Engineering the ovarian niche: Environmental control of folliculogenesis in vitro

Advancements in cancer therapies have significantly improved patient survival, but gonadotoxic treatments often compromise fertility, particularly in female patients. While ovarian tissue cryopreservation and transplantation are well-established fertility preservation options, they are not recommended for patients with blood-borne cancers or highly metastatic malignancies due to the risk of ovarian involvement. In these cases, follicle in vitro culture offers a promising alternative. However, folliculogenesis is a complex process that requires meticulous environmental control to mimic the ovarian niche. Key factors include biochemical signals delivered through culture media, biophysical support provided by three-dimensional biomaterials or the native extracellular matrix, and crucial cellular interactions that drive follicular development. Recent advances in biomaterial design have led to the creation of scaffolds that not only preserve structural integrity but also facilitate nutrient exchange and cell communication. Moreover, dynamic culture systems have shown superior outcomes compared to static models, offering a more physiologically relevant environment. This review explores the interplay of biochemical, biophysical, and mechanical factors in in vitro folliculogenesis. By synthesizing current innovations in scaffold design, culture systems, and bioactive supplementation, we outline key strategies for optimizing in vitro follicular development. These advances pave the way toward safer and more effective fertility preservation approaches for patients at high risk of ovarian metastasis and offer broader insights into reproductive biology and regenerative medicine. However, to fully realize this potential, further standardization, long-term safety studies, and critical evaluation of emerging technologies remain essential to enable robust clinical translation and personalized reproductive applications.