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A microphysiological system of tendon inflammation and fibrosis for drug screening and efficacy testing

Award Number: UH3TR003281
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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A microphysiological system of tendon inflammation and fibrosis for drug screening and efficacy testing - Acute and chronic tendon injuries are among the most common musculoskeletal health problems. Typically, an injured tendon experiences fibrotic scarring that leaves the tissue mechanically compromised and prone to debilitating adhesions that impair joint function. In a fibrotic tendon scar, the cell-cell and paracrine signaling between inflammatory cells, such as macrophages, and tendon fibroblasts activate the latter into fibroproliferative myofibroblasts, ultimately differentiating into a senescent phenotype. Our previous studies using next-generation sequencing and gene set enrichment analysis mechanistically linked fibrosis and senescence in injured mouse tendons with TGF-beta activated mTOR signaling. To further elucidate this pathology, the goal of this proposal is to engineer a microfluidic human tendon-on-chip (hToC) system and use it to more accurately model the biological aspects of the inflammation and fibrosis in injured tendons. In the UG3 phase of this proposal, the chip will be fabricated featuring a multicompartmental design and microfluidic channels to incorporate a fibroblast-seeded collagen hydrogel and simulate vascular blood flow, respectively. Ultrathin, highly permeable, and optically transparent porous silicon membranes (SiM) will separate the hydrogel from circulation and provide a substrate for an endothelial barrier in between. The signaling between the fibroblasts, hydrogel-resident- and circulating-macrophages, and endothelial cells will be enabled through nanoporous SiM (~60 nm), while a microporous SiM (~ 8 µm) will allow extravasation of circulating macrophages and infiltration of the hydrogel under TGF-beta stimulation. To allow for a patient-centric chip, tendon fibroblasts will be used to create the tendon hydrogel and to reprogram donor-matching iPSCs to derive the endothelial cells and macrophages, respectively. An additional innovation will be the integration of label- free photonic sensors into the microfluidic device to allow on-chip sensing, which has been long appreciated as a critical, unmet need for organ-on-chip devices. The UG3 studies will use the chip to validate the role of mTOR in the disease model and identify biologically relevant biomarkers. In the UH3 phase, we will utilize the chip as a pre-clinical trial platform for testing efficacy and safety of FDA-approved mTOR inhibitors as potential disease modifying drugs, and as a drug screening platform to identify and prioritize safer and more potent inhibitors of mTOR and senescence in tendon injury for clinical trials. To successfully complete this innovative project, we have assembled a team of accomplished experts in tendon tissue engineering and surgery, immunology, iPSC technology, GMP cell manufacturing, nano- and micro-fabrication, sensor technology, and high throughput screening. The proposed studies will develop a human microphysiological system to catalyze clinical trials and accelerate drug discovery for acute and chronic tendon 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 = $0 )
2026	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	National Center for Advancing Translational Sciences	000	5	1/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $710,273 )
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	National Center for Advancing Translational Sciences	001	5	8/22/2024	NON-COMPETING CONTINUATION	$710,273
2024	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	National Center for Advancing Translational Sciences	000	4	12/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $710,273

Issue Date FY: 2023 ( Subtotal = $775,928 )
2023	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	National Center for Advancing Translational Sciences	001	4	8/16/2023	NON-COMPETING CONTINUATION	$721,927
2023	2022	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	National Center for Advancing Translational Sciences	000	3	5/17/2023	EXTENSION WITH OR WITHOUT FUNDS	$54,001
														Subtotal = $775,928

Issue Date FY: 2022 ( Subtotal = $740,400 )
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	National Center for Advancing Translational Sciences	000	3	7/29/2022	EXTENSION WITH OR WITHOUT FUNDS	$740,400
														Subtotal = $740,400

Grand Total All Awards = $2,226,601

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A microphysiological system of tendon inflammation and fibrosis for drug screening and efficacy testing

Award Number: UH3TR003281

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/15/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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