Towards ischemic tissue regeneration and protection: design of a drug-loaded multilayered cardiac patch with synergistic degradation and release.

Abstract

Myocardial infarction remains a global health challenge, necessitating advanced therapeutic strategies to address both acute injury and chronic ventricular remodeling. This study presents an innovative tri-layered bioartificial patch engineered to modulate degradation kinetics and drug release for prolonged cardiac regeneration. By integrating a slower-degrading polycaprolactone (PCL) and gelatine-based inner layer into a microstructured polylactic-co-glycolic acid (PLGA) and gelatine architecture, we developed a system with a highly controlled biphasic degradation profile. Hydrolytic degradation tests revealed that while the external PLGA-based layers undergo bulk degradation and complete dissolution by 60 to 90 days, the internal PCL-based membrane successfully retains its structural integrity and biomimetic micropatterning for up to 90 days. This structural stability also enabled a tailored dual-release of bioactive molecules: a rapid 50-70% burst release of the cardioprotective agent adenosine within the first 5 hours to target acute reperfusion injury, paired with a restricted about 6% release of the antifibrotic drug pirfenidone over 7 days, effectively preserving it for the later stages of tissue healing. Furthermore, the incorporation of the Fmoc-FF peptide conferred a stable electrical conductivity of 4.6 µS cm^-1 at 1 Hz without compromising the matrix structure. In vitro biological assessments confirmed excellent cytocompatibility across all layers, supporting an H9c2 cardiomyoblast viability of roughly 90% after 72 hours. Human iPSC-CMs cultured on the patch maintained spontaneous and synchronous beating activity. Moreover, the patch loaded with PIR exhibited significant antifibrotic activity, confirming that the released drug remained biologically active. Ultimately, this multi-layered design provides a promising and functionally active platform for counteracting pathological remodeling and restoring myocardial tissue.