Exogenous miR-29B Delivery Through a Hyaluronan-Based Injectable System Yields Functional Maintenance of the Infarcted Myocardium

Michael G. Monaghan, Monika Holeiter, Eva Brauchle, Shannon L. Layland, Yan Lu, Arjun Deb, Abhay Pandit, Ali Nsair, Katja Schenke-Layland

Myocardial infarction results in debilitating remodeling of the myocardial extracellular matrix. In this proof-of-principle study it was sought to modulate this aggressive remodeling by injecting a hyaluronic acid-based reservoir delivering exogenous microRNA-29B (miR-29B). This proof-of-principal study was executed whereby myocardial ischemia/reperfusion was performed on C57BL/6 mice for 45 minutes after which five 10 µl boluses of a hydrogel composed of thiolated hyaluronic acid crosslinked with poly (ethylene glycol) diacrylate, containing exogenous miR-29B as an active therapy, were injected into the borderzone of the infarcted myocardium. Following surgery, the myocardial function of the animals was monitored up to five weeks. Delivering miR-29B locally using an injectable hyaluronan-based hydrogel resulted in a maintenance of myocardial function at two and five weeks following myocardial infarction in this proof-of-principle study. Additionally, while animals treated with the control of a non-targeting microRNA delivered using the hyaluronan-based hydrogel had a significant deterioration of myocardial function; those treated with miR-29B did not. Histological analysis revealed a significantly decreased presence of elastin and significantly less immature/newly deposited collagen fibers at the borderzone of the infarct. Increased vascularity of the myocardial scar was also detected and Raman microspectroscopy discovered significantly altered extracellular matrix-specific biochemical signals at the borderzone of the infarct. This preclinical proof-of-principle study demonstrates that an injectable hyaluronic acid hydrogel system could be capable of delivering miR-29B towards maintaining cardiac function following myocardial infarction. Additionally, Raman microspectroscopy revealed subtle, yet significant changes in ECM organization and maturity. These findings have great potential with regard to using injectable biomaterials as a local treatment for ischemic tissue and exogenous microRNAs to modulate tissue remodeling.