Abstract
Hydrogel-based bio-inks have recently attracted more attention for 3D printing applications in tissue engineering due to their remarkable intrinsic properties, such as a cell supporting environment. However, their usually weak mechanical properties lead to poor printability and low stability of the obtained structures. To obtain good shape fidelity, current approaches based on extrusion printing use high viscosity solutions, which can compromise cell viability. This paper presents a novel bio-printing methodology based on a dual-syringe system with a static mixing tool that allows in situ crosslinking of a two-component hydrogel-based ink in the presence of living cells. The reactive hydrogel system consists of carboxymethyl chitosan (CMCh) and partially oxidized hyaluronic acid (HAox) that undergo fast self-covalent crosslinking via Schiff base formation. This new approach allows us to use low viscosity solutions since in situ gelation provides the appropriate structural integrity to maintain the printed shape. The proposed bio-ink formulation was optimized to match crosslinking kinetics with the printing process and multi-layered 3D bio-printed scaffolds were successfully obtained. Printed scaffolds showed moderate swelling, good biocompatibility with embedded cells, and were mechanically stable after 14 days of the cell culture. We envision that this straightforward, powerful, and generalizable printing approach can be used for a wide range of materials, growth factors, or cell types, to be employed for soft tissue regeneration.
Highlights
3D bioprinting is a booming additive manufacturing technology that allows the layer-by-layer deposition of a cell-laden material to fabricate 3D constructs with spatial control over scaffold design. This technology has been widely used in the last few years for tissue engineering and regenerative medicine applications as it allows the artificial reconstruction of the complexity of native tissues or organs [1,2,3]
As the system began to crosslink through the formation of Schiff base linkages, G0 increased at a faster speed than G”, which indicates a change in the viscoelastic behavior of the system to a more solid-like state
These differential growth speeds led to crossover point of G0 and G”, defined as a gelation point, which indicates that the 3D hydrogel network was formed [66,72]
Summary
This technology has been widely used in the last few years for tissue engineering and regenerative medicine applications as it allows the artificial reconstruction of the complexity of native tissues or organs [1,2,3]. Traditional approaches based on increasing the polymer content and viscosity or the crosslinking density have been attempted to improve printability of naturally derived hydrogel bio-inks and the mechanical performance of their printed scaffolds [5,27]. The partially crosslinked hydrogel is extruded from the printhead This approach has several advantages for 3D extrusion printing: (1) it uses low viscosity starting solutions of the hydrogel precursors and avoids high shear stress during extrusion, (2) the in situ crosslinking provides appropriate structural integrity to the printed thread to maintain the printed shape, (3) it avoids post-printing cell seeding (cells are embedded in the ink), washing steps, or additional physical factors that may complicate the fabrication process [28]. This printing methodology has been optimized in order to fulfil the requirements for successful bioprinting to lead to cell laden 3D hydrogel constructs with good resolution and shape fidelity
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