Catalyst-Free Click Chemistry for Engineering Chondroitin Sulfate-Multiarmed PEG Hydrogels for Skin Tissue Engineering

Abstract

The quest for an ideal biomaterial perfectly matching the microenvironment of the surrounding tissues and cells is an endless challenge within biomedical research, in addition to integrating this with a facile and sustainable technology for its preparation. Engineering hydrogels through click chemistry would promote the sustainable invention of tailor-made hydrogels. Herein, we disclose a versatile and facile catalyst-free click chemistry for the generation of an innovative hydrogel by combining chondroitin sulfate (CS) and polyethylene glycol (PEG). Various multi-armed PEG-Norbornene (A-PEG-N) with different molecular sizes were investigated to generate crosslinked copolymers with tunable rheological and mechanical properties. The crosslinked and mechanically stable porous hydrogels could be generated by simply mixing the two clickable Tetrazine-CS (TCS) and A-PEG-N components, generating a self-standing hydrogel within minutes. The leading candidate (TCS-8A-PEG-N (40 kD)), based on the mechanical and biocompatibility results, was further employed as a scaffold to improve wound closure and blood flow in vivo. The hydrogel demonstrated not only enhanced blood perfusion and an increased number of blood vessels, but also desirable fibrous matrix orientation and normal collagen deposition. Taken together, these results demonstrate the potential of the hydrogel to improve wound repair and hold promise for in situ skin tissue engineering applications.

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“…Hot colors indicate higher blood flow. 42 , 43 The MoorLDI V5.3 software (Moor Instruments, Axminster, UK) was used to calculate the mean pixel value of each scanned image, and the mean flux was expressed as relative units, representing the average blood flow of the tumor area.…”

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“…Moreover, 5-fluorouracil-coumarin conjugation ( Figure 1E ) as anti-cancer drug candidate ( ópez et al, 2022 ) and pH responsive doxorubicin delivery polymers nano-particles ( Wallat et al, 2018 )for treatment of breast and ovarian cancer were generated by modification of natural products via CuAAC. In addition, quercetin-gold quantum dots for adenocarcinoma treatment ( Pansare et al, 2022 ) and chondroitin sulfate-multiarmed PEG hydrogels for skin tissue engineering ( Sousa et al, 2022 ) had been developed by modification of natural products ( Figure 1F ).…”

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“…The gel had stable mechanical properties, mechanical properties, and adjustable rheology, and its biocompatibility was also very good. At the same time, it effectively increased the number of transport blood vessels and enhanced blood irrigation, providing a new strategy for trauma repair and skin tissue repair in situ ( Figure 3 D) [ 50 ].…”

“…( C ) Schematic diagram of the preparation of the gelatin/chitosan/PVA/nHAp (GCPH) composite scaffold [ 49 ]. ( D ) Schematic diagram of the preparation of the TCS-A-PEG-N porous hydrogel network [ 50 ].…”