(342d) Engineering Ovarian Follicle Maturation

In vitro culture and maturation of ovarian follicles is a promising method for treating infertility when IVF is not suitable, such as chemotherapy induced sterility or disorders such as polycystic ovarian syndrome (PCOS). Immature follicles, consisting of a centrally located oocyte surrounded by 1-2 layers of granulosa cells, can be isolated from the ovary and cryopreserved. The development of methods to promote follicle development and oocyte maturation in vitro, or to transplant early stage follicles with high engraftment and controlled development could provide reproductive options. We have pioneered the development of controllable environments for the in vitro culture and in vivo transplantation of immature ovarian follicles.

Our three-dimensional culture systems promote growth of early stage follicles that can produce fertilizable oocytes and live births. The 3D culture maintains the follicular architecture and cell-cell connectivity, while allowing for growth. Maintaining the architecture is particularly critical for small follicles and has enabled the individual culture of primary follicles, which was not possible with previous culture systems. Our culture systems has been extended to the culture of canine, rhesus macaques, baboons, and human follicles. We identified that the mechanical properties of the gel are critical regulators of follicle development, and the changes associated with the mechanical environment were recently correlated with patients that have PCOS in a genome wide association study. Ongoing research is applying systems biology tools to analyze folliculogenesis, and is identifying mechanisms governing follicle growth and oocyte quality. Modifications to the media composition derived from our analysis has substantially enhanced growth and survival of primary follicles. Identifying a TF regulatory network that underlies the highly coordinated process of folliculogenesis can be employed to engineer systems that promote follicle development in vitro and in vivo. 

Ovarian tissue transplantation is an alternative to follicle culture that has restored fertility for women; however, survival, engraftment, and duration of function of the transplanted tissue remain challenging. Early stage follicles can be transplanted, however these follicles may not persist due to low survival following transplantation, or recruitment into the growing pool by the local environment. Our biomaterials facilitated host-graft integration for graft function, which was enhanced by delivery of angiogenic factors locally. Live births conceived naturally resulted from transplantation. Taken together, results from these biomaterial systems will contribute to our understanding of folliculogenesis and the impact of the local environment, which may ultimately lead to novel fertility options for women.