Single-component immunomodulatory hyaluronic acid hydrogel patch for accelerated chronic wound healing application.

Abstract

Chronic wounds often suffer from persistent inflammation, which hinders tissue regeneration. In this study, we present a multifunctional hyaluronic acid (HA)-based hydrogel patch with controlled reactive oxygen species (ROS) scavenging and immunomodulatory properties to accelerate chronic wound healing. A novel single-component strategy was developed in which HA was simultaneously modified with carbodihydrazide groups and gallic acid (GA) derivatives. We demonstrate, for the first time, that hydrogel formation can occur solely from carbodihydrazide-modified HA, without the need for an aldehyde-functionalized counterpart. Incorporation of GA not only consolidated hydrogel formation but also enabled material fabrication with tunable shapes and high fluid-absorbance capacity, as well as intrinsic antioxidant and immunomodulatory activities. This design offers significant clinical advantages by providing a user-friendly, ready-to-apply wound dressing that eliminates the need for precursor mixing, ensuring reproducibility and ease of use. In vitro studies further revealed that treatment of pro-inflammatory macrophages (M1) with the hydrogel formulations promoted a phenotypic shift toward anti-inflammatory M2 macrophages. When applied to chronic wounds in vivo, the multifunctional HA hydrogel patch effectively scavenged ROS, suppressed inflammation, and established a favorable microenvironment for tissue repair and regeneration.