Bioengineered Tissues For Uterine Reconstruction

用于子宫重建的生物工程组织

• 批准号: 10582724
• 负责人: ANTHONY ATALA
• 金额: $ 49.69万
• 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/10582724
• 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; Legal patent; 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; implantation; myometrium; natural Blastocyst Implantation; nonhuman primate; offspring; older women; 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.

摘要 子宫因素不孕症影响高达8.0%的不孕妇女，13.3%有流产史的妇女，24.5% 在流产和不孕不育的人中，全世界有1：500或150万妇女。人类同种异体基因的使用 子宫组织是子宫重建的一个很好的选择，但其临床应用可能会受到捐赠者的影响。 短缺和免疫并发症。我们需要其他选择。最近，我们在《自然》杂志上报道 自体细胞接种-生物工程子宫构建在次全器官生物技术中的应用 在兔子模型中进行替换。工程化的结构保持了管腔的通畅，形成了自然的子宫 组织样细胞和无细胞结构和生物力学特性；以及支持的胚胎附着， 自然交配后胎盘形成、妊娠和可存活后代的足月分娩。而兔子则提供 这种方法的原则证明，她们没有单纯性子宫或每月月经周期。最多的 与女性子宫结构和功能相对应的合适的临床前模型是东半球的猴子 他们有相对较厚的单纯子宫，每月的月经周期包括生长、分化、 退化(月经)，并在生殖过程中再生。最近，我们完成了一系列测试 使用生物工程植入物适应NHP较厚的单侧子宫并评估结构 成熟；但没有评估种子细胞与外周细胞和基质产生在结构 再生，或它们与自然子宫/子宫内膜生物学和功能的关系。为此，这一目标是 一项研究是测量自体细胞种植聚合物支架复制灵长类子宫的能力 组织样的结构和功能，有明显的外科手术造成的子宫缺陷。方法是找出 结构和功能再生的细胞和非细胞起源；从而探索了 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 因素不孕症包括子宫腺肌病/子宫腺肌瘤修复术和子宫肌瘤切除术； Asherman综合征患者的子宫内膜功能及正常子宫解剖和功能重建 患有先天畸形的女性。目标1将评估种子生物工程的结构发展 植入物并测试这些植入物形成天然子宫组织样结构和大小的假设； 标记播种的肌层/子宫内膜和外周细胞对细胞和非细胞的贡献 类似于天然组织的发育。目标2将评估生物工程子宫的功能发育 构建并将测试假设，即它们具有类似的生物力学和收缩特性 以及与正常子宫容受性、着床和功能一致的子宫内膜标志物。 怀孕了。这些研究将把在兔子身上所做的工作转化为灵长类动物模型，这种模型与 的结构和生理学，并帮助我们更好地理解 治疗子宫因素不孕症的生物工程方法。