Advances in the construction of human organs-on-chips

Drug development is expensive, time-consuming and high-risk. Although great progress has been made in the understanding of human physiology and pathology, the average cost of a new drug has been growing during the past halfcentury. About 80% drug candidates failed in the clinical trials attributing to their low efficacy and toxicity. These issues indicate that the pre-clinical models could not accurately predict the behaviors of the investigational drugs in human bodies. To date, animal studies remain the gold standard in preclinical testing of new drugs. However, the discordance between animal models and human bodies frequently causes poor reproducibility of new drug behaviors in clinical trials, in addition to the limitations of animal studies such as low throughput, long cycle, high cost, and ethical issues. Therefore, alternative tools to animal models are highly demanded in drug development to bridge the gap between animal models and human bodies. Human organs-on-a-chips (OOCs), also known as human microphysiological systems, are engineered devices aimed at mimicking the structures, functions and microenvironments of human tissues/organs by constructing miniature tissues/ organs in microfluidic chips with specific designs. The concept of OOC was proposed in the late 1990s and representatively demonstrated by the research of lung-on-a-chip, where the breath motion of lung was recapitulated through the construction of the alveolar-capillary interface in a microfluidic chip. Distinct from tissue engineering and organoids, currently OOCs focus on mimicking specific structures and functions of human tissues/organs rather than reproducing the entire tissues/organs, enabling OOCs with advantages in cost, time, and throughput. Meanwhile, with the help of engineering technologies, OOCs could not only precisely reconstruct the tissue/organ-level architectures but also manipulate the inner physical, chemical and mechanical cues in a spatiotemporal manner, providing bio-mimicking microenvironments for the reconstructed tissues/organs. Owing to these advantages, OOCs have obtained extensive attention in the past decade and have been widely applied in life science research, disease studies, drug screening, and precision medicine. Different types of OOC devices, such as heart-on-a-chip, skin-on-a-chip, liver-on-a-chip, kidney-on-achip, brain-on-a-chip, have been proposed by numerous researchers, and series of commercial approachable OOC devices have been launched by spin-off companies such as Emulate, Mimetas, Avatarget, Daxiang, showing the great potentials of OOCs as alternatives to animal models in preclinical studies of new drugs. In this review, we comprehensively overview the recent advances in the construction of human OOCs. The concepts, types, and features of the current human OOCs are first summarized and discussed. The general design strategies and working principles in the construction of human OOCs are then concluded. The key points in generating human OOCs are summarized into four aspects: Cell culture, chip materials and manufacturing, microenvironment construction, and measurement of OOCs, and progress in each aspect is described in detail with corresponding examples. In the end, the current challenges and future opportunities covering laboratory research, government policies, and commercial products are revealed.