Biofilm in Diabetic Foot Ulcers: A Systematic Narrative Review

George Theodorakopoulos^1,2,3,4,5,6 | David G. Armstrong^7,8,9

¹Wound and Foot Specialist, Athens, Greece | ²Technological Educational Institute of Patras, Patras, Greece | ³Queen Margaret University, Edinburgh, UK | ⁴University of West Attica, Aigaleo, Greece | ⁵University of Thessaly, Larisa, Greece | ⁶National and Kapodistrian University of Athens, Athens, Greece | ⁷Southwestern Academic Limb Salvage Alliance (SALSA), Los Angeles, California, USA | ⁸Center to Stream Healthcare in Place (C2SHiP), Alexandria, Virginia, USA | ⁹Keck School of Medicine, University of Southern California, Los Angeles, California, USA

Correspondence: George Theodorakopoulos (该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。)

Received: 27 June 2025 | Revised: 29 October 2025 | Accepted: 6 November 2025

ABSTRACT

Biofilms are a key driver of chronicity and treatment failure in diabetic foot ulcers (DFUs), yet clinical evidence quantifying their impact and management remains fragmented. This systematic narrative review synthesised recent evidence (2015–2025) on the prevalence, diagnostics, and management of biofilm in DFUs. A Systematic Review of the Literature (SRL) was conducted following PRISMA 2020 guidelines across PubMed/MEDLINE, Scopus, Cochrane Library and ScienceDirect. Eligible studies included adults with DFUs reporting biofilm/bioburden metrics or interventions aimed at biofilm disruption. Risk of bias was assessed using RoB 2 for randomised trials and ROBINS-I for non-randomised studies. Data were narratively synthesised by evidence tier (Tier 1=clinical; Tier 2=preclinical/mechanistic). Of 600 records screened, 25 studies met inclusion criteria (Tier 1 n=9; Tier 2 n=5; reviews n=11). Over half of bacterial isolates in DFUs were biofilm producers, with multidrug resistance exceeding 90% in several cohorts. Fungi were detected in 31% of ulcers by qPCR but only 9% by culture. Tier 1 clinical evidence supports standard care components—debridement, antiseptics, and negative-pressure wound therapy—for improved healing, though direct anti-biofilm outcomes remain limited. Emerging strategies (enzymatic agents, peptides, cold plasma, smart dressings) show promise in vitro but lack clinical translation. Evidence for direct antibiofilm efficacy in DFUs remains scarce. Current data justify maintaining guideline-based care while prioritising trials that integrate validated biofilm endpoints, standardised microbiological methods, and antifungal components. Distinguishing established from experimental approaches is essential to advancing safe, evidence-based biofilm management in DFUs.

Role of an acidic environment in the treatment of diabetic foot infections: A review

Basavraj Nagoba, Ajay Gavkare, Abhijit Rayate, Sachin Mumbre, Arunkumar Rao, Basavraj Warad, Neeta Nanaware, Nawab Jamadar

Basavraj Nagoba, Department of Microbiology, MIMSR Medical College, Latur 413512, Maharashtra, India

Ajay Gavkare, Department of Physiology, MIMSR Medical College, Latur 413512, Maharashtra, India

Abhijit Rayate, Basavraj Warad, Department of Surgery, MIMSR Medical College, Latur 413512, Maharashtra, India

Sachin Mumbre, Department of Community Medicine, Ashwini Rural Medical College, Solapur 413001, Maharashtra, India

Arunkumar Rao, Department of Orthopedics, MIMSR Medical College, Latur 413512, India

Neeta Nanaware, Department of Physiology, Government Medical College, Latur 413512, Maharashtra, India

Nawab Jamadar, Department of Anesthesiology, MIMSR Medical College, Latur 413512, Maharashtra, India

Corresponding author: Basavraj Nagoba, PhD, Assistant Dean, Research, Professor, Department of Microbiology, MIMSR Medical College, Vishwanathpuram, Ambejogai Road, Latur 413512, Maharashtra, India. 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

