Microfluidic-Based Multi-Organ Platforms for Drug Discovery

Abstract

Development of predictive multi-organ models before implementing costly clinical trials is central for screening the toxicity, efficacy, and side effects of new therapeutic agents. Despite significant efforts that have been recently made to develop biomimetic in vitro tissue models, the clinical application of such platforms is still far from reality. Recent advances in physiologically-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling, micro- and nanotechnology, and in silico modeling have enabled single- and multi-organ platforms for investigation of new chemical agents and tissue-tissue interactions. This review provides an overview of the principles of designing microfluidic-based organ-on-chip models for drug testing and highlights current state-of-the-art in developing predictive multi-organ models for studying the cross-talk of interconnected organs. We further discuss the challenges associated with establishing a predictive body-on-chip (BOC) model such as the scaling, cell types, the common medium, and principles of the study design for characterizing the interaction of drugs with multiple targets.

Keywords: body-on-chip; drug discovery; in silico modeling; microfluidics; organ-on-chip.

Figure 1

The design of multi-organ-on-chip platforms and the analysis of biological systems relying on the physiologically-based pharmacokinetic (PBPK) simulation. The drug action is recorded and used for the simulation process. The figure is modified from Reference [31].

Figure 2

Organoid hanging drop cultures for 3D coculturing of single or multiple tissues. (a) HepG2 spheroid formed by the spinner flask method in day 10 of the cultivation, Bar = 100 mm [49]; (b) The top-view of the culture device and the side-view of the magnified laminar flow condition, Bar = 5 mm [10]; (c) 384-well plate for the formation of hanging drops [50]; (d) The spheroid’s self-assembly in wells after pipetting the cell suspension [50]; (e) Spheroids formed in the culture device illustrated in (b) 60 h after seeding, Bar = 100 μm [10].

Figure 3

Examples of sophisticated organ-on-chip applications. (a) Compartmentalized polydimethylsiloxane (PDMS) microchannels for breathing activities in the lung. A thin, porous, and flexible PDMS membrane coated with the extracellular matrix (ECM) forms an alveolar-capillary barrier. The device recreates physiological breathing movements by applying a vacuum to side chambers and leads to mechanical stretching of the PDMS membrane to form the alveolar-capillary barrier. The inhalation in the living lung contracts the diaphragm and reduces the intrapleural pressure and physical stretching of the alveolar-capillary interface [78]; (b) The morphology of epithelial cells cultured in the (i) static Transwell system for 21 days, gut-on-a-chip with a microfluidic flow without (ii) or with (iii) the application of cyclic mechanical deformation for three days. The schematic layout of (left); fluorescence views (center) of the occludin as the tight junction (TJ) protein, and the confocal fluorescence views (right) of the epithelium (nuclei in blue and F-actin in green) [80]; (c) The design of the developed microfluidic blood-brain barrier (BBB) with integrated electrodes for measuring the trans-epithelial resistance across the barrier [98]; (d) The microfluidic cell culture device with embedded electrofluidic pressure sensors. The PDMS membrane is sandwiched between two other PDMS layers: an electrofluidic circuit layer and a microfluidic cell culture layer. The layout of the electrofluidic circuit layer for pressure sensing at four locations, and an equivalent Wheatstone bridge circuit of the pressure sensor [84].

Figure 4

Multi-organ on-chip platforms for the disease modeling and drug studies. (a) The 3D schematic of the liver-skin co-culture microfluidic device; and (b) The metabolic activity of the co-culture of liver and skin [158]. Analyzing the integrity and functionality of the intestinal barrier after 24 h of dynamic co-culture; (c) Transepithelial resistance (TEER) measures; (d) The apparent permeability (Papp) to the Lucifer yellow (e) and the staining of tight junction components: (i) occludin and (ii) claudin. The tight junction (open arrows) components were stained in green by specific antibodies and the nuclei (closed arrows) in blue by 4′,6-diamidino-2-phenylindole (DAPI); (f) The Pgp activity was investigated by the measures of efflux ratio of rhodamine 123. The results obtained after one day of the static culture in Petri dish (D2 static) or the dynamic co-culture (D2 IIDMP) are expressed relative to the control consisted of the static culture of Caco-2 TC7 after 21 days (D1 control) [13]; (g) Staining of the small intestinal epithelial tissue for the transporter NaK-ATPase (red) and cytokeratin 8/18 (green); (h) Staining of the small intestinal epithelial tissue for the ATP-dependent export pump MRP-2 (red); (i) qRT-PCR data of liver tissues from the control (normalized to 1) and treated co-cultures analyzed for the expression of albumin, BSEP, CPS1, Cyp3A4, MMP7, MRP-1, PPARa, UGT1A1 and ZO-1 [14]; (j) The glucose consumption of Madin Darby Canine kidney cells cultured in dynamic biochips made from PDMS and PTFE [15].