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A Bio-inspired Latent TGF-beta Conjugated Scaffold for Patient-specific Cartilage Regeneration

Award Number: R01AR078299
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: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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A Bio-inspired Latent TGF-beta Conjugated Scaffold for Patient-specific Cartilage Regeneration - Summary Transforming growth factor beta (TGF-) has become one of the most widely utilized mediators to promote cartilage growth in tissue engineering (TE) applications. Conventionally, for in vitro culture phases, TGF- is supplemented in the culture medium with the expectation that it will readily diffuse into tissues and promote the biosynthesis of a healthy cartilage ECM. However, a growing body of evidence brings to light a central paradox with this conventional TGF- delivery strategy: physiologic TGF- doses exhibit limited penetration into the tissue, giving rise to undesirable non-uniform growth, while the alternative use of higher, supraphysiologic TGF- doses promotes the formation of cartilage with compromised tissue quality (e.g., fibrosis, hypertrophy, hyperplasia). In contrast to conventional TE TGF- delivery strategies, the natural process of TGF- delivery in native cartilage occurs quite differently, where chondrocytes are surrounded by large stores of TGF- that are sequestered in an inactive form, termed latent TGF- (LTGF-). Chondrocytes activate LTGF- stores via integrins or secreted enzymes, leading to highly advantageous, need-based activity throughout the tissue, which allows for essential ECM biosynthesis while avoiding the induction of pathological tissue formation. This proposal capitalizes on this native regulatory mechanism by creating a bio-inspired TE strategy, whereby chondrogenic cells are encapsulated in a hydrogel scaffold conjugated with large stores of LTGF-, akin to the native environment. This platform allows cells to endogenously activate these LTGF- stores, giving rise to the highly beneficial delivery of uniform and moderated, near-physiologic TGF- doses to cells, which promote biosynthetic enhancements in the absence of tissue quality limitations. Further, a novel reaction-diffusion modeling framework is developed to predict the activity of TGF- exposed to cells in constructs while accounting for the critical patient-specific chemical reactions applied to TGF- in the tissue. These patient-specific models can guide optimal LTGF- design parameters, allowing for optimal activity doses and giving rise to improved TE cartilage quality and mitigation of pathogenic off-target desorption of TGF- from the construct. In the current project, we examine the efficacy of this bio-inspired LTGF- scaffold platform by assessing: 1) the capability of reaction-diffusion models to optimize growth outcomes in patient-specific cell populations (human chondrocytes and MSCs), 2) the capability of model-optimized LTGF- scaffolds to improve TE cartilage performance in the hostile mechanochemical environment of the OA synovial joint through use of an ex vivo synovial joint bioreactor, and 3) the capability of LTGF- scaffolds to improve TE cartilage performance in an in vivo porcine focal defect model.


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: 2026 ( Subtotal = $585,747 )
2026	2026	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	5/25/2026	NON-COMPETING CONTINUATION	$585,747
														Subtotal = $585,747

Issue Date FY: 2025 ( Subtotal = $608,459 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	5/7/2025	NON-COMPETING CONTINUATION	$608,459
														Subtotal = $608,459

Issue Date FY: 2024 ( Subtotal = $608,459 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/11/2024	NON-COMPETING CONTINUATION	$608,459
														Subtotal = $608,459

Issue Date FY: 2023 ( Subtotal = $437,650 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/18/2023	NON-COMPETING CONTINUATION	$437,650
														Subtotal = $437,650

Issue Date FY: 2022 ( Subtotal = $478,735 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/1/2022	NEW	$478,735
														Subtotal = $478,735

Grand Total All Awards = $2,719,050

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A Bio-inspired Latent TGF-beta Conjugated Scaffold for Patient-specific Cartilage Regeneration

Award Number: R01AR078299

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: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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