# Engineering the Immune and Fibrotic Response in Volumetric Muscle Loss

> **NIH NIH R01** · UNIVERSITY OF OREGON · 2024 · $317,397

## Abstract

ABSTRACT
 Extremity trauma involving large tissue loss presents a significant clinical challenge for both general and military
populations. When these injuries involve Volumetric Muscle Loss (VML), the current gold standard surgery is treatment
with muscle flap autografts or free tissue transfer. However, these result in significant fibrosis and fatty infiltration, impaired
regeneration, chronic pain, and significant long-term functional disabilities. There is currently a fundamental lack of
understanding of the molecular and cellular processes in the hostile environment of a full thickness, critically sized VML
defect which leads to the fibrotic and poor healing outcomes regardless of the treatment approach. In a series of recent
publications in pre-clinical VML models, our group has defined the critical size threshold above which the characteristic
VML hallmarks are observed: fibrosis and fatty infiltration, chronic inflammation, and lack of myofiber bridging across the
defect. We now present preliminary evidence that there is a distinct and dysregulated cellular response in the critically sized
defect with rapid proliferation of fibro-adipogenic progenitor cells (FAPs). FAPs are a dynamic mesenchymal stromal cells
that play a critical support and coordination role for muscle stem cells, also known as satellite cells (MuSCs), during
regeneration; however, in chronic muscle pathologies, like muscular dystrophies, FAPs can differentiate into fibrotic and
adipogenic lineages in a process that is thought to be directed by macrophages and specific subsets of M2 macrophages.
The overall objective of this proposal is to regenerate functional muscle after VML by engineering an immunomodulatory
biomaterial system to direct the FAPs towards a pro-regenerative state, thus creating an environmental niche conducive to
MuSCs transplantation and muscle regeneration. Our central hypothesis posits that following VML injury, local FAPs
undergo a transition to an aberrant phenotype that directly differentiates into fibrotic and fatty tissue and that controlled
delivery of pro-resolving lipid mediators will resolve these FAPs and restore the regenerative potential of MuSCs. We
propose the following aims: Aim 1: To determine the role of aberrant FAPs in fatty infiltration and fibrosis associated with
VML injuries. Aim 2: To assess the contribution of increased pro-fibrotic signaling of M2 polarized macrophages on FAPs
function in VML. Aim 3: To test whether co-delivery of pro-regenerative FAPs and MuSC within PEG-4MAL hydrogel
enhance muscle regeneration and functional recovery following VML. Impact – VML is a pervasive clinical challenge with
poor functional outcomes even after gold standard autograft treatment. We will define the critical roles of immune and FAP
cells in this process and develop newly engineered immunomodulatory and regenerative treatment strategies that will
provide a foundation to translate into clinical treatments for VML.

## Key facts

- **NIH application ID:** 10892181
- **Project number:** 5R01AR078375-04
- **Recipient organization:** UNIVERSITY OF OREGON
- **Principal Investigator:** Nick J Willett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $317,397
- **Award type:** 5
- **Project period:** 2021-09-16 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892181

## Citation

> US National Institutes of Health, RePORTER application 10892181, Engineering the Immune and Fibrotic Response in Volumetric Muscle Loss (5R01AR078375-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10892181. Licensed CC0.

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