Smart Multi-Responsive Biomaterials and Their Applications for 4D Bioprinting

Abstract

The emergence of 4D printing has become a pivotal tool to produce complex structures in biomedical applications such as tissue engineering and regenerative medicine. This chapter provides a concise overview of the current state of the field and its immense potential to better understand the involved technologies to build sophisticated 4D-printed structures. These structures have the capability to sense and respond to a diverse range of stimuli, which include changes in temperature, humidity, or electricity/magnetics. First, we describe 4D printing technologies, which include extrusion-based inkjet printing, and light-based and droplet-based methods including selective laser sintering (SLS). Several types of biomaterials for 4D printing, which can undergo structural changes in various external stimuli over time were also presented. These structures hold the promise of revolutionizing fields that require adaptable and intelligent materials. Moreover, biomedical applications of 4D-printed smart structures were highlighted, spanning a wide spectrum of intended applications from drug delivery to regenerative medicine. Finally, we address a number of challenges associated with current technologies, touching upon ethical and regulatory aspects of the technologies, along with the need for standardized protocols in both in vitro as well as in vivo testing of 4D-printed structures, which are crucial steps toward eventual clinical realization.

Keywords: 4D printing; biomaterials; regenerative medicine; smart structures; tissue engineering.

Figure 1

(A) (a) Four-dimensional bioprinting of cell-laden structures fabricated by moisture-responsive methacrylated alginate (AA-MA) or hyaluronic acid (HA-MA) hydrogels. (b) Green light was used for mild drying of structures. (c) Instant folding into tubes obtained upon immersion of crosslinked films in water, PBS or cell culture media. (B) The tube responsiveness; upper panel (cartoon), lower panel (representative images in water). (a) The same tube immersed in CaCl₂ solution, (b) additional crosslinking of alginate with Ca²⁺ ions led to unfolding of the tube, and (c) folded tube immersed in EDTA solution. Reproduced with permission [36].

Figure 2

Schematics of the 4D-printed structure fabricated by temperature-responsive hydrogels. (A) The transformation behaviors of the thermo-responsive microgripper, reproduced with permission [42]. (B) Swelling behaviors of the 3D PNIPAAm hydrogel structures. When the temperature increased, the height of the structure decreased, reproduced from [43] under a creative common attribution 4.0 (https://creativecommons.org/licenses/by/4.0/, Accessed on 27 April 2024.).

Figure 3

(A) Schematics of the fabrication of muscle fiber structures through the electrically assisted cell printing process. (B) SEM images of cell-laden GelMA fibers together with the shape morphing gelatin film, adapted from [45].

Figure 4

Evolution of bioprinting technology. (A) Multi-dimensional bioprinting and (B) emergence of 6D printing, reproduced from [78,79] under a creative common attribution 4.0 (https://creativecommons.org/licenses/by/4.0/, Accessed on 27 April 2024).