The Use of the Integrated Discrete Multiple Organ Co-culture (IdMOC^®) System for the Evaluation of Multiple Organ Toxicity

Abstract

The application of the Integrated Discrete Multiple Organ Co-culture (IdMOC®) system in the evaluation of organ-specific toxicity is reviewed. In vitro approaches to predict in vivo toxicity have met with limited success, mainly because of the complexity of in vivo toxic responses. In vivo properties that are not well-represented in vitro include organ-specific responses, multiple organ metabolism, and multiple organ interactions. The IdMOC system has been developed to address these deficiencies. The system uses a ‘wells-within-a-well’ concept for the co-culturing of cells or tissue slices from different organs as physically separated (discrete) entities in the small inner wells. These inner wells are nevertheless interconnected (integrated) by overlying culture medium in the large outer containing well. The IdMOC system thereby models the in vivo situation, in which multiple organs are physically separated but interconnected by the systemic circulation, permitting multiple organ interactions. The IdMOC system, with either cells or tissue slices from multiple organs, can be used to evaluate cell type-specific or organ-specific toxicity.

Physiologically relevant organs on chips

“…The microscale CCA is a physical representation of a PBPK model, in which multiple cell culture compartments, representing different organs with physiological tissue-to-tissue size ratio, are interconnected through microfluidic channels under physiologically relevant fluid flow conditions to predict the time-dependent absorption, metabolism, distribution, and elimination (ADME) of drugs in the human body and human responses to drugs. Li [99, 100] also proposed the integrated discrete multiple organ co-culture (IdMOC) system to overcome the shortcomings of in vitro biological models, such as the lack of multiple organ metabolism and interactions (Fig. 4B).…”

“…(B) Integrated discrete multiple organ co-culture (IdMOC) system, consisting of multiple inner wells with cells from specific organs, representing physically discrete organs, within a large outer well containing the overlying medium, which interconnects the physically discrete organ cells. Reproduced from [6, 7, 100] with permission.…”

Organs-on-a-Chip: A Focus on Compartmentalized Microdevices

“…Li and co-workers developed the integrated discrete multiple organ cell culture (IdMOC) system, in which various cells and tissue explants are cultured in wells, and allowed to communicate via soluble signals through an overlying layer of cell culture media. [47][48][49] As these systems do not leverage microengineering approaches, they are not reviewed in detail here. Simultaneously however, the Shuler group pioneered microfabricated multi-culture systems in which fluid flow is controlled between distinct organ compartments.…”

Human Tissue in the Evaluation of Safety and Efficacy of New Medicines: A Viable Alternative to Animal Models?

“…This is particularly important in considering the effects not only of the drugs themselves, but also of their metabolic products, and these are likely to be generated by tissue(s) other than that in which an adverse effect may originate. Such integrated modelling is being provided in a range of different forms (Figure 3), for example, using microfluidics [45, 46], the so-called quasi-vivo multicompartmental modular system [47], or wells within wells [48], all of which allow drugs to be exposed to key tissues in a fashion approximating that in vivo . Such approaches allow for example the exposure of a drug to liver cells prior to contact with cells of a target organ(s), allowing an understanding of the activity not only of the drug itself, but also of its metabolic products, more closely mimicking what is likely to occur in vivo .…”