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Dynamic Acellular Materials for Repairing Dense Connective Tissues

Award Number: R01AR056624
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: 07/14/2009
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Dynamic Acellular Materials for Repairing Dense Connective Tissues - Abstract Dense musculoskeletal tissues, such as the meniscus, are plagued by poor healing. Meniscal tears disrupt load transfer in the knee and instigate more widespread degenerative and inflammatory processes. Unfortunately, there are no current treatment options that restore meniscus function and joint homeostasis. To address this, we developed an injectable (shear-thinning) bicontinuous hydrogel that can be delivered in a minimally invasive manner to a meniscal tear to promote rapid colonization by cells. This hydrogel, composed of gelatin and hyaluronic acid (HA), exhibits unique microinterfaces with a high interfacial surface area that allows for rapid cell infiltration from adjacent tissue. Beyond a material that can be delivered to the damaged meniscus and supports subsequent cellularization, meniscus repair strategies must also address the physical and biological impediments to healing. We previously identified nuclear mechanics as a key impediment to meniscus cell migration and transiently reduced nuclear stiffness (using the histone deacetylase inhibitor trichostatin A, TSA) to enable rapid endogenous cell migration. We also found that inflammation present in the joint post-injury reduced meniscus cell migration, and that this could be reversed by applying FDA-approved interleukin antagonists (IL1ra). To deliver these factors, we developed a novel class of mechano-activatable microcapsules (MAMCs) that enable efficient encapsulation and staged release of sensitive biologic factors. In this renewal, we combine these exciting biomaterial (Aim 1) and drug delivery (Aim 2) advances to translate an innovative injectable hydrogel platform that concomitantly releases factors to enable cell migration, quell inflammation, and promote matrix production via controlled delivery in a load bearing joint setting. We test this novel therapy in vivo, in our large animal meniscus injury model (Aim 3) in the setting of established joint disease. Our overall hypothesis is that injectable bicontinuous materials coupled with mechanically activatable delivery of pro- migratory and anabolic agents will improve meniscus repair after injury. The proposed studies build on over 15 years of collaboration by our team of engineers and clinicians on the development of implantable and injectable biomaterials for meniscus injury. If successful, this work will provide a novel therapeutic material designed to treat meniscus tears that are otherwise considered irreparable, restoring joint health to the millions of patients with meniscal injuries.


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 = $496,955 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	4/9/2026	NON-COMPETING CONTINUATION	$496,955
														Subtotal = $496,955

Issue Date FY: 2025 ( Subtotal = $526,360 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	16	4/28/2025	COMPETING CONTINUATION	$526,360
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	4/18/2025	NON-COMPETING CONTINUATION	$0
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	15	8/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $526,360

Issue Date FY: 2024 ( Subtotal = $516,327 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	15	6/10/2024	NON-COMPETING CONTINUATION	$37,259
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	1/12/2024	NON-COMPETING CONTINUATION	$479,068
														Subtotal = $516,327

Issue Date FY: 2023 ( Subtotal = $532,296 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	14	2/16/2023	NON-COMPETING CONTINUATION	$53,228
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	12/16/2022	NON-COMPETING CONTINUATION	$479,068
														Subtotal = $532,296

Issue Date FY: 2022 ( Subtotal = $526,973 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	13	5/5/2022	NON-COMPETING CONTINUATION	$47,906
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	11/22/2021	NON-COMPETING CONTINUATION	$479,067
														Subtotal = $526,973

Issue Date FY: 2021 ( Subtotal = $501,533 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	12	5/17/2021	NON-COMPETING CONTINUATION	$36,193
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	1/6/2021	NON-COMPETING CONTINUATION	$465,340
														Subtotal = $501,533

Issue Date FY: 2020 ( Subtotal = $491,104 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	11	2/29/2020	COMPETING CONTINUATION	$8,704
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	1/31/2020	COMPETING CONTINUATION	$491,104
2020	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	10	2/29/2020	NON-COMPETING CONTINUATION	-$8,704
														Subtotal = $491,104

Issue Date FY: 2018 ( Subtotal = $453,153 )
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	8/15/2018	NON-COMPETING CONTINUATION	$453,153
														Subtotal = $453,153

Issue Date FY: 2017 ( Subtotal = $452,516 )
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	8/9/2017	NON-COMPETING CONTINUATION	$452,516
														Subtotal = $452,516

Issue Date FY: 2016 ( Subtotal = $451,900 )
2016	2016	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	8/23/2016	NON-COMPETING CONTINUATION	$451,900
														Subtotal = $451,900

Issue Date FY: 2015 ( Subtotal = $437,221 )
2015	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	8/3/2015	NON-COMPETING CONTINUATION	$437,221
														Subtotal = $437,221

Issue Date FY: 2014 ( Subtotal = $394,560 )
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	8/29/2014	COMPETING CONTINUATION	$394,560
2014	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	8/26/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $394,560

Issue Date FY: 2013 ( Subtotal = $310,617 )
2013	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	7/10/2013	NON-COMPETING CONTINUATION	$16,348
2013	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/11/2013	NON-COMPETING CONTINUATION	$294,269
														Subtotal = $310,617

Issue Date FY: 2012 ( Subtotal = $326,966 )
2012	2012	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	3/26/2012	NON-COMPETING CONTINUATION	$326,966
														Subtotal = $326,966

Issue Date FY: 2011 ( Subtotal = $319,588 )
2011	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/24/2011	NON-COMPETING CONTINUATION	$299,614
2011	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/8/2011	NON-COMPETING CONTINUATION	$19,974
														Subtotal = $319,588

Issue Date FY: 2010 ( Subtotal = $334,184 )
2010	2010	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/23/2010	NON-COMPETING CONTINUATION	$334,184
														Subtotal = $334,184

Issue Date FY: 2009 ( Subtotal = $381,290 )
2009	2009	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Trans-NIH Recovery Act Research Support	001	1	7/10/2009	SUPPLEMENT FOR EXPANSION	$39,476
2009	2009	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/17/2009	NEW	$341,438
2009	2009	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Trans-NIH Recovery Act Research Support	002	1	8/10/2009	SUPPLEMENT FOR EXPANSION	$376
														Subtotal = $381,290

Grand Total All Awards = $7,453,543

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Dynamic Acellular Materials for Repairing Dense Connective Tissues

Award Number: R01AR056624

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: 07/14/2009

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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