Hepatic organoids for microfluidic drug screening

Abstract

We introduce the microfluidic organoids for drug screening (MODS) platform, a digital microfluidic system that is capable of generating arrays of individually addressable, free-floating, three-dimensional hydrogel-based microtissues (or 'organoids'). Here, we focused on liver organoids, driven by the need for early-stage screening methods for hepatotoxicity that enable a "fail early, fail cheaply" strategy in drug discovery. We demonstrate that arrays of hepatic organoids can be formed from co-cultures of HepG2 and NIH-3T3 cells embedded in hydrogel matrices. The organoids exhibit fibroblast-dependent contractile behaviour, and their albumin secretion profiles and cytochrome P450 3A4 activities are better mimics of in vivo liver tissue than comparable two-dimensional cell culture systems. As proof of principle for screening, MODS was used to generate and analyze the effects of a dilution series of acetaminophen on apoptosis and necrosis. With further development, we propose that the MODS platform may be a cost-effective tool in a "fail early, fail cheaply" paradigm of drug development.

Comparison of the uptake of methacrylate-based nanoparticles in static and dynamic in vitro systems as well as in vivo

“…In particular new screening methods to test toxicity, permeability and transport of drugs are under investigation. [23,26] In a recent study, where liver-specific PLGA-based nanoparticles were used, the relevance of shear stress on nanoparticle-uptake in an artificial liver was presented. [13] To gain more insight into the impact of shear stress and co-culture of HUVECs and primary macrophages, well-known methacrylate-based nanoparticles can be applied.…”

Digital microfluidic three-dimensional cell culture and chemical screening platform using alginate hydrogels

“…This ensured that the gel always remained in place during excess liquid removal and never got carried away with excess liquid. Since no barrier or hydrophilic patterning was required to retain the gel in place unlike other EWOD DMF devices reported for hydrogel based 3D cell culture and screening, 28,29 this design proved to be easy to fabricate and implement and offers a simple solution not just for alginate hydrogels but any other hydrogel based system.…”

“…26,27 More recent studies have further developed the concept using thermally cross-linked hydrogels such as collagen, agarose, or Geltrex for 3D cell culture 28 and for drug screening applications. 29 However, depending on the kind of cells being cultured and studies being conducted, a wide variety of hydrogels have been used. Not all of these hydrogels are cross linked thermally.…”

Inventions and Innovations in Preclinical Platforms for Cancer Research

“…They have been designed with various purposes including shear stress analysis [117], drug screening [118], multi organ-on-a-chip [119] and analysis of the spheroid fusion process [120]. Digital microfluidic platforms also are used for spheroid formation and culture [121]. In these devices, the cell suspension of droplets is directed towards hydrophilic of hanging droplet sites for culturing [122,123].…”