Big losses can start
from small misses
Diabetes is the disease that contributes to the greatest number of diagnosed chronic wounds.1
The global prevalence of diabetes increases every year. This increase is so fast that diabetes is now considered by the World Health Organization (WHO) as a global fast-growing epidemic.2
People with diabetes 2,3
537 million people worldwide have diabetes
The repercussions of diabetes extend beyond metabolic disturbances. The imbalance of local and systemic factors delays, or even interrupts, the highly complex and dynamic process of wound healing, with increased susceptibility to bacterial infections.3,4
People with diabetes are especially prone to develop a certain type of chronic wound known as a diabetic foot ulcer (DFU),1 with infection being the most common, severe, and costly complication, with high risk of mortality and morbidity due to lower limb amputation.5
Of the estimated 537 million people worldwide who have diabetes, 19% to 34% will develop a DFU in their lifetime. Approximately 20% of people who develop a DFU will require lower-extremity amputation, either minor (below the ankle), major (above the ankle), or both, and 10% will die within 1 year of their first DFU diagnosis.6
Pathways to ulceration and lower-extremity amputation in DFU
Adapted from McDermott K, Fang M, Boulton AJM, Selvin E, Hicks CW. Etiology, Epidemiology, and Disparities in the Burden of Diabetic Foot Ulcers.
Diabetes Care. 2023;46(1):209-221. doi:10.2337/dci22-0043
Why do DFUs fail to heal?
The imbalance of local and systemic factors delays, or even interrupts, the highly complex and dynamic process of wound healing, with increased susceptibility to bacterial infections.3,4
Combined bacterial infections and biofilm formation further complicate the wound microenvironment:
- Infection is a well-established critical factor for non-healing and persistent DFUs.1,5,7
- Biofilms are one of the main reasons why DFUs are so difficult to heal, promoting wound inflammation and a remarkable lack of response to host defences and treatment options, which can lead to disease progression and chronicity.2
Adapted from Da Silva J, Leal EC, Carvalho E, Silva EA. Innovative Functional Biomaterials as Therapeutic Wound Dressings for Chronic Diabetic Foot Ulcers. Int J Mol Sci. 2023;24(12):9900. Published 2023 Jun 8. doi:10.3390/ijms24129900
What is the burden of DFUs?
Associated with poor clinical outcomes, and a long-term impact on morbidity, mortality, and quality of life (QoL),8 DFUs are a major public health problem, resulting in considerable clinical and economic burden for society.7
- The risk of death at 5 years for a patient with a DFU is 2.5 times as high as the risk for a patient with diabetes who has no foot ulcer.9,10
- Every 20 seconds a diabetic patient undergoes an amputation.7 A literature review2 reports that lower limb amputation has a greater negative impact on the patient’s quality of life than any other complication of diabetes, such as renal failure or blindness, with depression and anxiety highly associated and a significant impact on patient’s lives.
- 40% of patients have a recurrence within 1 year after their ulcer healing, almost 60% within 3 years, and 65% within 5 years.11 16.8 million Years Living with a Disability (YLDs) (2.07% of global YLDs) resulted from diabetic foot complications in 2016, including 2.5 million from DFUs, 1.1 million from amputation with no prosthesis, and 0.4 million from amputation with prosthesis.7,12
DFU management should aim to promote rapid and complete wound closure, to minimise the risk of ulcer complications and to restore a patient’s quality of life.13,14
1Malone-Povolny MJ, Maloney SE, Schoenfisch MH. Nitric Oxide Therapy for Diabetic Wound Healing. Adv Healthc Mater. 2019;8(12):e1801210. doi:10.1002/adhm.201801210.
2Afonso, A.C., Oliveira, D., Saavedra, M.J., Borges, A., Simões, M. Biofilms in Diabetic Foot Ulcers: Impact, Risk Factors and Control Strategies. Int J Mol Sci. 2021, 22, 8278. https://doi.org/10.3390/ ijms22158278.
3Darwitz BP, Genito CJ, Thurlow LR. Triple threat: how diabetes results in worsened bacterial infections. Infect Immun. Published online March 25, 2024. doi:10.1128/iai.00509-23.
4Da Silva J, Leal EC, Carvalho E, Silva EA. Innovative Functional Biomaterials as Therapeutic Wound Dressings for Chronic Diabetic Foot Ulcers. Int J Mol Sci. 2023;24(12):9900. Published 2023 Jun 8. doi:10.3390/ijms24129900.
5Pouget C, Dunyach-Remy C, Pantel A, et al. Alternative Approaches for the Management of Diabetic Foot Ulcers. Front Microbiol. 2021;12:747618. Published 2021 Oct 5. doi:10.3389/fmicb.2021.747618.
6McDermott K, Fang M, Boulton AJM, Selvin E, Hicks CW. Etiology, Epidemiology, and Disparities in the Burden of Diabetic Foot Ulcers. Diabetes Care. 2023;46(1):209-221. doi:10.2337/dci22-0043.
7Edmonds ME, Manu C, Prashanth Vas. The current burden of diabetic foot disease. Journal of Clinical Orthopaedics and Trauma. 17;(2021):88-93.
8Edmonds ME, Bodansky HJ, Boulton AJM, Chadwick PJ, Dang CN, D‘Costa R, Johnston A, Kennon B, Leese G, Rajbhandari SM, Serena TE, Young MJ, Stewart JE, Tucker AT, Carter MJ. Multicenter, randomized controlled, observer-blinded study of a nitric oxide generating treatment in foot ulcers of patients with diabetes-ProNOx1 study. Wound Repair Regen. 2018 Mar;26(2):228-237. doi: 10.1111/wrr.12630. Epub 2018 Jul 17. PMID: 29617058.
9Walsh JW, Hoffstad OJ, Sullivan MO, et al. Association of diabetic foot ulcer and death in a population-based cohort from the United Kingdom. Diabet Med. 2016;33(11):1493-1498. doi:10.1111/ dme.13054.
10Lu Q, Wang J, Wie X, Wang G, Xu Y. Risk factors for major amputation in Diabetic Foot Ulcer patients. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14.
11Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376:2367e2375.
12Zhang Y, Lazzarini PA, McPhail SM, van Netten JJ, Armstrong DG, Pacella RE. Global disability burdens of diabetes-related lower-extremity complications in 1990 and 2016. Diabetes Care. 2020 May;43(5):964e974. https://doi.org/ 10.2337/dc19-1614. Epub 2020 Mar 5. PMID: 32139380.
13Frykberg RG. Diabetic foot ulcers: pathogenesis and management. Am Fam Physician 2002;66:1655-1662.
14Guest JF, Fuller GW, Vowden P. Diabetic Foot Ulcer management in clinical practice in the UK: costs and outcomes. Int Wound J. 2018;15:43-52.
The invisible barrier to healing
One of the main reasons why wounds are so difficult to heal is related to the presence of biofilms, which affect all phases of wound healing and are considered to be independent factors in delaying normal wound healing.
What if you could say NO to biofilm?
Tackling biofilms as part of infection management is challenging. Nitric Oxide (NO)'s specific properties make it a promising antimicrobial agent, to help support wound healing.