Abstract
BackgroundImproved cancer therapeutics and enhanced cancer survivorship have emphasized the severe long-term side effects of chemotherapy. Specifically, studies have linked many chemotherapy agents with primary ovarian insufficiency, although an exact insult model has not yet been determined. To investigate and ultimately solve this problem, a novel device for extended study of mammalian ovaries in vitro was developed.MethodsA bioreactor was fabricated for bovine ovarian culture that provides intravascular delivery of media to the ovary through isolation and cannulation of a main ovarian artery branch. Whole ovaries were cultured in vitro using three methods: (1) continuously supplied fresh culture media, (2) recirculated culture media, or (3) continuously supplied fresh culture media supplemented with 500 nM doxorubicin for 24 or 48 h. TUNEL assay was used to assess apoptotic cell percentages in the three groups as compared to uncultured baseline ovaries.ResultsThe ovary culture method was shown to maintain cell viability by effectively delivering nutrient-enriched pH-balanced media at a constant flow rate. Lower apoptosis observed in ovaries cultured in continuously supplied fresh culture media illustrates that this culture device and method are the first to sustain whole bovine ovary viability for 48 h. Meanwhile, the increase in the percentage of cell apoptosis with doxorubicin treatment indicates that the device can provide an alternative model for testing chemotherapy and chemoprotection treatments to prevent primary ovarian insufficiency in cancer patients.ConclusionsAn ovarian bioreactor with consistent culture media flow through an ovarian vasculature-assisted approach maintains short-term whole bovine ovary viability.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0249-4) contains supplementary material, which is available to authorized users.
Highlights
Improved cancer therapeutics and enhanced cancer survivorship have emphasized the severe long-term side effects of chemotherapy
These factors provide motivation to determine the cellular cause of chemotherapy-induced primary ovarian insufficiency (POI) and develop drug-based measures to inhibit its development in cancer patients
Bioreactor system setup and functionality To study the bioreactor system functionality and efficacy, we examined fluid distribution through the ovarian tissue over time
Summary
Improved cancer therapeutics and enhanced cancer survivorship have emphasized the severe long-term side effects of chemotherapy. Studies have linked many chemotherapy agents with primary ovarian insufficiency, an exact insult model has not yet been determined. While innovations in cancer chemotherapy allow patients to live longer, they have been shown to lead to subsequent long-term complications, such as primary ovarian insufficiency (POI) [1]. Further complications have been associated with POI, including onset of osteoporosis and cardiovascular disease [2, 3]. These factors provide motivation to determine the cellular cause of chemotherapy-induced POI and develop drug-based measures to inhibit its development in cancer patients. The effects of DXR have been documented in mice as well as marmoset ovaries including DNA damage within 2 h, follicular attrition in as little as 12 h postinjection, and permanent reduction in ovary size up to Zanotelli et al Journal of Ovarian Research (2016) 9:47
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