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Manyi Wang, Jiankang He, Yaxiong Liu, et al.

Figure 4. Illustration of components and working principles of in vivo nozzle-based bioprinting which are transferrable to the current
in vitro systems. From the left to right: (A) thermal-sensitive; (B) ion-sensitive; and (C) photo-sensitive in vivo gelation.

depend largely on the development of advanced hyd- micking but at least highly-hydrated, three-dimen-
rogel systems or building blocks, i.e., cells, bio- sional biomimetic environment, which is the basis of
materials or their mixtures. Biomaterial has been bioprinting. This has been achieved by the develop-
defined as “…any substance (other than a drug) or ment of advanced hydrogels. Hydrogels can assist the
combination of substances synthetic or natural in ori- transplanted cells in synthesizing natural ECMs
gin, (that) …can be used … as a whole or as a part of through cellular metabolism, and eventually form de-
a system which treats, augments, or replaces any tis- sired functional tissues through cellular proliferation.
sue, organ or function of the body…” [32] . Being Various biologically-relevant hydrogels have been
shelters to cells, ideal biomaterials should provide developed for cell encapsulation during the bioprint-
cells with comfortable bio-environments and suffi- ing process. Based on different gelation mechanisms,
cient mechanical/biochemical protection throughout the majority of these hydrogels fall into three catego-
the bioprinting process. The significance of develop- ries: photo-sensitive, ion-sensitive and thermally-sen-
ing a favorable three-dimensional micro-bio-environ- sitive hydrogels.
ment for cells in successful tissue regeneration strate- Photo-sensitive hydrogels are commonly used in
gies has already been proven both in vitro and in vi- photo-patterning or light-based bioprinting techniques,
vo [33] . To be ideal building blocks, biomaterial com- which involve a photo-polymerization reaction be-
ponents should be highly process-tolerant and printa- tween the hydrogel precursor and photo-initiator to
ble, with optimal biochemical and mechanical proper- form a user-specific pattern. This kind of hydrogel
ties which can maintain cellular viability and facilitate precursors can be synthesized by modifying natural or
tissue fusion and formation. Here, we will briefly re- synthetic polymers (gelatin and alginate) with metha-
view the needs, advances and challenges in cellular crylates or acrylates etc. [34–36] . Recent advances indi-
and biomaterial science that can contribute to the rea- cate that by choosing proper parameters, relatively
lization of in vivo bioprinting. high viability of the encapsulated cells could be ach-
(1) Cell-encapsulating hydrogels for bioprinting. In ieved in photo-patterning or bioprinting process [37,38] .
native tissues or organs, the ECM is an organized mo- More importantly, naturally-derived hydrogels like
lecular media secreted and regulated by cells. It pro- methacrylated gelatin exhibited comparable biological
vides not only sufficient structural and biochemical properties with collagen to support the encapsulated
support to the local cells, but also important mechani- cells’ distribution and growth in both in vitro and in
cal and chemical information for cellular metabolism vivo studies [39–41] . However, to apply existing photo-
to mediate cell–cell and cell–matrix interactions. In sensitive hydrogels in in vivo bioprinting, further op-
such a natural environment, nutrients and oxygen are timization should be conducted to significantly
constantly supplied to cells while toxic cellular wastes shorten the gelatin time as well as developing ad-
are continuously removed through extracellular fluids vanced biocompatible photo-initiators to be safely
and adjacent capillaries. To date, artificial replication used in the body.
of the fine architectures of multiple-material ECM Alginate is the most used ion-sensitive hydrogel for
remains a challenge that lies beyond the capability of cell encapsulation in bioprinting [42–46] . The remarkable
all existing micro-biofabrication technologies. How- feature of alginate is its ability to rapidly form hydro-
ever, we can encourage cells to produce their own gels in a cell-friendly condition upon contact with cal-
ECMs by providing a temporary, partially ECM-mi- cium ions, which makes it a promising hydrogel can-

International Journal of Bioprinting (2015)–Volume 1, Issue 1 21