Bacteria-Inspired Bioadhesives for Enhanced Mucoadhesion and Drug Delivery

Mucoadhesive polymers have gained attention for their ability to adhere effectively to mucosal surfaces for enhanced drug delivery, wound healing, and tissue engineering. Since mucosal tissues, such as ocular, buccal, and gastric tissues, have high turnover rates and secrete viscous mucin glycoproteins, effective adhesion is a significant challenge. Mucoadhesive polymers often require modification to improve or prolong adhesion with mucosal tissues. Notable strategies include thiolation and catechol modifications, which result in relatively weak bonds at the interface and limited stability. The use of N-hydroxysuccinimide (NHS) or functional groups to form covalent bonds with tissues could provide stronger adhesion but may hinder drug release and compromise biocompatibility.
To address these issues, we propose the use of a mucoadhesive chitosan biopolymer conjugated to a peptide from the Vibrio cholerae bacteria, which can adhere to and colonize small intestine walls. Specifically, a select sequence of the 51 amino acid loop from the V. cholerae Bap1 adhesin protein is utilized, which was recently identified as a primary contributor of biofilm adherence to lipids and abiotic surfaces and is expected to promote interactions with epithelial cells in the mucosal tissue [1]. Using this, we develop and evaluate an adhesive system composed of a polyacrylamide (PAAm) hydrogel and peptide-modified chitosan bridging polymer. Advantages of this bioadhesive design include improved adhesion via electrostatic and secondary interactions, superior biocompatibility, and enhanced drug transport compared with conventional approaches.
The peptide-modified chitosan was prepared by conjugating the synthesized peptide to chitosan using carbodiimide chemistry and confirmed with Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). The rheological properties of the chitosan were found mostly unchanged after conjugation with the peptide. T-peel test with ex vivo porcine large intestine tissue was used to evaluate adhesion energy of this bioadhesive approach. Average adhesion energy was observed to double when using the peptide-modified chitosan as compared to pristine chitosan. The peptide-modified chitosan also provided improved adhesion energy when used at a concentration of at least 1.5%. Similar increases in adhesion energy were also seen with double-network polyacrylamide-alginate (PAAm-alg) hydrogels. Adhesion mechanism of the peptide-modified chitosan was investigated with mucin binding assay and penetration depth of the chitosan bridging polymer. An increase in mucin binding was observed for the peptide-modified chitosan, indicative of enhanced interactions with mucin after modification. However, the peptide-modified chitosan did not penetrate any further than unmodified chitosan, though both were observed to interact with the epithelial cell layer.
In addition to adhesion performance, the peptide-modified chitosan was also evaluated for drug delivery application. Firstly, the peptide-modified chitosan demonstrated good cytocompatibility as expected since the small peptide fragment does not carry any pathogenic or biological risks. Drug diffusion on ex vivo tissue revealed improved drug diffusion for an adhesive system using peptide-modified chitosan as compared to pristine chitosan supplemented with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and NHS. These results demonstrate that a bacterial peptide modified chitosan may provide a novel, effective, and safe approach for improved bioadhesion with intestinal tissues. This work will motivate the future development of bioinspired bioadhesives and their potential use for biomedical applications.
References
[1] Huang, X., Nero, T., Weerasekera, R. et al. Vibrio cholerae biofilms use modular adhesins with glycan-targeting and nonspecific surface binding domains for colonization. Nat Commun 14, 2104 (2023).