Life-preserving strategies in the face of a cancer diagnosis, including radiation, surgery, and chemotherapy, can compromise nearly all aspects of the female reproductive axis resulting in infertility, subfertility, or premature menopause. In addition, several conditions and disease states can have a similar consequence. Fortunately for females, the ovary has the potential for diverse fertility preservation options ranging from standard (i.e. IVF, ICSI, embryo banking) to investigational (ovarian tissue cryopreservation, ovarian transplant). In vitro follicle growth is another emerging technology that has tremendous promise for a subset of individuals who have blood-borne malignancies, cannot tolerate supraphysiological hormone levels, cannot delay treatment, or do not have a sperm donor. Tremendous success has been achieved in performing IVFG in the mouse to the degree that live births have been achieved using gametes derived from nearly all methods attempted to date. The translation of this technology to large mammalian species, however, has not been trivial due to significant differences in factors such as follicle size, development, metabolic requirements, and physical niche. In this project, we will develop """"""""smart"""""""" biomaterials that will provide human follicles with the ability to self-regulate their physical environment as they grow to terminal stages of development. We anticipate that such an environment will maintain the coordinated growth of the oocyte and its companion granulosa cells, which is required for optimal endocrine function and gamete quality. We will also develop new non-invasive endocrine measures of follicle health that, through a precise algorithm, could be used in association with conventional steroid and peptide assays to predict the maturity of individual follicles. Follicles developed to the right stage of maturity will contain the highest quality gamete, and we will use innovative nanonewton force measurements to quantitatively understand the mechanisms by which a chromosomally normal egg is generated both in vivo and in vitro during meiosis These experiments have broad implications on human health as a chromosomally normal egg is a fundamental pre-requisite to create a healthy offspring.
Our aims are based on experiments that integrate three model organisms - mouse, cow, and human - and span multiple disciplines - reproductive medicine, cell and molecular biology, bioengineering, and biophysics. This union will allow us to advance our understanding of human reproductive biology in a quantitative way, and at the same time provide key insights into the possible clinical translation of in vitro follicle culture systems to preserve fertility in young patients with cancer or other reproductive disorders.
The ovarian follicle as it is found in the ovary is a unique structure that contains the oocyte completely surrounded by and intimately connected to supporting granulosa cells, and this architecture is essential for informing follicle function and gamete quality. This architecture can be recapitulated and maintained in vitro using alginate-based hydrogels, and is essential for human follicle development which cannot be supported using culture methods on flat surfaces where the follicle structure rapidly disintegrates. We propose to develop new ways to support human in vitro follicle growth and to test egg quality with the goal of inventing methods that provide reliable ways to obtain high quality female gametes.
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