An injectable sulfonated reversible thermal gel for therapeutic angiogenesis to protect cardiac function after a myocardial infarction

David J Lee,Daewon Park,Maria A Cavasin,Danielle E Soranno,Xianzhong Meng,Adam J Rocker,Robin Shandas

doi:10.1186/s13036-019-0142-y

Abstract

BackgroundCardiovascular disease and myocardial infarction are associated with high mortality and morbidity and a more effective treatment remains a major clinical need. The intramyocardial injection of biomaterials has been investigated as a potential treatment for heart failure by providing mechanical support to the myocardium and reducing stress on cardiomyocytes. Another treatment approach that has been explored is therapeutic angiogenesis that requires careful spatiotemporal control of angiogenic drug delivery. An injectable sulfonated reversible thermal gel composed of a polyurea conjugated with poly(N-isopropylacrylamide) and sulfonate groups has been developed for intramyocardial injection with angiogenic factors for the protection of cardiac function after a myocardial infarction.ResultsThe thermal gel allowed for the sustained, localized release of VEGF in vivo with intramyocardial injection after two weeks. A myocardial infarction reperfusion injury model was used to evaluate therapeutic benefits to cardiac function and vascularization. Echocardiography presented improved cardiac function, infarct size and ventricular wall thinning were reduced, and immunohistochemistry showed improved vascularization with thermal gel injections. The thermal gel alone showed cardioprotective and vascularization properties, and slightly improved further with the additional delivery of VEGF. An inflammatory response evaluation demonstrated the infiltration of macrophages due to the myocardial infarction was more significant compared to the foreign body inflammatory response to the thermal gel. Detecting DNA fragments of apoptotic cells also demonstrated potential anti-apoptotic effects of the thermal gel.ConclusionThe intramyocardial injection of the sulfonated reversible thermal gel has cardioprotective and vascularization properties for the treatment of myocardial infarction.

Highlights

Cardiovascular disease and myocardial infarction are associated with high mortality and morbidity and a more effective treatment remains a major clinical need
poly(serinol hexamethylene urea) (PSHU)-PNIPAM slowed the clearance of VEGF, but no significant amount of VEGF was remaining after 14 days
The sulfonation groups in SPSHU-PNIPAM provided a decrease in the initial burst release compared to PSHU-PNIPAM and localized VEGF can still be seen after 14 days

Summary

Introduction

Cardiovascular disease and myocardial infarction are associated with high mortality and morbidity and a more effective treatment remains a major clinical need. The intramyocardial injection of biomaterials has been investigated as a potential treatment for heart failure by providing mechanical support to the myocardium and reducing stress on cardiomyocytes. Another treatment approach that has been explored is therapeutic angiogenesis that requires careful spatiotemporal control of angiogenic drug delivery. Biomaterial injections combined with the controlled release of biologicals may encourage cardiac regeneration and functional improvement as the material will localize and sustain biomolecule delivery, while protecting the biologic factors and extend their half-live in vivo [7]. The incorporation of heparin in a hydrogel system can be used to regulate drug release, while maintaining bioactivity and improving controlled microvessel growth [13]

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