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Jang T-S, et al.

anisotropic swelling and allows precise control over the recent developments of 3D printing system tend to bring
printed structure’s curvature (Figure 12B) [92] . Thus, by the hydrogel-based tissue engineering on the next level. In
utilizing the swelling behaviors of hydrogel composite recent years, hydrogel composite 3D printing techniques
structures, bio-origami hydrogel scaffolds can be developed have gone through tremendous technological improvements
with self-folding behavior under the appropriate external in the form of material design and printing system
stimuli, which can greatly contribute to the fabrication of optimizations. However, there are still several critical issues
functional 3D tissues. and problems that needs to be addressed.
4D printing technique is also attractive for drug First of all, hydrogel cross-linking methods that are
delivery systems in which precise control over the available in 3D printing systems are severely limited.
shape of the carrier is desirable to release drugs or cells For the construction of stable 3D structures, hydrogel
in a programmable manner. For example, in the case of materials which crosslink rapidly is essential to support
mucoadhesive drug delivery systems, hydrogel bilayer each printing layer before they collapse under their own
structures composed of two differentially swelling layers weight, and until now, only photo- and ionic-crosslinking
can induce self-folding property, which makes it more strategies are applicable for 3D printing due to their high
likely to stick to the mucus tissue. The less or non-swelling crosslinking efficiency. However, the limited materials and
layer acts as a diffusion barrier and incorporated drugs can printing systems could not meet the stringent requirements
be released unidirectionally towards the adhered tissues, demanded by tissue engineering applications. Therefore,
which minimizes drug leakage and enhances drug delivery material diversity and cross-linking strategies should be the
efficiency [134,137] . focus of future research.
Until now, existing self-assembly or self-folding 4D Secondly, most hydrogel composites are produced
printing systems are limited to macroscale deformations, from simple mixing of different components at different
which restricts the precise spatial manipulation of 4D-printed weight ratios, which can induce severe agglomeration
structures. In addition, most responsive materials only respond of reinforcements inside the hydrogel matrix. Poorly
to one type of external stimulus. For tissue engineering distributed reinforcements directly affect the performance
applications, printed scaffolds need to adapt to complicated of the hydrogel composite, thus new strategies for obtaining
microenvironments of within the human body [134,138] . a uniform distribution or alignment of reinforcements are
Therefore, the future of 4D printing requires a stronger focus impertinent for practical applications involving hydrogel
on microscale controllability over the shape, orientation, or composites.
biocompatibility of printed structures. This can be achieved by Finally, the alignment or continuity of the reinforcements
improving printing resolution and material design in response are also restricted to the X-Y plane because of the layer-by-
to multiple physiological signals. layer additive fabrication process of 3D printing systems.
5. Conclusion and Future Outlook Printing paths are only allowed in two dimensions(X-
and Y-axis), and the mechanical strengthening is also
In this paper, the pros and cons of utilizing hydrogel limited to directions parallel with the printing paths. This
composite materials as printing ink in 3D printing systems is the reason why only simple shapes such as rod, bar,
has been thoroughly discussed. This information will be and dog-bone have been fabricated and evaluated using
useful for selecting the printing method and appropriate one-directional mechanical characterizations. For tissue
materials for the desired biological performances. The engineering applications, implanted materials undergo
complex loading conditions in vivo, and the mechanical
properties of hydrogel composites are strongly dependent
on their internal microstructure. Therefore, new 3D printing
systems focusing on 3D alignment or continuity of internal
reinforcements should be developed to improve the
mechanical performance of hydrogel composites.
While many problems remain to be unsolved, various
fascinating and promising results of the 3D printing system
have been reported continuously, and hydrogel composite
materials with enhanced printability, mechanical properties,
and biological performances have been also designed and
proposed. We expect that the classification of 3D printing
systems, categorization of hydrogel composite materials,
Figure 12. (A) Schematic images of cellulose fibrils alignment- and their applications that have been discussed in this
induced anisotropic stiffness E and swelling strain α, and (B) its
water-activated 4D printing effect.(reproduced with permission review article will provide a fundamental understanding
from [92]. Copyright 2016, Macmillan Ltd). of hydrogel composite materials and 3D printing systems,

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