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International Journal of Bioprinting Microfluidic-assisted 3D bioprinting

crosslinking, 110,111 which determines the final properties of junction upstream, the central compartment can be
the product, as well as the effect of embedding living cells sheathed by a second fluid before crosslinking to form a
within biomaterials over ink rheology. 112,113 These subjects core-shell flow profile. To integrate all these elements,
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are left out of explicit consideration from this section as Guimarães et al. developed a unique microfluidic chip
it aims at describing the spinning of microfibers within based on a flow-focusing geometry for the production of
microfluidic devices, excluding cell-laden materials. (i) multi-compartment, (ii) core-shell, (iii) hollow, and (iv)
fibers containing oil droplets for the creation of complex
4. MST for biofabrication purposes biological micromodels (Figure 5a). As a unique example,
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core-shell gelatin methacryloyl (GelMA) fibers with
The stunning ability in controlling the composition and straight and helical morphologies embedded in an alginate
compartmentalization of fibers with micrometric precision shell have been fabricated harnessing the coflow rope-coil
allows to customize fiber characteristics to build complex effect (Figure 5b). In the case of hollow fibers generation,
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quasi-3D environments for living cells that resemble more a sacrificial material is flowed in the core and then
closely the physiological microstructures (Table 1). dissolved to leave an empty cavity for nutrient delivery.
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To increase the complexity of spun fibers, additional This technique is widely used to simulate microvasculature
microfluidic devices can be combined with coaxial environment 81,133 or to guide the vascularization of fiber-
needles or glass capillaries to manipulate bioinks before shaped tissues, which is a crucial aspect in biofabrication
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spinning fibers. Microfluidic tools can vary a lot in terms of contexts. 134
dimensions, design, and function as they may serve as fluid A remarkable example of accurate fabrication of multi-
mixers, splitters, combiners, etc. to create sophisticated compartment and multi-hollow fibers is provided by
patterns along and across the fiber. The precision in Cheng et al. who designed a device made of aligned scalable
handling microflows enables the continuous and controlled multi-barrel capillaries to fabricate microheterogeneous
formation of fine filaments with a wide range of structural fibers in one step. As shown in Figure 5c, Janus and multi-
and functional properties. 88,115-117 Indeed, fluids can be prior shell hollow alginate fibers of 40–120 µm in diameter were
combined within the microchannels and then extruded as formed. In a further study, the authors demonstrated
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uniform, hollow, 119,120 core-shell, 121,122 or heterogeneous the possibility to create anisotropic fibers with two or three
(i.e., Janus) 33,123,124 filaments. In the case of multi-material compartments, which can be independently provided
deposition, microfluidic systems can provide seamless with a single or double hollow core (Figure 5d and e).
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transitions between biomaterial inks harnessing valves 125,126 A similar approach has been proposed by Yu et al. where
or flow withdrawal. On the other hand, progressive and a PDMS chip was employed to fabricate multiple hollows
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controlled variation of material composition is often sought (up to five cavities) and multi-compartment fibers with
to replicate the intricate in vivo environment, especially in extreme control (Figure 5f).
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tissue interface portions. Functionally graded structures
can be obtained by adding a microfluidic mixer to the system When spinning cell-laden fibers, morphological
that allows to gradually modify fiber composition to create and mechanical cues are fundamental for functional
mechanical, chemical, or cellular gradients. Alternatively, cell development. MST allows to generate fibers with
microfluidic operators can be used to generate and pattern diverse cross-section 99,137 to provide morphological
monodispersed bubbles containing cells or functional guidance for cell proliferation. Specifically, it has been
agents inside the fibers. 129,130 demonstrated that the formation of grooves on the surface
of fibers contributes to improved directional alignment
4.1. Fiber production via MST: building quasi-3D of cultured cells. 88,90,138 Alternatively, extruded fibers can
environments be mechanically stimulated by stretching either when
One of the first pioneers in this field was Kim et al., who collected around a rotating tool by adjusting the intensity
in 2008 spun chondrocytes-laden alginate fibers in a CaCl 2 of pulling or after printing. As an example, Rinoldi et al.
bath harnessing a flow-focusing PDMS chip dipped exploited a rotating mandrel to collect fibers laden with
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in the crosslinking solution. Although rudimentary human bone marrow stromal cells (hBMSCs) followed
equipment was used, the basic principles are still used by mechanical and biochemical stimulation for tendon
today for spinning cell-laden fibers. Evidently, more regeneration purposes. The authors showed how static
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complex fiber profiles can be generated thanks to the stretching of fibers before culture, along with biochemical
fluid linearity in microchannels. In particular, by allowing stimulation, leads to enhanced expression of tendon
two or more fluids to flow aside and fixing through target genes. Likewise, Costantini et al. exploited a similar
crosslinking, hybrid and multi-compartment fibers can be version of the aforementioned microfluidic system, in
produced. 117,132 Alternatively, integrating a flow-focusing which the coaxial needle is replaced with a milled PC

Volume 10 Issue 1 (2024) 55 https://doi.org/10.36922/ijb.1404