Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.).
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.Y., A.M.K., L.P., Y.Z., J.X.S., S.K.G., R.Z.S., C.M.S., V.M.L.); Department of Drug Metabolism and Pharmacokinetics (DMPK), Merck KGaA, Darmstadt, Germany (L.P.); Department of Health Technology, Technical University of Denmark, Lyngby, Denmark (S.D.C., J.U.L.); Synthetic Physiology Laboratory, Department of Civil Engineering and Architecture, University of Pavia, Pavia, Italy (F.S.P.); Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden (Z.S.); and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (V.M.L.)
Pharmacol Rev. 2022 Jan;74(1):141-206. doi: 10.1124/pharmrev.120.000238.
The number of successful drug development projects has been stagnant for decades despite major breakthroughs in chemistry, molecular biology, and genetics. Unreliable target identification and poor translatability of preclinical models have been identified as major causes of failure. To improve predictions of clinical efficacy and safety, interest has shifted to three-dimensional culture methods in which human cells can retain many physiologically and functionally relevant phenotypes for extended periods of time. Here, we review the state of the art of available organotypic culture techniques and critically review emerging models of human tissues with key importance for pharmacokinetics, pharmacodynamics, and toxicity. In addition, developments in bioprinting and microfluidic multiorgan cultures to emulate systemic drug disposition are summarized. We close by highlighting important trends regarding the fabrication of organotypic culture platforms and the choice of platform material to limit drug absorption and polymer leaching while supporting the phenotypic maintenance of cultured cells and allowing for scalable device fabrication. We conclude that organotypic and microphysiological human tissue models constitute promising systems to promote drug discovery and development by facilitating drug target identification and improving the preclinical evaluation of drug toxicity and pharmacokinetics. There is, however, a critical need for further validation, benchmarking, and consolidation efforts ideally conducted in intersectoral multicenter settings to accelerate acceptance of these novel models as reliable tools for translational pharmacology and toxicology. SIGNIFICANCE STATEMENT: Organotypic and microphysiological culture of human cells has emerged as a promising tool for preclinical drug discovery and development that might be able to narrow the translation gap. This review discusses recent technological and methodological advancements and the use of these systems for hit discovery and the evaluation of toxicity, clearance, and absorption of lead compounds.
尽管在化学、分子生物学和遗传学方面取得了重大突破，但成功的药物研发项目数量已经停滞了几十年。不可靠的靶点鉴定和临床前模型的低转化性被认为是失败的主要原因。为了提高对临床疗效和安全性的预测能力，人们的兴趣已经转向三维培养方法，在这种方法中，人类细胞可以在很长一段时间内保留许多生理和功能相关的表型。在这里，我们回顾了现有的器官型培养技术的最新进展，并批判性地回顾了对药代动力学、药效学和毒性具有关键重要性的新兴人类组织模型。此外，还总结了生物打印和微流控多器官培养技术在模拟系统药物处置方面的最新进展。最后，我们强调了在器官型培养平台的制造和平台材料选择方面的重要趋势，以限制药物吸收和聚合物浸出，同时支持培养细胞的表型维持，并允许可扩展的器件制造。我们得出的结论是，器官型和微生理的人类组织模型是有前途的系统，可以通过促进药物靶点鉴定和改善药物毒性和药代动力学的临床前评估来促进药物发现和开发。然而，迫切需要进一步的验证、基准测试和整合工作，理想情况下在跨部门的多中心环境中进行，以加速这些新型模型作为转化药理学和毒理学可靠工具的接受度。意义：器官型和微生理的人类细胞培养已经成为一种很有前途的临床前药物发现和开发工具，它可能能够缩小转化差距。这篇综述讨论了最近的技术和方法上的进步，以及这些系统在发现药物靶点和评估毒性、清除率和先导化合物的吸收方面的应用。
