Stem cell secretome- and extracellular vesicle-based therapies for retinal pathologies

Table 5 Review-specific evidence-maturity framework

Level	Evidence category	Interpretation in this review	Principal limitations
Level 1	In-vitro, ex-vivo, or organoid mechanistic evidence	Biological plausibility and mechanistic proof-of-concept	Does not establish in-vivo exposure, biodistribution, safety, or therapeutic efficacy
Level 2	In-vivo animal efficacy evidence	Preclinical proof-of-concept in an intact biological system	Species/model differences, heterogeneous products and doses, and limited prediction of human efficacy
Level 3	Early uncontrolled human feasibility or safety evidence	Preliminary human feasibility, safety, or efficacy signal	Small samples, lack of concurrent controls, confounding/co-interventions, and inability to establish efficacy
Level 4	Controlled human clinical efficacy evidence	Comparative clinical evidence capable of testing efficacy	Requires adequate power, standardized products, appropriate controls, clinically meaningful endpoints, and external validity

This is a review-specific conceptual framework. It is not a validated grading system, a formal risk-of-bias instrument, or a substitute for GRADE. The level reflects translational maturity and evidence directness rather than overall methodological quality.