TABLE 6.

Evidence levels and critical appraisal of hydrogel-EV systems for skin wound healing.

Highest evidence level	Representative studies	Wound/model types	Main findings	Major limitations
In vitro	(De Cesare et al., 2026; Nurfajrin et al., 2026)	Fibroblast/MSC-related skin-repair assays; human 1BR3 skin fibroblast model	EV-loaded hydrogels showed favorable cytocompatibility and promoted wound-relevant cellular responses, including fibroblast activity, migration/proliferation, and regenerative responses	Simplified cell-culture systems cannot reproduce the inflammatory, vascular, immune, metabolic, and mechanical complexity of wounds and provide no direct evidence regarding in vivo retention, biodistribution, systemic safety, or whole-wound efficacy
Small animal	(Li et al., 2021; Han et al., 2022; Song et al., 2023; Tang et al., 2023; Wang et al., 2023; Liu S. et al., 2024; Wang et al., 2024; Liu B. et al., 2025; Meng et al., 2025; Vipin and Kumar, 2025; Zhang Y. et al., 2025; Subhan et al., 2026; Taghdi et al., 2026; Wang S. et al., 2026; Yang et al., 2026)	Predominantly mouse and rat models of full-thickness/acute, diabetic, infected, chronic inflammatory, and burn wounds	Collectively, EV-hydrogel systems improved wound closure and re-epithelialization, angiogenesis, collagen deposition/remodeling, and inflammatory regulation. Recent studies additionally evaluated controlled EV release, local retention/biodistribution, and defined molecular mechanisms	Evidence remains dominated by rodents. Rodent skin healing relies more strongly on contraction than human healing. Marked heterogeneity in EV source/preparation, hydrogel composition, EV dose, treatment regimen, wound model, follow-up duration, and outcome measures limits cross-study comparison and clinical extrapolation
Large animal	(Cui et al., 2026)	Porcine full-thickness skin excision model	Chitosan hydrogel combined with MSC-derived exosomes accelerated wound closure and epithelialization, reduced wound contraction and inflammation, enhanced angiogenesis and type I collagen deposition, and produced more mature skin architecture	Large-animal evidence remains extremely sparse. Independent replication, standardized dosing, EV release/retention, long-term safety remain insufficient
Human	Direct clinical hydrogel-EV wound-healing evidence not identified	Not applicable	Not applicable	Clinical efficacy, optimal EV dose, hydrogel formulation, treatment frequency, manufacturing consistency, long-term safety, and clinically meaningful endpoints remain to be established in prospective controlled human studies

Studies were classified according to the highest level of experimental validation. Studies containing both in vitro and small-animal experiments were classified as small-animal evidence and were not duplicated in vitro evidence.