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Optimizing Ultrasound Regimens for Achieving Cartilage Repair

Award Number: R01AR079499
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: 02/11/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Optimizing Ultrasound Regimens for Achieving Cartilage Repair - ABSTRACT As cartilage has poor innate repair and regeneration capacity, therapies that can address early cartilage injury and prevent further osteoarthritic deterioration would have a large clinical impact. Due to the ease of isolation and multi-lineage differentiation potential of mesenchymal stromal cells (MSCs), methods that rely either on matrix assisted mesenchymal-stromal-cell-implantation (MSCI) or microfracture (MF) have attracted clinical attention. Currently, the functional outcomes of MSCI or MF, including approaches that deliver growth factors in vivo, are characterized by biomechanically inferior fibrocartilage, and poor integration scores. Joint inflammation has been identified to inhibit chondrogenesis of MSCs, thus contributing to the low efficacy of cartilage repair outcomes. Critically, approaches that offer chondroprotection by the mitigating the catabolic effects of the pro- inflammatory joint environment while promoting in situ chondrogenesis are required. To address the critical challenge of improving functional-cartilage-repair outcomes, a non-invasive adjunct; continuous low- intensity ultrasound (cLIUS) with recently published chondroinductive and chondroprotective properties to demonstrate enhanced chondral repair for both MACI and MF procedures will be employed. The ability of cLIUS to improve cartilage repair outcomes will be demonstrated via three specific aims: AIM 1: Demonstrate cLIUS-induced chondrogenesis of MSCs in a pro-inflammatory environment. RNA-sequencing will be employed to gather an in-depth transcriptomic profiling and underlying pathways that drive MSC chondrogenesis under cLIUS in a pro-inflammatory environment. AIM 2: Develop a computationally validated and optimized regimen of cLIUS therapy. Computational grids will be built from magnetic resonance images (MRIs) coupled with a biphasic finite element model for wave propagation in the joints to determine the specific cLIUS regimen for sheep joints. Models will be validated with acoustic propagation experiments in sheep-cadaver knee joints. AIM 3: Demonstrate Improved Functional Outcomes of Cartilage Repair Under cLIUS. Demonstrate the superior repair of critically sized chondral defects via MF and MSCI in the articular cartilage of sheep using an optimized transdermal delivery of cLIUS and evaluate at six months. Analysis of regenerated cartilage will be through histological, biomechanical and biochemical methods. Successful completion of this work is expected to lead to the development of a cLIUS-based regimen and delivery system capable of generating a stable hyaline cartilage phenotype via minimally invasive procedures, while advancing the fundamental understanding of MSC preconditioning under cLIUS. This would, in turn, directly address the treatment of 46 million Americans who suffer from OA at an estimated cost of $128 billion annually.


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 = $417,264 )
2025	2025	THE UNIVERSITY OF ALABAMA IN HUNTSVILLE	301 SPARKMAN DR NW	HUNTSVILLE	AL	35805	MADISON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/20/2024	NON-COMPETING CONTINUATION	$417,264
2025	2025	THE UNIVERSITY OF ALABAMA IN HUNTSVILLE	301 SPARKMAN DR NW	HUNTSVILLE	AL	35805	MADISON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $417,264

Issue Date FY: 2024 ( Subtotal = $489,996 )
2024	2024	THE UNIVERSITY OF ALABAMA IN HUNTSVILLE	301 SPARKMAN DR NW	HUNTSVILLE	AL	35805	MADISON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/21/2024	NON-COMPETING CONTINUATION	$35,362
2024	2024	THE UNIVERSITY OF ALABAMA IN HUNTSVILLE	301 SPARKMAN DR NW	HUNTSVILLE	AL	35805	MADISON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	11/2/2023	NON-COMPETING CONTINUATION	$454,634
														Subtotal = $489,996

Issue Date FY: 2023 ( Subtotal = $495,204 )
2023	2023	UNIVERSITY OF ALABAMA IN HUNTSVILLE, THE	301 SPARKMAN DR NW	HUNTSVILLE	AL	35805	MADISON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	11/30/2022	NON-COMPETING CONTINUATION	$445,683
2023	2023	UNIVERSITY OF ALABAMA IN HUNTSVILLE, THE	301 SPARKMAN DR NW	HUNTSVILLE	AL	35805	MADISON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	2/22/2023	NON-COMPETING CONTINUATION	$49,521
														Subtotal = $495,204

Issue Date FY: 2022 ( Subtotal = $493,923 )
2022	2022	UNIVERSITY OF ALABAMA IN HUNTSVILLE, THE	301 SPARKMAN DR NW	HUNTSVILLE	AL	35805	MADISON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/11/2022	NEW	$493,923
														Subtotal = $493,923

Grand Total All Awards = $1,896,387

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Optimizing Ultrasound Regimens for Achieving Cartilage Repair

Award Number: R01AR079499

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: 02/11/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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