Abstract

Management of diabetic foot ulcers is the biggest challenge to the clinician, as conventional antibiotic therapies and local wound care have their own limitations. They are not effective for control of infections and promotion of healing because of cytotoxic effects. In view of cytotoxicity of routinely used topical antiseptic agents, this article focuses on the search of an ideal topical antiseptic agent that is safe and effective in controlling infectious agents and also in promoting the healing process. This review focuses on the use of various acids such as citric, acetic, hyaluronic, and hypochlorous acids as topical agents in diabetic foot infections. This article also focuses on the different roles of acids in the treatment of diabetic foot infections.

Key Words: Diabetic foot ulcer; Infection; Management; Topical agents; Acids; Role of acids

Core Tip: Diabetic foot ulcer is the most serious complication of diabetes mellitus. The biggest challenge is to find an ideal topical antiseptic agent that is safe and effective in controlling infectious agents and promoting the healing process. This article focuses on

the use of acids as topical agents to control diabetic foot infections, with special emphasis on the different roles of citric, acetic, hyaluronic, and hypochlorous acids in the effective management of diabetic foot ulcers.

Citation: Nagoba B, Gavkare A, Rayate A, Mumbre S, Rao A, Warad B, Nanaware N, Jamadar N. Role of an acidic environment in the treatment of diabetic foot infections: A review. World J Diabetes 2021; 12(9): 1539-1549

Evidence-Based Review of Antibiofilm Agents for Wound Care

Maximillian A. Weigelt,^1,* Stephanie A. McNamara,¹ Daniela Sanchez,² Penelope A. Hirt,¹ and Robert S. Kirsner¹

¹Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA.

²Boston University School of Medicine, Boston, Massachusetts, USA.

Significance: Biofilms in vivo are small densely packed aggregations of microbes that are highly resistant to host immune responses and treatment. They attach to each other and to nearby surfaces. Biofilms are difficult to study and identify in a clinical setting as their quantification necessitates the use of advanced microscopy techniques such as confocal laser scanning microscopy. Nonetheless, it is likely that biofilms contribute to the pathophysiology of chronic skin wounds. Reducing, removing, or preventing biofilms is thus a logical approach to help clinicians heal chronic wounds.

Recent Advances: Wound care products have demonstrated varying degrees of efficacy in destroying biofilms in in vitro and preclinical models, as well as in some clinical studies.

Critical Issues: Controlled studies exploring the beneficial role of biofilm eradication and its relationship to healing in patients with chronic wounds are limited. This review aims to discuss the mode of action and clinical significance of currently available antibiofilm products, including surfactants, dressings, and others, with a focus on levels of evidence for efficacy in disrupting biofilms and ability to improve wound healing outcomes.

Future Directions: Few available products have good evidence to support antibiofilm activity and wound healing benefits. Novel therapeutic strategies are on the horizon. More high-quality clinical studies are needed. The development of noninvasive techniques to quantify biofilms will facilitate increased ease of research about biofilms in wounds and how to combat them.

Keywords: biofilm, wound, healing, treatment, therapy

Electrolyzed hypochlorous acid water exhibits potent disinfectant activity against various viruses through irreversible protein aggregation

Rahmi Dianty^1,2 , Junki Hirano^1,2 , Itsuki Anzai^1,3 , Yuta Kanai^1,4 , Tsuyoshi Hayashi⁵ , Masae Morimoto⁶ , Chikako Kataoka-Nakamura⁶ , Sakura Kobayashi⁵ , Kentaro Uemura^1,2 , Chikako Ono^1,2 , Tokiko Watanabe^1,3,7 , Takeshi Kobayashi^1,4,7 , Kosuke Murakami⁵ , Kenji Kikuchi⁸ , Kunimoto Hotta⁸ , Toshikazu Yoshikawa⁸ , Shuhei Taguwa^{1,2,7 *} and Yoshiharu Matsuura^{1,2,7 *}

