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In Vivo Model of Human Enthesis Regeneration

Award Number: K76AG057021
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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In Vivo Model of Human Enthesis Regeneration - Tendinopathies are ubiquitous and age-related. The natural history of tendinosis includes age-related tissue degeneration of the tendon mid-substance, or of the enthesis – the tendon-bone interface – often resulting in acute pain, loss of function and chronic disability. The primary reason for poor outcomes after surgical repair is failure of the endogenous cells to recreate fibrocartilage at the tendon-bone interface. Our prior studies of aged and young human tendon have revealed tenocytes develop a fibrochondrocyte and mineralized fibrochondrocyte phenotype depending on relative intracellular levels of Rac1 and RhoA GTPase activity, which are determined by the cell microenvironment. We have characterized this effect of RhoA/Rac1 GTPase activity on the human tenocyte phenotype, and have discovered an essential role of combined Rac1 in-activity and RhoA over-activity in development of the fibrochondrocyte phenotype. The goal of this proposal is to create a fibrocartilage construct fit for eventual clinical translation. First we will create a human tenocyte-engrafted electrospun nanofiber scaffold and culture it under conditions of hypoxia or normoxia, under tension or compression in a bioreactor. Biochemical, immunohistochemical and kinematic assays will be used to evaluate time and oxygen-dependent changes in human tenocyte phenotype on the scaffolds, via expression of selected markers, assessment of tissue organization and mechanical strength. Human tenocytes will then be treated with RhoA/Rac1 agents to produce Rac-1 in-activity and RhoA over- activity and cultured as above. The final objective of this proposal is to create an in vivo rabbit model for enthesis regeneration. First we will perform proof-of-concept studies: enthesis defects will be created in the Achilles tendon of rabbits and observed for healing at week 6 and 12 after defect creation, harvested and analyzed as above. Using the same enthesis defect model, tenocyte-engrafted scaffolds with stable Rac1 in-activity and RhoA over-activity will then be used to repair the enthesis defects, harvested at week 6 and 12, and analyzed as described above to evaluate maintenance of the enthesis phenotype as well as construct integrity during physiologic loading in vivo. Our aging patient population is in dire need of an innovative, consistent therapy for tendinosis. Our proposed interdisciplinary approach using cell biology, biochemical, tissue engineering and translational techniques will create a novel enthesis construct, fit to undergo clinical testing, with the goal of decreasing pain and restoring function in the elderly.


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 = -$1,872 )
2026	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	000	5	12/9/2025	NON-COMPETING CONTINUATION	-$1,872
														Subtotal = -$1,872

Issue Date FY: 2023 ( Subtotal = $230,497 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	000	5	6/9/2023	NON-COMPETING CONTINUATION	$230,497
														Subtotal = $230,497

Issue Date FY: 2022 ( Subtotal = $233,716 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	000	4	6/23/2022	NON-COMPETING CONTINUATION	$233,716
														Subtotal = $233,716

Issue Date FY: 2021 ( Subtotal = $236,872 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	000	3	6/30/2021	NON-COMPETING CONTINUATION	$236,872
														Subtotal = $236,872

Issue Date FY: 2020 ( Subtotal = $239,967 )
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	000	2	6/23/2020	NON-COMPETING CONTINUATION	$239,967
														Subtotal = $239,967

Issue Date FY: 2019 ( Subtotal = $243,000 )
2019	2019	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Aging Research	000	1	8/21/2019	NEW	$243,000
														Subtotal = $243,000

Grand Total All Awards = $1,182,180

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In Vivo Model of Human Enthesis Regeneration

Award Number: K76AG057021

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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