Mechanically Compliant Hydrogel Bioelectronics Promote Diabetic Skeletal Muscle Regeneration Through Immunomodulatory and Electrocoupling Effects

Abstract

Although hydrogel-based therapies have demonstrated promising results in treating volumetric muscle loss (VML), addressing diabetic skeletal muscle defects remains a major challenge due to the interplay of chronic inflammation and impaired regenerative capacity associated with diabetes mellitus. This study presents a novel multifunctional hydrogel bioelectronic conductor designed specifically for diabetic VML repair. The hydrogel, which self-assembles from mannose receptor-binding glucomannan, polydopamine-functionalized conductive polypyrrole, and gelatin, mimics the mechanical properties of native muscle tissue while providing immunomodulatory and electrocoupling effects. Multiple crosslinking mechanisms, involving both dynamic covalent and noncovalent interactions, endow the hydrogel with enhanced tissue adhesion (adhesion strength of 69.41 kPa to soft tissue), elasticity (100% self-recovery), and rapid self-healing ability (less than 1 min). The electrically conductive hydrogel-based elastic bioelectronics can reestablish effective electrical coupling with electroactive muscle tissue, while its intrinsic immunomodulatory properties induce M2-type macrophage polarization to alleviate chronic inflammatory response. In a diabetic rat VML defect model, the hydrogel bioelectronic conductor facilitated effective immunomodulation, muscle regeneration, and functional recovery of injured VML. These results suggest that the integration of tissue-mimicking mechanics with both immunomodulatory and conductive properties offers a promising therapeutic approach for diabetic skeletal muscle repair.