3D printing for the design and fabrication of polymer-based gradient scaffolds

Abstract

To accurately mimic the native tissue environment, tissue engineered scaffolds often need to have a highly controlled and varied display of three-dimensional (3D) architecture and geometrical cues. Additive manufacturing in tissue engineering has made possible the development of complex scaffolds that mimic the native tissue architectures. As such, architectural details that were previously unattainable or irreproducible can now be incorporated in an ordered and organized approach, further advancing the structural and chemical cues delivered to cells interacting with the scaffold. This control over the environment has given engineers the ability to unlock cellular machinery that is highly dependent upon the intricate heterogeneous environment of native tissue. Recent research into the incorporation of physical and chemical gradients within scaffolds indicates that integrating these features improves the function of a tissue engineered construct. This review covers recent advances on techniques to incorporate gradients into polymer scaffolds through additive manufacturing and evaluate the success of these techniques. As covered here, to best replicate different tissue types, one must be cognizant of the vastly different types of manufacturing techniques available to create these gradient scaffolds. We review the various types of additive manufacturing techniques that can be leveraged to fabricate scaffolds with heterogeneous properties and discuss methods to successfully characterize them.

Statement of significance: Additive manufacturing techniques have given tissue engineers the ability to precisely recapitulate the native architecture present within tissue. In addition, these techniques can be leveraged to create scaffolds with both physical and chemical gradients. This work offers insight into several techniques that can be used to generate graded scaffolds, depending on the desired gradient. Furthermore, it outlines methods to determine if the designed gradient was achieved. This review will help to condense the abundance of information that has been published on the creation and characterization of gradient scaffolds and to provide a single review discussing both methods for manufacturing gradient scaffolds and evaluating the establishment of a gradient.

Keywords: Additive manufacturing; Gradient scaffolds; Regenerative medicine; Scaffold fabrication; Tissue engineering.

Figure 1

A flow chart depicting a decision tree to select a 3D printing approach based on desired scaffold and gradient characteristics based on literature data. For example, to build a scaffold with increasing porosity with depth, that is initially acellular, with less than 10 µm resolution, one may choose to use SLA printing with a PPF polymer resin. Images at the end of the flow chart represent achievable design parameters using the specified print approach and material. More information on PPF, GelMA, PCL, and keratin is available in recently published studies [–99].

Figure 2

A summary of various techniques that can be used to characterize and evaluate the designed gradient, including physical visualization (micro–computed tomography (µCT), scanning electron microscopy (SEM), and tagging or marking chemical groups), chemical analysis (Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA)), and finally with functional assays.