Premature ovarian failure (POF) is a common complication of anticancer treatments due to extreme toxicity of chemotherapy and bone marrow transplantation. In female cancer survivors POF causes sterility, along with the consequences of absent ovarian endocrine function: premature osteopenia and muscle wasting, and accelerated cardiovascular diseases. These long lasting effects are significant, particularly for young girls reaching puberty. The overall goal of the proposal is to develop means to restore ovarian endocrine function in young women with POF by utilizing allogeneic transplantation of ovarian tissue. We will engineer an advanced synthetic hydrogel carrier with spatially controlled degradation to provide a dynamic environment to support prolonged survival and function of the allogeneic ovarian transplant. First, we will investigate how the physical properties of the hydrogel, such as stiffness, degradation rate and pore size affect tissue survival and physiological function and longevity. We will design a dual hydrogel system, with a degradable core to support follicle growth and function, and non-degradable immune-isolating shell. The shell will prevent the infiltration of the immune cells into the graft and leaking of the implanted cells from the graft. Second, we will investigate how graft size and composition (the balance between stromal cells, and early and late stage follicles) determines graft longevity. Ovarian follicles have an ?expiration date? and degenerate after one cycle, thus the initial number of the follicles in the graft sets up the maximum longevity of the graft. Other factors, like hypoxia and stiff environment, can limit the function of the graft. We will determine the optimal size and composition of the follicular pool that maximize graft longevity and function a syngeneic mouse model. Lastly, we will determine whether immunity against the graft limits graft function. We will investigate the mechanism and the timeline of the ovarian graft rejection and answer two questions: 1) is the recipient sensitized to the allogeneic tissue encapsulated in the hydrogel and 2) whether T cells infiltrate through the protective layer around the graft and destroy the tissue. With respect to outcomes, this project will engineer an immunoisolating system for allotransplantation of the ovarian tissue and will present a real clinical opportunity to initiate normal puberty in young women with POF. 1

Public Health Relevance

The proposed research aims to restore ovarian endocrine function in young women with premature ovarian failure by utilizing allogeneic transplantation of ovarian tissue in immuno-isolating hydrogel based system. We will engineer a synthetic hydrogel based system with spatially controlled degradation that maximizes the survival and function of allogeneic ovarian tissue in vivo. The primary innovation of this proposal stems from the design of immuno-isolating device that considers the uniqueness of the physiology of ovarian tissue, while using well-characterized biomaterials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB022033-04
Application #
9698346
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Selimovic, Seila
Project Start
2016-09-30
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Day, James R; David, Anu; Cichon, Alexa L et al. (2018) Immunoisolating poly(ethylene glycol) based capsules support ovarian tissue survival to restore endocrine function. J Biomed Mater Res A 106:1381-1389
Day, James R; David, Anu; Kim, Jiwon et al. (2018) The impact of functional groups of poly(ethylene glycol) macromers on the physical properties of photo-polymerized hydrogels and the local inflammatory response in the host. Acta Biomater 67:42-52
David, Anu; Day, James Ronald; Cichon, Alexa Leigh et al. (2017) Restoring Ovarian Endocrine Function with Encapsulated Ovarian Allograft in Immune Competent Mice. Ann Biomed Eng 45:1685-1696
Platt, Jeffrey L; Kaufman, Christina L; Garcia de Mattos Barbosa, Mayara et al. (2017) Accommodation and related conditions in vascularized composite allografts. Curr Opin Organ Transplant 22:470-476