Tunable bio-inspired hybrid hydrogels reprogram stem cell-derived extracellular vesicles for superior wound regeneration.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Clinical translation of adipose-derived stem cell (ADSC)-derived extracellular vesicles (EVs) for cutaneous regeneration is challenged by variable secretion levels, heterogeneous molecular cargo, and inconsistent therapeutic potency. Here, we developed a mechanically tunable and biomolecularly instructive photocurable hybrid hydrogel (GelMA/HAMA/PEGDA) that serves both as a 3D culture microenvironment for ADSCs and as an EV-delivery scaffold. Systematic screening of PEGDA-controlled crosslinking identified GH11P (97% [15% GelMA : 1% HAMA = 1 : 1 (v/v)] + 3% PEGDA) as a formulation with balanced stiffness, controlled degradation, and cytocompatibility, supporting EV production under 3D culture. Multi-omics profiling suggested that EVs produced in this 3D matrix (3D-hcEVs) exhibit regenerative-associated signatures, including ECM-integrin interactions, focal adhesion-related pathways, PI3K-AKT signaling, and a keratin-enriched proteomic signature compared with dish-cultured EVs (dcEVs). Additional in vitro validation showed that 3D-hcEVs enhanced HaCaT migration and more strongly increased p-AKT/AKT than dcEVs at 30 and 60 min. An NTA-based in vitro release assay further demonstrated partial, sustained EV release from GH11P over 7 days. In a full-thickness dorsal wound model, GH11P scaffolds loaded with 3D-hcEVs accelerated wound closure compared with dcEV-loaded scaffolds and hy

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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