Multiscale Mechanobiology of Growth and Remodeling During Wound Healing

在伤口愈合过程中，一系列生长和重塑过程将最初的纤维蛋白凝块转化为主要由胶原蛋白组成的疤痕，与正常皮肤相比，胶原蛋白的机械性能通常较差。虽然在了解创伤愈合过程中组织的力学性质如何变化方面取得了进展，但对于愈合过程中细胞水平细胞外基质(ECM)的局部重塑如何导致组织水平的新力学性质的研究却知之甚少。这个项目的目的是了解成纤维细胞如何在微观尺度上重塑细胞外基质，以及这些细胞外基质的变化如何导致组织(宏观)尺度上的观察到的变化。这将通过实验和计算建模的努力相结合来解决。该框架将增加关于细胞如何在微观层面上感知和响应其机械环境的方式与组织水平的生长和重塑有关的知识。通过促进对这一领域的理解，有可能将这些知识转化为改进的干预措施，以支持伤口愈合--这是医学上的一个关键问题。为了进一步扩大该奖项的影响，通过这项研究开发的开源软件将通过Github向社区提供。此外，研究人员将在一次以生物系统多尺度建模为重点的全国会议上组织一次研讨会，以培训下一代科学家。这项工作将进一步得到教育和指导活动的补充，旨在通过继续参加普渡大学S暑期本科生研究奖学金和院系之路计划来增加少数族裔的代表性。这个项目的总体目标是阐明在Will愈合过程中，微观尺度上的潜在细胞事件是如何与宏观尺度机制相联系的。假设可以用基于微观ECM重塑的多尺度模型来预测宏观尺度上的生长和重塑。这一过程预计将依赖于纤维降解、纤维沉积和细胞驱动的收缩。在目标1中，该项目将把有限元组织水平模型连接到详细的微尺度模型，在该模型中，纤维网络由以试剂表示的成纤维细胞群来重构。在目标2中，种植成纤维细胞的纤维蛋白和胶原凝胶在初始变形和控制细胞因子浓度下的生长和重塑将被跟踪数天到数周。这些测量值将用于校准计算模型。该模型将在目标3中通过实验扰动系统来改变胶原沉积、纤维降解和细胞收缩能力，从而进一步验证该模型。最后，该项目将创建一个由胶原凝胶中的纤维蛋白结构域组成的体外伤口模型，并将几何结构的变化与计算模型的预测进行比较。该奖项反映了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。

During wound healing, a series of growth and remodeling processes transform an initial fibrin clot into a scar primarily made out of collagen, which usually has inferior mechanical properties compared with normal skin. While progress has been made towards understanding how the mechanical properties of the tissue change during wound healing, much less is known about how local remodeling of the extracellular matrix (ECM) at the cell level during would healing leads to the new mechanical properties at the tissue level. The objective of this project is to understand how the extracellular matrix (ECM) is remodeled at the microscale by fibroblasts, and how these changes of the ECM lead to the observed changes at the tissue (macro) scale. This will be tackled through a combination of experimental and computational modeling efforts. The framework will increase knowledge about how the way in which cells sense and respond to their mechanical environment at the microscale is linked to tissue level growth and remodeling. By advancing understanding in this area, it may be possible to translate the knowledge to improved interventions to support wound healing - a key problem in medicine. In order to further broaden the impact of the award, the open-source software developed through this research will be made available to the community through Github. In addition, the researchers will organize a workshop at a national conference focused on multiscale modeling of biological systems in order to train the next generation of scientists. The work will further be complemented with educational and mentoring activities aimed at increasing representation of minorities by continuing to participate in the Purdue?s Summer Undergraduate Research Fellowship and Pathways to the Faculty Programs. The overall goal of this project is to elucidate how the underlying cellular events at the microscale are connected to the macroscale mechanics during would healing. It is hypothesized that growth and remodeling at the macroscale can be predicted with a multiscale model based on microscale ECM remodeling. This process is expected to be dependent on fiber degradation, fiber deposition, and cell-driven contraction. In Objective 1, the project will connect a finite element tissue level model to a detailed microscale model where a fiber network is remodeled by a fibroblast population represented as agents. In Objective 2, the growth and remodeling of fibrin and collagen gels seeded with fibroblasts subjected to an initial deformation and controlled cytokine concentration will be tracked for days to weeks. These measurements will be used to calibrate the computational model. The model will be further validated in Objective 3 by experimentally perturbing the system to alter collagen deposition, fiber degradation, and cell contractility. Finally, the project will create an in vitro wound model consisting of a fibrin domain inside a collagen gel and compare changes in geometry with the computational model's prediction.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.