pharmacodynamics (PD), and toxicity studies, of the past century and continue to provide a wealth of knowledge and understanding of various diseases mechanism and therapy. [1][2][3] However, the use of these models in research and industrial applications has been a subject of heated debate, particularly, due to ethical matters and the increasing pressure by the animalright activists. [4] In addition, the phylogenetic difference between laboratory animals and humans may lead to drug failure during human clinical studies. [5] Furthermore, the inherent complexity of the animal's body tissue makes it difficult to interpret the physiological events that characterize the interaction of a particular organ or cells with exogenic factors. [6] In line with regulatory developments precluding the use of animal testing, human in vitro methodologies is required to replace the animal-based testes while permitting equivalent or superior prediction. [7,8] Despite many efforts, no sufficiently acceptable in vitro approaches have been developed to date, and the major gap to predict drug response in human still existed. Utilizing animal models can lead to significant insights into the complex pathophysiology of the disease. [9] However, the pathophysiology may differ between humans and animals. [10,11] Comparing to animal model-based studies, these interactions are less well understood in humans. This is a necessity considering the differences between animal and human immune responses and outcomes in preclinical models versus clinical trials. [10,11] There is consequently a real need for in vitro models of the human organs that closely mimic the physiological processes of disease development with an acceptable level of flexibility, accuracy, and reproducibility for efficient screening of potential drug candidates. Such models would increase the predictability of human response to drugs and reduce experimentation expenses and speed up the screening processes. Failing to produce safe and efficient preclinical leads and drug candidates is associated with overall low R&D efficiency and high cost. The cost of developing a new drug that gains marketing approval is estimated to be $2.6 billion (as of 2013) which includes the in vitro and in vivo animal models during the preclinical and clinical trials stages which may last several Despite many ongoing efforts across the full spectrum of pharmaceutical and biotech industries, drug development is still a costly undertaking that involves a high risk of failure during clinical trials. Animal models played vital roles in understanding the mechanism of human diseases. However, the use of these models has been a subject of heated debate, particularly due to ethical matters and the inevitable pathophysiological differences between animals and humans. Current in vitro models lack the sufficient functionality and predictivity of human pharmacokinetics and toxicity, therefore, are not capable to fully replace animal models. The recent development of microphysiological systems has shown great potentia...

Studying the immune system in vitro aims to understand how, when, and where the immune cells migrate/differentiate and respond to the various triggering events and the decision points along the immune response journey. It becomes evident that organ‐on‐a‐chip (OOC) technology has a superior capability to recapitulate the cell‐cell and tissue‐tissue interaction in the body, with a great potential to provide tools for tracking the paracrine signaling with high spatial‐temporal precision and implementing in situ real‐time, non‐destructive detection assays, therefore, enabling extraction of mechanistic information rather than phenotypic information. However, despite the rapid development in this technology, integration of the immune system into OOC devices stays among the least navigated tasks, with immune cells still the major missing components in the developed models. This is mainly due to the complexity of the immune system and the reductionist methodology of the OOC modules. Dedicated research in this field is demanded to establish the understanding of mechanism‐based disease endotypes rather than phenotypes. Herein, we systemically present a synthesis of the state‐of‐the‐art of immune‐cantered OOC technology. We comprehensively outlined what is achieved and identified the technology gaps emphasizing the missing components required to establish immune‐competent OOCs and bridge these gaps.