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Jang T-S, et al.
[87]
ratio . bioglass-reinforced alginate/gelatin hydrogel composites
Nanoparticle-reinforced hydrogels offer better mechanical showed significant enhancement of proliferation and
[83]
and biological properties than microparticle-reinforced mineralization of bioprinted SaOS-2 cells .
hydrogels. For example, Wüst et al. added HAp nanoparticles In spite of the superior mechanical and biological
to a gelatin/alginate hydrogel system for bone tissue performances of inorganic particles, the major problem
engineering applications, as shown in (Figure 6A). Gelatin of the ex situ incorporation approach is the limit on the
provided the initial viscosity and mechanical stability required maximum amount of particles that can be added to the
for the hydrogel ink to be printable due to its temperature- hydrogel; introducing nanoparticles into the hydrogel
dependent physical crosslinking behavior. The long-term rendered the printing ink more viscous and harder to print in
stability of the printed structure is achieved by the ionic the desired way. In previous studies, maximal nanoparticle
crosslinking of alginate (Figure 6B). They fabricated simple inclusion to ensure proper printability and structural
structures using 3D-bioplotter printing which was modified accuracy was found to be limited to 10%. Nearing the 10%
with an in-house-fabricated heatable cartridge up to 40 °C to nanoparticle inclusion, slight irregular filament shape and
[16]
enhance the printability of composite hydrogels. By adding ununiform size distribution were induced . Skardal et al.
HAp nanoparticles (8% w/v), the Young’s modulus was introduced gold nanoparticles (AuNPs) into semi-synthetic
significantly increased with during the 3 day incubation period extracellular matrix (sECM) hydrogel composites which
(Figure 6C). However, varying HAp concentrations from 0 to can generate dynamic crosslinking between intra-gel and
4% did not induce a significant enhancement in the mechanical inter-gel during and after printing. In particular, 2.5% w/
properties. Incorporation of HAp nanoparticles additionally led v of 25 nm gold nanoparticle provided enough mechanical
to radiopacity and thus visibility of constructed scaffolds under stability to support multilayered 3D structures by the
[16]
X-ray based medical detection, as shown in Figure 6D . physical reinforcement effect, and after 60 min of printing,
Wang et al. investigated the effect of bioglass nanoparticles, adjacent filaments were completely joined by slow rate
with the size of 55 nm, on encapsulated SaOS-2 cells. An of inter-filament crosslinking between AuNP and sECM
[86]
alginate/gelatin/SaOS-2 cell suspension supplemented with hydrogel . This dynamically crosslinked AuNP-sECM
bioglass nanoparticles was placed into sterile 3D-bioplotter hydrogel may provide new strategies in the ex situ particle
printing cartridges, and printed into a hydrogel scaffold (13 × incorporation approach for the 3D printing hydrogel
13 × 1.5 mm). During the incubation periods of 3 and 5 days, composite system.

Figure 6. Schematic images of (A) gelatin/alginate hydrogel and its composite with Hap nanoparticles and (B) two-step hydrogel gelationprocess. (C)
Rheological properties of hydrogel composites (left: shear stress plotted over a shear rate, right: elastic modules over 3 day). (D) Opticalmicroscopic and
micro-CT images of 3D printed patterns. (reproduced with permission from [16]. Copyright 2014, Elsevier Ltd).

International Journal of Bioprinting (2018)–Volume 4, Issue 1 13