):975-986, 2019) had shown the importance of active elastocapillarity in cell-laden microtissues, but modeling the distinct mechanosensitive migration of cells on the periphery and the interior of highly deforming tissues has not been possible thus far, especially in the presence of active elastocapillary effects. This paper presents a framework for understanding the interplay between cellular contractility, migration, and ECM mechanics in dynamically morphing soft tissues accounting for distinct cellular responses in the bulk and the surface of tissues. The major novelty of this approach is that it enables modeling the distinct migratory and contractile response of cells residing on the tissue surface and the bulk, where concurrently the morphing soft tissues undergo large deformations driven by cell contractility. Additionally, the simulation results capture the changes in shape and cell concentration for wounded and intact microtissues, enabling the interpretation of experimental data. The numerical procedure that accounts for mechanosensitive stress generation, large deformations, diffusive migration in the bulk and a distinct mechanism for diffusive migration on deforming surfaces is inspired from recent work on bulk and surface poroelasticity of hydrogels involving elastocapillary effects, but in this work, a two-field weak form is proposed and is able to alleviate numerical instabilities that were observed in the original method that utilized a three-field mixed finite element formulation.
细胞收缩性、迁移和细胞外基质 (ECM) 力学对于广泛的生物学过程至关重要，包括胚胎发育、伤口愈合、组织形态发生和再生。尽管先前已经观察到细胞外基质中的细胞对组织边缘的独特反应，包括更快的动力学和更突出的细胞-ECM 相互作用，但目前没有模型可以完全结合表面和体力学和动力学来再现这些结构的形态发生反应。Mailand 等人（Biophys J 117(5):975-986, 2019）已经表明了活性弹性毛细作用在细胞外基质中的重要性，但到目前为止，还不可能对高度变形组织中细胞在边缘和内部的独特机械敏感迁移进行建模，尤其是在存在活性弹性毛细作用的情况下。本文提出了一个框架，用于理解动态变形软组织中细胞收缩性、迁移和 ECM 力学之间的相互作用，该框架考虑了组织体和表面上细胞的不同反应。该方法的主要新颖之处在于，它能够模拟位于组织表面和体上的细胞的独特迁移和收缩反应，同时变形软组织由细胞收缩性驱动发生大变形。此外，模拟结果还捕获了受伤和完整微组织的形状和细胞浓度变化，从而能够解释实验数据。该数值程序考虑了机械敏感应力产生、大变形、体扩散迁移和变形表面上的独特扩散迁移机制，这是受到最近涉及弹性毛细作用的水凝胶体和表面多孔弹性力学的启发，但在这项工作中，提出了一个两字段弱形式，能够缓解原始方法中观察到的数值不稳定性，该原始方法使用了三字段混合有限元格式。
