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INTRODUCTION: Major challenges in bioprinting tissues with functional, native-like behavior revolve around enabling the use of hydrogels with low elastic modulus, while also ensuring high shape fidelity and printing resolution. Such materials are necessary to allow cells to migrate, and to facilitate intercellular communication and reorganization of the neo-synthesized extracellular matrix. In this perspective, suspended bath bioprinting was previously developed as a printing technique that solves this problem by extruding bioinks within a yield-stress support bath that keeps bioinks with low viscosity in place until cured. Moreover, in order to increase the printing speed and overcome the geometric constraints of conventional layer-by-layer AM approaches, volumetric bioprinting was recently developed as a new light-based approach. However, the possibility to create high resolution features comprising multiple, independent structural elements intertwined into a single construct remains a major challenge, especially when using multiple materials and cell types in a single printing process. The current study describes a new biofabrication strategy that synergizes the multimaterial printing ability of extrusion in suspension media, and the layerless 3D patterning provided by visible-light tomographic printing, in order to rapidly fabricate complex tissue models with tunable mechanical properties, while embedding different cells types.
METHODOLOGY: A novel photo-crosslinkable bioresin was designed and characterized, based on Gelatin-Methacryloyl (GelMA) hydrogel microparticles that act like a Bingham plastic. This bioresin was used both as a support bath to enable deposition of soft hydrogels, and subsequently sculpted into a desired architecture via volumetric bioprinting, to leverage the microporosity provided by the packing of the microgels for cell infiltration and nutrient diffusion. In addition, two (bio)inks for the extrusion process were designed and mechanically characterized: i) a gellan gum (GG) and Poly(ethylene glycol) diacrylate (PEGDA) blend, used to create different mechanically-competent, reinforcing scaffolds within the volumetrically crosslinked GelMA microgels, ii) a blend of methylcellulose and fibrinogen, used as medium for cell printing.
RESULTS: Features smaller than 500 µm can be volumetrically printed in less than a minute with the microgel-bioresin, and ⁓300 µm width filaments can be extruded within it with both bioinks. With a compression modulus ranging between 3 and 4 kPa, microgel-based samples have shown lower mechanical properties than bulk GelMA gels, but these could be enhanced and tuned using the GG/PEGDA ink. Printed reinforcing GGPEGDA/GelMA meshes taking up a 2.5% volume fraction of the whole slurry-based construct lead to increasing the compression modulus of the composite by 40%. Printing of multiple cell types including vasculature forming endothelial cells and pancreatic cells was finally investigated to build complex biofabricated constructs for vascularized tissue engineering.
CONCLUSIONS: Combining extrusion-based bioprinting in a suspension media and volumetric bioprinting is an advantageous approach that allows to create complex cm3-scale and vascularized structures in a fast and accurate process, combining different biomaterials to tune both mechanical and biological characteristics. These features are crucial to better mimic the heterogeneous characteristics of living tissues (e.g., the complex architecture of the trabecular bone and the bone marrow, or the endocrine pancreatic tissue within the exocrine one).
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