Cardiac failure incurs a major economic and social burden on the United States populace, while also providing a distinct technical challenge since options for treating this condition remain highly limited. In ischemic cardiomyopathy ventricular wall thinning is coupled with dilation of the ventricular cavity. This remodeling process is associated with elevated ventricular wall stress that positively drives the thinning and dilation process towards end-stage heart failure. In the proposed work we will create novel designs for injectable biomaterials to bulk the thinning, post-infarct cardiac wall, reducing elevated wall stress, and potentially improving cardiac remodeling outcomes. The design objectives include synthesizing materials with tensile properties suitable for reducing wall stresses, degradation properties that maintain the hydrogel in the infarcted wall for a period of months during the remodeling process, and drug delivery properties that allow the controlled release of multiple growth factors that may stimulate beneficial cardiac remodeling. We will evaluate 3 distinct hydrogel designs with increasing complexity, utilizing both rat and porcine models of ischemic cardiomyopathy and a minimally invasive robotic technology (the HeartLander device) designed to effectively deliver the targeted hydrogel injections. The project specific aims are to: 1) Evaluate the functional and histopathologic effect of injecting the thermoresponsive hydrogel, poly(NIPAAm-co-acrylic acid-co-2-hydroxyethyl methacrylate-poly(trimethylene carbonate) into the central and border regions of a myocardial infarct in a porcine model for ischemic cardiomyopathy using a modified HeartLander minimally invasive robotic system. 2) Evaluate the functional and histopathologic effect of injecting the thermoresponsive hydrogel, poly(NIPAAm-co-HEMA-co-polylactide-methacrylate) into the central and border regions of a myocardial infarct in rat and then porcine (with HeartLander) models for ischemic cardiomyopathy. Hydrogel design optimization will be based on in vitro and rat in vivo results. 3) Develop and characterize the thermoresponsive hydrogel poly(NIPAAm-co-N-hydroxysuccinimide- methacrylate-co-HEMA-co-MAPLA) and the ability of this gel to deliver bFGF in vitro, as well as the ability to load this gel with microspheres containing IGF-1 for more extended controlled release. 4) Evaluate the functional and histopathologic effect of injecting growth factor loaded hydrogel from Aim #3, into infarcted myocardium in rat and porcine (with HeartLander) models for ischemic cardiomyopathy. Relevance: Once the early period following a heart attack passes, there are limited options for treating the heart failure that can develop. At the end of the proposed funding period we will have developed innovative injectable materials to treat heart failure following a heart attack as well as a robotic delivery system to allow material delivery in a manner that would minimize patient discomfort, complications and recovery time.

Public Health Relevance

It is estimated that 785,000 Americans will have a heart attack annually, and many of those who survive will ultimately face deteriorating function of their heart leading to later death. This research seeks to develop an approach where a gel-like material is injected into the heart after a heart attack to prevent the deterioration in heart function. This gel is being designed to protect the heart mechanically from further damage after the heart attack and to help stimulate the heart to heal itself.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105911-02
Application #
8207868
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lundberg, Martha
Project Start
2011-01-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$359,712
Indirect Cost
$84,941
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nelson, Devin M; Hashizume, Ryotaro; Yoshizumi, Tomo et al. (2014) Intramyocardial injection of a synthetic hydrogel with delivery of bFGF and IGF1 in a rat model of ischemic cardiomyopathy. Biomacromolecules 15:1-11
Nelson, Devin M; Ma, Zuwei; Leeson, Cory E et al. (2012) Extended and sequential delivery of protein from injectable thermoresponsive hydrogels. J Biomed Mater Res A 100:776-85