Multi-Organs-on-Chips: Towards Long-Term Biomedical Investigations

Abstract

With advantageous features such as minimizing the cost, time, and sample size requirements, organ-on-a-chip (OOC) systems have garnered enormous interest from researchers for their ability for real-time monitoring of physical parameters by mimicking the in vivo microenvironment and the precise responses of xenobiotics, i.e., drug efficacy and toxicity over conventional two-dimensional (2D) and three-dimensional (3D) cell cultures, as well as animal models. Recent advancements of OOC systems have evidenced the fabrication of ‘multi-organ-on-chip’ (MOC) models, which connect separated organ chambers together to resemble an ideal pharmacokinetic and pharmacodynamic (PK-PD) model for monitoring the complex interactions between multiple organs and the resultant dynamic responses of multiple organs to pharmaceutical compounds. Numerous varieties of MOC systems have been proposed, mainly focusing on the construction of these multi-organ models, while there are only few studies on how to realize continual, automated, and stable testing, which still remains a significant challenge in the development process of MOCs. Herein, this review emphasizes the recent advancements in realizing long-term testing of MOCs to promote their capability for real-time monitoring of multi-organ interactions and chronic cellular reactions more accurately and steadily over the available chip models. Efforts in this field are still ongoing for better performance in the assessment of preclinical attributes for a new chemical entity. Further, we give a brief overview on the various biomedical applications of long-term testing in MOCs, including several proposed applications and their potential utilization in the future. Finally, we summarize with perspectives.

An adaptable soft-mold embossing process for fabricating optically-accessible, microfeature-based culture systems and application toward liver stage antimalarial compound testing

“…In vitro organ models are gaining popularity as tools for drug discovery, due to their potential to serve as more predictive models of human diseases. 1 However, medium-and highthroughput drug discovery approaches utilize standard robotic liquid handling and automated high-content and high-resolution imaging (HC/RI) equipment for screening of compound libraries, requiring biological constituents to conform to the basic shape and sizes of standard microtiter plates, the design specifications of which have been set by ANSI SLAS industry standards. Yet many in vitro organ models require microenvironments that are more complex than the simple, two dimensional-bottom architecture of microtiter plates.…”

Organ-on-a-chip: recent breakthroughs and future prospects

“…The "multi-organ-on-a-chip", otherwise referred to as the "human-on-a-chip" [98] simultaneously constructs multiple organs attracting obvious research attention. Multi-organs-on-a-chip culture cells of different organs and tissues simultaneously which are connected by channels (bionic blood vessel [99]), to achieve multi-organ integration, permitting the examination of interactions to establish a system [100,101]. These can be separated into static, semi-static and flexible approaches [102].…”

3D Cell Printing of Tissue/Organ-Mimicking Constructs for Therapeutic and Drug Testing Applications

“…While the development of new printing techniques and bioinks provides advanced tissue/organ constructs, a multi-organ system should also be considered. Since the organs in the human body are connected and interact with each other, realistic functionality cannot be achieved without this interconnected system [ 94 , 182 , 183 ]. A conventional machining process and MEMs-based multi-organ-on-a-chip was reported and showed enhanced functionality and suitability for pharmacology studies [ 184 , 185 , 186 ].…”