Thomas H. Leung,^1,2 Lillian F. Zhang,¹ Jing Wang,¹ Shoucheng Ning,³ Susan J. Knox,³ and Seung K. Kim^1,4,5

¹Department of Developmental Biology, 2Department of Dermatology, 3Department of Radiation Oncology, 4Howard Hughes Medical Institute, and 5Department of Medicine, Oncology Division, Stanford University School of Medicine, Stanford, California, USA.

Nuclear factor-κB (NF-κB) regulates cellular responses to inflammation and aging, and alterations in NF-κB signaling underlie the pathogenesis of multiple human diseases. Effective clinical therapeutics targeting this pathway remain unavailable. In primary human keratinocytes, we found that hypochlorite (HOCl) reversibly inhibited the expression of CCL2 and SOD2, two NF-κB–dependent genes. In cultured cells, HOCl inhibited the activity of inhibitor of NF-κB kinase (IKK), a key regulator of NF-κB activation, by oxidizing cysteine residues Cys114 and Cys115. In NF-κB reporter mice, topical HOCl reduced LPS-induced NF-κB signaling in skin. We further evaluated topical HOCl use in two mouse models of NF-κB–driven epidermal disease. For mice with acute radiation dermatitis, topical HOCl inhibited the expression of NF-κB–dependent genes, decreased disease severity, and prevented skin ulceration. In aged mice, topical HOCl attenuated age-dependent production of p16INK4a and expression of the DNA repair gene Rad50. Additionally, skin of aged HOCl-treated mice acquired enhanced epidermal thickness and proliferation, comparable to skin in juvenile animals. These data suggest that topical HOCl reduces NF-κB–mediated epidermal pathology in radiation dermatitis and skin aging through IKK modulation and motivate the exploration of HOCl use for clinical aims.

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.

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

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