ROS-Responsive Sequential Release Systems with Excellent Biofilm Permeability for Enhanced Antibacterial and Regeneration-promoting Therapy in Periodontitis

Abstract

Abstract Periodontitis is the sixth most common chronic inflammatory disease caused by plaque biofilms and closely related to many systemic diseases. In particular, the problems of deep lesion location and sequential treatment of antibacterial and pro-regenerative abilities need to be addressed. We created a novel ROS responsive system (CHX@PCL-PLG) for efficient therapy of refractory periodontitis based on a “three-birds-with-one-stone” strategy, which integrates the biofilm penetration, nitric oxide (NO) sterilization, and NO-mediated pro-angiogenic property into one system. The above system was fabricated by self-assembling vesicles formed by amphiphilic polymers containing poly-ε-caprolactone and guanidinated-poly-ε-lysine as carriers (PCL-PLG) loaded with chlorhexidine (CHX). CHX@PCL-PLG can efficiently penetrate into biofilm under the action of abundant guanidine groups on the vesicle’s surface. Subsequently, the guanidine groups of vesicles respond to the high level of ROS within the biofilm by releasing NO and CHX in a targeted manner to play a synergistic antibacterial and biofilm scavenging function. More importantly, following effective elimination all bacteria from the periodontal pockets, the residual guanidine groups could further produce trace amounts of NO, which promoted angiogenesis and epithelialization of the wound tissue to significantly facilitating wound healing. In conclusion, this study demonstrates that CHX@PCL-PLG makes full use of the characteristics of guanidine groups to significantly disrupt biofilms and promote tissue regeneration for the effective treatment of periodontitis as well as various biofilm-related diseases.