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The trend towards in vivo bioprinting

didate for in vivo bioprinting. However, due to the vitro bioreactor in 2010 [54] . To provide the fragile tis-
lack of cell-affinity proteins, the ion-crosslinked algi- sue spheroids with necessary mechanical supports,
nate hydrogel showed limited capability to support the rigid internal micro-scaffolds, or macro-porous carriers
spreading and migration of the encapsulated cells. It is with micron-sized features were developed [55] , and
commonly necessary to modify alginate hydrogels proven to be effective in the cell protection during
with cell-adhesive peptide or mix it with ECM-like bioprinting processes. The so-called ‘‘jamming effect’’
components such as gelatin or collagen to improve its was exploited to accelerate the transition from fluid
biological properties [47–49] . suspensions of spheroids to jammed spheroids sol-
Due to their simple and fully-biocompatible gela- id [56] .
tion mechanism, thermally-sensitive hydrogels have For in vivo bioprinting, traditional approaches for
attracted extensive attentions in bioprinting [27,50] . For tissue fusion and maturation are not rapid enough,
example, collagen, as one of the most important com- while the rudimentary constructs currently being built
ponents of ECM, remains in its liquid state at 4℃ and without a prefabricated scaffold generally lack me-
form hydrogel at 37℃, which is ideal for in vivo bio- chanical strength and stiffness. Therefore, new inno-
printing. A newly developed polypeptide-DNA hy- vative approaches must be explored to achieve rapid
drogel not only showed similar thermoresponsive fusion of cell aggregates or microtissues, and rapid
property as collagen but also possess rapid gelation formation of tissue-like structures with sufficient ini-
response. It has been successfully used for in situ 3D tial mechanical properties. In addition, a scalable, fast,
multi-layer bioprinting [51] . To fully mimic the complex and safe way to mass produce cell aggregates or mi-
components of native ECM, Pati et al. has recently crotissues needs to be established to guarantee an am-
developed a novel thermally-sensitive bioink derived ple supply of building blocks for in vivo bioprinting.
from decellularized matrix, which can be mixed with According to a report by Rezende et al., scalable bio-
cells to be used for nozzle-based bioprinting [29] . The fabrication of tissue spheroids is technically feasible
printed 3D tissue analogue has shown high cell viabil- and it is now a subject of ongoing commercializa-
[57]
ity and long-term functions. The continuous innova- tion .
tion in biologically-relevant hydrogel especially the Considering the diversity of cell/tissue types, we
advances in ECM-like, thermally-sensitive hydrogels can hardly find one universal recipe to make bioinks
would accelerate the practice of in vivo bioprinting. for bioprinting which can repair all tissues/organs.
Novel methods such as the combination of ther- Tissue engineering is a tissue-specific technique per se,
mo-sensitive properties with chemical crosslinking in which the specific choice of biomaterial for a spe-
into a multi-step gelation mechanism may also be cific delivery matrix plays an important role in deter-
helpful to improve the stability of the printed con- mining the final properties of the regenerated biologi-
structs [52] . cal structures. Fortunately, materials engineers have
(2) Cell aggregates, tissue spheroids and micro- been working closely with cell biologists to improve
tissues for bioprinting. Inspired by developmental specifically tailored bioinks for various tissues/org-
[58]
biology, cell aggregates or tissue spheroids are inten- ans . These purpose-driven biomaterial researches
sively studied for their intrinsic capacity to fuse to- will provide the essential foundation for the success of
gether into a functional construct. By mimicking the organ-specific applications of in vivo bioprinting.
tissue fusion phenomenon observed during embryonic 4. Prospects for the Future
development, tissue biofabrication employs delicate
positioning of cell aggregates or tissue spheroids to In the future, when in vivo bioprinting technology is
allow them to spontaneously “melt” into macro-tissue ready, the majority of its users will be surgeons. It is
constructs [53] . A remarkable property of tissue sphe- therefore important to integrate advanced surgical
roids is that maximal possible initial cell density can techniques, such as robot-assisted control systems
be achieved, which is essential for rapid fluid–solid with user-friendly interfaces, in the commercialization
transition, tissue assembly and maturation to maintain of in vivo bioprinting systems. Rigorous requirements
the morphological and compositional integrity of the on the steadiness of printing units, and the repeatabil-
newly fabricated construct. Kelm et al. created living ity and consistency of printing construct with micro-
vessel tissues based exclusively on self-assembly structures, pose great challenges to surgeons if they
(living cellular re-aggregates) of microtissues in an in are to handle all bioprinting manually in the operating

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