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Li, et al.
precision fabrication of cell-laden scaffolds with high cell This study presents an optimization of the
viability . Advancements based on this technology have printability of extrusion-based bioprinting with a
[12]
been demonstrated, including mandible bones , liver consideration of the thermal effects. A quantitative
[7]
tissue , cardiac patches , brain microenvironment , thermal model was established that considered the
[15]
[14]
[13]
and multi-layered skin . printing system’s temperatures (nozzle, ambient, and
[16]
The differing properties of bioinks are a primary bioink) to demonstrate the extrudate’s thermal effects.
consideration in 3D bioprinting for fabricating different The model can be applied for the precise regulation of
tissues/organs [17,18] . Extrusion-based bioprinting requires extrudate temperature. A mathematical model revealing
the use of biocompatible materials that must be fluid the relationship between the extrudate’s temperature,
in the nozzle and solid after printing . Increasingly, pressure, velocity, and linewidth was established to
[19]
temperature-sensitive materials, such as gelatin, gelatin optimize the printing process. The experimental results
methacryloyl, collagen, and agarose, which are tunable agreed reasonably well with the physical model, which
in a sol–gel state through the alternation of temperatures, outperformed conventional models. Nozzles with
are becoming the focus of research attention [1,20] . Among gauges (G) of 32 and 23 were used, and the temperature,
these materials, a sodium alginate–gelatin composite pressure, and velocity of the extrudates were varied,
hydrogel can be crosslinked just with divalent ions . respectively. Several sets of lines were fabricated using
[21]
It is widely used because of its mild gelation, good the established physical model with a linewidth step of 50
printability, and high biocompatibility [3,22-28] . μm. The precise linewidth step control demonstrated by
Bioink printability is critical to the in vitro the proposed optimization model suggests it could guide
reproduction of the complex micro-architectures of soft biomaterials’ fabrication with precise shape control
native tissues [29,30] . It is regarded as the ability to form and high cell viability.
complex 3D structures with high accuracy, integrity,
and cell viability . The intrinsic properties and printing 2. Materials and methods
[27]
parameters of bioinks affect their printability. Researchers 2.1. Bioprinting system design
have created several physical models to enhance this
property that considers such variables, including pressure, As shown in Figure 1A, a customized bioprinter was
the inner diameter (ID) of the nozzle, and the nozzle’s produced comprising a temperature control module, a nozzle
moving velocity. However, as all these models ignore motion control module, and a bioink dispensing system.
temperature, the experimental results in the original Two nozzles with precise temperature control were
research could not be fitted accurately [31-33] . installed on the x–y–z stage. The low-temperature (LT)
Many studies have found that temperature is a module was tunable from 0°C to 70°C with individual
critical variable that affects printability [3,27,34] . When temperature control for the nozzle tip. The high-
alginate–gelatin composite hydrogel is kept at 37°C, temperature (HT) module was tunable from ambient
even low pressure and a fast printing velocity cause temperature (AT) to 250°C. The temperature tuning
the width of the printed lines to increase, resulting in range of the printing platform ranged between −5°C
variations in width from those lines printed near the sol- and 45°C. Since the AT has a significant impact on the
gel transition temperature . Ouyang et al. demonstrated printing process, this parameter was controlled using
[3]
that temperature affects the printing region in which a temperature-adjustable (between 10°C and 40°C)
the printability of a bioink is excellent [27] . Chen et al. chamber. The modules were designed to allow the precise
found that the thermal parameters of a bioink obtained temperature control of the bioink’s flow path to produce
from a rheometer differed from those measured a bioink with predictable thermal properties, a suitable
experimentally through a printing test. This disparity viscoelastic modulus, and high cell activity [24,25,35] . The
was attributed to the temperature difference between output pressure regulated by the pneumatic circuit was
the two systems [34] . tunable from 1 kPa to 1 MPa with a resolution of 1 kPa.
In addition, both the holding time and holding Bioink properties must be controlled precisely to
temperature have been proven to affect the viability of achieve excellent printability. A low-viscosity material
cells . Although significant progress has been made in will deform and collapse after printing, while a high-
[25]
studying the printability of bioinks, a quantitative and viscosity material will become clogged and excessively
comprehensive law is required to guide the printing swollen. This study tested the rheological properties of
process. Consequently, the printing capability of the the prepared bioink (Figure 1B). The obtained thermal
3D bioprinting technique remains compromised [22,23] . parameters were entered into the established physical
Furthermore, a lack of research regarding the thermal model. To achieve controllable deposition and to predict
effects makes it challenging to construct large-scale tissue the printed linewidth, the model considered the pipe flow,
scaffolds using temperature-sensitive materials [7,9,34] . the die swell, and the deposition stages.

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