Watson David E, Hunziker Rosemarie, Wikswo John P
1 Eli Lilly and Company, Indianapolis, IN 46225, USA.
2 National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA.
Exp Biol Med (Maywood). 2017 Oct;242(16):1559-1572. doi: 10.1177/1535370217732765.
Microphysiological systems (MPS), which include engineered organoids (EOs), single organ/tissue chips (TCs), and multiple organs interconnected to create miniature in vitro models of human physiological systems, are rapidly becoming effective tools for drug development and the mechanistic understanding of tissue physiology and pathophysiology. The second MPS thematic issue of Experimental Biology and Medicine comprises 15 articles by scientists and engineers from the National Institutes of Health, the IQ Consortium, the Food and Drug Administration, and Environmental Protection Agency, an MPS company, and academia. Topics include the progress, challenges, and future of organs-on-chips, dissemination of TCs into Pharma, children's health protection, liver zonation, liver chips and their coupling to interconnected systems, gastrointestinal MPS, maturation of immature cardiomyocytes in a heart-on-a-chip, coculture of multiple cell types in a human skin construct, use of synthetic hydrogels to create EOs that form neural tissue models, the blood-brain barrier-on-a-chip, MPS models of coupled female reproductive organs, coupling MPS devices to create a body-on-a-chip, and the use of a microformulator to recapitulate endocrine circadian rhythms. While MPS hardware has been relatively stable since the last MPS thematic issue, there have been significant advances in cell sourcing, with increased reliance on human-induced pluripotent stem cells, and in characterization of the genetic and functional cell state in MPS bioreactors. There is growing appreciation of the need to minimize perfusate-to-cell-volume ratios and respect physiological scaling of coupled TCs. Questions asked by drug developers are followed by an analysis of the potential value, costs, and needs of Pharma. Of highest value and lowest switching costs may be the development of MPS disease models to aid in the discovery of disease mechanisms; novel compounds including probes, leads, and clinical candidates; and mechanism of action of drug candidates. Impact statement Microphysiological systems (MPS), which include engineered organoids and both individual and coupled organs-on-chips and tissue chips, are a rapidly growing topic of research that addresses the known limitations of conventional cellular monoculture on flat plastic - a well-perfected set of techniques that produces reliable, statistically significant results that may not adequately represent human biology and disease. As reviewed in this article and the others in this thematic issue, MPS research has made notable progress in the past three years in both cell sourcing and characterization. As the field matures, currently identified challenges are being addressed, and new ones are being recognized. Building upon investments by the Defense Advanced Research Projects Agency, National Institutes of Health, Food and Drug Administration, Defense Threat Reduction Agency, and Environmental Protection Agency of more than $200 million since 2012 and sizable corporate spending, academic and commercial players in the MPS community are demonstrating their ability to meet the translational challenges required to apply MPS technologies to accelerate drug development and advance toxicology.
微生理系统（MPS），包括工程化类器官（EO）、单个器官/组织芯片（TC）以及相互连接以创建人体生理系统微型体外模型的多个器官，正迅速成为药物开发以及对组织生理学和病理生理学进行机制理解的有效工具。《实验生物学与医学》的第二期MPS专题包含了来自美国国立卫生研究院、IQ联盟、食品药品监督管理局、环境保护局、一家MPS公司以及学术界的科学家和工程师撰写的15篇文章。主题包括芯片上器官的进展、挑战和未来、TC在制药行业的推广、儿童健康保护、肝脏分区、肝脏芯片及其与互联系统的耦合、胃肠道MPS、芯片上心脏中未成熟心肌细胞的成熟、人体皮肤构建物中多种细胞类型的共培养、使用合成水凝胶创建形成神经组织模型的EO、芯片上的血脑屏障、耦合女性生殖器官的MPS模型、耦合MPS设备以创建芯片上的人体以及使用微配方仪重现内分泌昼夜节律。自上一期MPS专题以来，MPS硬件相对稳定，然而在细胞来源方面取得了重大进展，对人诱导多能干细胞的依赖增加，并且在MPS生物反应器中对遗传和功能细胞状态的表征方面也有进展。人们越来越认识到需要尽量减少灌注液与细胞体积比，并尊重耦合TC的生理尺度。药物开发者提出的问题之后是对制药行业潜在价值、成本和需求的分析。价值最高且转换成本最低的可能是开发MPS疾病模型以辅助发现疾病机制；新型化合物，包括探针、先导物和临床候选药物；以及候选药物的作用机制。影响声明 微生理系统（MPS），包括工程化类器官以及单个和耦合的芯片上器官和组织芯片，是一个快速发展的研究主题，它解决了传统细胞在平面塑料上进行单培养的已知局限性——这是一套完善的技术，能产生可靠的、具有统计学意义的结果，但可能无法充分代表人类生物学和疾病。正如本文及本专题中的其他文章所综述的，MPS研究在过去三年中在细胞来源和表征方面都取得了显著进展。随着该领域的成熟，目前已识别的挑战正在得到解决，同时也在认识新的挑战。基于国防高级研究计划局、美国国立卫生研究院、食品药品监督管理局、国防威胁降低局和环境保护局自2012年以来超过2亿美元的投资以及大量企业支出，MPS领域的学术和商业参与者正在展示他们应对将MPS技术应用于加速药物开发和推进毒理学所需的转化挑战的能力。
