Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02110, USA.
The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA.
Lab Chip. 2020 Feb 7;20(3):468-476. doi: 10.1039/c9lc00925f. Epub 2020 Jan 28.
The human kidney contains approximately one million nephrons. As the functional unit of the kidney, the nephron affords an opportunity to approximate the kidney at a microphysiological scale. Recent emergence of physiologically accurate human tissue models has radically advanced the possibilities of mimicking organ biology and multi-organ combinations in vitro. Anatomically, the nephron is one of the most complex, sequentially integrated microfluidic units in the body making the miniaturized microfluidic systems excellent candidates for capturing the kidney biology in vitro. While these models are promising, there are a number of considerations for practical implementation into a drug development paradigm. Opportunities for pharmaceutical industry applications of new MPS models often start with drug safety testing. As such, the intent of this article is to focus on safety and ADME applications. This article reviews biological functions of the kidney and options for characterizing known roles in nephrotoxicity. The concept of "context-of-use" is introduced as a framework for describing and verifying the specific features of an MPS platform for use in drug development. Overall, we present a perspective on key attributes of microphysiological kidney models, which the pharmaceutical industry could leverage to improve confident safety and ADME evaluations of experimental therapies.
人类肾脏大约包含一百万个肾单位。作为肾脏的功能单位，肾单位提供了一种在微观生理学尺度上模拟肾脏的机会。最近出现的生理准确的人体组织模型极大地推动了模拟器官生物学和多器官组合的可能性。从解剖学上讲，肾单位是人体中最复杂、顺序集成的微流控单元之一，这使得微型化微流控系统成为体外捕捉肾脏生物学的优秀候选者。虽然这些模型很有前景，但在实际应用于药物开发范式时需要考虑许多因素。新的 MPS 模型在药物安全性测试方面为制药行业的应用提供了机会。因此，本文的目的是重点关注安全性和 ADME 应用。本文综述了肾脏的生物学功能以及在肾毒性中表征已知作用的方法。引入“使用情境”的概念作为描述和验证用于药物开发的 MPS 平台特定特征的框架。总的来说，我们提出了一种观点，即认为微生理肾脏模型的关键属性可以被制药行业利用，以提高对实验性治疗的安全和 ADME 评估的信心。