¹ Laboratory of Virus Control, Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan, 2Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan, 3Laboratory of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan, 4Laboratory of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan, 5Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan, 6Innovative Vaccine Research and Development Center, The Research Foundation for Microbial Diseases of Osaka University, Osaka, Japan, 7 Center for Advanced Modalities and DDS, Osaka University, Osaka, Japan, 8Louis Pasteur Center for Medical Research, Kyoto, Japan

It is essential to employ efficient measures to prevent the transmission of pathogenic agents during a pandemic. One such method involves using hypochlorous acid (HClO) solution. The oxidative properties of HClO water (HAW) can contribute to its ability to eliminate viral particles. Here, we examined a highly purified slightly acidic hypochlorous acid water (Hp-SA-HAW) obtained from the reverse osmosis membrane treatment of an electrolytically-generated SA-HAW for its anti-viral activity and mode of action on viral proteins. Hp-SA-HAW exhibited broad-spectrum antiviral effects against various viruses, including adenovirus, hepatitis B virus, Japanese encephalitis virus (JEV), and rotavirus. Additionally, Hp-SA-HAW treatment dose-dependently resulted in irreversibly aggregated multimers of the JEV envelope and capsid proteins. However, Hp-SA-HAW treatment had no discernible effect on viral RNA, indicating that Hp-SA HAW acts against amino acids rather than nucleic acids. Furthermore, Hp-SA-HAW substantially reduced the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including the ancestral variant and other multiple variants. Hp-SA-HAW treatment induced the aggregation of the SARS-CoV-2 spike and nuclear proteins and disrupted the binding of the purified spike protein of SARS-CoV-2 to human ACE2. This study demonstrates that the broad-spectrum virucidal activity of highly purified HClO is attributed to viral protein aggregation of virion via protein oxidation.

KEYWORDS

hypochlorous acid, virucide, SARS-CoV-2, oxidation, protein aggregation

Hypochlorous acid is antipruritic and anti-inflammatory in a mouse model of atopic dermatitis

T. Fukuyama¹ | B. C. Martel¹ | K. E. Linder² | S. Ehling¹ | J. R. Ganchingco¹ | W. B€aumer^1,3

Summary

Background: It has been reported that topical hypochlorous acid (HOCl) formulations lead to relief of itch in human patients with atopic dermatitis; however, the specific antipruritic mechanism of action remains unclear.

Objective: To confirm itch relief and reduction of lesions in a mouse model of atopic dermatitis and to elucidate possible HOCl’s mode of action.

Methods: In this study, the effects of topical administration of HOCl hydrogel (0.05%) on atopic dermatitis-like lesions in NC/Nga mice model as well as in vitro effects of HOCl on dorsal root ganglia neurons and mouse bone marrow-derived dendritic cells (mBMDCs) were investigated. NC/Nga mice were sensitized with house dust mite allergen and treated topically with HOCl hydrogel both preventively and therapeutically against established lesions. Allergen challenge was continued during HOCl hydrogel application.

Results: Treatment with HOCl hydrogel prevented the development of lesions and scratching bouts during the whole observation period. When administered after full development of lesions, HOCl reduced lesions and scratching behaviour to a similar extent as a positive control 0.1% betamethasone dipropionate ointment. The reduced inflammatory response by HOCl treatment was demonstrated by reduced secretion of inflammatory cytokines in affected skin tissue from NC/Nga mice. In addition, HOCl significantly reduced IL-12 production in mBMDC. The diminished scratching behaviour was confirmed by impaired response to several pruritogens in dorsal root ganglia neurons excised from NC/Nga mice after termination of the studies. The response to the stimuli was also reduced by pre-incubation of sensory neurons from untreated BALB/c mice with 0.0001% HOCl. Conclusions and Clinical Relevance: These data indicate a direct reduction in sensory response by HOCl, leading to significantly reduced itch and inflammation in vivo.

