An injectable multifunctional hydrogel for cardiac spatiotemporal repair via modulating oxidative stress and the inflammatory microenvironment

Abstract

Myocardial infarction (MI), a leading cause of global cardiovascular mortality, is characterized by a vicious cycle of oxidative stress and inflammatory responses, resulting in irreversible myocardial damage and ventricular remodeling. To address the limitations of current therapies in comprehensively targeting the post-MI pathological microenvironment, this study developed an injectable hydrogel system, termed CPH (DS/CMCS), through the rational integration of carboxymethyl chitosan (CMCS), dextran sulfate (DS), and oxidized dextran (ODex) as a dynamic crosslinker. The CPH hydrogel not only mimicked the mechanical properties of the native myocardial extracellular matrix but also integrated multifunctional capabilities, including antioxidant activity, anti-inflammatory effects, pro-angiogenic potential, and enhanced electrical signal conduction. Through both cellular and animal studies, it was conclusively shown that the CPH hydrogel effectively scavenged reactive oxygen species (ROS), protected cardiomyocytes from oxidative damage, modulated macrophage polarization to mitigate inflammatory cascades, and promoted vascular regeneration and myocardial remodeling. In the rat MI model, the CPH hydrogel significantly improved cardiac function and achieved comprehensive structural restoration of infarcted myocardium. This study introduces an innovative acellular spatiotemporal approach for the treatment of MI and advances the rational design of cardiac tissue-engineered biomaterials, highlighting its substantial clinical translation potential for regenerative medicine.