Hepatic and cardiac drug adverse effects are among the leading causes of attrition in drug development programs, in part due to predictive failures of current animal or in vitro models. Hepatocytes and cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs) hold promise for predicting clinical drug effects, given their human-specific properties and their ability to harbor genetically determined characteristics that underlie inter-individual variations in drug response. Currently, the fetal-like properties and heterogeneity of hepatocytes and cardiomyocytes differentiated from iPSCs make them physiologically different from their counterparts isolated from primary tissues and limit their use for predicting clinical drug effects. To address this hurdle, there have been ongoing advances in differentiation and maturation protocols to improve the quality and use of iPSC-differentiated lineages. Among these are in vitro hepatic and cardiac cellular microsystems that can further enhance the physiology of cultured cells, can be used to better predict drug adverse effects, and investigate drug metabolism, pharmacokinetics, and pharmacodynamics to facilitate successful drug development. In this article, we discuss how cellular microsystems can establish microenvironments for these applications and propose how they could be used for potentially controlling the differentiation of hepatocytes or cardiomyocytes. The physiological relevance of cells is enhanced in cellular microsystems by simulating properties of tissue microenvironments, such as structural dimensionality, media flow, microfluidic control of media composition, and co-cultures with interacting cell types. Recent studies demonstrated that these properties also affect iPSC differentiations and we further elaborate on how they could control differentiation efficiency in microengineered devices. In summary, we describe recent advances in the field of cellular microsystems that can control the differentiation and maturation of hepatocytes and cardiomyocytes for drug evaluation. We also propose how future research with iPSCs within engineered microenvironments could enable their differentiation for scalable evaluations of drug effects.

Impact statement

Cardiac and hepatic adverse drug effects are among the leading causes of attrition in preclinical and clinical drug development programs as well as marketing withdrawals. The insufficiency of animal testing models has led to considerable interest in the employment of cardiac and hepatic models using human-induced pluripotent stem cells (iPSCs) for drug toxicity testing. However, current batches of iPSC-derived cardiomyocytes and hepatocytes are variable and not matured as adult primary tissues, which limit their prediction of drug effects. This article discusses how the use of microfluidics can create microenvironments to better control differentiation protocols and increase the physiological relevance of iPSC-derived cardiomyocytes and hepatocytes. Development and standardization of technologies will enable evaluation of the potential value of cellular microsystems to improve the in vitro models used in drug development programs. Future steps in this field include controlled connections of organ systems to better recreate clinical metabolism and pharmacokinetics.

中文翻译：

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具有 iPSC 衍生的心脏和肝细胞的微工程系统，用于评估药物不良反应。

肝脏和心脏药物不良反应是药物开发计划中损耗的主要原因之一，部分原因是当前动物或体外的预测失败楷模。从人类诱导多能干细胞 (iPSCs) 分化而来的肝细胞和心肌细胞有望用于预测临床药物作用，因为它们具有人类特异性，并且能够携带基因决定的特征，这些特征是药物反应的个体间差异的基础。目前，从 iPSC 分化出的肝细胞和心肌细胞的胎儿样特性和异质性使它们在生理上不同于从原代组织中分离出来的对应物，并限制了它们在预测临床药物作用方面的应用。为了解决这一障碍，分化和成熟方案不断取得进展，以提高 iPSC 分化谱系的质量和使用。其中有体外肝和心脏细胞微系统可以进一步增强培养细胞的生理机能，可用于更好地预测药物不良反应，并研究药物代谢、药代动力学和药效学，以促进药物开发的成功。在本文中，我们讨论了细胞微系统如何为这些应用建立微环境，并提出如何将它们用于潜在地控制肝细胞或心肌细胞的分化。通过模拟组织微环境的特性，例如结构维度、培养基流动、培养基成分的微流体控制以及与相互作用的细胞类型的共培养，细胞的生理相关性在细胞微系统中得到增强。最近的研究表明，这些特性也会影响 iPSC 的分化，我们进一步阐述了它们如何控制微工程设备的分化效率。总之，我们描述了细胞微系统领域的最新进展，这些系统可以控制肝细胞和心肌细胞的分化和成熟以进行药物评估。我们还提出了未来在工程微环境中对 iPSC 的研究如何能够使其差异化，从而对药物作用进行可扩展的评估。

影响陈述

心脏和肝脏的药物不良反应是临床前和临床药物开发计划以及市场退出的主要原因之一。动物试验模型的不足导致人们对使用人类诱导多能干细胞 (iPSC) 进行药物毒性试验的心脏和肝脏模型产生了极大的兴趣。然而，当前批次的 iPSC 衍生的心肌细胞和肝细胞是可变的，并且没有成熟为成人原代组织，这限制了它们对药物作用的预测。本文讨论了微流体的使用如何创建微环境以更好地控制分化方案并增加 iPSC 衍生的心肌细胞和肝细胞的生理相关性。用于药物开发计划的体外模型。该领域的未来步骤包括器官系统的受控连接，以更好地重建临床代谢和药代动力学。