A Sustained-Release Nanosystem with MRSA Biofilm-Dispersing and -Eradicating Abilities Accelerates Diabetic Ulcer Healing

Shan He; Huangding Wen; Nannan Yao; Lu Wang; Junqun Huang; Zhiqing Li

doi:10.2147/IJN.S410996

A Sustained-Release Nanosystem with MRSA Biofilm-Dispersing and -Eradicating Abilities Accelerates Diabetic Ulcer Healing

Int J Nanomedicine. 2023 Jul 19:18:3951-3972. doi: 10.2147/IJN.S410996. eCollection 2023.

Authors

Shan He^#¹, Huangding Wen^#¹, Nannan Yao², Lu Wang³, Junqun Huang⁴, Zhiqing Li¹

Affiliations

¹ Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
² Department of Neurology, Cangzhou Central Hospital, Cangzhou, 061000, People's Republic of China.
³ Department of Neurology, Hebei General Hospital, Shijiazhuang, 050000, People's Republic of China.
⁴ Department of Anaesthesia, The Seventh Affiliated Hospital, Southern Medical University, Foshan, 528000, People's Republic of China.

^# Contributed equally.

Abstract

Introduction: Drug-resistant bacterial infections and biofilm formation play important roles in the pathogenesis of diabetic refractory wounds. Tea tree oil (TTO) exhibits antimicrobial, antimycotic, and antiviral activities, especially against common clinically resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA), making it a potential natural antimicrobial for the treatment of acute and chronic wounds. However, TTO is insoluble in water, volatile, light-sensitive, and cytotoxic. While previous macroscopic studies have focused on sterilization with TTO, none have sought to alter its structure or combine it with other materials to achieve sustained release.

Methods: Electrospun TTO nanoliposomes (TTO-NLs), arranged linearly via high-pressure homogenization, could stabilize the structure and performance of TTO to achieve slow drug release. Herein, we established a composite nano-sustained release system, TTO-NL/polyvinyl alcohol/chitosan (TTO-NL@PCS), using high-voltage electrospinning.

Results: Compared with the control, TTO-NL@PCS exhibits higher concentrations of the active TTO drug components, terpinen-4-ol and 1,8-cineole. Owing to its increased stability and slow release, early exposure to TTO-NL@PCS increases the abundance of reactive oxygen species in vitro, ultimately causing the biofilm to disperse and completely killing MRSA without inducing cytotoxic effects to the host. Moreover, in BKS-Lepr^em2Cd479/Gpt mice with a whole-layer skin infection, untargeted metabolomics analysis of wound exudates reveals upregulated PGF2α/FP receptor signaling and interleukin (IL)-1β and IL-6 expression following application of the composite system. The composite also ameliorates the chemotaxis disorder in early treatment and attenuates the wound inflammatory response during the repair stage of diabetic inflammatory wounds, and upregulates VEGF expression in the wound bed.

Conclusion: TTO-NL@PCS demonstrates the remarkable potential for accelerating diabetic and MRSA-infected wound healing.

Keywords: MRSA biofilm; antibacterial material; diabetic ulcer; electrospinning; wound healing.

MeSH terms

Animals
Biofilms
Delayed-Action Preparations
Diabetes Mellitus*
Methicillin-Resistant Staphylococcus aureus*
Mice
Ulcer

Substances

Delayed-Action Preparations

Grants and funding

This work was supported, in whole or in part, by the Science and Technology Planning Project of Guangdong Province (Z.L; Grant Number 2017A020215042) and President Foundation of Nanfang Hospital, Southern Medical University (H.W; No: 2021C036).