Direct 3D Printed Biomimetic Scaffolds Based on Hydrogel Microparticles for Cell Spheroid Growth

Biocompatible hydrogel inks with shear-thinning, appropriate yield strength, and fast self-healing are desired for 3D bioprinting. However, the lack of ideal 3D bioprinting inks with outstanding printability and high structural fidelity, as well as cell-compatibility, has hindered the progress of extrusion-based 3D bioprinting for tissue engineering. In this study, novel self-healable pre-cross-linked hydrogel microparticles (pcH mu Ps) of chitosan methacrylate (CHMA) and polyvinyl alcohol (PVA) hybrid hydrogels are developed and used as bioinks for extrusion-based 3D printing of scaffolds with high fidelity and biocompatibility. The pcH mu Ps display excellent shear thinning when injected through a syringe and subsequently self-heal into gels as shear forces are removed. Numerical simulations indicate that the pcH mu Ps experience a plug flow in the nozzle with minimal disturbance, which favors a steady and continuous printing. Moreover, the pcH mu Ps show a self-supportive yield strength (540 Pa), which is critical for the fidelity of printed constructs. A series of biomimetic constructs with very high aspect ratio and delicate fine structures are directly printed by using the pcH mu P ink. The 3D printed scaffolds support the growth of bone-marrow-derived mesenchymal stem cells and formation of cell spheroids, which are most important for tissue engineering.