Integrative bioengineering strategies for endometrial regeneration: From biomaterials and stem cells to organoids and organ-on-a-chip technologies

Endometrial regeneration remains a significant clinical challenge for women with intrauterine adhesions (IUAs), thin endometrium, or uterine factor infertility, conditions that severely impair fertility and reproductive outcomes. Traditional hormonal and surgical interventions often fail to restore the structural and functional integrity of damaged endometrial tissue. This review comprehensively examines integrative bioengineering strategies for endometrial regeneration, focusing on the synergistic applications of biomaterials, stem cells, organoids, and organ-on-a-chip technologies. Natural polymers such as collagen, gelatin, alginate, hyaluronic acid, and synthetic polymers including PCL, PLA, PGA, and PLGA have been comprehensively evaluated for their ability to mimic extracellular matrix, support cell proliferation, angiogenesis, and modulate immune responses. The incorporation of mesenchymal stem cells, extracellular vesicles, and growth factors into bioengineered scaffolds, such as hydrogels and nanofiber membranes, enhances regenerative efficacy. Furthermore, emerging platforms, such as endometrial organoids, 3D bioprinting, and organ-on-a-chip systems, offer physiologically relevant models for precision regenerative medicine. Innovations such as AI-assisted monitoring, 4D printing, and advanced drug delivery systems represent transformative approaches to overcome current therapeutic limitations. This review highlights the convergence of materials science, stem cell biology, and microengineering as a foundation for next-generation, personalized therapies aimed at restoring endometrial function and fertility. In addition, the review highlights biomaterial-based strategies as the foundation of endometrial regeneration, by detailing how natural polymers (e.g., collagen, gelatin, alginate, hyaluronic acid) and synthetic polymers (e.g., PCL, PLA, PLGA) support tissue repair structurally and by mediating biological functions. The integration of advanced technologies, such as 4D printing, AI-assisted monitoring, and stem cell-derived extracellular vesicle delivery has emerged as a transformative direction for overcoming current clinical challenges. Collectively, these approaches offer a next-generation therapeutic paradigm for restoring endometrial function and fertility.