Thursday, August 21, 2025 8/21/2025

Engineering the Immune and Fibrotic Response in Volumetric Muscle Loss

Award Number: R01AR078375
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Engineering the Immune and Fibrotic Response in Volumetric Muscle Loss - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $294,859 )
2025	2025	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	5	8/18/2025	NON-COMPETING CONTINUATION	$294,859
2025	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	7/11/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/30/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/27/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $294,859

Issue Date FY: 2024 ( Subtotal = $433,484 )
2024	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/24/2024	SUPPLEMENT FOR EXPANSION	$26,793
2024	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	7/30/2024	NON-COMPETING CONTINUATION	$317,397
2024	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	7/31/2024	SUPPLEMENT FOR EXPANSION	$89,294
														Subtotal = $433,484

Issue Date FY: 2023 ( Subtotal = $327,346 )
2023	2023	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/21/2023	NON-COMPETING CONTINUATION	$327,346
														Subtotal = $327,346

Issue Date FY: 2022 ( Subtotal = $323,620 )
2022	2022	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	9/15/2022	NON-COMPETING CONTINUATION	$323,620
2022	2021	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/14/2022	NEW	$0
														Subtotal = $323,620

Issue Date FY: 2021 ( Subtotal = $337,432 )
2021	2021	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/16/2021	NEW	$337,432
														Subtotal = $337,432

Grand Total All Awards = $1,716,741

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Engineering the Immune and Fibrotic Response in Volumetric Muscle Loss

Award Number: R01AR078375

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/16/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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