Efficacy and safety of stem cell therapy for dry eye disease: a systematic review and meta-analysis

Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by loss of tear film homeostasis, inflammation, neurosensory abnormalities, and epithelial damage. Despite the availability of topical immunomodulators and procedural interventions, a substantial proportion of patients with moderate-to-severe or refractory DED experience persistent symptoms and inadequate ocular surface recovery. Stem cell-based therapies, particularly mesenchymal stem cells (MSCs) and MSC-derived exosomes, have emerged as regenerative and immunomodulatory strategies aimed at restoring epithelial integrity and tear film stability rather than providing solely symptomatic relief. We conducted a systematic review and meta-analysis to evaluate the clinical efficacy and safety of stem cell and stem cell-derived therapies in human DED.

This study followed PRISMA 2020 guidelines and was prospectively registered in PROSPERO (CRD420251057372). Six databases were searched from inception to May 14, 2025. Eligible studies were peer-reviewed human clinical investigations evaluating stem cell-based interventions for DED and reporting objective efficacy outcomes such as Schirmer test, tear break-up time (TBUT), corneal fluorescein staining (CFS), or patient-reported outcomes including the Ocular Surface Disease Index (OSDI). Pooled mean differences (MDs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Statistical heterogeneity was assessed using the I² statistic. Risk of bias was evaluated using RoB 2 for randomized controlled trials and ROBINS-I for non-randomized studies.

Six studies comprising 131 patients were included. Stem cell-based therapies demonstrated significant improvements in tear production, tear film stability, epithelial integrity, and symptom burden. Schirmer test improved by MD = 4.70 mm (95% CI, 4.18-5.22; p < 0.001; I² = 12.59%), indicating a consistent enhancement of aqueous tear secretion. TBUT showed a large standardized improvement with pooled SMD = 1.125 (95% CI, 0.821-1.428; p < 0.001), although randomized trials demonstrated smaller effect sizes than non-randomized studies. OSDI scores decreased by MD = -11.44 points (95% CI, -22.71 to -0.17; p = 0.047), reflecting symptomatic improvement but with substantial between-study variability. Corneal fluorescein staining decreased by MD = -1.04 (95% CI, -1.23 to -0.84; p < 0.001; I² = 0%), supporting epithelial recovery. No serious treatment-related adverse events were reported; however, safety reporting was heterogeneous and follow-up durations were limited.

Stem cell and stem cell-derived therapies are associated with significant improvements in both objective and subjective outcomes in DED and demonstrate a favorable short-term safety profile. Nevertheless, heterogeneity in cell source, delivery route, dosage, and study design limits generalizability. Larger, rigorously designed randomized trials with standardized protocols and longer follow-up are required to confirm efficacy and establish long-term safety.