Heparin-binding domains in elastin-like proteins for improved tissue integration

Abstract

A heart attack leads to irreversible damage to the heart muscle. Current treatment methods mainly focus on the prevention of secondary infarcts and do not replace the lost cells. Consequently, a myocardial infarction often initiates a chain of events leading to the development of cardiac arrhythmias and ultimately heart failure. New stem cell therapies are under development, but are impeded by the limited retention of these cells at the infarct site. As a result, the majority of injected cells do not have ample time to differentiate into functional cardiomyocytes. Injectable hydrogels offer an elegant approach to increase stem cell retention. Elastin-like proteins (ELPs) have a long history in this field as a result of their intrinsic lower critical solution temperature (LCST). Dynamic hydrogels based on oxidised hyaluronic acid and hydrazide-functionalised ELPs have been previously demonstrated to increase cell retention without impeding injectability. We used these materials as a benchmark and built on this concept by incorporating heparin-binding domains (HBDs) in the ELP structure. This class of positively charged protein domains has been previously studied as affinity tag in protein purification and was expected to also interact with negatively charged components in the extracellular matrix (ECM), such as hyaluronic acid and sulphated glycosaminoglycans (GAGs). By relying on an custom-built injectability set-up, we studied the interaction of the incorporated HBDs with other ECM components such as hyaluronic acid and collagen in an indirect way by relating changes in the injectability of hydrogel formulations to changes in viscosity induced by coacervation.