Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.
Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, United States.
Curr Pharm Des. 2017;23(40):6115-6124. doi: 10.2174/1381612823666170825142649.
Preterm birth (PTB) is clinically defined as process of giving birth before 37 weeks of gestation and is a leading cause of death among neonates and children under the age of five. Prematurity remains a critical issue in developed countries, yet our understanding of the pathophysiology of PTB remains largely unknown. Among pregnancy complications, subclinical infections such as chorioamnionitis (CAM) are implicated in up to 70% of PTB cases. Specifically, CAM is characterized by the infection of the fetal membranes that surround the developing fetus and extend from the placenta, and is often associated with preterm, premature rupture of the fetal membranes (PPROM). The fetal membrane plays a key structural role in maintaining the fetal and maternal compartments of the gravid uterus. However, our understanding of the mechanisms of PPROM and the spatio-temporal progress of CAM remains vastly unknown. A lack of human-derived models have hindered our understanding of the mechanism that govern spontaneous PTB. Thus, in this short review, we discuss the emerging microfabrication technologies, specifically, organ-on-chip (OoCs) models, that seek to recapitulate the cellular and molecular context of the gestational membranes in vitro. These models show promise to facilitate the investigation of pathologic mechanisms that drive these disease conditions by mimicking the interactive contribution of the major cell types that make up the microenvironment of the fetal membrane and enable high throughput screening. Herein, we histologically characterize the microenvironment of the fetal membrane as a metric for scaling to recapitulate the functional components of the human fetal membrane. We review the current OoC models of the gravid uterus and conceptualize an "Instrumented Fetal Membrane on a Chip" (IFMOC) design as a prototype for PPROM and CAM research. Lastly, we discuss further applications of these OoC models for toxicological or pharmacological screening and personalized medicine. Fetal membrane OoCs offer an innovative and valuable platform to explore complex interactions between multiple drug types, toxic substances, and/or pathogenic microbes and their potential impacts on pregnancy outcomes. Further work will be required by integrating technological and analytical capabilities in order to characterize the fetal membrane microenvironment for preterm birth research.
早产（PTB）是指妊娠 37 周前分娩的过程，是新生儿和五岁以下儿童死亡的主要原因。早产仍然是发达国家的一个关键问题，但我们对 PTB 病理生理学的理解在很大程度上仍然未知。在妊娠并发症中，亚临床感染，如绒毛膜羊膜炎（CAM），在多达 70%的 PTB 病例中起作用。具体来说，CAM 的特征是感染包围发育中的胎儿并从胎盘延伸的胎儿膜，并且通常与早产、胎膜早破（PPROM）有关。胎膜在维持妊娠子宫的胎儿和母体隔室方面起着关键的结构作用。然而，我们对 PPROM 的机制和 CAM 的时空进展的理解仍然知之甚少。缺乏人源模型阻碍了我们对控制自发性 PTB 的机制的理解。因此，在这篇简短的综述中，我们讨论了新兴的微制造技术，特别是器官芯片（OoC）模型，这些模型试图在体外再现妊娠膜的细胞和分子环境。这些模型有望通过模拟构成胎膜微环境的主要细胞类型的相互作用贡献，并实现高通量筛选，从而促进对驱动这些疾病状态的病理机制的研究。在这里，我们从组织学上描述了胎膜的微环境，作为衡量标准来再现人类胎膜的功能成分。我们回顾了当前的妊娠子宫 OoC 模型，并将“芯片上的胎儿膜仪器”（IFMOC）设计概念化为 PPROM 和 CAM 研究的原型。最后，我们讨论了这些 OoC 模型在毒理学或药理学筛选和个性化医学中的进一步应用。胎儿膜 OoC 为探索多种药物类型、有毒物质和/或致病微生物之间的复杂相互作用及其对妊娠结局的潜在影响提供了一个创新和有价值的平台。为了进行早产研究，需要进一步整合技术和分析能力来描述胎儿膜微环境。
