Abstract
The gonadotoxic effects of chemotherapy and radiation may result in premature ovarian failure in premenopausal oncology patients. Although autotransplantation of ovarian tissue has led to successful live births, reintroduction of latent malignant cells inducing relapse is a significant concern. In this report, we investigated the design of biomaterial grafts for transplantation of isolated ovarian follicles as a means to preserve fertility. Primordial and primary ovarian follicles from young female mice were extracted and encapsulated into biomaterials for subsequent transplantation into adult mice. Among the formulations tested, aggregated follicles encapsulated within fibrin had enhanced survival and integration with the host tissue following transplantation relative to the fibrin-alginate and fibrin-collagen composites. All mice transplanted with fibrin-encapsulated follicles resumed cycling, and live births were achieved only for follicles transplanted within VEGF-loaded fibrin beads. The extent to which these procedures reduce the presence of metastatic breast cancer cells among the isolated follicles was evaluated, with significantly reduced numbers of cancer cells present relative to intact ovaries. This ability to obtain live births by transplanting isolated primordial and primary follicles, while also reducing the risk of re-seeding disease relative to ovarian tissue transplantation, may ultimately provide a means to preserve fertility in premenopausal oncology patients.
Highlights
The gonadotoxic effects of chemotherapy and radiation may result in premature ovarian failure in premenopausal oncology patients
While ovarian tissue transplantation has resulted in fertility preservation in primates[24] and in humans (> 60 live births to date)[25,26,27,28,29,30,31,32,33], this technique can present a potential risk for reintroduction of malignant cells[34], and has previously resulted in cancer relapse[35]
We evaluated the efficacy of our procedures in reducing the number of associated cancer cells relative to transplanted ovarian tissue using mice transplanted with human metastatic breast cancer cells[46]
Summary
The gonadotoxic effects of chemotherapy and radiation may result in premature ovarian failure in premenopausal oncology patients. Such biomaterial systems have been used to encapsulate and culture secondary follicles in vitro, demonstrating that oocytes could be retrieved, fertilized, and implanted to produce live births in a mouse model[36,37,38], as well as support development of nonhuman primate follicles[39,40,41] and human secondary[39] and pre-antral follicles[42] These materials were employed for the encapsulation and transplantation of early stage follicles (primordial and primary, with some secondary), yet the material design was altered due to the significantly different requirements for in vivo transplantation relative to in vitro culture (e.g., integration with host tissue). Methods for follicle transplantation could have an important impact on the field of fertility preservation by extending transplantation-based options to cancer patients while minimizing the risk of subsequent ovarian tissue-transplant related cancer relapse
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