Lipoic Acid-Intervened Decellularized Stem Cell Spheroid-Based Injectable Granular Gel for Diabetic Tissue Regeneration.

Advancements in tissue engineering have revolutionized therapeutic paradigms for diabetic tissue defects; however, the lack of applicable scaffold containing various bioactive substance aggregates remained a critical bottleneck hindering satisfactory repair effect. In this study, adipose-derived stem cells (ADSCs) were functionally re-engineered using lipoic acid (LA) to fabricate a novel LA-intervened stem cell spheroid (LA-SCS) with enhanced paracrine activity and extracellular matrix (ECM) biosynthetic capacity. Subsequent decellularization mitigated immunogenicity, yielding LA-intervened decellularized stem cell spheroid (LA-dSCS). In vitro assays confirmed its immunomodulatory potency, as evidenced by the activation of signaling cascades associated with macrophage reprogramming, homeostasis, and autophagy. Furthermore, leveraging the intrinsic viscoelastic properties of the LA-dSCS, a convenient preparation method for preparing LA-dSCS derived injectable material was established, wherein LA-dSCS micro-particles assemble into LA-dSCS granular gel. In vivo studies using diabetic rat models demonstrated closure of both wound and cranial defects. Collectively, this study established a biomimetic engineering strategy that integrates cell-free bioactive aggregates with injectable granular gels, offering a novel proof‑of‑concept strategy for the regeneration of complex diabetic tissue defects.