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The trend towards in vivo bioprinting

based bioprinting systems. The group successfully control a four-channel pneumatically driven dispenser,
fabricated complex cellular patterns and 3D structures which contains collagen hydrogel precursor, fibro-
of NT2 cells [23] , micro channels with human micro- blasts and keratinocytes, in the in vitro bioprinting of
vascular endothelial cells (HMVEC) [24] , and cardiac multi-layered skin substitute [27] . A nozzle-based multi-
pseudo tissues with biomaterials as the bio-cartri- head bioprinter based on a similar working principle
dges [25] . has been developed by Cho and his coworkers, with
However, the major drawback of inkjet printing lies which 3D open porous structures of decellularized
in the lack of suitable biomaterials which can accom- ECM with polycaprolactone (PCL) framework were
modate the adverse impacts induced by printing successfully fabricated [28,29] . To further improve the
through a small orifice. Lack of effective structural flexibility and controllability of multi-head bioprinters,
integration is another issue related to inkjet-based bio- a “Multi-arm Bioprinter (MABP)” was developed in
printing [16] . It is crucial for the printed structures to 2014 by Ozbolat et al. [30] . This nozzle-based printer
attain integrity rapidly since the new tissues/organs had two independent arms which allowed concurrent
are expected to survive in the in vivo environment deposition of multiple materials with independently
immediately after printing, hence for load-bearing controlled arm motions and material dispensing. A
tissues, quick establishment of satisfactory mechanical hybrid structure to support the cell spheroids in three
properties through novel biomaterials or/and optim- dimensions was fabricated using the MABP. It was a
ized architectural construction poses a challenge to brilliant example of how robot-assisted integral fabri-
both biomaterial scientists and engineers that needs to cation of multiple cells/biomaterials can be done, with
be solved. Due to the size of printing units and their great precision in the 3D structures and a vastly acce-
working principle (motors drive printing heads to lerated fabrication process.
move on carriage rails), inkjet-based printers seem to Possible in vivo nozzle-based bioprinting tech-
be only suitable for in vivo repair/fabrication of sup- niques inspired by some modern in vitro systems are
erficial tissues such as skin. Applying inkjet-based demonstrated in Figure 4. In addition to similar
techniques in in vivo bioprinting of internal tissues/ designs such as co-axial nozzles and dexterous robotic
organs, either through minimization of the entire inte- arms that are currently applied in the in vitro systems,
gral printing unit, or through hybridization of inkjet novel designs with significant microminiaturization
printing with other methods to form novel working features are required to allow maneuverable delivery
principles is possible will require further improve- of bioinks for in vivo bioprinting, particularly when
ments in robotics and engineering science. access to the internal defect is quite limited. Instead of
(3) Nozzle-based bioprinting. Nozzle- or extrusion- manually dispensing bioinks at the defective site, mi-
based approaches apply continuous deposition of bio- crorobots should be used to control the motion of noz-
materials through needles or syringes to construct new zles under the monitor of surgeons to precisely con-
tissues/organs. Four major nozzle designs are curr- struct biomimetic architectures. In addition, conti-
ently developed for bioprinters of this kind: pressure- nuous deposition is necessary since this can effective-
actuated, solenoid-actuated, piezoelectric, and volu- ly reduce the fabrication time, and also minimize oc-
me-actuated nozzles [26] . Nozzle-based bioprinting nor- currences of nozzle blockage which is mainly caused
mally offers a more gentle approach than inkjet bio- by material clogging under static conditions. Com-
printing with regards to cell viability. The most attrac- pared to other bioprinting modalities covered in this
tive feature of this technique is that multiple cells and paper, current nozzle-based bioprinting has relatively
biomaterials can be synchronously applied through lower spatial resolutions of the construct [31] . Therefore,
multiple syringes in a three-dimensional synthesis. In developing novel nozzle mechanisms with finer feed
addition, nozzle-based bioprinting seems to be the control will be of great value for the construction of
modality most ready for in vivo applications, since fine biomimetic structures by nozzle-based bioprinting.
arthroscopy-compatible extrusion-based tissue repair 3.2 Bioinks
has already been clinically applied for decades.
The majority of recently developed bioprinters, or Though the three aforementioned biofabrication mod-
“organ printers”, is based on extrusion-based modality alities are distinct in their working principles, each have
due to its intrinsic advantages as mentioned above. various technical obstacles that need to be overcome,
Lee et al. used a three-axis Cartesian robotic stage to ultimately, success of any bioprinting technologies

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