Multiscale Mechanobiology of Growth and Remodeling During Wound Healing

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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.