Developments with 3D bioprinting for novel drug discovery

Abstract

Introduction: Although there have been significant contributions from the pharmaceutical industry to clinical practice, several diseases remain unconquered, with the discovery of new drugs remaining a paramount objective. The actual process of drug discovery involves many steps including pre-clinical and clinical testing, which are highly time- and resource-consuming, driving researchers to improve the process efficiency. The shift of modelling technology from two-dimensions (2D) to three-dimensions (3D) is one of such advancements. 3D Models allow for close mimicry of cellular interactions and tissue microenvironments thereby improving the accuracy of results. The advent of bioprinting for fabrication of tissues has shown potential to improve 3D culture models. Areas covered: The present review provides a comprehensive update on a wide range of bioprinted tissue models and appraise them for their potential use in drug discovery research. Expert opinion: Efficiency, reproducibility, and standardization are some impediments of the bioprinted models. Vascularization of the constructs has to be addressed in the near future. While much progress has already been made with several seminal works, the next milestone will be the commercialization of these models after due regulatory approval.

Keywords: 3D bioprinting; drug discovery; drug testing; tissue models.

Figure 1.

Schematic illustration of (A) droplet-, (B) extrusion-, and (C) laser-based bioprinting modalities.

Figure 2.

Bioprinted tumor models (A) Hematoxylin-eosin (H&E) staining of 3D bioprinted glioma cells cultured in vitro at Day 7 and Day 21 (reproduced from Ref. [64] with permission of IOP publishing); (B) an optical image and Nanog, Oct-4 and DAPI immunofluorescent images showing pluripotency, non-differentiated and nucleous of cells at Day 3 (reproduced from. [65] with permission of the Royal Society of Chemistry); (C) 2D and 3D cultures of Hela cells in gelatin/alginate/fibrinogen blend at Day 5 and Day 7 (reproduced from Ref. [69] with permission of the American Chemical Society); (D) confocal microscopy images of co-culture of MDA-MB-231 and human osteoblast cells in 10 % Gelma and nanocrystalline hydroxyapatite (nHA) (reproduced from Ref. [68] with permission of IOP publishing).

Figure 3.

Bioprinted skin and heart models (A1) a H&E staining image of bioprinted murine fibroblast (NIH 3T3) and human keratinocyte (HaCaT) construct on Matriderm™, (A2) immunoperoxidase staining of cytokeratin demonstrates keratinocytes where all nuclei stained with Hoechst 33342 (blue), (A3-A4) fluorescence images showing distribution of fibroblasts (red) and keratinocytes (green) where cell nuclei are stained in Hoechst 3342 (blue), (A5-A6) while Ki-67 (red) staining represents the proliferating cell nuclei, anti-laminin (green) staining demonstrates the basement membrane (reproduced from [73] with permission of John Wiley and Sons); (B) H&E stained samples of skin model at Day 7 and 14 (yellow dash line represents the interface between epidermis and dermis) (reproduced from Ref. [76] with permission of IOP publishing); (C) immunofluorescent images of a string and patch forms of the bioprinted cardiac tissues express actinin (red), connexin (green) and cell nuclei (blue) at Day 4, Day 7, Day 21 (with low and high magnification) (reproduced from [93] with permission of Elsevier); (D) projection and 3D rendering confocal images showing the distribution of encapsulated HUVECs inside the bioprinted microfibers in the endothelium at Day 14 (reproduced from [96] with permission of Elsevier).

Figure 4.

Bioprinted liver models (A1) Masson`s trichrome staining of 3D liver tissue showing ECM deposition, (A2) IHC staining represents E-cadherin (green) and albumin (red) expressions (reproduced from [99] with permission of PLOS One); (B1) DAPI and GFP-HUVEC layers of 3D vascularized liver tissue model (B2-B3) top and cross-sectional views of in GelMa hydrogel after 2 days, (B4) DAPI and CD31 staining of bioconstruct from top view (reproduced from [102] with permission of AIP Publishing); (C) optical and confocal images showing E-cadherin, albumin, and DAPI staining at Day 0 and Day 7 (reproduced from [104] with permission of National Academy of Sciences of the United States of America (NAS)).