Human heart-on-a-chip microphysiological system comprising endothelial cells, fibroblasts, and iPSC-derived cardiomyocytes.

In recent years, research on organ-on-a-chip technology has been flourishing, particularly for drug screening and disease model development. Fibroblasts and vascular endothelial cells engage in crosstalk through paracrine signaling and direct cell-cell contact, which is essential for the normal development and function of the heart. Therefore, to faithfully recapitulate cardiac function, it is imperative to incorporate fibroblasts and vascular endothelial cells into a heart-on-a-chip model. Here, we report the development of a human heart-on-a-chip composed of induced pluripotent stem cell (iPSC)-derived cardiomyocytes, fibroblasts, and vascular endothelial cells. Vascular endothelial cells cultured on microfluidic channels responded to the flow of culture medium mimicking blood flow by orienting themselves parallel to the flow direction, akin to in vivo vascular alignment in response to blood flow. Furthermore, the flow of culture medium promoted integrity among vascular endothelial cells, as evidenced by CD31 staining and lower apparent permeability. The tri-culture condition of iPSC-derived cardiomyocytes, fibroblasts, and vascular endothelial cells resulted in higher expression of the ventricular cardiomyocyte marker IRX4 and increased contractility compared to the bi-culture condition with iPSC-derived cardiomyocytes and fibroblasts alone. Such tri-culture-derived cardiac tissues exhibited cardiac responses similar to in vivo hearts, including an increase in heart rate upon noradrenaline administration. In summary, we have achieved the development of a heart-on-a-chip composed of cardiomyocytes, fibroblasts, and vascular endothelial cells that mimics in vivo cardiac behavior.

Development of lung tissue models and their applications.

The lungs are important organs that play a critical role in the development of specific diseases, as well as responding to the effects of drugs, chemicals, and environmental pollutants. Due to the ethical concerns around animal testing, alternative methods have been sought which are more time-effective, do not pose ethical issues for animals, do not involve species differences, and provide easy investigation of the pathobiology of lung diseases. Several national and international organizations are working to accelerate the development and implementation of structurally and functionally complex tissue models as alternatives to animal testing, particularly for the lung. Unfortunately, to date, there is no lung tissue model that has been accepted by regulatory agencies for use in inhalation toxicology. This review discusses the challenges involved in developing a relevant lung tissue model derived from human cells such as cell lines, primary cells, and pluripotent stem cells. It also introduces examples of two-dimensional (2D) air-liquid interface and monocultured and co-cultured three-dimensional (3D) culture techniques, particularly organoid culture and 3D bioprinting. Furthermore, it reviews development of the lung-on-a-chip model to mimic the microenvironment and physiological performance. The applications of lung tissue models in various studies, especially disease modeling, viral respiratory infection, and environmental toxicology will be also introduced. The development of a relevant lung tissue model is extremely important for standardizing and validation the in vitro models for inhalation toxicity and other studies in the future.