A Multiscale Material Approach to Understanding the Effects of Viscoelasticity on Cell Adhesion, Migration, and TGF-beta Activation/Signaling

细胞能够通过一种被称为机械转导的过程感知其微环境的机械特性的变化并作出反应。周围环境的影响影响细胞的附着、迁移、增殖和分化。然而，包括细胞在内的大多数组织并不是以一种简单的、有弹性的方式活动的。事实上，它们的性质通常是非线性和粘弹性的，这意味着它们会随着组织的拉伸以及施加力或拉伸的速度而变化。重要的研究工作正在进行，以寻找使细胞发育成健康组织的最佳方法，以替代或增强组织。了解细胞对周围环境的反应是设计优化这些工程组织的系统的关键。该项目将重点研究底物的粘弹性特性（根据施加力的快慢耗散能量的能力）对常见生长因子（TGF-Beta）细胞受体聚集的影响，以及细胞如何对产生的信号做出下游反应。除了科学上的影响外，项目团队还将重点培养学生在多学科环境中的能力，以便他们将来能够在跨学科团队中有效地工作，解决工程、材料科学和生物医学科学的复杂问题。为了研究非线性粘弹性底物变化对成纤维细胞行为的影响，建立了三个目标。首先，确定发育好的微凝胶、胶体薄膜的粘弹性如何影响成纤维细胞的粘附、扩散、迁移和肌成纤维细胞分化。其次，分析tgf - β受体聚集、激活和信号作为微凝胶膜粘弹性的功能。最后，通过DNA折纸检查底物上tgf - β受体的预图图化对细胞粘附、扩散、迁移和肌成纤维细胞分化的影响。这些研究将为细胞如何在微环境中对粘弹性的变化做出反应提供新的见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Cells are able to sense and react to changes in the mechanical properties of their microenviroment through a process known as mechanotransduction. The effect of the surrounding environment affects cell attachment, migration, proliferation, and differentiation. However, most tissues that include cells do not behave in a simple, elastic fashion. In fact, their properties are generally non-linear and viscoelastic -- meaning that they vary as the tissue is stretched and based on how quickly the force or stretch is applied. Significant research effort is being conducted into the best ways to get cells to develop into healthy tissues for tissue replacement or enhancement. Understanding how cells respond to their surroundings is key to being able to design systems that will optimize these engineered tissues. This project will focus on the effect of the viscoelastic properties of a substrate -- its ability to dissipate energy based on how quickly the force is applied -- on the clustering of a cellular receptor for a common growth factor (TGF-Beta) as well as how cells respond downstream to signals that are generated. In addition to the scientific impact, the project team will focus on training students in a multidisciplinary environment so that they can in the future work effectively on interdisciplinary teams to tackle complex problems at the interface of engineering, materials science, and biomedical science.In order to investigate the nonlinear, viscoelastic substrate variation on fibroblast behavior, three objectives have been established. First, to determine how the viscoelasticity of a developed microgel, colloidal thin film influences fibroblast adhesion, spreading, migration, and myofibroblastic differentiation. Second, to analyze TGF-Beta receptor clustering, activation, and signaling as a function of microgel film viscoelasticity. And, finally, to examine the effect of pre-patterning TGF-Beta receptors on the substrate via DNA origami on cell adhesion, spreading, migration, and myofibroblastic differentiation. The studies will provide new insights into how cells respond to changes in viscoelasticy in their microenvironment.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.