Rebecca Franklin

Background: Diabetes mellitus (DM) is one of the most prevalent endocrine diseases worldwide.¹ It is estimated that 25% of patients will develop a non-healing wound with a recurrence rate of 40% (<1 year) and 65% (<5 years).² The most common non-healing wound is a diabetic foot ulcer (DFU) which can lead to infection, amputation, and potentially even death.¹ DFUs can be colonized by bacteria that produce biofilms, conferring simultaneous protection from the host immune system and antibiotics.¹ While 70% of all lower limb amputations are due to DFUs, this has a greater negative impact on quality of life than any other complication of diabetes.¹  Traditional antibiotic therapies are not effective against biofilm-associated infections, necessitating the development of innovative non-antibiotic solutions that can break biofilm and enhance wound healing. While electrical stimulation, bacteriophage therapy, and the utilization of scavenging nanoparticles have each demonstrated efficacy independently in targeting and treating DFUs— they collectively offer a complementary approach that can address intrinsic shortcomings of individual treatments, enhancing overall therapeutic outcomes.^3–5

Methods: The literature review synthesized information from scholarly databases, including PubMed/MEDLINE, Nature, and Front Med. A systematic search strategy was employed to identify literature published within the last 5 years (2019-2024) utilizing the following search terms, in various combinations:

• “diabetic foot ulcers”
• “diabetes foot complications”
• “diabetic foot management”
• “wound healing in diabetes”
• “biofilm for diabetic foot ulcers”

Results: The proposed solution involves a multifaceted approach: firstly, employing low-voltage, pulsed, electrical stimulation to disrupt the biofilm structure, followed by the application of SeC@PA nanoparticles that will scavenge glutathione peroxidase, thereby inhibiting the biofilm’s ability to protect itself from damage.^3,4 Lastly, bacteriophages would be utilized to specifically target and eliminate pathogenic bacteria and those possessing the highest number of biofilm-producing genes, facilitating the restoration of bacterial populations to their normal levels.⁵ Mice studies have demonstrated the independent efficacy of each component highlighting the potential of this synergistic approach for personalized therapy.^3–5

Conclusions: DFU research emphasizes the need for novel therapeutics to combat biofilm infections in DFUs. The findings suggest that a multifaceted strategy integrating electrical stimulation, scavenging nanoparticles, and bacteriophage therapy holds promise in disrupting biofilms and promoting wound healing. Implementation of this approach in clinical practice could lead to faster healing times and reduced complications for patients. Further research is essential to optimize parameters, refine interventions, and assess long-term efficacy.

Works Cited:

1. Afonso AC, Oliveira D, Saavedra MJ, Borges A, Simões M. Biofilms in Diabetic Foot Ulcers: Impact, Risk Factors and Control Strategies. Int J Mol Sci. 2021;22(15):8278. doi:10.3390/ijms22158278
2. Burgess JL, Wyant WA, Abdo Abujamra B, Kirsner RS, Jozic I. Diabetic Wound-Healing Science. Medicina (Mex). 2021;57(10):1072. doi:10.3390/medicina57101072
3. Ashrafi M, Novak‐Frazer L, Morris J, Baguneid M, Rautemaa‐Richardson R, Bayat A. Electrical stimulation disrupts biofilms in a human wound model and reveals the potential for monitoring treatment response with volatile biomarkers: Wound Repair & Regeneration. Wound Repair Regen. 2019;27(1):5-18. doi:10.1111/wrr.12679
4. Yang L, Zhang D, Li W, et al. Biofilm microenvironment triggered self-enhancing photodynamic immunomodulatory microneedle for diabetic wound therapy. Nat Commun. 2023;14(1):7658. doi:10.1038/s41467-023-43067-8
5. Albac S, Medina M, Labrousse D, et al. Efficacy of Bacteriophages in a Staphylococcus aureus Nondiabetic or Diabetic Foot Infection Murine Model. Antimicrob Agents Chemother. 2020;64(2):10.1128/aac.01870-19. doi:10.1128/aac.01870-19