KEYWORDS

atopic dermatitis, dorsal root ganglia, hypochlorous acid, IgE, IL-13, IL-4, NC/Nga mice, sensory neurons

中国肝细胞癌经动脉介入治疗 临床实践指南（2026版）

中国医师协会介入医师分会临床诊疗指南专委会

通信作者：滕皋军，东南大学附属中大医院介入与血管外科，南京 210009，Email：该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

【摘要】 经动脉介入治疗（TAI）应用于肝细胞癌（HCC），主要包括经动脉化疗栓塞（TACE）、经动脉栓塞（TAE）、肝动脉灌注化疗（HAIC）和选择性内放射治疗（SIRT）。TACE是治疗不可切除HCC的首选方法，中国医师协会介入医师分会（CCI）分别于2018、2021和2023年制订并更新了《中国肝细胞癌经动脉化疗栓塞（TACE）治疗临床实践指南》，为规范我国 TACE 临床实践发挥了重要作用。近年来，HAIC、SIRT在国内的应用日趋广泛并不断规范。随着TAI技术的进步、治疗理念的更新以及近年来高级别循证医学证据的出现，CCI在既往指南内容基础上，整合TACE、HAIC、SIRT内容并更新颁布《中国肝细胞癌经动脉介入治疗临床实践指南（2026版）》。本指南以最新循证医学证据为基础，结合我国临床实践，涵盖了TAI应用于HCC治疗的新进展，从临床诊断标准与分期、患者适应证与禁忌证、操作流程及要求、围手术期处理、常见并发症及处理、随访及疗效评价、联合治疗、质量控制及热点和展望等方面阐述，旨在进一步规范TAI在HCC治疗中的应用。

【关键词】 癌，肝细胞； 介入放射学，治疗性； 实践指南； 经动脉介入治疗

实践指南注册：国际实践指南注册与透明化平台（PREPARE‑2025CN046）

Chinese clinical practice guidelines for transarterial interventions of hepatocellular carcinoma (2026 edition)

Clinical Guidelines Committee of Chinese College of Interventionalists

Corresponding author: Teng Gaojun, Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Southeast University, Nanjing 210009, China, Email: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

【Abstract】 Transarterial interventions (TAI) for hepatocellular carcinoma (HCC) include transarterial chemoembolization (TACE), transarterial embolization (TAE), hepatic arterial infusion chemotherapy (HAIC), and selective internal radiation therapy (SIRT). TACE remains the first‑line treatment for unresectable HCC. Chinese College of Interventionalists (CCI) previously issued and updated the Chinese Clinical Practice Guidelines of TACE for HCC in 2018, 2021, and 2023, which have played a pivotal role in standardizing TACE procedures in China. In recent years, the application of HAIC and SIRT has become increasingly widespread and standardized in China. With the continuous advancement of TAI techniques, the evolution of therapeutic concepts, and the emergence of high‑level evidence, CCI has comprehensively revised and expanded its previous guidelines. The updated Chinese clinical practice guidelines for transarterial interventions of hepatocellular carcinoma (2026 edition) now formally incorporates TACE, HAIC, and SIRT as standard treatment modalities. With the aims to further standardize the use of TAI in the management of HCC, this guideline is developed based on the most current evidence‑based medical research, integrates China‑specific clinical practices, and incorporates the latest advancements in TAI for HCC. It elaborates on clinical diagnostic criteria and staging, patient indications and contraindications, operational procedures and requirements, perioperative management, common complications management, follow‑up and efficacy evaluation, combination therapy, quality control, as well as hot topics and prospects.

【Key words】 Carcinoma, hepatocellular; Interventional radiology, therapeutic; Practice guideline; Transarterial interventions

Practice guideline registration: Practice Guideline Registration for Transparency (PREPARE‑2025CN046)