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International Journal of Bioprinting Microfluidic-assisted 3D bioprinting

complexity. In light of this, microfluidic-enhanced 3D idea of discrete microfluidics. 199,200 In this manner, multiple
bioprinting ought to become an outstanding strategy to microfluidic components can be combined to form a single
produce highly biomimetic human tissue substitutes in device using plastic tubes or other joining techniques, akin
a single step, resembling physiological architecture from to the Lego® brick concept or magnetic connectors.
202
201
the nanometric (microarchitecture) up to the millimetric
(macroarchitecture) scale. As addressed in this review, From a broader perspective, a considerable effort must
microfluidic technology does indeed provide high control be spent on scaling up the biofabrication process to produce
over the inter- and intrafiber composition. The integration compact macrotissues (or even organs) while maintaining
of microfluidic operators (e.g., combiners, splitter, mixers, the microarchitectural control offered by 3DMB. Printing
and filters) not only enables the fabrication of multi- larger structures with high cellular density requires tissue
compartment and microhollowed fibers but also provides vascularization to ensure nutrients diffusion throughout
the possibility to modulate fiber composition and shape the whole construct. Thus, we need to further expand
on-demand while printing, opening unlimited possibilities the potential and versatility of microfluidic printheads to
to realize hierarchical in vitro models of human tissues. produce large dense tissues embedding vasculature—a
complex network of multi-scale hollow structures. Last
Recently, however, 3D biomanufacturing systems but not least, the clinical application of this technology
based on the extrusion of bioinks from metallic needles requires a transition of 3DMB into a user-friendly system
have been employed in the field of biofabrication, limiting that can be operated also by non-specialized professional
the complexity and functionality of biological models figures (i.e., doctors) so that it will become an instrument
obtained. In fact, the use of metallic connectors not only routinely employed in hospitals.
raises the amount of shear stress generated, which is
detrimental for encapsulated cells, 140,188 but also restricts However, to date, 3DMB-based approaches are still
internal fluid handling. In fact, metallic parts are not poorly investigated and need improvements so that it will
transparent and represent physical constraints for fluid become a standard in biofabrication contexts. We envision
flowing, also increasing the possibility of disturbances of that the potential for creating multi-layered, multi-core,
flow profiles. Moreover, manufacturing variability is often hollow, and hierarchical fibers with real-time control on
introduced since metallic elements are manually inserted a single platform is limitless. In turn, the employment of
within or at the outlet of microfluidic chips. In conclusion, microfluidic-assisted biofabrication systems will enable
even though the integration of a microfluidic chip the engineering of more 3D functional structures that
enables the realization of more sophisticated 3D-printed recapitulate the native environment to an unparalleled
biomodels, these issues must be taken into consideration degree.
when employing such platforms.

With advanced 3D microfluidic printheads, which are Acknowledgments
designed through CAD software and rapidly manufactured, None.
manual fabrication steps are minimized, thus enhancing the
quality of the final microdevice and the printing performances. Funding
In this context, connector-free microfluidic printheads can be
designed to avoid the need for metallic needles, allowing for G.C. acknowledges funding from AIRC Aldi Fellowship
the extrusion of cell-laden fibers in a milder and damage-free under grant agreement No. 25412. The research leading
manner. Indeed, compared to any other nozzle-based system, to these results was also supported by European Research
these biofabrication platforms not only enhance versatility Council Synergy grant ASTRA (n. 855923).
of manufacturing but also increase viability of bioprinted
constructs, a crucial aspect when printing high-sensitive Conflict of interest
cellular species or high-cell density bioinks.
The authors declare no conflict of interest.
a3DMB platforms are usually provided with a flow-
focusing junction downstream and can be coupled with Author contributions
additional microfluidic units upstream to execute several
operations on bioinks including mixing, splitting and cell Conceptualization: Federico Serpe, Chiara Scognamiglio,
concentration. In general, such microfluidic printheads are Gianluca Cidonio
monolithic pieces of a transparent material (PDMS, PC, Methodology: Carlo Massimo Casciola, Giancarlo Ruocco
etc.); however, at the same time, these devices might also be Writing – original draft: Federico Serpe, Chiara
built from standardized independent pieces, exploiting the Scognamiglio

Volume 10 Issue 1 (2024) 64 https://doi.org/10.36922/ijb.1404