Biomedical Engineering pres.
Ph.D Defense: James R. Day
ngineering an Immuno-Isolating Hydrogel-Based Capsule to Restore Ovarian Endocrine Function
First, we developed a dual poly(ethylene glycol) (PEG) that was appropriate for both ovarian tissue transplantation and immuno-isolation. The Dual PEG capsule contained a proteolytically degradable core crosslinked via Michael-type addition which was conducive for the dynamic growth of ovarian tissue and a non-degradable PEG shell that would serve as the immuno-protective barrier. We demonstrated in an ovariectomized syngeneic murine model that ovarian tissue encapsulated in Dual PEG survived and functioned until removed 60 days after implantation, which was shown through resumption of cyclicity, restoration of the hypothalamic-pituitary-gonadal (HPG) axis, and presence of healthy developed follicles.
Next, we demonstrated the capsule was immuno-isolating as allogeneic ovarian tissue encapsulated in Dual PEG and implanted in recipient mice did not evoke a significant allo-specific antibody response compared to controls and the capsule did not allow cellular infiltration; protecting the encapsulated allograft from the outside immune environment and leading to ovarian endocrine restoration. After we proved that the Dual PEG capsule can prevent cellular infiltration, we demonstrated that the capsule can also retain cells encapsulated within, which can possibly be applied towards ovarian tissue auto-transplantation through retention of cancerous cells present in the graft and preventing cancer spreading and metastasis. We then demonstrated that encapsulation of ovarian allografts in Dual PEG precludes sensitization of the host immune system which proves the capsule is immuno-isolating and the host immune system is not exposed to allo-antigens while the graft is encapsulating, possibly allowing multiple implantations of the capsule.
Lastly, we demonstrate that non-human primate ovarian tissue can survive and develop in the Dual PEG capsule restoring ovarian endocrine function, while being protected from an immune response as indicated by the lack of active, dividing T cells in a syngeneic and allogeneic NHP model. This proves the capsule can withstand the volumetric change present in NHP folliculogenesis, protecting the encapsulated allograft, which promotes graft survival and ovarian endocrine restoration. Taken together, this dissertation works towards allowing the implantation of allogeneic ovarian tissue to restore ovarian endocrine function in a physiological manner without the risk of immune rejection.
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