Polyphenolic Gelatin-Based Bioadhesives

ConspectusBioadhesives are important for the future of medicine in their roles in wound closure and as measures to enhance wound healing. These adhesives are more effective and less invasive than conventional wound closure methods, such as surgical sutures or staples. Adhesive substances based on naturally occurring biological materials from living organisms harness phenolic compounds for their attachment to wet surfaces. For example, plants, such as Boston ivy, or animals, such as mussels, have evolved tissues that create optimal adhesion under a variety of challenging conditions, including in aqueous and saline environments. Current research aims at using biomimetic strategies to create a new generation of bioadhesives that will be better suited for medical use. Biomaterials design has evolved around integration of phenols with protein backbones among which gelatin has received particular attention due to its excellent bioactivity, biocompatibility, biodegradability, low cost, facile chemical tunability, and tissue-mimetic properties. Bioadhesion performance in these biomaterials is a strong function of polyphenolic functionality and the processing approach for their integration into hydrogel networks. A number of studies have used phenolic small molecules to modify biomacromolecules chemically for bioadhesion. One of the major hurdles in these studies is insufficient phenolic uptake due to low-yield modification chemistries and inherently limited functionalization capacity of proteins. Polyphenols are an attractive toolbox for bioadhesive design, as they not only enable stronger interactions with various substrates but also act as cross-linking points, strengthening polymer network cohesion. In addition, the cross-linking mechanism used for gelation of bioadhesives should be compatible with polyphenolic moieties, as, for instance, free-radical polymerization in the presence of phenolic compounds is compromised by their free-radical scavenging effects. Polyphenolic compounds derived synthetically from phenolic small molecules as well as those occurring naturally, such as tannins, have added a large library of additional functionality, such as antimicrobial and photothermal responsiveness, calling for further developments for applications in wound management.In this Account, we review several recent breakthroughs in polyphenol-integrated gelatin that have been analyzed in the context of their use as bioadhesives. Polyphenols play important roles in covalent and noncovalent interactions with functional groups in biological substrates, including keratins, connective tissue, or soft internal tissues. We consider different polyphenol-carrying compounds for modification including catecholamines, phenolic amino acids, tannins, and lignins. We then discuss how these polyphenolic materials can be fabricated to mimic naturally derived bioadhesives through infusion, physical mixing, and copolymerization. We discuss the implications of using these bioadhesives, questioning their viability and prospects. Finally, we highlight current challenges and future opportunities for taking polyphenolic bioadhesives closer to clinical translation.