Microfluidics-based 3D cell culture models: Utility in novel drug discovery and delivery research

Abstract

The implementation of microfluidic devices within life sciences has furthered the possibilities of both academic and industrial applications such as rapid genome sequencing, predictive drug studies, and single cell manipulation. In contrast to the preferred two-dimensional cell-based screening, three-dimensional (3D) systems have more in vivo relevance as well as ability to perform as a predictive tool for the success or failure of a drug screening campaign. 3D cell culture has shown an adaptive response to the recent advancements in microfluidic technologies which has allowed better control over spheroid sizes and subsequent drug screening studies. In this review, we highlight the most significant developments in the field of microfluidic 3D culture over the past half-decade with a special focus on their benefits and challenges down the lane. With the newer technologies emerging, implementation of microfluidic 3D culture systems into the drug discovery pipeline is right around the bend.

Keywords: chip; matrix; microfluidics; nanoparticles; spheroid; three‐dimensional culture.

Figure 1

Comparison of 2D and 3D cell culture. Cells grown on conventional 2D surfaces adopt a typical flattened morphology covering mainly x‐y plane and have a reduced height in the vertical z plane. In comparison, 3D culture allows more cuboidal morphology and 3D structure, particularly in z plane (modified from Ref. 4)

Figure 2

Conventional methods for 3D cell culture. (a) Hanging drop. (b) Forced floating. (c) Matrices and scaffolds. (d) Agitation based approaches, (i) spinner flask and (ii) rotating cell culture bioreactors. (e) Microfluidic systems (modified from Refs. 31, 32, 33, 47, 56)

Figure 3

Microfabricated methods to establish 3D culture systems. (a) Photolithography, the core microfabrication technique. (b) Replica molding and microcontact printing. (c) Bonding of microfluidic devices and laminar flow (adapted from Ref. 60)

Figure 4

PDMS‐/glass‐based microfluidic system for the culture of A549 cells. This microchip consisted of an integrated concentration gradient generator and was used for cytotoxicity and cell‐splitting experiments (adapted from Ref. 64)

Figure 5

Paper‐based systems for 3D culture of cells of defined physical dimensions. Permeation of Matrigel or other hydrogel precursors into chromatography or filter paper is done to yield paper‐supported hydrogels (adapted from Ref. 71)

Figure 6

Gel‐free 3D microfluidic cell culture system for A549 cells. (a) The system has two inlets (one for culture medium infusion, one as cell reservoir) and one outlet. (b) Prototype and (c) dimensions of the system (adapted from Ref. 81)

Figure 7

Different components of 3D cell culture for tissue engineering. A perfect combination of cells, scaffold and continuous perfusion with adequate vascular supply and host responses along with functional readout is required to develop tissue/organ substitutes

Figure 8

Different human organs microfabricated on chip. (a) Spleen. (b) Lung. (c) Neurons. (d) Endothelium. (e) Skeletal muscle. (f) Marrow/tumor/liver. (g) Cardiac network. (h) Vessel. (i) Vessel co‐culture. (j) Intestinal villi (adapted from Ref. 86)