Abstract：
BACKGROUND: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: https://osf.io/th8yf/.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: https://osf.io/th8yf/.
摘要：
背景：妊娠的建立和维持取决于子宫内膜功能。Asherman综合征（AS）和宫腔粘连（IUA），或子宫内膜萎缩（EA）和薄子宫内膜（TE），可以自主起源或由于疾病（即子宫内膜炎或先天性发育不全）而引起，或医疗干预(例如手术，荷尔蒙疗法,刮宫或放疗）。受影响的患者可能会出现子宫内膜改变或不足，从而阻碍胚胎植入并增加不良妊娠结局和流产的风险。在人类中,AS/IUA和EA/TE主要采用手术或药物治疗，然而,这些治疗方法的疗效报道尚不清楚.因此，利用干细胞的新型再生技术，生长因子，或组织工程已经出现，以改善生殖结果。
目的：这篇综述全面总结了新兴生物技术的方法和成果(细胞，无细胞,和生物工程方法）来治疗人类子宫内膜病变。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体组织或血液的再生疗法。
方法：对PubMed和Embase中提供的全文文章进行了系统搜索，以确定在2000年1月至2023年9月之间以英文发表的原始同行评审研究。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,薄薄的子宫内膜，子宫内膜炎,先天性发育不全,刮宫,放射治疗,再生疗法,生物工程,干细胞,囊泡，富血小板血浆,生物材料,微流体,生物打印,类器官，水凝胶，脚手架,床单,miRNA,西地那非,硝化甘油，阿司匹林,生长激素,黄体酮,和雌激素。细胞的临床前和临床研究，无细胞,包括修复或再生人类子宫内膜的生物工程策略。通过手动搜索确定了其他研究。
结果：从确定的4366条记录中，164项研究（3.8%）纳入系统评价。由于临床前和临床研究中研究设计和测量结果参数的异质性，我们对研究结果进行了定性和定量评估,而不进行荟萃分析.使用基于干细胞的治疗子宫内膜病变的组通常采用源自人骨髓或脐带的间充质干细胞(MSC)。或者，基于富含血小板的血浆(PRP)或细胞外囊泡的无细胞疗法越来越受欢迎。这些伴随着基于细胞外基质（ECM）衍生的水凝胶或维持细胞和生长因子局部递送的合成生物仿制药的生物工程策略的出现。报告有希望的结果。针对组织修复和再生的多个方面的联合疗法仍在临床前测试中，但已显示出转化价值。这篇综述强调了无数的治疗材料来源，管理方法，和经过测试的载体。
结论：促进子宫内膜增殖的疗法，血管发育,和组织修复可能有助于恢复子宫内膜功能，最终,生育率。根据现有证据,成本,可访问性,以及治疗方法的可用性，我们建议制定三重再生战略，可能将高产量的MSC（例如来自骨髓或脐带）与无细胞治疗（PRP）相结合，可能整合在ECM水凝胶中。生物技术的进步以及临床前模型的见解将为开发导致子宫内膜疾病（如AS/IUA）的患者的个性化治疗方案铺平道路。EA/TE,还有子宫内膜炎.
背景：https://osf.io/th8yf/。
目的：这篇综述全面总结了新兴生物技术的方法和成果(细胞，无细胞,和生物工程方法）来治疗人类子宫内膜病变。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体组织或血液的再生疗法。
方法：对PubMed和Embase中提供的全文文章进行了系统搜索，以确定在2000年1月至2023年9月之间以英文发表的原始同行评审研究。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,薄薄的子宫内膜，子宫内膜炎,先天性发育不全,刮宫,放射治疗,再生疗法,生物工程,干细胞,囊泡，富血小板血浆,生物材料,微流体,生物打印,类器官，水凝胶，脚手架,床单,miRNA,西地那非,硝化甘油，阿司匹林,生长激素,黄体酮,和雌激素。细胞的临床前和临床研究，无细胞,包括修复或再生人类子宫内膜的生物工程策略。通过手动搜索确定了其他研究。
结果：从确定的4366条记录中，164项研究（3.8%）纳入系统评价。由于临床前和临床研究中研究设计和测量结果参数的异质性，我们对研究结果进行了定性和定量评估,而不进行荟萃分析.使用基于干细胞的治疗子宫内膜病变的组通常采用源自人骨髓或脐带的间充质干细胞(MSC)。或者，基于富含血小板的血浆(PRP)或细胞外囊泡的无细胞疗法越来越受欢迎。这些伴随着基于细胞外基质（ECM）衍生的水凝胶或维持细胞和生长因子局部递送的合成生物仿制药的生物工程策略的出现。报告有希望的结果。针对组织修复和再生的多个方面的联合疗法仍在临床前测试中，但已显示出转化价值。这篇综述强调了无数的治疗材料来源，管理方法，和经过测试的载体。
结论：促进子宫内膜增殖的疗法，血管发育,和组织修复可能有助于恢复子宫内膜功能，最终,生育率。根据现有证据,成本,可访问性,以及治疗方法的可用性，我们建议制定三重再生战略，可能将高产量的MSC（例如来自骨髓或脐带）与无细胞治疗（PRP）相结合，可能整合在ECM水凝胶中。生物技术的进步以及临床前模型的见解将为开发导致子宫内膜疾病（如AS/IUA）的患者的个性化治疗方案铺平道路。EA/TE,还有子宫内膜炎.
背景：https://osf.io/th8yf/。
