Endometrial Repair and Regenerative Medicine: From Broad-Spectrum Regeneration to Precision Intervention.

Endometrial injury-related disorders, including intrauterine adhesions, thin endometrium, and chronic endometritis, are a major cause of female infertility. Conventional therapeutic approaches, primarily hormone therapy and surgical interventions, show limited effectiveness in patients with moderate to severe endometrial damage. In this context, regenerative medicine has emerged as a promising direction to overcome current therapeutic limitations and promote functional reconstruction of the endometrium. A comprehensive literature search was conducted across PubMed, Web of Science, Embase, and Scopus to identify relevant studies on endometrial repair and regenerative medicine. The search covered publications from January 2000 to August 2025. The following keyword combinations and MeSH terms were used: ("endometrial repair" OR "endometrial regeneration" OR "intrauterine adhesion" OR "Asherman syndrome" OR "thin endometrium" OR "chronic endometritis") AND ("mesenchymal stem cells" OR "platelet-rich plasma" OR "exosomes" OR "extracellular vesicles" OR "biomaterials" OR "hydrogel" OR "scaffold" OR "regenerative medicine"). Both basic science investigations and clinical studies were included to provide a comprehensive overview of current developments in the field. To minimize the risk of omission, the reference lists of included articles and relevant reviews were manually screened, and potentially pertinent studies were further evaluated. Inclusion criteria: (1) Original research articles or meta-analyses; (2) Focus on therapeutic interventions for endometrial regeneration; (3) Human clinical studies or mammalian animal models. Exclusion criteria: (1) Non-English articles, letters, conference proceedings, etc.; (2) Purely descriptive studies of endometrial physiology without therapeutic intervention, articles lacking quantitative data or sufficient methodological details. The screening process followed the PRISMA 2020 guidelines (Fig. 1). After removing duplicates, 1936 records were screened by title and abstract, and 605 full-text articles were assessed for eligibility. Finally, 102 studies were included in this qualitative synthesis. This review provides a systematic synthesis of recent advances in cell-based therapies, cell-free approaches, and bioengineering strategies for endometrial repair. Evidence derived from different sources of mesenchymal stem cells, including bone marrow, umbilical cord, and endometrium, is comparatively evaluated alongside platelet-rich plasma and extracellular vesicles, with an emphasis on hierarchical assessment of evidence levels. Several critical issues are further examined. Current stem cell-based interventions are largely characterized by a broad reparative profile, yet precise targeting of key molecular mechanisms remains insufficient. To date, no studies have demonstrated the capacity to directly reverse suppression of signaling pathways such as the GZMA-PARD3 axis or to restore depleted regenerative stromal subpopulations, including IGFBP3⁺ cells. Clinical investigations of platelet-rich plasma exhibit substantial heterogeneity, which appears to stem mainly from the absence of standardized preparation protocols and the frequent reliance on surrogate endpoints, particularly endometrial thickness. However, the predictive value of endometrial thickness for live birth is limited, and its use as a primary endpoint may overestimate clinical benefit. Therefore, emphasis should shift toward patient-centered outcomes such as live birth rate. Concerns also arise regarding the degradation kinetics of biomaterials, as mismatches between material resorption and the cyclical regenerative dynamics of the endometrium may increase the risk of secondary adhesions. In addition, the actual delivery efficiency of microneedle-based systems within the enclosed and humid uterine environment has not yet been fully clarified. Based on this critical appraisal, we propose a translational framework that links mechanistic discovery with precision intervention. The importance of long-term follow-up is emphasized, with live birth rate regarded as a more clinically meaningful primary endpoint for evaluating therapeutic efficacy in endometrial regenerative medicine. Endometrial regenerative medicine is transitioning from empirical repair toward mechanism-informed reconstruction. Current evidence is dominated by short-term (< 12 months), small-sample (n < 50) exploratory studies with high interventional heterogeneity. Clinical translation will require unified preparation standards, individualized treatment strategies, and well-designed multicenter randomized controlled trials with live birth rate as the primary endpoint and minimum 2-year follow-up.