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International Journal of Bioprinting Microfluidic-assisted 3D bioprinting

non-experts. Nowadays, current technologies are starting single or multiple materials that are processed into fine
to replace the gold standard provided by photolithography. filaments or tiny droplets. It is possible to divide extrusion-
Despite the resolution and surface roughness achieved with based approaches into two main categories named fused
modern fabrication approaches being often far inferior to deposition modeling (FDM) and multi-jet modeling
the ones obtained via photolithography, these parameters (MJM).
are adequate for most biological-related applications, as In FDM printers, a motorized dispenser nozzle is used
the typical dimensions commonly used are in the order of to mechanically extrude thermoplastic materials following
100 µm. heating in the form of a filament (in the range between 0.2
Moreover, particular care should be taken when and 1 mm ) that is rapidly cooled down upon deposition.
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handling and cultivating cells on 3D-printed substrates as FDM printers have recently reached the public as they
they may contain a variety of leachates that could impart are generally safe, reliable, simple to use, and affordable.
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cell functionality. 23-25 Despite the cytocompatibility issue However, the fabrication of microfluidic devices
that reduces the number of available materials, it has been harnessing FDM-based approaches has been challenging.
recently shown that PDMS microfluidic devices obtained The intrinsic structural fragility due to lack of interlayer
from 3D-printed molds may successfully support the fusion, the excessive filament size, and the elevated
viable culture of cells, offering a convenient alternative to surface roughness (average roughness R around 10 μm )
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a
SU-8 molds. 26 of printed pieces hamper the realization of micrometric
features with high precision. Interestingly, Zeraatkar et
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2.2.1. Micromilling al. leveraged the ridges arising from the high roughness
Milling is a subtractive manufacturing method that relies of FDM-printed objects to enhance the stochastic mixing
on machining a bulk piece of material (the workpiece) with of fluids in microfluidic channels. Recently, significant
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sub-millimetric precision through a rotating cutting object improvements of this manufacturing technique have
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(the endmill). Using a spindle-driven movement along the enabled the engineering of a number of FDM-printed
Z-axis and computer-controlled motion in the XY plane, a microfluidic devices for bio-related applications 42-45 but
milling system enables the sectioning of fine channels into not remarkably for fiber spinning purposes. A novel
polymeric transparent surfaces.
solution for microfluidic manipulation of biomaterials
Today, micromilling allows for the machining of came from the fabrication method proposed by Ching
microchannels with resolution up to 10 μm with an average et al., who created microfluidic platforms embedding
surface roughness of 2.5 μm that, in addition to the short complex operators such as mixers, valves, and droplet
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manufacturing time, makes micromilling a powerful tool generators by directly depositing quick-curing silicone-
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for rapid prototyping microfluidic devices with acceptable based resin on diverse transparent substrates. 46,47
resolution 29,30 and suitable for bio-related applications. Different from the previous technologies, MJM builds
Indeed, several biocompatible materials including hard 3D objects by depositing femtoliter droplets onto a tray
plastics like polycarbonate (PC), polystyrene (PS), in a line-by-line, layer-by-layer process. MJM-based 3D
polymethyl methacrylate (PMMA), and cycloolefins (COC printers are equipped with an array of inkjet printheads to
or COP) can be machined to obtain master molds or entire allow for multi-material ink deposition. Inks used in MJM
microfluidic devices.
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printing are typically distinguished in build and support
At present, the application of micromilling is gradually materials, which are deposited in parallel. Besides the ability
adopted by the microfluidic community to realize to perform multi-material, MJM ensures fast printing speed,
bioinspired platforms and support biomedical research. high precision, and extreme printing quality.
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As a prime example, Costantini et al. harnessed milled PC Nevertheless, the high cost of MJM printers as well
microfluidic devices to build microfluidic printheads for as the poorly investigated biocompatibility of inks
the biofabrication of cell-laden 3D constructs 32-34 while employed represents a huge barrier to the realization of
Behroodi et al. combined 3D printing and micromilling to biomicrofluidic devices. Moreover, the removal of the
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realize PDMS devices and produce tumor spheroids. 35
sacrificial material from enclosed structures limits channel
2.2.2. Extrusion-based technologies dimension to about 200 μm. Some efforts to employ MJM-
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Despite extrusion-based technologies being the most used based printing to fabricate molds 50-53 or entire microfluidic
additive manufacturing approaches to build 3D objects, devices 54,55 have been made. As a major example, Sochol
their use in microfluidic fabrication is quite uncommon. et al. fabricated complex integrated microfluidic circuits
These approaches, which fall under the term of direct ink consisting of fluidic capacitors, diodes, and transistors to
writing (DIW), construct a microfluidic chip or a stamp perform multiple fluidic operations with great accuracy. 56
to cast PDMS by a layer-by-layer deposition of either

Volume 10 Issue 1 (2024) 50 https://doi.org/10.36922/ijb.1404