Lack of efficacy, unacceptable safety, or unpredictable toxicity remain the main cause of attrition in drug discovery and development researches in recent decades. Microphysiological systems (MPS) containing organ-on-a-chip may have a potential to be a clinically relevant tool for better understanding of human physiology through microfluidic cell culture systems connecting living engineered human cells or tissue engineered 3D organs in a controlled microenvironment. This article describes advanced technologies and MPS products in oversea countries, overview of national MPS project focusing on user-driven MPS development, and future prospects as follows.

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Microfluidics is a general term describing tools and techniques which utilize microchannels and functional elements to realize high-throughput and high-efficiency chemical reactions and analyses by virtue of the scaling effect. Recently, microphysiological systems (MPSs) based on microfluidics have attracted attention as a platform for drug discovery due to high-accuracy evaluations of efficacy and toxicity of novel drug candidates in non-clinical studies. MPSs of major organs such as the lung, liver, small intestine and kidney have been proposed, and expression and maintenance of cell functions that cannot be achieved by conventional cell culture systems are successfully realized by mimicking the physiological environment. This paper describes previously developed MPSs focusing on the basic concepts of microfluidics.

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The Caco-2 cell line, which is derived from human colon carcinoma, and the cryopreserved human primary hepatocytes are currently used as an in vitro model for evaluating the bioavailability of orally administrated drugs. The bioavailability is predicted by integrating pharmacokinetic data obtained from these evaluation systems. However, the evaluation systems are limited to predicting bioavailability of drugs in humans, since it is hypothesized that both the small intestine and liver do not interfere with each other. The Caco-2 cell line is partially similar to the small intestine in morphology and in expression and function of efflux transporters. On the other hand, drug-metabolizing enzyme activities and robustness of tight junctions are dramatically different from those of the small intestine. Therefore, it is necessary to develop novel prediction systems for drug bioavailability, such as small intestinal epithelial cell-like cells as an alternative to Caco-2 cells. In addition, a microphysiological system has been a recent topic of interest, and is expected to have various applications in drug development studies, such as prediction of bioavailability, drug-drug interactions, and research on the drug delivery system. In this review, we describe our research regarding the development of small intestinal epithelial cells differentiated from human induced pluripotent stem cells and liver-gut device.

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The placental barrier is a multilayered cellular structure that serves as a permeable barrier between fetal and maternal blood circulation. Establishment of an in vitro system for the analysis of placental barrier function is of great interest in the pharmacokinetic study, because the barrier regulates the permeability not only of nutrients and metabolites but also of drugs and chemicals harmful to the developing fetus. A number of studies have been performed using a confluent monolayer of human placental barrier cells cultured on porous membrane support and, in most of the studies, the placental material transport assay is carried out under the static culture condition, although the barrier cells are continuously exposed to the maternal blood flow in vivo. These conventional assay systems are too simple to recapitulate the in vivo barrier property due to the lack of some tissue environmental factors such as structural arrangement of cells, cell-cell interactions, and mechanical stimuli in the tissue. Moreover, species differences of the placental structure make the animal experiments difficult to extrapolate the findings to human. From these reasons, permeability assay system with highly functional placental barrier has been expected to be developed. In this review, we introduce the bio-fabrication of human placental barrier structure integrated with microfluidic system which we reported recently. Microvillous surface of the placental barrier is successfully induced by utilizing fluid shear stress, which resulted in the restricted localization of glucose transporters to the induced microvilli. This polarized localization pattern of glucose transporters can’t be achieved under the conventional static culture system. We further describe the recent progress of placental barrier chip and the prospects for the use of microfluidic system as an analytical system of placental drug transport.

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There is a large gap between conventional 2D cell cultures and inside the body where cells reside in 3D microenvironments that are comprised of a complex set of cellular, chemical, and physical cues and are dynamically fed by blood vessels. This physiological gap raises various challenges in basic cell biology, drug testing, and cellular therapeutics because cells in traditional dish cultures respond very differently than in the body. Recent advances in microsystems technology and tissue engineering have led to the development of organ-on-a-chip microsystems that reconstitute key functional units of organs. By mimicking natural tissue architecture and microenvironmental chemical and physical signals within microfluidic devices, this technology realizes tissue-level functionality in vitro that cannot be recapitulated with conventional culture methods. Since the physiological microenvironments in living systems are mostly microfluidic in nature, microfluidic systems facilitate engineering of cellular microenvironments. Microfluidic systems allow for control of local chemical gradients and dynamic mechanical forces, which play important roles in organ development and function. Organ-on-a-chip technology has great potential to facilitate drug discovery and development, to model human physiology and disease, to model pharmacokinetics and pharmacodynamics, and to replace animal models for efficacy and toxicity testing. Here, I describe current strategies to engineer vascular networks within microfluidic devices and to develop vascularized organ-on-a-chip microsystems. The vascular system is responsible for transporting nutrients and oxygen as well as blood cells and removing waste products, which is essential to maintain cellular viability and function in organs. Current conventional cell culture methods, however, lack the vasculature. For larger cell aggregates or organoids, diffusive transport of nutrients and oxygen is insufficient to support their growth and function. Thus, engineering perfusable vascular networks that can deliver nutrients and blood cells to cell constructs or tissues could be a useful platform to recapitulate cellular microenvironments and tissue-level cell functions. By faithfully recapitulating the complexity of cellular microenvironment including the vasculature in the body, it has been possible to create more reliable in vitro systems to predict responses in humans.

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Collategene^® Intramuscular Injection 4 mg is a plasmid DNA encoding human HGF（Hepatocyte growth factor） gene （cDNA）, and is the first gene therapy product in Japan. Collategene is transcribed and translated in the cells at the injection site of muscle, thereby expressing and secreting HGF. The angiogenic effect of HGF develops collateral to improve ischemia. Collategen is the first gene therapy in Japan to provide a novel and innovative treatment for severe diseases that require treatment but have no cure. Collategene is indicated for gene therapy for the patient who has arteriosclerosis obliterans and Buerger’s disease accompanying “critical limb ischaemia for who is not amenable surgical revascularization,” and no effective treatments available. This article describes the characteristics of this drug and clinical results.

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