Self-contained, low-cost Body-on-a-Chip systems for drug development

Abstract

Integrated multi-organ microphysiological systems are an evolving tool for preclinical evaluation of the potential toxicity and efficacy of drug candidates. Such systems, also known as Body-on-a-Chip devices, have a great potential to increase the successful conversion of drug candidates entering clinical trials into approved drugs. Systems, to be attractive for commercial adoption, need to be inexpensive, easy to operate, and give reproducible results. Further, the ability to measure functional responses, such as electrical activity, force generation, and barrier integrity of organ surrogates, enhances the ability to monitor response to drugs. The ability to operate a system for significant periods of time (up to 28 d) will provide potential to estimate chronic as well as acute responses of the human body. Here we review progress towards a self-contained low-cost microphysiological system with functional measurements of physiological responses. Impact statement Multi-organ microphysiological systems are promising devices to improve the drug development process. The development of a pumpless system represents the ability to build multi-organ systems that are of low cost, high reliability, and self-contained. These features, coupled with the ability to measure electrical and mechanical response in addition to chemical or metabolic changes, provides an attractive system for incorporation into the drug development process. This will be the most complete review of the pumpless platform with recirculation yet written.

Keywords: Pumpless; functional measurement; microphysiological systems; organ on a chip; organ–organ interactions; serum free.

Figure 1

Self-contained low-cost Body-on-a-Chip (BOC) systems hold great potential for high-content, high-throughput drug screening. There are five core aspects of such systems: (1) controlled culture environment with defined culture medium formulations and surface chemistry helps with generating reproducible conditions and extending the depth of functional analysis. (2) Pumpless microfluidic platforms are the basis of a self-contained BOC system; (3) non-invasive functional measurements are enabled with integrated biosensors; (4) advanced single organ models provide improved organ mimics for BOC systems. Image shows a three-dimensional model of gastrointestinal (GI) macrovilli, reproduced from Esch et al. with permission from Springer. (5) Integration of multiple organ units based on proper scaling rules and integration strategies recreates physiologically relevant organ–organ interactions. (A color version of this figure is available in the online journal.)

Figure 2

Functional measurements for Body-on-a-Chip systems. (a) Extracellular electrical activity recording with microelectrode arrays (MEAs) for conductive tissues, such as myotubes, cardiac microtissues,^, and nerves.^, (b) Measurement of force generation by muscles^, using a microfabricated cantilever-based system. Illustration reproduced from Smith et al. with permission from World Scientific Publishing. (c) Barrier function analysis through transepithelial electrical resistance (TEER) monitoring and permeability studies for barrier tissue, such as skin, gastrointestinal tract,^, and blood–brain barrier. (d) Analysis of hepatic enzymatic activity and immune response.^,, *Organ-specific functional measurements that have been incorporated in a pumpless microfluidic system. (A color version of this figure is available in the online journal.)

Figure 3

Currently developed self-contained multi-organ systems. Integrated Body-on-a-Chip (BOC) systems that support coculture of two to 13 organs have been developed on pumpless microfluidic platforms. (a) A liver–tumor–marrow three-organ system. Reproduced from Sung et al. with permission from the Royal Society of Chemistry; (b) a modular system for the coculture of GI tract epithelium and 3D primary liver tissue with in situ transepithelial electrical resistance (TEER) measurement capacity. (c) A palm-size system for 4–5-organs with integrated electrical activity and contractile force sensors for non-invasive functional read-outs. (d, e) BOC systems for 10 or more organs. (A color version of this figure is available in the online journal.)