Three-Dimensional In Vitro Cell Culture Models for Efficient Drug Discovery: Progress So Far and Future Prospects

Abstract

Despite tremendous advancements in technologies and resources, drug discovery still remains a tedious and expensive process. Though most cells are cultured using 2D monolayer cultures, due to lack of specificity, biochemical incompatibility, and cell-to-cell/matrix communications, they often lag behind in the race of modern drug discovery. There exists compelling evidence that 3D cell culture models are quite promising and advantageous in mimicking in vivo conditions. It is anticipated that these 3D cell culture methods will bridge the translation of data from 2D cell culture to animal models. Although 3D technologies have been adopted widely these days, they still have certain challenges associated with them, such as the maintenance of a micro-tissue environment similar to in vivo models and a lack of reproducibility. However, newer 3D cell culture models are able to bypass these issues to a maximum extent. This review summarizes the basic principles of 3D cell culture approaches and emphasizes different 3D techniques such as hydrogels, spheroids, microfluidic devices, organoids, and 3D bioprinting methods. Besides the progress made so far in 3D cell culture systems, the article emphasizes the various challenges associated with these models and their potential role in drug repositioning, including perspectives from the COVID-19 pandemic.

Keywords: 3D bioprinting; 3D cell culture; drug repositioning; hydrogel; microfluidic devices; organoid; spheroids.

Figure 1

Diagrammatic representation of 2D cell culture and 3D cell culture.

Figure 2

Various approaches used in 3D cell culturing; (A) showing hydrogels, organoids, spheroids, and microfluidic chip, (B) showing the extrusion-based, laser-assisted, and inkjet-based methods used in 3D Bioprinting.

Figure 3

Diagram showing different approaches used to develop 3D spheroids. (A) Non-adhesive surfaces: modified culture plates with reduced surface adhesive force allows spontaneous cell aggregation to form cellular spheroids, (B) Spinner flasks or gyratory rotator: continuous medium mixing or a constant flask rotation prevents cell adhesion causing massive production of 3D spheroids, (C) Hanging drop method: cells suspended in small drops onto the underside of an inverted hanging drop plate induces accumulation of spheroidal aggregates due to gravity forces, (D) Microcarrier beads: solid beads of natural or synthetic origins allows surface coating to produce minispheroids that subsequently aggregate to form bigger spheroids, (E) Hydrogel matrices: natural or synthetically composed hydrogels are incubated with the cells for their aggregation [This figure is adopted with permission from Manuela et al., 2017 [44]].