Functional and Tunable Synthetic Hydrogel for Reproductive Tissue Engineering.

Biomaterials;Tissue Engineering;Synthetic Hydrogel;Animal Model of Premature Ovarian Failure;Biomedical Engineering;Engineering;Macromolecular Science and Engineering

Kim, JiwonTakayama, Shuichi ;

University of Michigan

关键词: Biomaterials;    Tissue Engineering;    Synthetic Hydrogel;    Animal Model of Premature Ovarian Failure;    Biomedical Engineering;    Engineering;    Macromolecular Science and Engineering;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/133460/jiwonk_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Many prepubertal girls and young women suffer from premature ovarian insufficiency induced by chemotherapy given for treatment of cancer and autoimmune diseases. Auto-transplantation of cryopreserved ovarian tissue could restore the lost ovarian endocrine function and fertility. Unfortunately, tissue ischemia, inconsistent graft quality and the risk of re-introducing malignant cells may stand in the way of the clinical translation of this approach. Therefore, isolation and re-implantation of multiple follicles may serve as a safer alternative; individual follicles can be isolated from the stromal environment in the ovarian tissue, and encapsulated in a hydrogel functioning as a supportive matrix for these isolated follicles. In the present study, we engineered an artificial ovarian tissue from the early stage follicles using a synthetic hydrogel, poly(ethylene glycol) vinyl-sulfone (PEG-VS), as a supportive matrix. The chemistry of the multi-arm PEG-VS formed by Michael-type addition allows: [1] modification with integrin binding peptides (such as RGD) for cell adhesion and migration and [2] a precise control over mechanical properties, making it suitable for reproductive tissue engineering applications.In this work, first we characterized the crosslinking kinetics of multi-arm PEG hydrogel. We investigated the role of PEG functionality on bioactive modification and mechanical properties of hydrogels, and the combined effect of mechano-biological properties on behavior of encapsulated cells. While the molar concentration of the reactive functional groups was identical in all the conditions, PEG with a larger number of functional groups on each unit allowed a greater degree of modification as well as a more precise control of mechanical properties, making it more suitable for supporting three-dimensional culture. Next, we modeled premature ovarian failure in mice to analyze the capability of PEG hydrogels to support folliculogenesis, vascularization, steroidogenesis and graft longevity in vivo. PEG hydrogels supported folliculogenesis of enzymatically-isolated follicles, leading to repeating estrous cycles and functioning hypothalamus-pituitary-gonadal axis with physiological levels of follicle-stimulating hormone. Furthermore, we demonstrated re-vascularization of the hydrogel, suggesting its capability of undergoing remodeling process. In summary, this is the first study proving the concept of a fully functional artificial ovarian tissue transplant built on the platform of the synthetic PEG hydrogel.