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Bioinspired Mechanically Stiff Hydrogels for Osteochondral Tissue Regeneration

Award Number: R01AR069060
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: 07/25/2016
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Bioinspired Mechanically Stiff Hydrogels for Osteochondral Tissue Regeneration - Lesions to articular cartilage and underlying subchondral bone eventually lead to osteoarthritis, a debilitating disease with no cure. A successful therapy will need to promote tissue regeneration, support integrative repair, and protect the surrounding tissue from further degeneration. The overarching goal for this project is to develop a mechanically competent, stem cell-based regenerative approach to treat osteochondral (OC) defects. During the initial funding period, our team developed an OC-mimetic hydrogel with a design that decoupled the load- bearing (i.e., structural) component from the soft cellular biomimetic component. This allowed us to create a functionally graded, stiff structure with cartilage-matched mechanical stiffness, while creating soft cellular niches that supported mesenchymal stem cell (MSC) differentiation. Building from key in vitro milestones, this renewal aims to translate the OC-mimetic hydrogel in vivo. We will test the hypothesis that the OC-mimetic hydrogel induces rapid and targeted differentiation of exogeneous MSCs in vivo, enabling their direct participation in OC- tissue regeneration while simultaneously protecting and supporting integration with the surrounding tissue. A new feature of our design is a cement line-mimetic within the structural support that similar to the native cement line will be impervious to cell migration across the cartilage-bone interface, but pervious to nutrient transport. This will protect the MSCs in the cartilage layer, enabling their rapid differentiation and contribution to regeneration. We will test the overarching hypothesis in three specific aims. In Aim1, we will identify mechanotransduction pathways that differentially control MSC fate in the OC-mimetic hydrogel, which will allow us to establish a mechanistic understanding of the physiochemical cues that achieve robust MSC differentiation in a dynamic environment with loading. In Aim 2, we will determine MSC fate in vivo within the OC-mimetic hydrogel after implantation in a rat OC defect model by tracking differentially labeled MSCs isolated from DsRed+ and GFP+ rats. This aim will confirm MSC fate and their direct and indirect contribution to OC-tissue regeneration. In Aim 3, we will create a structural support that undergoes surface degradation to maintain its mechanical properties. We will evaluate the effectiveness of this fully degradable and mechanically competent OC-mimetic hydrogel using three models of increasing complexity: an OC explant defect model to monitor the health of and integration with articular cartilage adjacent to the defect as the support structure degrades; a rat OC defect model for longitudinal studies to monitor in vivo degradation of the structure concomitant with tissue regeneration and integrative repair; and, testing in a pre-clinical animal (swine) model. At the conclusion of this project, we expect to have (1) advanced our fundamental understanding of the mechanotransduction pathways in MSCs and their fate in vivo and (2) established a mechanically competent and degradable OC-mimetic hydrogel that achieves OC-tissue regeneration and integrative repair, while maintaining joint health.


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 = $678,679 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	7	8/25/2025	SUPPLEMENT FOR EXPANSION	$84,326
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	4/23/2025	NON-COMPETING CONTINUATION	$551,462
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	7	5/19/2025	NON-COMPETING CONTINUATION	$42,891
2025	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	4/30/2025	TERMINATION	$0
2025	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	6	7/11/2025	OTHER REVISION	$0
														Subtotal = $678,679

Issue Date FY: 2024 ( Subtotal = $663,077 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	6/11/2024	NON-COMPETING CONTINUATION	$42,705
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	2/21/2024	NON-COMPETING CONTINUATION	$549,057
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	6	6/18/2024	SUPPLEMENT FOR EXPANSION	$71,315
														Subtotal = $663,077

Issue Date FY: 2023 ( Subtotal = $603,233 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/21/2023	NON-COMPETING CONTINUATION	$603,233
														Subtotal = $603,233

Issue Date FY: 2022 ( Subtotal = $618,267 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	4/20/2022	COMPETING CONTINUATION	$618,349
2022	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/4/2021	NON-COMPETING CONTINUATION	-$82
														Subtotal = $618,267

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/3/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $321,459 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST., RM 479 572 UCB	BOULDER	CO	80303	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/3/2018	NON-COMPETING CONTINUATION	$321,459
														Subtotal = $321,459

Issue Date FY: 2017 ( Subtotal = $341,609 )
2017	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST., RM 479 572 UCB	BOULDER	CO	80303	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/27/2017	NON-COMPETING CONTINUATION	$341,609
														Subtotal = $341,609

Issue Date FY: 2016 ( Subtotal = $352,248 )
2016	2016	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/22/2016	NEW	$352,248
														Subtotal = $352,248

Grand Total All Awards = $3,578,572

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Bioinspired Mechanically Stiff Hydrogels for Osteochondral Tissue Regeneration

Award Number: R01AR069060

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: 07/25/2016

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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