Multiscale Mechanobiology of Growth and Remodeling During Wound Healing

伤口愈合过程中生长和重塑的多尺度力学生物学

• 批准号: 1911346
• 负责人: Adrian Buganza Tepole
• 金额: $ 41.59万
• 依托单位: Purdue University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1911346&HistoricalAwards=false
• 关键词: Multiscale; Mechanobiology; Growth; Remodeling; During

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.

在伤口愈合过程中，一系列的生长和重塑过程将初始的纤维蛋白凝块转化为主要由胶原蛋白制成的瘢痕，其与正常皮肤相比通常具有较差的机械性能。虽然已经朝着理解在伤口愈合期间组织的机械性质如何改变取得了进展，但是关于在伤口愈合期间细胞水平上的细胞外基质（ECM）的局部重塑如何导致组织水平上的新的机械性质知之甚少。本项目的目的是了解细胞外基质（ECM）如何在微观尺度上被成纤维细胞重塑，以及ECM的这些变化如何导致组织（宏观）尺度上观察到的变化。 这将通过实验和计算建模工作相结合来解决。 该框架将增加有关细胞在微观尺度上感知和响应其机械环境的方式与组织水平生长和重塑有关的知识。 通过推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-这是医学中的一个关键问题。 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提供给社区。 此外，研究人员还将在一次全国性会议上组织一个研讨会，重点讨论生物系统的多尺度建模，以培养下一代科学家。这项工作将进一步辅之以教育和辅导活动，旨在通过继续参加普渡大学？的夏季本科生研究奖学金和教师课程的途径。这个项目的总体目标是阐明在伤口愈合过程中，微观尺度上的潜在细胞事件如何与宏观尺度力学联系起来。据推测，在宏观尺度上的生长和重塑可以用基于微观尺度ECM重塑的多尺度模型来预测。 预计该过程取决于纤维降解、纤维沉积和细胞驱动的收缩。在目标1中，该项目将连接有限元组织水平模型到详细的微观模型，其中纤维网络由代表代理的成纤维细胞群体重塑。在目标2中，将跟踪接种有成纤维细胞的纤维蛋白和胶原凝胶的生长和重塑数天至数周，所述成纤维细胞经受初始变形和受控的细胞因子浓度。这些测量值将用于校准计算模型。目标3将通过实验扰动系统以改变胶原蛋白沉积、纤维降解和细胞收缩性来进一步验证该模型。最后，该项目将创建一个由胶原凝胶内的纤维蛋白域组成的体外伤口模型，并将几何形状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。

项目成果

Predicting the mechanical properties of biopolymer gels using neural networks trained on discrete fiber network data

使用在离散纤维网络数据上训练的神经网络预测生物聚合物凝胶的机械性能

• DOI: 10.1016/j.cma.2021.114160
• 发表时间: 2021
• 期刊: Computer Methods in Applied Mechanics and Engineering
• 影响因子: 7.2
• 作者: Leng, Yue;Tac, Vahidullah;Calve, Sarah;Tepole, Adrian B.
• 通讯作者: Tepole, Adrian B.

Multiscale mechanical characterization and computational modeling of fibrin gels

纤维蛋白凝胶的多尺度力学表征和计算模型

• DOI: 10.1016/j.actbio.2023.03.026
• 发表时间: 2023
• 期刊: Acta Biomaterialia
• 影响因子: 9.7
• 作者: Jimenez, Julian M.;Tuttle, Tyler;Guo, Yifan;Miles, Dalton;Buganza-Tepole, Adrian;Calve, Sarah
• 通讯作者: Calve, Sarah

Computational mechanobiology model evaluating healing of postoperative cavities following breast-conserving surgery

• DOI: 10.1016/j.compbiomed.2023.107342
• 发表时间: 2023-08-28
• 期刊: COMPUTERS IN BIOLOGY AND MEDICINE
• 影响因子: 7.7
• 作者: Harbin，Zachary;Sohutskay，David;Tepole，Adrian Buganza
• 通讯作者: Tepole，Adrian Buganza

Multiscale mechanobiology: Coupling models of adhesion kinetics and nonlinear tissue mechanics

• DOI: 10.1016/j.bpj.2022.01.012
• 发表时间: 2022-02-15
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Guo, Yifan;Calve, Sarah;Tepole, Adrian Buganza
• 通讯作者: Tepole, Adrian Buganza