Bioreactor Actuated Ovarian Development

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DESCRIPTION (provided by applicant): The follicle is the essential unit of the ovary, providing both oocytes and the steroid hormones necessary for female development and reproduction. Follicle growth is a prolonged process that involves progressive development of the follicle unit through specific histologically defined stages of development. Because of the advent of new infertility treatments and artificial reproductive technologies over the last two decades, we have built up an excellent understanding of late-stage follicle development. In contrast, we know very little about the earlier stages of follicle development. Recently many groups around the world have begun ovarian cryopreservation programs for young girls and women undergoing potentially sterilizing surgery or chemotherapy with the hope that follicles can be isolated from these tissues and grown in vitro at a later date, when the woman desires to become pregnant. Since growing follicles do not survive freezing, only the very small primordial follicles remain after cryopreservation. Though follicles derived from mice can be grown up to maturity using conventional culture techniques, scientists have been unsuccessful with the in vitro development of follicles from species that have larger follicles, such as rats, pigs and humans. Therefore there is no current technology in which these preserved ovarian tissues can be utilized to study follicle development or even to restore fertility. We have recently performed studies to determine why rat follicles fail to progress beyond the preantral follicle stage in vitro. Our preliminary studies demonstrated that under conventional conditions, rat follicles frequently undergo flattening and rupture with loss of anatomic integrity that is important to the normal egg maturation process. When follicles were cultured in suspension culture systems, consisting of orbiting test tubes and rotating-wall vessels, the follicles did not rupture and exhibited more robust growth. Therefore we believe that advances in bioreactor technologies hold great promise toward the development of a system that can support the complex needs of the developing follicle. The lack of knowledge surrounding early stage follicle development makes this a high-risk project because reactor design will have to be empirical rather than based on known biological imperatives. We propose that bioengineering can overcome empiricism and provide solutions that support the growth of early stage follicles and establish markers of healthy follicle development that can be used to fine tune culture conditions to obtain optimized follicle growth and development.