Click chemistry improved wet adhesion strength of mussel-inspired citrate-based antimicrobial bioadhesives

Abstract

For the first time, a convenient copper-catalyzed azide-alkyne cycloaddition (CuAAC, click chemistry) was successfully introduced into injectable citrate-based mussel-inspired bioadhesives (iCMBAs, iCs) to improve both cohesive and wet adhesive strengths and elongate the degradation time, providing numerous advantages in surgical applications. The major challenge to developing such an adhesive was the mutual inhibition effect between the oxidant used for crosslinking catechol groups and the Cu(II) reductant used for CuAAC, which was successfully minimized by adding a biocompatible buffering agent typically used in cell culture, 4-(2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), as a copper chelating agent. Among the investigated formulations, the highest adhesion strength achieved (223.11 ± 15.94 kPa) was around 13 times higher than that of a commercially available fibrin glue (15.4 ± 2.8 kPa). In addition, dual-crosslinked (i.e. click crosslinking and mussel-inspired crosslinking) iCMBAs still preserved considerable antibacterial and antifungal capabilities that are beneficial for the bioadhesives used as hemostatic adhesives or sealants for wound management.

Development of tannin-inspired antimicrobial bioadhesives

“…4, the wet lap shear strengths of various Gel-TA-SN formulations ranged from 16.6 ± 4.0 kPa (for F-75) and 52.8 ± 8.7 kPa (for B-100). The lap shear strengths of FGel-TA-SN formulations to wet decellularized porcine small intestine submucosa (OASIS, HealthPoint Ltd. Fort Worth, TX) were close to that of the gold standard, fibrin glue [4, 5, 30], while the bovine-derived counterpart yielded even higher wet adhesion strengths, reflecting the stronger dry/wet mechanical properties above. Increasing of TA content also improved the adhesion strength of the crosslinked bioadhesives.…”

“…One possible antibacterial mechanisms of tannic acid was reported as the interactions of tannic acid with bacterial cell wall leading to the complexation with cell wall protein and membrane disruption metal ions [29]. Silver nanoparticles resulted from the redox reaction between oxidative of tannic acid with reductive silver nitrate (SN) could also serve as antimicrobial agents [5, 6, 35]. …”

“…The bacterial inhibition ratios of SN crosslinked Gel-TA hydrogels against S. aureus and E. coli were evaluated using F2-S75 (F-75), F2-S100 (F-100), B2-S75 (B-75), and B-2-S100 (B-100) as the representative experimental samples and PEGDA/HEMA (w/w = 1/1) as negative control [5, 6, 32]. Briefly, 0.2 g of freeze-dried hydrogels were immersed in 20 mL of germ containing broth with bacterial concentrations of around 1×10 6 CFUs/mL (CFU: colony forming unit) [32].…”

Citrate chemistry and biology for biomaterials design

“…Click chemistry (copper-catalyzed azide-alkyne cycloaddition) and alkyne modified gelatin can also be introduced to iCMBA to improve the wet adhesion strength (highest adhesion strength: 223.11±15.94 KPa; 13 times higher than clinically used fibrin) and slow down its initial degradation rate (Fig. 3B) [37]. In addition, by incorporating clinically applied and inexpensive anti-fungal agent, 10-undecylenic acid (UA), iCMBAs has been engineered to possess longterm anti-bacteria and anti-fungal capability (Fig.…”

“…Also, iCMBAs were fully degraded day 28, supporting iCMBAs’ potential for biological applications. In addition, click chemistry has been introduced into the mussel-inspired cross-linking network of iCMBA [37], which greatly improved the cohesive strength under wet conditions to 223.11±15.94 KPa, almost 13 times higher than that of conventional fibrin glue, while decreasing the initial degradation, critical for sustaining mechanical integrity in the early tissue regeneration stage. Further modification of iCMBA with anti-fungal activity can be achieved by a two-step synthesis: first, 10-undecenoyl chloride as the anti-fungal agent is synthesized with citric acid to generate anti-fungal undecylenate citric acid (U-CA) [38], which was subsequently incorporated into iCMBAs prepolymer to generate a new family of anti-bacterial and anti-fungal iCBMA termed AbAf iCs.…”