pH-Triggered Cellulose Nanofibrils-Reinforced Hydrogel Bioadhesives for Tissue Sealant

Bioadhesives are natural or synthetic materials that can adhere to biological surfaces under wet conditions, thereby allowing their use as tissue sealants and patches for tissue regeneration, drug delivery systems, and biosensors. Owing to their excellent biocompatibility as well as adhesion performance under wet conditions, they are of special interest in the field of tissue regeneration. For example, because catechol groups form covalent and non-covalent bonds with various organic/inorganic material substrates, they undergo rapid curing to form adhesive plaques with high interfacial binding strength, durability, and mechanical toughness to tissues. However, some catechol groups incorporated in the adhesive are readily oxidized to quinone groups, resulting in the loss of adhesive strength through such irreversible oxidation. As a substitute for catechol groups, phenyl boronic acid has a cis-diol moiety that exhibits adhesive properties similar to catechol cis-diols in mussel adhesive proteins. Curing of catechol moieties in mussel adhesive proteins is triggered by alkaline pH, which deprotonates the diol groups of catechol. Similarly, boronic acid can be cured under weakly basic conditions, reinforcing binding between cis-diols presented from alginate backbones and boronic acid. Before curing of boronic acid-conjugated alginate (Al-BA) solutions, Al-BA chains are effectively diffused and entangled with hydrogel polymeric chains in the presence of boronic acid-mediated hydrogen bonds with gel backbone polymers. However, Al-BA itself has a limitation to tissue suturing due to formation of intrinsic soft gel phase. Therefore, it is necessary to develop a technology to reinforce the gel phase which has suitable adhesion strength for tissue sealant. For example, there are techniques such as controlling the kinetics of polymer hydrogelation in an adhesive matrix, fiber complexing and inorganic hybrid reinforcement. In this study, we present a pH-sensitive bioadhesive for skin tissue sealant with enhanced mechanical properties by introducing bacterial cellulose nanofibers (BCNFs). BCNFs, known as bacterial-derived celluloses, have revealed outstanding potential in wound treatment due to their valuable properties such as high crystallinity, water holding and absorption capacity, and high mechanical strength. Additionally, when the surface of BCNF itself, which has strong physical properties, is modified with cations, it can help to effectively adhere to the tissue through electrostatic interaction. For this, we conjugated 3-aminophenylboronic acid onto an alginate backbone via 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS)-mediated reaction, and then hybridized with positive charged BCNFs, which is fabrcated by amination reaction. Finally, we demonstrated that our bioadhesives exhibited effective skin tissue sealing even under wet conditions, thus promising a variety of biological applications in the field of tissue engineering.