Engineering an immuno-isolating hydrogel for restoring ovarian endocrine function

设计用于恢复卵巢内分泌功能的免疫隔离水凝胶

• 批准号: 9357581
• 负责人: Ariella Shikanov
• 金额: $ 37.45万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9357581
• 关键词: Affect; Allogenic; Allografting; Biocompatible Materials; Bone Marrow Transplantation; Cancer Survivor; Cardiovascular Diseases; Cells; Clinical; Complication; Data; Devices; Dose; Encapsulated; Endocrine; Engineering; Environment; Equilibrium; Estradiol; Estrogens; Event; Face; Female; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Gonadotropins; Graft Rejection; Graft Survival; Growth; Health; Homologous Transplantation; Hormone replacement therapy; Hormones; Hydrogels; Hypoxia; Immune; Immune response; Immunity; Implant; Infiltration; Islets of Langerhans; Islets of Langerhans Transplantation; Life; Longevity; Malignant Childhood Neoplasm; Malignant neoplasm of ovary; Mechanics; Mediating; Menstrual cycle; Microencapsulations; Modernization; Muscular Atrophy; Osteopenia; Outcome; Ovarian; Ovarian Follicle; Ovarian Tissue; Physiological; Physiology; Premature Ovarian Failure; Production; Progesterone; Puberty; Radiation; Research; Resistance; Sterility; Stromal Cells; Structure; Survival Rate; System; T-Lymphocyte; Testing; TimeLine; Tissue Grafts; Tissue Survival; Tissue Transplantation; Tissues; Toxic effect; Toxicity due to chemotherapy; Transplantation; Transplanted tissue; United States; anticancer treatment; base; cancer therapy; chemotherapy; clinically translatable; cytotoxic; design; ethylene glycol; expiration; folliculogenesis; girls; graft function; improved; in vivo; innovation; malignant breast neoplasm; mouse model; novel; nutrition; ovary transplantation; physical property; premature; prevent; research study; response; standard of care; stem; young woman

Project Summary 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

项目摘要 卵巢过早衰竭（POF）是抗癌治疗的常见并发症，这是由于极端毒性 化学疗法和骨髓移植。在女性癌症中，生存的pof引起不育，以及 缺乏卵巢内分泌功能的后果：过早的骨质减少和肌肉浪费，以及 加速心血管疾病。这些持久的效果很重要，特别是对年轻女孩 到达青春期。该提案的总体目标是开发手段以恢复卵巢内分泌功能 使用卵巢组织的同种异体移植具有POF的年轻女性。我们将设计高级 具有空间控制定义的合成水凝胶载体，提供一个动态环境以支持 同种异体卵巢移植的长期生存和功能。首先，我们将研究身体如何 水凝胶的特性，例如刚度，降解速率和孔径会影响组织存活和 生理功能和寿命。我们将设计一个双水凝胶系统，并具有可降解的核心以支持 卵泡生长和功能，以及不可降解的免疫溶解壳。外壳将防止 免疫细胞进入移植物并从移植物中泄漏。第二，我们将调查 移植物的大小和成分如何（基质细胞之间的平衡以及早期和晚期卵泡） 确定移植寿命。卵巢卵泡的“到期日期”，一个周期后退化，因此 移植物中卵泡的初始数量设置了移植物的最大寿命。其他因素，例如缺氧 和僵硬的环境可以限制移植物的功能。我们将确定最佳尺寸和组成 最大化移植物寿命和功能合成小鼠模型的卵泡池。最后，我们会的 确定对移植物限制移植功能是否免疫。我们将研究机制和 卵巢移植拒绝的时间表并回答两个问题：1）接受者对同种异体敏感 封装在水凝胶中的组织和2）T细胞是否通过周围的保护层浸润 移植并破坏组织。关于结果，该项目将设计一个免疫共溶体系统 卵巢组织的同种异体移植，并将提供真正的临床机会，以启动正常青春期 年轻女性有POF。 1