Conductive Hydrogen Sulfide-Releasing Hydrogel Encapsulating ADSCs for Myocardial Infarction Treatment

Abstract

Hydrogen sulfide (H₂S) exhibits extensive protective actions in cardiovascular systems, such as anti-inflammatory and stimulating angiogenesis, but its therapeutic potential is severely discounted by the short half-life and the poorly controlled releasing behavior. Herein, we developed a macromolecular H₂S prodrug by grafting 2-aminopyridine-5-thiocarboxamide (a small-molecule H₂S donor) on partially oxidized alginate (ALG-CHO) to mimic the slow and continuous release of endogenous H₂S. In addition, tetraaniline (a conductive oligomer) and adipose-derived stem cells (ADSCs) were introduced to form a stem cell-loaded conductive H₂S-releasing hydrogel through the Schiff base reaction between ALG-CHO and gelatin. The hydrogel exhibited adhesive property to ensure a stable anchoring to the wet and beating hearts. After myocardial injection, longer ADSCs retention period and elevated sulfide concentration in rat myocardium were demonstrated, accompanied by upregulation of cardiac-related mRNA (Cx43, α-SMA, and cTnT) and angiogenic factors (VEGFA and Ang-1) and downregulation of inflammatory factors (tumor necrosis factor-α). Echocardiography and histological analysis strongly demonstrated an increase in the ejection fraction value and smaller infarction size, suggesting a remarkable improvement of the cardiac functions of Sprague-Dawley rats. The ADSC-loaded conductive hydrogen sulfide-releasing hydrogel dramatically promoted the therapeutic effects, offering a promising therapeutic strategy for treating myocardial infarction.