Regenerating the uterus: translational advances in endometrial bioengineering and immunotherapeutics

Uterine disorders, such as thin endometrium and intrauterine adhesions, remain significant challenges in reproductive medicine, often leading to infertility and poor pregnancy outcomes. Recent advances in regenerative medicine and tissue engineering have led to the development of innovative therapeutic strategies aimed at restoring endometrial structure and function. Biomaterials play a central role in these advancements, serving not only as structural scaffolds and delivery vehicles for stem/progenitor cells and bioactive molecules but also as modulators of the tissue microenvironment by promoting angiogenesis and regulating immune responses. Mesenchymal stem cells from various sources, including female reproductive tissues, along with their extracellular vesicles, have demonstrated potential in promoting angiogenesis, reducing fibrosis, and modulating immune responses for endometrial repair. Additionally, platelet-rich plasma and a range of pharmacological agents-often with advanced drug delivery systems, such as nanocarriers-further contribute to endometrial regeneration. Engineered scaffolds, particularly those derived from decellularized extracellular matrix or fabricated using three-dimensional bioprinting technologies, closely mimic the biomechanical and biochemical properties of native endometrium. These scaffolds facilitate cellular engraftment and provide valuable platforms for in vitro modeling of endometrial physiology. The development of uterus-derived extracellular matrix scaffolds with immunologically compatible biomaterials and organoids marks a pivotal step toward reducing immune rejection and improving clinical applicability. This review highlights recent progress in biomaterial-based therapeutics for uterine regeneration and discusses the remaining challenges in shifting therapeutic paradigms of personalized and tissue-specific regenerative strategies.