Cardiomyocyte-Mimetic Conductive Hydrogel Microspheres for Enhanced Myocardial Repair

Conductive hydrogels hold great promise for treating myocardial infarction (MI) by electrically coupling with the myocardium to improve the local microenvironment. However, their dense network often limits cellular infiltration and angiogenesis, while a mechanical mismatch with native heart tissues may provoke arrhythmia. Here, inspired by the biochemical and electrical microenvironment of the myocardium, we fabricated conductive hydrogel microspheres by first modifying a myocardial tissue-derived decellularized extracellular matrix (d-ECM) with methacryloyl groups to yield a photo-cross-linkable ECM hydrogel precursor. We generated uniformly sized ECM microspheres via a cross-shaped PDMS microfluidic chip, which were subsequently endowed with electrical conductivity via in situ oxidative polymerization of polypyrrole (PPY), resulting in ECM-PPY microspheres. In vitro studies demonstrated that ECM-PPY significantly upregulated the connexin 43 (Cx43) expression in cardiomyocytes. Moreover, the conductive microspheres promoted human umbilical vein endothelial cell migration and tube formation. In a rat MI model, treatment with ECM-PPY microspheres improved the cardiac function. Furthermore, the conductive microspheres reduced the fibrotic area, stimulated microvessel formation, increased the level of Cx43 expression, and suppressed cardiomyocyte apoptosis in the infarcted region. These findings demonstrate a conductive and bioactive microsphere-based strategy for myocardial repair after an MI.