Micelle-facilitated gelation kinetics and viscoelasticity of dynamic hyaluronan hydrogels for bioprinting of mimetic constructs and tissue repair
Hua Zhang, Yang Luo, Guanrong Li, Zeming Hu, Rong Xu, Tong Zhu, Xu Cao, Yudong Yao, Wei Jian, Jun Chen, Gordon G. Wallace, Jun Fu
Abstract
Engineered tissues created through cell-laden hydrogel bioprinting offer a promising therapeutic approach for tissue regeneration. However, considerable challenges persist in the development of hydrogels that possess optimal gelling kinetics and viscoelastic properties, and sufficient stability to facilitate both the printing of biomimetic structures and the formation of engineered tissues. Herein, we present a rapidly gelling and long-term dynamic hyaluronate hydrogel achieved through the introduction of self-assembled F127 diacrylate (F127DA) micelles to modulate the kinetics of hydrazone crosslinking and the extent of dual-crosslinking network formation. The investigation demonstrates that the introduction of F127DA strengthens the interactions among the hyaluronate components, significantly accelerating gelation and increasing the mechanical stability of the optimal hydrogels. The rapidly formed ink permits low-shear mixing-injection printing, facilitating the construction of precise structures with high cell viability. The viscoelastic microenvironment fosters fibroblast spreading within the bioprinted matrices and supports the development of a biomimetic skin construct characterized by multilayer keratinocytes on the surface. Application of this dynamic hydrogel in a full-thickness mouse skin wound model accelerates tissue healing by inflammation suppression, angiogenesis and extracellular matrix promotion. This study demonstrates innovative modulation of gelation kinetics and viscoelasticity of dynamic hyaluronic hydrogels using block copolymer micelles for tissue engineering. A long-term dynamic hydrogel with rapid gelation and controllable viscoelasticity is designed using dual-crosslinked hyaluronan and Pluronic F127 diacrylate nano-micelles. The ingenious interactions between Pluronic F127 diacrylate and hyaluronan derivatives enable the micelle-mediated dynamic hyaluronan hydrogel to accurately bioprint complex organ structures and enhance tissue regeneration. • A dynamic hydrogel is developed by modulating the dual-crosslinked hyaluronan network with F127 diacrylate micelles. • Micelles enable tailored gelation and stiffness of hydrogels for precise 3D bioprinting with high cell viability. • The viscoelastic microenvironment promotes cell spread and proliferation, successfully engineering a bilayer skin construct. • Dynamic hydrogels accelerate wound closure by inflammation suppression, angiogenesis, and extracellular matrix promotion.