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International Journal of Bioprinting Microfluidic-assisted 3D bioprinting

and macromorphology. In this review, the strategies To replicate the gradual variation of physical and
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employed to pair microfluidics and 3D bioprinting are morphological properties present in human tissues,
divided into two categories: (i) conventional microfluidic microfluidic mixers are devised to deposit fibers that are
3D bioprinting (c3DMB), which relies on the connection uniform across the cross-section and gradually vary along
of a microfluidic device to a conventional coaxial wet- the fiber length. 181,182 One notable example is provided
spinning system, and (ii) advanced 3D microfluidic by Idaszek et al., who adopted micromilling technology
bioprinting (a3DMB) that implements the sole microfluidic to engrave a micromixer into a thick polycarbonate
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chip with an inbuilt PDMS coaxial nozzle to pattern and sheet. By regulating the two bioink flowrates and
spin fibers. progressively switching between them, a continuous
axial gradient is created. A coaxial extruder is positioned
4.3.1. Conventional 3D microfluidic bioprinting (c3DMB) downstream of the microfluidic device to enable
One of the most representative examples of the integration continuous manufacturing of thin fibers using CaCl as
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of a microfluidic device with the coaxial wet-spinning the crosslinking solution. With the use of two bioinks
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method has been developed by Colosi et al. in 2016. specifically formulated to resemble the native ECM and
The proposed system consisted of a microfluidic platform laden with human articular chondrocytes and hBMSCs, it
comprising separated inlets where two biomaterials flow was feasible to replicate the interface between hyaline and
and eventually converge into a single channel connected calcified cartilage. Another strategy has been proposed by
to the internal needle of a coaxial system. The processed Kuzucu et al., in which two syringe pumps are connected
biomaterial ink is then solidified through a CaCl solution to a mixing unit placed right before the extruder. In this
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flushing in the outer shell. Despite its simplicity, this instance, both planar (2D) and axial (3D) gradients in
spinning platform has been employed to fabricate micro- terms of stiffness, peptide, and cell concentration have
compartmentalized fibers with configurable composition, been successfully realized. 183
offering great potential for cardiovascular applications
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(Figure 7c). A new system for multi-material deposition c3DMB has been extensively harnessed to print hollow
was proposed by Feng et al. in 2019, a Y-shaped PDMS fibers for the creation of vascular microchannels, enabling
120,171,175
microfluidic chip mounted on a rotating motor coupled to tissue vascularization. Attalla et al. devised a
a simple metallic nozzle or a coaxial needle. To retain multi-axial extrusion system by connecting a winding
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the same heterogeneous morphology of the alginate-based hollow channel made in PDMS to embedded needles
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filaments across the layers, path variations are matched with increasing size, enabling the formation of bi- and
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with chip rotation. In addition, multi-cellular concentric tri-axial flow. Fibers with concentric layers housing
rings including human umbilical vein endothelial endothelial cells and fibroblasts were generated by blending
cells (HUVECs) and H9C2 myoblasts were fabricated alginate with collagen and fibrin.
by depositing the Janus fiber on a rotating substrate 4.3.2. Advanced 3D microfluidic bioprinting (a3DMB)
(Figure 7d). Even though the majority of efforts have focused on the
Despite achieving efficient mixing is challenging coupling of microfluidic tools with traditional metallic
in microfluidic devices, new passive micromixers have nozzles, recent studies have also demonstrated the
been recently designed to tune the microtopography of possibility to realize an entirely-microfluidic printhead. 185,186
the section of the fiber and control cellular arrangement. Following this strategy, the conventional coaxial wet-
In last years, the Kenics-type static mixer geometry spinning system is replaced by a flow-focusing-based chip,
has been established as a gold standard to spin which operates as the actual printhead moving in the 3D
complex heterogeneous fibers made up of two or more space while depositing the fiber.
components. 177-179 In fact, a series of helical Kenics The core-sheath flow profile generated enables fast
elements can passively produce chaotic mixing in a few solidification of material precursor, via either ionic
millimeters with high efficiency. Samandari et al. realized crosslinking or fast chemical reactions. a3DMB
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a 3D microfluidic chip to create multi-compartmentalized platforms allow to tailor the ultimate fiber diameter in real-
hydrogel fibers with micro- and nanometric control time and on-chip by adjusting the relative flow rate of core
and showed how fiber microarchitecture affects cell and sheath components, ultimately achieving a range of
187
proliferation and differentiation. Specifically, mixed fiber diameters much wider than the one obtained with
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filaments of alginate and GelMA are obtained by c3DMB. In fact, in the latter case, the insertion of physical
harnessing up to 7 helical Kenics elements, then extruded constraints (e.g., metallic connectors, glass capillaries)
through a coaxial needle with a CaCl solution, and binds the fiber dimension and only the printing speed
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subsequently crosslinked with UV light. can modulate the effective fiber diameter. Moreover, as

Volume 10 Issue 1 (2024) 62 https://doi.org/10.36922/ijb.1404