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来感知微环境的机械特性的变化并对其做出反应。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的行为并不是简单的、有弹性的。事实上，它们的性质通常是非线性的和粘弹性的--这意味着它们随着组织的拉伸而变化，并基于作用力或拉伸的速度。目前正在进行大量的研究工作，寻找最好的方法让细胞发育成健康的组织，用于组织替代或增强。了解细胞对周围环境的反应是设计优化这些工程化组织的系统的关键。该项目将重点研究底物的粘弹性特性--基于作用力的速度而分散能量的能力--对共同生长因子的细胞受体(转化生长因子-β)的聚集的影响，以及细胞如何对下游产生的信号做出反应。除了科学上的影响，项目团队将专注于在多学科环境中培训学生，以便他们能够在未来有效地在跨学科团队中工作，解决工程、材料科学和生物医学科学之间的复杂问题。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，为了确定已开发的微凝胶、胶体薄膜的粘弹性如何影响成纤维细胞的黏附、扩散、迁移和肌成纤维细胞分化。第二，分析微凝胶膜粘弹性对转化生长因子-β受体聚集、激活和信号转导的影响。最后，检查通过DNA折纸在底物上预构图的转化生长因子-β受体对细胞黏附、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应对微环境中粘弹性的变化提供新的见解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.