Human Recombinant Collagen Hydrogel for Control of Ventricular Remodeling and Repair After Myocardial Infarction

Abstract

Myocardial infarction (MI) leads to permanent loss of cardiac muscle due to the limited regenerative potential of the mammalian heart. The affected heart muscle is replaced by a fibrotic scar; however, the scar is not able to offset the increase in wall stress placed on the remaining myocardium. This distending pressure can lead to dilative remodeling of the ventricle, progressive loss of cardiac function, and heart failure. Despite current medical therapy, heart failure continues to have a high mortality rate. Therefore, there is a clinical need for treatments that can both improve cardiac function post-MI and reduce ventricular remodeling to prevent progression to heart failure. Injectable biomaterials aim to provide a scaffold to stimulate infarct repair by mimicking the healthy cardiac extracellular matrix (ECM). The ECM plays a critical role in tissue regeneration but after a MI it is pathologically modified. Injection of biomaterials post-MI can provide a scaffold that better stimulates infarct repair. In this study, hydrogels were developed from recombinant human type I and type III collagen (rHCI and rHCIII), the two most prevalent structural proteins in the cardiac ECM. Injection of rHCI and rHCIII hydrogels in a mouse model of MI improved cardiac function and reduced infarct size 28 days post-treatment. Infarcted hearts treated with rHCI exhibited improved myocardial salvage in the region bordering the scar with improved capillary density. rHCI hydrogel was also superior to rHCIII in reducing ventricular remodeling. The injection of rHCI hydrogel into the border zone post-MI resulted in an acute improvement of contractile function two days after treatment that was maintained long-term. At two days post-injection, rHCI treated animals had reduced apoptotic cardiomyocytes and lower levels of oxidative stress. Methylglyoxal modifies and crosslinks collagen in the ECM, leading to oxidative stress. Two days after injection, the rHCI hydrogel at the epicardial surface was modified by methylglyoxal, while methylglyoxal-derived advanced glycation end-product levels in the underlying myocardium were lower than in control animals. It appears that rHCI hydrogel injection is soaking up free methylglyoxal from the myocardium, reducing levels of oxidative stress in cardiac muscle and improving contractility of cardiomyocytes bordering the scar. These results suggest that rHC therapy is a promising approach to improve cardiac contractility, and limit ventricular remodeling post-MI.