One‐Pot Synthesis of Antibacterial and Antioxidant Self‐Healing Bioadhesives Using Ugi Four‐Component Reactions

Bioadhesive materials are extensively utilized as alternatives to surgical sutures and wound dressings. Despite significant advancements in their synthesis, current bioadhesives suffer from inadequate mechanical stability, suboptimal wet tissue adhesion, and a lack of inherent antibacterial and antioxidant properties, while requiring multistep synthesis processes, complicating their production for biomedical applications. To address these limitations, we developed a new bioadhesive, named UgiGel, synthesized through a one-pot Ugi four-component reaction (Ugi-4CR). Our strategy utilized gelatin as the backbone, 4-formylphenylboronic acid (4-FPBA) as an aldehyde source for improved adhesion and antibacterial activity, gallic acid (GA) as a carboxylic acid source for improved antioxidant activity and wound healing, and cyclohexyl isocyanide (CyIso) to induce pseudopeptide structures. The internal crosslinking between GA and 4-FPBA via dynamic boronate ester bond formation, triggered by slight pH changes (7.4-7.8) and temperature elevation (25°C-40°C), resulted in the formation of viscoelastic and self-healing hydrogels with water as the only byproduct without the need for initiator/light activation. UgiGel showed higher adhesion to porcine skin tissue (139.8 ± 8.7 kPa) as compared to commercially available bioadhesives, Evicel (26.3 ± 2.6 kPa) and Coseal (19.3 ± 9.9 kPa). It also demonstrated effective antibacterial properties against both Gram-negative and Gram-positive bacteria, as well as antioxidant activity. Additionally, the in vitro studies using NIH-3T3 cells confirmed the biocompatibility of the UgiGel over 7 days of culture. Moreover, in vivo biocompatibility and biodegradation of UgiGel were confirmed via subcutaneous implantation in rats for up to 28 days. Our results demonstrated that UgiGel outperformed commercially available bioadhesives in terms of adhesion, self-healing, and antibacterial activity, without compromising biocompatibility or physical properties, representing a promising multifunctional bioadhesive for wound sealing and repair.