Polyphenolic Gelatin-Based Bioadhesives

Conspectus Bioadhesives are important forthe future of medicine in theirroles in wound closure and as measures to enhance wound healing. Theseadhesives are more effective and less invasive than conventional woundclosure methods, such as surgical sutures or staples. Adhesive substancesbased on naturally occurring biological materials from living organismsharness phenolic compounds for their attachment to wet surfaces. Forexample, plants, such as Boston ivy, or animals, such as mussels,have evolved tissues that create optimal adhesion under a varietyof challenging conditions, including in aqueous and saline environments.Current research aims at using biomimetic strategies to create a newgeneration of bioadhesives that will be better suited for medicaluse. Biomaterials design has evolved around integration of phenolswith protein backbones among which gelatin has received particularattention due to its excellent bioactivity, biocompatibility, biodegradability,low cost, facile chemical tunability, and tissue-mimetic properties.Bioadhesion performance in these biomaterials is a strong functionof polyphenolic functionality and the processing approach for theirintegration into hydrogel networks. A number of studies have usedphenolic small molecules to modify biomacromolecules chemically forbioadhesion. One of the major hurdles in these studies is insufficientphenolic uptake due to low-yield modification chemistries and inherentlylimited functionalization capacity of proteins. Polyphenols are anattractive toolbox for bioadhesive design, as they not only enablestronger interactions with various substrates but also act as cross-linkingpoints, strengthening polymer network cohesion. In addition, the cross-linkingmechanism used for gelation of bioadhesives should be compatible withpolyphenolic moieties, as, for instance, free-radical polymerizationin the presence of phenolic compounds is compromised by their free-radicalscavenging effects. Polyphenolic compounds derived synthetically fromphenolic small molecules as well as those occurring naturally, suchas tannins, have added a large library of additional functionality,such as antimicrobial and photothermal responsiveness, calling forfurther developments for applications in wound management. Inthis Account, we review several recent breakthroughs in polyphenol-integratedgelatin that have been analyzed in the context of their use as bioadhesives.Polyphenols play important roles in covalent and noncovalent interactionswith functional groups in biological substrates, including keratins,connective tissue, or soft internal tissues. We consider differentpolyphenol-carrying compounds for modification including catecholamines,phenolic amino acids, tannins, and lignins. We then discuss how thesepolyphenolic materials can be fabricated to mimic naturally derivedbioadhesives through infusion, physical mixing, and copolymerization.We discuss the implications of using these bioadhesives, questioningtheir viability and prospects. Finally, we highlight current challengesand future opportunities for taking polyphenolic bioadhesives closerto clinical translation.