자료유형  

 학위논문

Control Number  

0017164547

International Standard Book Number  

9798384045786

Dewey Decimal Classification Number  

610

Main Entry-Personal Name  

Brunette, Margaret A.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Michigan., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

139 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-04, Section: B.

General Note  

Advisor: Shikanov, Ariella.

Dissertation Note  

Thesis (Ph.D.)--University of Michigan, 2024.

Summary, Etc.  

요약The increase in pediatric cancer survivorship has concurrently resulted in growing numbers of young women suffering from premature ovarian insufficiency (POI) due to the gonadotoxic effects of chemotherapy and/or radiation. The loss of ovarian endocrine function and inability to undergo physiological puberty experienced by patients with POI is currently treated with hormone replacement therapy (HRT), which does not recapitulate physiological ovarian function and supplies only a fraction of hormones. We hypothesized that a cell-based therapy could fully recapitulate ovarian physiology and promote pubertal development in adolescent girls with POI. The long-term goal of this work is the development of an immune-isolating capsule for implantation of donor ovarian tissue to restore ovarian endocrine function in females with POI. Previous work has demonstrated that a poly(ethylene glycol) (PEG)-based capsule with a degradable core and non-degradable shell supported encapsulated murine ovarian allografts and prevented infiltration of immune cells. The work described in this dissertation focused on translating the immune-isolating technology to be used with human ovarian tissue and investigating survival and function of the encapsulated human ovarian tissue. The objectives of the work described in this dissertation were to (1) develop an encapsulation method for human ovarian tissue, (2) investigate the ability of the encapsulated tissues to interact with the host hormones to allow for antral follicle growth, and (3) evaluate whether growing human follicles remain protected from host rejection. We have demonstrated that human ovarian tissue survived the encapsulation process. Additionally, we conducted in vivo studies using fresh, vitrified, and slow frozen tissue subcutaneously implanted in mice, removing viable implants up to twelve weeks later. To address differences between murine and human ovarian tissue, specifically the heterogeneity of follicle distribution in human tissue, we increased the volume of the human graft by a factor of 20. We demonstrated that this modification maintained healthy stromal tissue with no signs of fibrosis. Next, we tested whether encapsulated human follicles could resume folliculogenesis, reach antral stages and secrete gonadal hormones. Ovariectomized immunocompromised mice subcutaneously implanted with immune-isolated human ovarian xenografts for 20 weeks (1) resumed estrous cyclicity (100% of the mice), (2) had significantly increased estradiol levels, and (3) had downward trending levels of follicle stimulating hormone after 18 weeks. Furthermore, large antral follicles (~3mm in diameter) were present in encapsulated and non-encapsulated tissues. Lastly, we investigated whether the immune-isolating capsule could protect human ovarian tissue xenografted in immunocompetent mice, which is a significantly more rigorous model. Analysis of the xenografts retrieved 6 weeks post implantation confirmed preclusion of CD4+/CD8+ T-cell infiltration and presence of ovarian follicles with normal morphology in the encapsulated tissue. The encapsulated human xenografts restored regular estrous cyclicity, increased levels of estradiol reaching pre-ovariectomy levels, and normal growing follicles persisted for 22 weeks.In summary, this work supported our hypothesis that encapsulated immune-isolated donor ovarian grafts remained protected from immune rejection, responded to circulating gonadotropins, and delivered gonadal hormones at physiological levels with reciprocal feedback with the rest of the body. The findings in this work support the use of a cell-based therapy for POI patients and provides a basis for large animal studies.

Subject Added Entry-Topical Term  

Biomedical engineering.

Subject Added Entry-Topical Term  

Physiology.

Subject Added Entry-Topical Term  

Oncology.

Subject Added Entry-Topical Term  

Endocrinology.

Subject Added Entry-Topical Term  

Immunology.

Index Term-Uncontrolled  

Human ovarian cortex

Index Term-Uncontrolled  

Immune-isolation

Index Term-Uncontrolled  

Chemotherapy

Index Term-Uncontrolled  

Pubertal development

Index Term-Uncontrolled  

Ovarian tissue

Added Entry-Corporate Name  

University of Michigan Biomedical Engineering

Host Item Entry  

Dissertations Abstracts International. 86-04B.

Electronic Location and Access  

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Control Number  

joongbu:656808