Self-Supporting Hyaluronic Acid-Functionalized G-Quadruplex-Based Perfusable Multicomponent Hydrogels Embedded in Photo-Cross-Linkable Matrices for Bioapplications

Dynamic G-quadruplexsupramolecular hydrogels have aroused greatinterest in a broad range of bioapplications. However, neither thedevelopment of native extracellular matrix (ECM)-derived natural biopolymer-functionalizedG-quadruplex hydrogels nor their use to create perfusable self-supportinghydrogels has been explored to date, despite their intrinsic potentialas carrier vehicles of therapeutic agents, or even living cells inadvanced regenerative therapies, or as platforms to enable the diffusionof nutrients and oxygen to sustain long-term cell survival. Herein,we developed a dynamic co-assembling multicomponent system that integratesguanosine (G), 3-aminophenylboronic acid functionalized hyaluronicacid (HA-PBA), and potassium chloride to bioengineer strong, homogeneous,and transparent HA-functionalized G-quadruplex hydrogels with injectable,thermo-reversible, conductive, and self-healing properties. The supramolecularpolymeric hydrogels were developed by hydrogen bonding and & pi;-& pi; stacking interactions between G coupled via dynamic covalent boronate ester bonds to HA-PBA andstabilized by K+ ions, as demonstrated by a combinationof experiments and molecular dynamics simulations. The intrinsic instabilityof the self-assembled G-quadruplex structures was used to bioengineerself-supporting perfusable multicomponent hydrogels with interconnectedsize and shape-tunable hollow microchannels when embedded in 3D methacrylatedgelatin supporting matrices. The microchannel-embedded 3D constructshave shown enhanced cell viability when compared to the bulk hydrogels,holding great promise for being use as artificial vessels for enablingthe diffusion of nutrients and oxygen essential for cell survival.The proposed approach opens new avenues on the use of ECM-derivednatural biopolymer-functionalized dynamic G-quadruplex hydrogels todesign next-generation smart systems for being used in tissue regeneration,drug screening, or organ-on-a-chip.

Automated summary

This study reported the development of strong, homogeneous, transparent HA-functionalized G-quadruplex hydrogels with injectable, thermo-reversible, conductive, and self-healing properties. The supramolecular polymeric hydrogels were formed through hydrogen bonding and π-π stacking interactions between G, HA-PBA, and K+ ions. Microchannel-embedded 3D constructs exhibited enhanced cell viability compared to bulk hydrogels, indicating their potential in tissue regeneration, drug screening, or organ-on-a-chip applications.