In Situ Self-Cross-Linkable, Long-Term Stable Hyaluronic Acid Filler by Gallol Autoxidation for Tissue Augmentation and Wrinkle Correction

Abstract

Injectable fillers mainly aim to augment tissue volume and correct wrinkles in cosmetic and plastic reconstructions. However, the development of long-lasting, injectable fillers with minimal complications of pain, toxicity, and displacement has been challenging because of the absence of reliable cross-linking chemistry. Here, we report a novel cross-linker-free injectable hydrogel formulated by autoxidation as a highly biocompatible, easily injectable, and long-term volumetrically stable filler agent. Self-cross-linkable hyaluronic acid (SC-HA) with gallol moieties could form a hydrogel via autoxidation of gallols in vivo without additional cross-linking agents. The gelation of SC-HA in situ after injection is accelerated by the self-production of oxygen species and endogenous peroxidase in vivo. The SC-HA filler does not require a high injection force, thus minimizing pain, bleeding, and tissue damage-associated complications. In addition, improved tissue adhesiveness of the SC-HA hydrogel by oxidized gallols (shear strength; 2 kPa) prevented displacement of the filler constructs from the injection site. The SC-HA filler retained its mechanical properties in vivo (600–700 Pa) for wrinkle correction and volumetric augmentation up to 1 year after injection. Overall, the performance of the SC-HA hydrogel as an injectable dermal filler was superior to that of commercially available, chemically cross-linked biphasic HA filler composites in terms of injectability, tissue adhesiveness, and long-term volumetric augmentation. Our injectable HA hydrogel with no need of cross-linkers provides a long-lasting filler that has clinical utility for cosmetic applications.

Anti-oxidant anti-inflammatory and antibacterial tannin-crosslinked citrate-based mussel-inspired bioadhesives facilitate scarless wound healing

“…These encouraging results may originate from the anti-oxidant, anti-inflammatory and antibacterial activities of DA and TA in 3A-TCMBAs, as well as their favorable photothermal activity. The wound closure study further demonstrated the potential of 3A-TCMBAs in scarless wound healing [ 76 , 77 ].…”

Unraveling the gallol-driven assembly mechanism of thermoreversible supramolecular hydrogels inspired by ascidians

“…36 Alternatively, pyrogallol-conjugated polymers have recently emerged as biomimetic precursors for hydrogel formation in biomedical applications. 37,38 Indeed, pyrogallol-tethered chitosan, 19,20 hyaluronic acid (HA), 18,39,40 and gelatin (GEL) 41 hydrogels were prepared via oxidation-mediated covalent crosslinking, Fe 3+ coordination, or multiple H-bonding interactions. Although these approaches showed to be highly efficient to obtain multifunctional supramolecular materials, the grafting of pyrogallol onto the polymers was demanded, requiring time and expensive chemicals.…”

Recent Advances in Injectable Hydrogels for Controlled and Local Drug Delivery

“…[94] More recently, injectable hydrogels have begun to be prepared by enzyme-mediated crosslinking due to its milder reactions (neutral pH and moderate temperatures) and low cytotoxicity. [95][96][97][98][99][100] Common enzymes used for hydrogel crosslinking include horseradish peroxidase (HRP), tyrosinase, and lysyl oxidase extracted from plant or animal sources. For example, HRP was used to mediate in situ forming gelatinhydroxyphenyl propionic acid tyrosine residues on tissue surfaces, [101] where enzymatic diphenol coupling was used to connect the phenol groups of the gelatin with the tyrosine residues on the tissue surfaces.…”