Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York, USA.
Institutes of Mechanical Engineering and Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Soft Matter. 2021 Nov 24;17(45):10198-10209. doi: 10.1039/d0sm01182g.
Tissue morphogenesis and regeneration are essentially mechanical processes that involve coordination of cellular forces, production and structural remodeling of extracellular matrix (ECM), and cell migration. Discovering the principles of cell-ECM interactions and tissue-scale deformation in mechanically-loaded tissues is instrumental to the development of novel regenerative therapies. The combination of high-throughput three-dimensional (3D) culture systems and experimentally-validated computational models accelerate the study of these principles. In our previous work [E. Mailand, , , 2019, , 975-986], we showed that prominent surface stresses emerge in constrained fibroblast-populated collagen gels, driving the morphogenesis of fibrous microtissues. Here, we introduce an active material model that allows the embodiment of surface and bulk contractile stresses while maintaining the passive elasticity of the ECM in a 3D setting. Unlike existing models, the stresses are driven by mechanosensing and not by an externally applied signal. The mechanosensing component is incorporated in the model through a direct coupling of the local deformation state with the associated contractile force generation. Further, we propose a finite element implementation to account for large deformations, nonlinear active material response, and surface effects. Simulation results quantitatively capture complex shape changes during tissue formation and as a response to surgical disruption of tissue boundaries, allowing precise calibration of the parameters of the 3D model. The results of this study imply that the organization of the extracellular matrix in the bulk of the tissue may not be a major factor behind the morphogenesis of fibrous tissues at sub-millimeter length scales.
组织形态发生和再生本质上是机械过程，涉及细胞力的协调、细胞外基质（ECM）的产生和结构重塑以及细胞迁移。发现机械加载组织中细胞-ECM 相互作用和组织尺度变形的原理对于新型再生疗法的发展至关重要。高通量三维（3D）培养系统和经过实验验证的计算模型的结合加速了这些原理的研究。在我们之前的工作中[E. Mailand，，，2019，，975-986]，我们表明，在受约束的成纤维细胞填充的胶原蛋白凝胶中会出现突出的表面应力，从而驱动纤维微组织的形态发生。在这里，我们引入了一种主动材料模型，该模型允许在 3D 环境中体现表面和体收缩应力，同时保持 ECM 的被动弹性。与现有模型不同，这些应力是由机械传感驱动的，而不是由外部施加的信号驱动的。该机械传感组件通过将局部变形状态与相关的收缩力生成直接耦合纳入模型中。此外，我们提出了一种有限元实现方法，以考虑大变形、非线性主动材料响应和表面效应。模拟结果定量地捕捉到组织形成过程中的复杂形状变化以及对组织边界手术破坏的反应，从而可以精确校准 3D 模型的参数。这项研究的结果表明，在亚毫米长度尺度下，组织内部的细胞外基质的组织可能不是纤维组织形态发生的主要因素。
