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Interdependence of Post-MI Local Revascularization and Remuscularization by Engineered Human Myocardium on Cardiac Remodeling and Regeneration

Award Number: R01HL173938
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/18/2024
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Interdependence of Post-MI Local Revascularization and Remuscularization by Engineered Human Myocardium on Cardiac Remodeling and Regeneration - Project Summary/Abstract Biomaterials enable the local, controlled delivery of therapeutics like proteins and cells to target tissues damaged by injury or disease. Customization of these biomaterial-therapeutics systems is essential to overcome challenges of specific microenvironments and achieve functional regeneration. The heart after myocardial infarction (MI) is one such injury bed that necessitates localized treatments for re-establishing microvessels and delivering new cardiomyocytes (CMs). The permanent decline in heart function in patients post-MI is due to CM death and compromised perfusion, leading to the onset of heart failure in over 3 million Americans. Persistent ischemia in the myocardium after acute MI limits the recovery and contractility of the surviving heart muscle, and treatments have yet to replace the lost CMs. Attempts to deliver (a) angiogenic growth factors to regenerate the vasculature and (b) new CMs derived from human induced pluripotent stem cells (hiPSCs) to the post-MI heart have suffered from multiple challenges due to a lack of optimized delivery systems. This project addresses this gap by advancing biomaterial systems for heart regeneration post-MI by integrating a revascularization strategy for repair and a remuscularization strategy for regeneration. Our long- term goal is to re-engineer contractility in the heart with a holistic approach to restore myocardium through the vasculature and replenish CMs using engineered human myocardium (EHM). The overall objective of this proposal is to demonstrate efficacy of customized biomaterials using an optimized angiogenic protein cocktail and EHM to alleviate arrhythmia risk and improve contractility. These studies aim to understand how repair and regeneration ensue by using longitudinal imaging to reveal dynamics of perfusion and contractility as well as integrated 3D analyses of structure, perfusion, excitation, and contractility. Our central hypothesis is that increasing perfused microvessel density in the infarct and EHM implant using local delivery of biomaterials for microvascular regeneration and EHM for remuscularization will promote tissue preservation and maturation of hiPSC-CMs to reduce arrhythmias and enhance contractility. We will rigorously test this hypothesis in two aims with implantation of an angiogenic biomaterial film alone or with EHM in a rat model of ischemia/reperfusion MI. Aim 1 is to evaluate how local controlled release of an angiogenic factor cocktail alters post-MI ventricular remodeling, perfusion, arrhythmia risk, and contractility. Aim 2 is to elucidate how angiogenic co-therapy modulates cellular remuscularization with EHM for post-MI regeneration of perfusion, excitation, and contraction. The parallel aims develop our understanding of how biomaterials and tissue engineering advance revascularization and remuscularization as effective angiogenic, anti-arrhythmic, and contractile therapies for the heart. This project uses innovative technologies and analyses to accelerate novel treatments to the clinic by revealing mechanistic insights into revascularization and remuscularization for heart repair and regeneration.


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 = $668,368 )
2025	2025	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Cardiovascular Diseases Research	001	2	9/3/2025	NON-COMPETING CONTINUATION	$66,836
2025	2025	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Cardiovascular Diseases Research	000	2	3/11/2025	NON-COMPETING CONTINUATION	$601,532
														Subtotal = $668,368

Issue Date FY: 2024 ( Subtotal = $696,163 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Cardiovascular Diseases Research	001	1	5/15/2024	NEW	$0
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Cardiovascular Diseases Research	000	1	3/15/2024	NEW	$696,163
														Subtotal = $696,163

Grand Total All Awards = $1,364,531

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Interdependence of Post-MI Local Revascularization and Remuscularization by Engineered Human Myocardium on Cardiac Remodeling and Regeneration

Award Number: R01HL173938

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/18/2024

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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