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.




Biochemistry & Molecular Biology; Chemistry; Polymer Science


Sousa, V; Amaral, AR; Castanheira, EJ; Marques, I; Rodrigues, JMM; Félix, V; Borges, J; Mano, JF

nossos autores


This work was funded by the European Union's Horizon Europe research and innovation programme under the Grant Agreement No. 101079482 ("SUPRALIFE"). This work was also supported by the Programa Operacional Regional do Centro - Centro 2020, in the component FEDER, and by national funds (OE) through Fundacao para a Ciencia e a Tecnologia/Ministerio da Ciencia, Tecnologia e Ensino Superior (FCT/MCTES), in the scope of the project "SUPRASORT" (PTDC/QUI-OUT/30658/2017, CENTRO-01-0145-FEDER-030658). This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020, financed by national funds through the FCT/MCTES (PIDDAC). The financial support by FCT through the individual Ph.D. grants (2020.06771.BD, V.S.; SFRH/BD/144880/2019, E.J.C.), and individual Junior Researcher (CEECIND/01363/2018, J.M.M.R.) and Assistant Researcher contracts (2020.00758.CEECIND, J.B.) under the Scientific Employment Stimulus - Individual Call is gratefully acknowledged. Part of the MD simulations were performed on the BOB supercomputing cluster installed at MACC, under FCT, I.P. Advanced Computing Project CPCA/A1/470074/2021.

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