Spatiotemporal Control of Growth Factors in Three-Dimensional Printed Scaffolds

Abstract

Three-dimensional printing (3DP) has enabled the fabrication of tissue engineering scaffolds that recapitulate the physical, architectural, and biochemical cues of native tissue matrix more effectively than ever before. One key component of biomimetic scaffold fabrication is the patterning of growth factors, whose spatial distribution and temporal release profile should ideally match that seen in native tissue development. Tissue engineers have made significant progress in improving the degree of spatiotemporal control over which growth factors are presented within 3DP scaffolds. However, significant limitations remain in terms in pattern resolution, the fabrication of true gradients, temporal control of growth factor release, the maintenance of growth factor distributions against diffusion, and more. This review summarizes several key areas for advancement of the field in terms of improving spatiotemporal control over growth factor presentation, and additionally highlights several major tissues of interest that have been targeted by 3DP growth factor patterning strategies.

Keywords: bioprinting; fabrication; gradient; growth factor; pattern; printing; spatiotemporal.

Fig 1:

Printing of drug-loaded aqueous cores, followed by deposition of AuNR-doped PLGA shells, and then wavelength-specific rupturing of shells to effect selective release of payloads. Reproduced with permission from (47).

Fig 2:

In vivo gradient of fluorescently-labeled PDGF-BB created by diffusion of the growth factor from its original area of burst release (red circle). Fluorescent images were taken at day 1 (A), day 7 (B), and day 21 (C). Also shown are the spatial distribution of growth factor fluorescence (D) as well as a comparison of the experimental growth factor distribution to the predicted distribution from mathematical modeling (E). Reproduced with permission from (51).

Fig 3:

Gradient-like distribution of CPC strands (white) and VEGF-loaded alginate-gellan hydrogel strands (red) generated by a two-channel plotting system. The 3D printed scaffold is shown from side (a) and top (b) views. Reproduced with permission from (28).

Fig 4:

3D printed scaffold scheme, displaying uniform PCL/DPSC/collagen (Group 1), PCL/DPSC/BMP-2/collagen (Group 2), and biphasic PCL/DPSC/collagen/BMP-2 exterior PCL/DPSC/gelatin/alginate/VEGF interior (Group 3) scaffolds used by Park et al. Reproduced with permission from (85).

Fig 5:

3D printed bifurcating sciatic nerve developed from computed tomography scanning used by Johnson et al. a) Sciatic nerve with branching sensory and motor nerves. b) Sciatic nerve pathway was transected for modelling. c,d) Several scans of the geometry are taken and aligned into a 3D model of the nerve pathway. e) The aligned scans are reconstructed into a full 3D template. f) Using the reconstructed images, the scaffold is printed into a model mirroring the original sciatic nerve pathway. g) Schematic of designed model with GF placement, and h) 3D bioprinted scaffolds with NGF and GDNF spatiotemporal patterns (green and red dyes used to indicate hydrogel droplet locations). Reproduced with permission from (18).