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Composite Bioprinting for Bio-fabrication
often involves physical field regulation that can regulate and equipment with the capacity of imposing different
filaments or cells during or after printing. temperature conditions have been developed [17-20] . Direct
It should be pointed out that the steps of multi- extrusion of biomaterials such as gel, slurry, particle,
physical field regulation are often adopted in the process and filament that represent temperature-dependent phase
of 3D composite bioprinting to form micro-scale transition is the main operating mode and the printing
structure inside the macro-scale 3D printing structure. path can be obtained from conventional 3D modeling,
Correspondingly, the computer-aided design and slicing, and path planning methods and software. One
computer-aided manufacturing (CAD/CAM) software research hotspot in this field is to improve the mechanical
for 3D composite bioprinting are different from the properties and biocompatibility of the printed construct
traditional 3D printing system. In other words, the CAM at the same time using a composite printing system
software for 3D composite bioprinting should be able to which combines the printing processes under different
combine the scale information that cannot be modeled in temperature field; some progress has already been made.
CAD software with the modellable information from the Chen et al. built a hierarchical construct by alternately
CAD software, presenting new challenges to the design depositing the Wharton’s jelly mesenchymal stem cells-
of 3D composite bioprinting system. coated polydopamine (PDA)-coated calcium silicate/
polycaprolactone (PCL) fibers and HUVECs-laden
2. The process of 3D composite bioprinting hydrogel in a composite printing system combining melt

The intention of 3D composite bioprinting is to effectively extrusion, normal temperature extrusion, and electrospray
overcome the limitations of a single-step printing process processes to obtain a bone scaffold with good mechanical
and ensure the inclusion of multiscale heterogeneous properties and the ability to promote angiogenesis and
[21]
characteristics in the final construction by the integration osteogenesis . Mekhileri et al. designed a singularization
device that was capable of capturing and extruding a single
of multiple process technologies. However, according microtissue of hydrogel spheroid with more than 80%
to the status quo of research, two principles are very
important for good integration: (i) The material structure accuracy. The integrated system of this device with melt
formed by different printing processes can form a good extrusion equipment was capable of precisely delivering a
single microstructure to a specific position in the scaffold
composite interface and (ii) the integration of different during the printing process, thereby realizing the preparation
printing processes has engineering realizability in the of complex hierarchical bioconstruct (Figure 1A) .
[22]
system implementation.
In addition, the introduction of ionic crosslinking
2.1. Combination of extrusion printing and and coaxial nozzle enables the extrusion process to
dynamic crosslinking effectively construct vessels like microchannels [23-26] .
Dynamic reactive extrusion printing technology, which
Extrusion printing is the most typical and common has shown good potential in the realization of cell printing
process method. It uses air pressure or mechanical force under room temperature, is a growing research interest.
as the driving energy to controllably extrude bioink, and Narayanan et al. produced meniscus by printing human
by the spatial motion of the platform and the print nozzle, adipose-derived stem cells (hASCs) with polylactic acid
different two-dimensional patterns can be depicted and (PLA) fibers and alginate hydrogel. Previous studies
stacked to form a 3D structure. In extrusion printing, indicated that the composite fiber structure enhanced cell
materials with different viscosity can be used as bioink. proliferation and promoted extracellular matrix (ECM)
The highly viscous materials can be extruded to form secretion and chondrogenic differentiation (Figure 1B)
continuous fibers, while the lower ones can be applied [27] . Tabriz et al. prepared a 3D cellular biological structure
to obtain discrete droplets. Therefore, various materials by extruding pre-crosslinked sodium alginate into calcium
are available for extrusion printing which are beneficial ion bathing. After that, the structural stability was further
for manufacturing structures with good mechanical enhanced by barium ion crosslinking (Figure 1C) .
[28]
properties. Recently, many studies on 3D composite Lozano et al. printed 3D brain-like structures composed
bioprinting based on extrusion printing have been carried of discrete layers of primary cortical neural cells with a
out and the most representative is the combination of coaxial nozzle. The result showed that the cortical cells
dynamic crosslinking technologies, which specifically inside the structure could develop into 3D neuronal
refer to a class of technologies that can achieve various networks in <5 days . Wang et al. prepared in vitro
[29]
degrees of crosslinking in extrusion printing process glioma model by coaxially extruding materials into the
through online control of process parameters or dynamic calcium chloride (CaCl ) solution. The shell consisted of
2
adjustment of external physical field. sodium alginate and glioma stem cells (GSC23), while the
At present, by adding temperature gradient in the cell suspension containing glioma cell U118 was taken as
process of extrusion printing, printing technologies the core material. The experimental results showed that

8 International Journal of Bioprinting (2021)–Volume 7, Issue 1