Abstract
Wound healing is a complex and dynamic biological process, and the treatment of chronic wounds remains a major clinical challenge. In this study, a novel probiotic microemulsion (LTE) based on Lactiplantibacillus plantarum-fermented tea was developed for wound healing treatment. Using the tea leaves of the De’ang ethnic group in Yunnan Province as raw materials, they were fermented by Lb. plantarum 75-2m-2. The results of targeted metabolism and qRT-PCR showed that the antioxidant polyphenols increased significantly during the fermentation process, and the key degradation enzymes were upregulated. By optimizing the microemulsion formulation, a stable and biocompatible LTE was obtained. In a rat full-thickness skin injury model, LTE accelerated wound closure, promoted re-epithelialization and collagen deposition, regulated the skin microbiota, and reduced the levels of pro-inflammatory cytokines. This study integrated traditional fermentation technology with modern nanotechnology, providing a novel and effective method for wound healing treatment, and indicating that LTE is a promising candidate for clinical wound dressings.
Introduction
As the largest organ of the human body, the skin has compromised integrity and functionality, which lead to wound formation [1]. Wound healing represents a highly intricate and dynamic biological process, encompassing three sequential yet overlapping phases: hemostasis, inflammation, proliferation and remodeling [2]. This process is fundamental for maintaining skin integrity, preventing opportunistic infections, and restoring physiological functions. Despite significant advancements in modern medicine, chronic wounds remain a formidable clinical challenge, often associated with prolonged treatment courses, high recurrence rates, and substantial healthcare costs [3]. Traditional wound care strategies, such as conventional gauze dressings, primarily focus on maintaining a moist environment but fail to address the multifaceted pathophysiological mechanisms underlying chronic wound progression, including oxidative stress, dysregulated inflammation, and microbial dysbiosis [4]. Consequently, there is an urgent need for the development of innovative, biocompatible therapeutic strategies capable of modulating multiple wound repair pathways simultaneously.
Plant-derived compounds have been utilized in wound management for millennia, leveraging their inherent bioactive properties [5]. Among these, tea-derived polyphenols, particularly catechins, have attracted significant attention due to their well-characterized antioxidant, anti-inflammatory, and antibacterial activities [6]. The significance of fermentation in enhancing the health benefits and market appeal of tea products is well-established [7]. However, the process of fermenting tea extracts using efficient bioprocessing tools faces significant challenges, particularly related to the selection and performance of microorganisms in the fermentation environment [8]. Fermentation processes, especially those mediated by lactic acid bacteria (LAB), can significantly enhance the bioactivity of tea polyphenols through microbial transformation and accumulate short-chain fatty acids, extracellular polysaccharides, vitamins, and bioactive peptides [9]. Lactiplantibacillus plantarum, a dominant species in many traditional fermented tea products, is capable of converting complex polyphenolic polymers into smaller bioactive metabolites [10]. These metabolites exhibit potent antioxidant capabilities, effectively scavenging reactive oxygen species (ROS) that contribute to tissue damage, extracellular matrix degradation, and delayed wound healing [11]. Thereby, they promote a more favorable microenvironment for wound healing.
The skin microbiota plays a critical role in maintaining skin homeostasis and wound repair. In healthy skin, a diverse and balanced microbial community promotes barrier function and immunomodulation [12]. However, chronic wounds often exhibit dysbiosis, characterized by the overgrowth of pathogenic bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa [13]. This microbial imbalance exacerbates inflammation, impairs tissue repair, and increases the risk of infection. Probiotics and their derivatives, including cell free supernatants (CFS) of LAB, can modulate the microbiota through the production of antimicrobial substances (e.g., bacteriocins) and immunomodulatory metabolites (e.g., short-chain fatty acids), thus creating a microbiome-friendly environment conducive to wound healing [14,15].
While previous research has extensively explored the antioxidant and antibacterial properties of fermented tea and LAB, translating these findings into practical wound care formulations remains a significant challenge [16]. For topical applications, bioactive compounds must overcome barriers related to solubility, skin permeability, and chemical stability. Microemulsions (MEs), nanoscale dispersions of oil, water, and surfactants with thermodynamic stability, offer a promising solution [17]. Their small droplet size (1–100 nm) enables enhanced skin penetration, improved bioavailability, and controlled release of active ingredients [18].
In this study, we developed a novel probiotic microemulsion (LTE) based on Lb. plantarum-fermented tea. The De’ang ethnic fresh tea from Yunnan Province was selected as the raw material and fermented with Lb. plantarum 75-2m-2, a strain isolated from traditional fermented tea. The results of targeted metabolism and qRT-PCR revealed a significant increase in antioxidant polyphenols and upregulation of key degradation enzymes during the fermentation process of traditional fermented tea. Inspired by this, the researchers formulated a tea medium by adding tea leaf extract to a small amount of De Man, Rogosa and Sharp (MRS) medium, and Lb. plantarum 75-2m-2 cultured in the tea medium had more efficient antioxidant activity due to the large amount of macromolecular polyphenol precursors provided therein. Through systematic optimization of the microemulsion formulation, we successfully developed LTE, a stable system with excellent physical properties and biocompatibility. In vivo studies using a rat full-thickness skin injury model demonstrated that LTE accelerated wound closure, promoted reepithelialization and collagen deposition, regulated the skin microbiota, and reduced the levels of pro-inflammatory cytokines. This study integrated traditional fermentation techniques with modern nanotechnology, presenting a novel and effective approach for wound healing therapy.
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Materials
Fermented tea was selected from fresh tea from Santai Mountain of De’ang Nationality in Yunnan Province, China. Lb. plantarum 75-2m-2 strain was isolated from fermented tea. Standards of Protocatechuic acid, Kaempferol, Quercetin, Syringic acid, Pyrogallol and Chlorogenic acid were purchased from Sigma-Aldrich (Saint Louis, MO, USA). Methanol, acetonitrile and formic acid were purchased from CNM Technologies GmbH (Bielefeld, North Rhine-Westphalia, Germany). Tween 80, span 80.
Yi-Xiao Shao, Peng Wei, Jia-wei Tu, Bao-Jun Li, Yong Li, Ning-Li Xu, Gui-Lan Xia, Chen-Jian Liu, Xiao-Ran Li, Lei Zhang, A probiotic microemulsion with antioxidant activity to promote wound healing, Journal of Drug Delivery Science and Technology, Volume 114, Part B, 2025, 107534, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.107534.
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