# Multiscale Modeling of Wound Healing

> **NIH NIH U01** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2020 · $513,586

## Abstract

PROJECT SUMMARY
Chronic wounds are a major threat to public health and present as a comorbid complication with major
diseases in humans. Although the proper healing of cutaneous wounds requires collective and
coordinated behaviors of multiple cell types, a critical step is the recruitment and function of dermal
fibroblasts, which are directed to invade the wound by gradients of a chemoattractant, platelet-derived
growth factor (PDGF). A handful of biologicals, most notably recombinant PDGF-BB, are currently
approved for treatment of wounds; however, the current treatments lack efficacy in accelerating wound
healing, and consequently they have not gained traction in the clinic. These disappointing results
underscore how poorly the dynamics of wound healing are understood at the tissue scale and the need
to connect knowledge of molecular, cellular, and tissue-level processes to inform and predict outcomes
of therapeutic strategies aimed at improving the rate and fidelity of wound repair. We have been
developing models of fibroblast chemotaxis with consideration of molecular (polarization of signal
transduction), supramolecular (assembly of actomyosin structures), cellular (biased cell movement),
and tissue-level (wound invasion) dynamics, which span disparate time (seconds to weeks) and spatial
(nm to cm) scales. Many challenges remain. First is the lack of a model connecting, in a mechanistic
way, signaling and cytoskeletal dynamics to the mechanics of membrane protrusion/retraction at the
cell's leading edge; we call this the molecules to motility problem (Aim 1). It is motivated by our recent
discoveries that PDGF chemotaxis and migration biased by gradients of extracellular matrix (ECM)
density (haptotaxis) are governed by distinct signaling pathways that affect F-actin dynamics and
mechanics in different ways. This fundamental difference is tied to the second critical need, which we
call the diversity of cues problem (Aim 2). PDGF is only one spatial cue for fibroblast migration, and
hence it is paramount to consider the confluence of chemotactic, haptotactic, and durotactic (gradients
in mechanical stiffness) cues that coexist in wounds. Preliminary modeling work has implicated an
additional form of spatial bias that we propose to explore: the influence of cell shape, or morphotaxis.
The third need is to integrate information about the spatial and biological heterogeneity of the wound.
Fast-moving macrophages secrete PDGF and are thus focal sources of chemoattractant, and ECM
density and stiffness are also expected to vary in space and time. We refer to the relation of
macrophage positions and the dynamic organization of ECM in vivo as the heterogeneous milieu
problem (Aim 3).

## Key facts

- **NIH application ID:** 10002331
- **Project number:** 5U01EB018816-07
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** Jason M. Haugh
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $513,586
- **Award type:** 5
- **Project period:** 2014-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002331

## Citation

> US National Institutes of Health, RePORTER application 10002331, Multiscale Modeling of Wound Healing (5U01EB018816-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10002331. Licensed CC0.

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