Engineering strategies and challenges in building the follicular microenvironment for a bioprosthetic ovary

Many individuals with ovaries that utilize fertility preservation because of their progressive disease or gonadotoxic treatment must use ovarian tissue cryopreservation (OTC). Currently, the only option for fertility and hormone restoration after OTC is ovarian tissue transplantation (OTT), or autologous grafting of ovarian tissue. Individuals with disease in their ovaries do not have options to produce a biological child or restore their full ovarian hormone milieu. The goal of developing a bioprosthetic ovary would support full fertility and hormone restoration long-term as a safer and ideally more efficient option than current OTT techniques. In order to develop a bioprosthetic ovary, the field must understand how to control the rate of primordial follicle activation and support the follicle growth through development and maturation into a good quality egg. The follicular microenvironment changes across the lifespan and the growing oocyte is surrounded by a different microenvironment as it is localized in different compartments within the ovary over folliculogenesis. The human ovarian interstitial cells, scaffold proteins and the juxtracrine, paracrine and endocrine signals that influence folliculogenesis are just being realized with the increased data generated by mapping technologies. Recent research has utilized bioengineering tools to interrogate these follicular microenvironment components and better understand the components that are necessary and sufficient to sustain folliculogenesis and produce good quality eggs. However, there are several biological, scalability and regulatory hurdles to overcome in order to realize a bioprosthetic ovary, including the ability to isolate sufficient primordial follicles from their dense stroma while maintaining their quiescence and subsequent transplant longevity. This chapter reviews these components and encourages researchers to continue on these research quests to increase the foundational understanding of human folliculogenesis and develop near-future solutions for infertility on the way to developing the ideal bioprosthetic ovary.