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.

总结 子宫因素不孕影响高达8.0%的不孕妇女，13.3%的有流产史的妇女，24.5%的有流产史的妇女，24.5%的有流产史的妇女。 流产和不孕症患者的比例为1：500或150万。使用人类同种异体 子宫组织是子宫重建的良好选择，但其临床应用可能受到供体的影响。 缺乏和免疫并发症。需要有替代办法。最近，我们在《自然》杂志上报道， 生物技术，自体细胞种子-生物工程子宫构建物在次全器官中的应用 在兔子模型中替换。工程化构建体保持管腔通畅，发育出天然子宫内膜， 组织样细胞和非细胞结构和生物力学性质;以及支持胚胎附着， 胎盘形成、妊娠和自然交配后存活后代的足月分娩。兔子提供 这种方法的原理证明，他们没有单一的子宫或每月月经周期。最 与女性子宫结构和功能相似的合适的临床前模型是旧世界猴 具有相对较厚的单一子宫、每月月经周期（包括生长周期、分化周期）的人， 退化（月经）和再生在他们的生殖生活。最近，我们完成了一系列测试 使用生物工程植入物，以适应NHP较厚的单一子宫，并评估结构 成熟;但没有评估接种细胞与外周细胞和基质产生在结构性细胞分化中的作用。 再生，或它们与天然子宫/子宫内膜生物学和功能的关系。为此，本次会议的目标 这项研究是为了测量自体细胞接种的聚合物支架复制灵长类动物样子宫的能力， 组织样结构和功能，具有显著的手术造成的子宫缺损。方法是确定 结构和功能再生的细胞和非细胞起源;从而探索生物学的 这些生物工程植入物的再生过程。成功治疗子宫内膜异位症的临床潜力 不孕因素包括子宫腺肌症/腺肌瘤的修复和子宫肌瘤切除术; Asherman综合征患者子宫内膜功能的研究;以及Asherman综合征患者正常子宫解剖和功能的重建。 患有先天性畸形的女性目的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;包括 标记的接种子宫肌层/子宫内膜和外周细胞， 类似于天然组织的发育。目的2评价生物工程子宫的功能发育 构建并将测试假设，他们开发的生物力学和收缩性能类似， 和与正常子宫容受性、着床和 怀孕这些研究将把在兔子身上所做的工作转化为灵长类动物模型， 结构和生理学，以妇女，并帮助我们更好地了解潜在的生物学， 治疗子宫因素不孕症的生物工程方法。