Minimally Invasive Targeted Injection of Thermoresponsive Hydrogels for Cardiomyopathy

The proposed research will develop an optimized strategy to interrupt the progressive ventricular wall remodeling that characterizes ischemic cardiomyopathy (ICM). Cardiac failure following myocardial infarction imposes a significant burden on the economy and society, and despite various efforts and strategies, there is still no definitive treatment preventing progression of ICM. The pathology is characterized by progressive thinning of the infarcted ventricular wall and dilation of the ventricular cavity coupled with elevated ventricular wall stress, resulting in decreasing global cardiac function toward end-stage heart failure. To break this pernicious cycle, we have advanced and refined an approach that reduces ventricular wall stress by injecting designed hydrogels into the infarcted wall, leading to preserved cardiac geometry and function. In this proposal we will leverage our extensive experience with cardiac injection therapy to integrate technological advances into a clinically translatable system for ICM treatment. This will include (aim #1) evaluating the functional, geometric, and histopathologic effects in a porcine ICM model by injecting one of three different types of hydrogel based on a synthetic thermoresponsive hydrogel (poly(NIPAAm-co-VP-co-MAPLA)). Hydrogel 1 is the non-porous form of this hydrogel. Hydrogel 2 develops porosity in situ by the integration of dissolvable mannitol particles, and hydrogel 3 builds upon this porous hydrogel with the addition of extracellular matrix components from enzymatically digested, decellularized cardiac tissue. In aim #2 a surgical robotic system will be developed for safe, spatially controlled, and minimally invasive delivery of the hydrogels from aim #1 to the ventricular wall. Innovations will include a navigation system based on preoperative 3D MRI images, intraprocedure detection of coronary vasculature with ultrasound, epicardial mapping of impedence and activation, clearing of pericardial adhesions, detection of heart wall thickness and controlled injection depth. In aim #3, by segmenting MRI images collected prior to injection, animal-specific finite element models will be built for mechanical modeling of cardiac wall stresses and strains. An optimization algorithm will be developed to create prescribed injection patterns to maximally reduce von Mises wall stress based on the infarct architecture and constraints on injection number and volume. The patient-specific developed approach will then be applied to a new set of infarcted pigs to create a specific hydrogel (from aim #1 results) injection pattern that will be accomplished by the robotic system developed in aim #2 and compared to the non-optimized injection pattern. Collectively, through these investigations, we will advance a new, minimally invasive strategy to treat ICM in a period where there are few options to interrupt the negative remodeling that leads to end-stage cardiac failure, and by doing so, reduce the profound morbidity and mortality of this condition. Project Number: 1R01HL174945-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: WILLIAM WAGNER | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $695,865 | Activity Code: R01 | Study Section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17494501A1