Engineering an immuno-isolating hydrogel for restoring ovarian endocrine function

项目摘要 卵巢早衰（POF）是一种常见的并发症的抗癌治疗，由于极端的毒性， 化疗和骨髓移植。在女性癌症幸存者中，POF导致不孕，沿着 卵巢内分泌功能缺失的后果：过早骨质减少和肌肉萎缩，以及 加速心血管疾病。这些长期的影响是显著的，特别是对年轻女孩来说 进入青春期该提案的总体目标是开发恢复卵巢内分泌功能的方法， 卵巢组织异基因移植治疗卵巢早衰。我们将设计一种先进的 具有空间受控降解的合成水凝胶载体， 延长同种异体卵巢移植的存活和功能。首先，我们将研究如何物理 水凝胶的性质，例如硬度、降解速率和孔径影响组织存活， 生理功能和寿命。我们将设计一个双水凝胶系统，用可降解的核心来支持 卵泡生长和功能，不可降解的免疫隔离壳。外壳会阻止 免疫细胞进入移植物和移植细胞从移植物中泄漏。第二，我们会调查 移植物的大小和组成（基质细胞之间的平衡，以及早期和晚期卵泡） 决定了移植物的寿命。卵巢卵泡有一个“到期日”，并在一个周期后退化，因此， 移植物中卵泡的初始数量决定了移植物的最长寿命。其他因素，如缺氧 和僵硬的环境，会限制移植物的功能。我们将确定最佳的大小和组成， 最大化移植物寿命和同基因小鼠模型功能的卵泡池。最后，我们将 确定对移植物的免疫是否限制了移植物功能。我们将研究其机制， 卵巢移植排斥反应的时间轴，并回答两个问题：1）受体是否对同种异体 和2）T细胞是否渗透通过水凝胶中包封的组织周围的保护层， 移植并破坏组织关于结果，该项目将设计一个免疫隔离系统， 卵巢组织的同种异体移植，并将提出一个真实的临床机会，开始正常的青春期， 年轻女性POF 1

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