IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
Hum Reprod Update. 2024 Oct 1;30(5):584-613. doi: 10.1093/humupd/dmae013.
The establishment and maintenance of pregnancy depend on endometrial competence. Asherman syndrome (AS) and intrauterine adhesions (IUA), or endometrial atrophy (EA) and thin endometrium (TE), can either originate autonomously or arise as a result from conditions (i.e. endometritis or congenital hypoplasia), or medical interventions (e.g. surgeries, hormonal therapies, uterine curettage or radiotherapy). Affected patients may present an altered or inadequate endometrial lining that hinders embryo implantation and increases the risk of poor pregnancy outcomes and miscarriage. In humans, AS/IUA and EA/TE are mainly treated with surgeries or pharmacotherapy, however the reported efficacy of these therapeutic approaches remains unclear. Thus, novel regenerative techniques utilizing stem cells, growth factors, or tissue engineering have emerged to improve reproductive outcomes.
This review comprehensively summarizes the methodologies and outcomes of emerging biotechnologies (cellular, acellular, and bioengineering approaches) to treat human endometrial pathologies. Regenerative therapies derived from human tissues or blood which were studied in preclinical models (in vitro and in vivo) and clinical trials are discussed.
A systematic search of full-text articles available in PubMed and Embase was conducted to identify original peer-reviewed studies published in English between January 2000 and September 2023. The search terms included: human, uterus, endometrium, Asherman syndrome, intrauterine adhesions, endometrial atrophy, thin endometrium, endometritis, congenital hypoplasia, curettage, radiotherapy, regenerative therapy, bioengineering, stem cells, vesicles, platelet-rich plasma, biomaterials, microfluidic, bioprinting, organoids, hydrogel, scaffold, sheet, miRNA, sildenafil, nitroglycerine, aspirin, growth hormone, progesterone, and estrogen. Preclinical and clinical studies on cellular, acellular, and bioengineering strategies to repair or regenerate the human endometrium were included. Additional studies were identified through manual searches.
From a total of 4366 records identified, 164 studies (3.8%) were included for systematic review. Due to heterogeneity in the study design and measured outcome parameters in both preclinical and clinical studies, the findings were evaluated qualitatively and quantitatively without meta-analysis. Groups using stem cell-based treatments for endometrial pathologies commonly employed mesenchymal stem cells (MSCs) derived from the human bone marrow or umbilical cord. Alternatively, acellular therapies based on platelet-rich plasma (PRP) or extracellular vesicles are gaining popularity. These are accompanied by the emergence of bioengineering strategies based on extracellular matrix (ECM)-derived hydrogels or synthetic biosimilars that sustain local delivery of cells and growth factors, reporting promising results. Combined therapies that target multiple aspects of tissue repair and regeneration remain in preclinical testing but have shown translational value. This review highlights the myriad of therapeutic material sources, administration methods, and carriers that have been tested.
Therapies that promote endometrial proliferation, vascular development, and tissue repair may help restore endometrial function and, ultimately, fertility. Based on the existing evidence, cost, accessibility, and availability of the therapies, we propose the development of triple-hit regenerative strategies, potentially combining high-yield MSCs (e.g. from bone marrow or umbilical cord) with acellular treatments (PRP), possibly integrated in ECM hydrogels. Advances in biotechnologies together with insights from preclinical models will pave the way for developing personalized treatment regimens for patients with infertility-causing endometrial disorders such as AS/IUA, EA/TE, and endometritis.
妊娠的建立和维持依赖于子宫内膜的功能。Asherman 综合征（AS）和宫腔粘连（IUA），或子宫内膜萎缩（EA）和薄型子宫内膜（TE），既可以自主发生，也可以由疾病（如子宫内膜炎或先天性发育不良）或医疗干预（如手术、激素治疗、刮宫或放疗）引起。受影响的患者可能会出现改变或不足的子宫内膜衬里，这会阻碍胚胎着床，并增加不良妊娠结局和流产的风险。在人类中，AS/IUA 和 EA/TE 主要通过手术或药物治疗，但这些治疗方法的疗效仍不清楚。因此，利用干细胞、生长因子或组织工程学的新型再生技术已经出现，以改善生殖结局。
本文全面总结了新兴生物技术（细胞、非细胞和生物工程方法）治疗人类子宫内膜病变的方法和结果。讨论了在临床前模型（体外和体内）和临床试验中研究的源自人类组织或血液的再生疗法。
在 PubMed 和 Embase 中进行了全面的全文文章检索，以确定 2000 年 1 月至 2023 年 9 月期间发表的英文同行评审原始研究。搜索词包括：人类、子宫、子宫内膜、Asherman 综合征、宫腔粘连、子宫内膜萎缩、薄型子宫内膜、子宫内膜炎、先天性发育不良、刮宫、放疗、再生疗法、生物工程、干细胞、囊泡、富含血小板的血浆、生物材料、微流控、生物打印、类器官、水凝胶、支架、薄片、miRNA、西地那非、硝酸甘油、阿司匹林、生长激素、孕酮和雌激素。纳入了用于修复或再生人类子宫内膜的细胞、非细胞和生物工程策略的临床前和临床研究。通过手动搜索还确定了其他研究。
从总共确定的 4366 条记录中，有 164 项研究（3.8%）被纳入系统评价。由于临床前和临床研究的研究设计和测量结果参数存在异质性，因此在没有进行荟萃分析的情况下，对这些发现进行了定性和定量评估。针对子宫内膜病变使用基于干细胞的治疗方法的研究小组通常使用源自人骨髓或脐带的间充质干细胞（MSCs）。或者，基于富含血小板的血浆（PRP）或细胞外囊泡的非细胞疗法也越来越受欢迎。同时，基于细胞外基质（ECM）衍生水凝胶或合成类似物的生物工程策略也随之出现，这些策略能够持续局部输送细胞和生长因子，报告了有希望的结果。针对组织修复和再生的多个方面的联合治疗仍处于临床前测试阶段，但已显示出转化价值。本文综述了众多治疗材料来源、给药方法和载体的测试情况。
促进子宫内膜增殖、血管发育和组织修复的治疗方法可能有助于恢复子宫内膜功能，并最终恢复生育能力。基于现有的证据、治疗的成本、可及性和可用性，我们提出了三重再生策略的发展，可能包括高产量的间充质干细胞（例如骨髓或脐带）与非细胞治疗（PRP）相结合，可能整合到 ECM 水凝胶中。生物技术的进步以及临床前模型的见解将为患有导致不孕的子宫内膜疾病（如 AS/IUA、EA/TE 和子宫内膜炎）的患者制定个性化治疗方案铺平道路。
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