Research progress of organoids-on-chips in biomedical application

Drug screening is traditionally based on the pharmacodynamic models from 2D cell culture or animal experiments. However, these models suffer from poor drug efficacy prediction due to their difference from human in vivo cell microenvironments. In recent years, advances in biotechnology and tissue engineering have enabled rapid growth of in vitro organoid culturing. These organoids cultured in matrigel can mimic human in vivo cell microenvironment and physiology more accurately than traditional 2D cell culture and animal models. Among them, tumor organoids, especially patient-derived tumour organoids, can be applied as effective cancer models for drug screening and personalized medicine. By integrating organoid culturing and microfluidics, organoid-on-a-chip platform has been developed to simulate the structure and function of human tissues or organs. In 2010, Ingber et al. reported a biomimetic microfluidic platform called lung-on-a-chip. Microscale engineering technologies were firstly utilized to create biomimetic microchips. Henceforth, increasing kinds of organ-on-a-chips were reported all over the world to mimic different organs, such as liver, kidney and brain. 2D planar cells were cultured in PDMS chambers in majority organ-on-a-chips. More and more studies focused on 3D cells or organoids instead recently due to their better biomimetic capability for drug screening and disease models. In 2018, Qin et al. reported a liver organoid from human iPSCs in a 3D perfusable chip system, which is the first study that uses human organoid in a microfluidic chip and executed drug testing successfully. The established liver organoid-on-a-chip system may provide a promising platform for engineering stem cell-based organoids with applications in regenerative medicine, disease modeling and drug testing. Conventionally, drug efficacy evaluation in organoid-on-a-chip was performed by cell staining. However, this approach only presents static results of live/dead cells, but cannot monitor the cells dynamically for long-term recording. Sensor integration with organoid-on-a-chips paves a new way for dynamic recording. Currently, Wang et al. developed a 3D electric cell/matrigel-substrate impedance sensing (3D-ECMIS) platform for real-time and non-invasive monitoring of 3D cell viability and drug susceptibility. This platform integrated impedance sensors to monitor the impedance changes during 3D cell culturing. Additionally, Wang et al. reported the 3D cardiomyocytes detection by combining microelectrode arrays (MEAs). Heart cells of neonatal rat were cultured on a tissue engineering scaffold, which was fabricated by 3D printing and electro-spinning. The experimental results demonstrated that extracellular field potential (spike amplitude and firing rate) of 3D cardiomyocytes can be recorded in real time. Moreover, non-invasive measurement of cellular metabolism is important to study the metabolism mechanism and drug efficacy. Thus, light-addressable potentiometric sensor (LAPS) was integrated with organoid-on-a-chip for chemical imaging of ions (H+, Na+, K+, Ca2+) induced by cellular metabolism, which enables accurate detection of different chemical parameters in organoid-on-a-chip. Multiple organoid chip linked by microfluidics, called human-on-a-chip is a newly emerging and frontier technology to mimic the interaction of multiple human organs in recent years. It can recapitulate the physiologically relevant structures and functions of the organs, as well as the interaction between multiple organs as in vivo , thereby offering alternative models for predicting human responses to various drugs and environmental stimulus. Organoid-on-a-chip demonstrates outstanding potential in drug screening, disease modeling and personalized precision medicine.