Bioengineered Tissues For Uterine Reconstruction

用于子宫重建的生物工程组织

• 批准号: 10420259
• 负责人: ANTHONY ATALA
• 金额: $ 58.98万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-02 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420259
• 关键词: Adenomyosis; Affect; Allogenic; Anatomy; Asherman Syndrome; Autologous; Biology; Biomechanics; Biomedical Engineering; Biotechnology; Cells; Cercopithecidae; Characteristics; Clinical; Complex; Congenital Abnormality; Defect; Development; Dimensions; Endometrial; Endometrium; Engineering; Excision; Extracellular Matrix; Failure; Female infertility; Fiber; Functional Regeneration; Gland; Goals; Gravid; Growth; Human; Immunologics; Immunosuppression; Implant; Infertility; Knowledge; Label; Life; Live Birth; Measures; Menstrual cycle; Menstruation; Modeling; Myometrial; Natural regeneration; Nature; Operative Surgical Procedures; Organ; Oryctolagus cuniculus; Partner in relationship; Pathology; Pattern; Periodicity; Peripheral; Physiological; Physiology; Placentation; Polymers; Pre-Clinical Model; Pregnancy; Primates; Process; Production; Property; Publishing; Recording of previous events; Relaxation; Reporting; Reproductive Physiology; Rhesus; Series; Source; Spontaneous abortion; Stimulus; Stress; Structure; Surface; Technology; Testing; Thick; Time; Tissue Engineering; Tissues; Translating; Transplantation; Uterine Fibroids; Uterus; Woman; Work; base; implantation; myometrium; natural Blastocyst Implantation; nonhuman primate; offspring; reconstruction; regenerative biology; repaired; reproductive; restoration; scaffold; uterine receptivity

Summary Uterine-factor infertility affects up to 8.0% of infertile women, 13.3% of those with a history of miscarriage, 24.5% of those with miscarriage and infertility and 1:500 or 1.5 million women worldwide. The use of human allogeneic uterine tissues is a good option for uterine reconstruction, but its clinical use can be compromised by donor shortage, and immunologic complications. Alternatives are needed. Recently, we reported, in Nature Biotechnology, the application of autologous cell seeded-bioengineered uterine constructs for subtotal organ replacement in a rabbit model. The engineered constructs maintained luminal patency, developed native uterine tissue-like cellular and acellular structure and biomechanical properties; and supported embryo attachment, placentation, pregnancy, and full-term delivery of viable offspring following natural mating. While rabbits provide proof-of principle for this approach, they do not have a simplex uterus or monthly menstrual cyclicity. The most appropriate preclinical model that parallels the uterine structure and function of women are old-world monkeys who have a relatively thick simplex uterus, a monthly menstrual cycle including cycles of growth, differentiation, degeneration (menses), and regeneration during their reproductive life. Recently, we completed a series of tests using bioengineered implants that accommodate the thicker simplex uterus of NHPs and assessed structural maturation; but did not assess the contribution of seeded vs. peripheral cells and matrix production in structural regeneration, or their relationship to native uterine/endometrial biology and function. To this end, the goal of this study is to measure the ability of autologous cell-seeded polymer scaffolds to reproduce primate-like uterine tissue-like structure and function with significant surgically created uterine defects. The approach is to identify the cellular and acellular origin of structural and functional regeneration; thus exploring the biology of the regeneration process in these bioengineered implants. The clinical potential for successful treatment of uterine factor infertility includes repair of adenomyosis/adenomyomas and uterine fibroid resection; restoration of endometrial function in Asherman’s Syndrome; and reconstruction of normal uterine anatomy and function in women with congenital abnormalities. Aim 1 will assess the structural development of the seeded bioengineered implants and test the hypotheses that these implants develop native uterine tissue-like structure and size; consist of both labeled seeded myometrial/endometrial and peripheral cells that contribute cellular and acellular development similar to native tissue. Aim 2 will assess the functional development of bioengineered uterine constructs and will test the hypotheses that they develop biomechanical and contractile properties similar to that of native uteri; and functional endometrial markers consistent with normal uterine receptivity, implantation and pregnancy. These studies will translate the work done in rabbits to a primate model that is highly relevant in structure and physiology to that of women, and help us better understand the underlying biology of a bioengineering approach for treating uterine factor infertility.

概括 子宫因素不孕影响高达 8.0% 的不孕女性，13.3% 有流产史的女性，24.5% 全世界有 1:500 或 150 万女性患有流产和不孕症。使用人类同种异体 子宫组织是子宫重建的一个很好的选择，但其临床使用可能会受到供体的影响 短缺和免疫并发症。需要替代方案。最近，我们在《自然》杂志上报道 生物技术，自体细胞接种生物工程子宫结构在次全器官中的应用 替换兔子模型。工程构建体保持管腔通畅，发育原生子宫 组织样细胞和非细胞结构和生物力学特性；并支持胚胎附着， 自然交配后的胎盘、妊娠和足月分娩。虽然兔子提供 这种方法的原理证明是，她们没有单一子宫，也没有每月的月经周期。最 与女性子宫结构和功能相似的合适临床前模型是旧世界的猴子 具有相对较厚的单一子宫，每月的月经周期包括生长周期、分化周期、 退化（月经）和生殖期间的再生。近期，我们完成了一系列的测试 使用生物工程植入物适应 NHP 较厚的单纯子宫，并评估结构 成熟；但没有评估种子细胞与外周细胞以及基质生产在结构中的贡献 再生，或其与天然子宫/子宫内膜生物学和功能的关系。为此，本次活动的目标 研究旨在测量自体细胞接种的聚合物支架复制灵长类动物子宫的能力 组织样结构和功能，具有明显的手术造成的子宫缺陷。方法是识别 结构和功能再生的细胞和非细胞起源；从而探索了生物学 这些生物工程植入物的再生过程。成功治疗子宫肌瘤的临床潜力 不孕因素包括子宫腺肌症/腺肌瘤修复术和子宫肌瘤切除术；恢复 阿谢曼综合征中的子宫内膜功能；以及正常子宫解剖结构和功能的重建 先天性畸形的女性。目标 1 将评估种子生物工程的结构发展 植入并测试这些植入物发育出天然子宫组织样结构和大小的假设；组成 标记的种子肌层/子宫内膜和外周细胞贡献细胞和非细胞 发育与天然组织相似。目标 2 将评估生物工程子宫的功能发育 构建并测试他们具有与此类似的生物力学和收缩特性的假设 原生子宫；功能性子宫内膜标志物与正常子宫容受性、着床和 怀孕。这些研究将把在兔子身上所做的工作转化为与以下领域高度相关的灵长类动物模型： 结构和生理学与女性的结构和生理学相似，并帮助我们更好地了解女性的潜在生物学 治疗子宫因素不孕症的生物工程方法。