European Journal of Cardiovascular Medicine

Diabetes Mellitus, commonly known as Diabetes, is a cluster of metabolic disorders, which is characterized by the occurrence of hyperglycemia in the absence of any medications. It has a diversified etiological background, that may include defects in insulin secretion, insulin action, or both. (WHO, 2021)

About 422 million people have diabetes, the majority of them living in low-and middle-income countries, and 1.5 million deaths are directly attributed to diabetes each year.(WHO, 2024)

The study by the Indian Council of Medical Research found that about 11.4% of the Indian adult population is suffering from this metabolic disorder, which could be translated as India is home to around 101 million people with diabetes. (1)

The long-term complications of diabetes include nephropathy, retinopathy, and neuropathy. Furthermore, diabetes is a significant risk factor for stroke, heart attacks, kidney failure, blindness, and amputation of a lower limb. (1; WHO, 2023)

Diabetic foot ulceration (DFU) is a devastating complication of diabetes that is associated with infection, amputation, and death and is affecting increasing numbers of patients with diabetes mellitus. (Wang X. et al, 2022) The multiple factors associated with the development of DFU, such as the complex process and complications of diabetes, may all lead to various degrees of neurological and vascular damage. Due to its high incidence and intractability, DFU strikes at a significant financial cost in terms of production loss and increased healthcare expenses. A multimodal approach is necessary for the right and timely treatment of DFU. This includes accurate and fast diagnosis and classification, numerous risk factor assessments, and the appropriate choice of treatments, all of which should be dependent on the patient's real state. (2)

The care for DFU includes pressure relief, debridement or de-sloughing, infection control, and wound dressing. Dressing is mostly used in wound care for both the protection of the wound as well as its healing. (3).

The antibacterial effect of silver ions (Ag+) has been known for centuries as ancient Greeks used silver for stomach pains or wound healing. Also, studies have shown that silver ions were identified as a highly efficient potent of antibiotics of different classes. Currently, silver nanoparticles rank among the most widely commercialized nanomaterials used in medical, bactericidal, and electrical products.(4).Silver ionscan bind to negatively charged bacteria, enhance the permeability of the bacterial outer membrane, and induce bacterial apoptosis.(4)

The study aims to compare the efficacy of silvernano gel versus normal saline dressing in wound healing among patients with diabetic foot ulceration.

Study setting

A hospital-based prospective study was conducted in a tertiary care hospital in Puducherry among the in-patients of both genders admitted for Diabetic foot ulceration under the Department of General Surgery. The study was conducted over a period of six months (July 2023-December 2023) among 60 patients.

Study population

Eligible participants for the study include diabetic patients under regular treatment, between the age group of 18 -75 years with diabetic foot ulcer (Grade-2, according to Wagner Classification)¹⁰. Patients with a history of Coronary artery disease, Cerebrovascular accidents, and peripheral artery disease were excluded from the study.  Patients who fulfilled the selection criteria were explained about the study and informed consent was obtained from willing patients.

Group Allotment and Procedure

Patients were randomly allocated into two equal groups. Dressing in group-1 was done with silver nanogel along with the conventional method, whereas in group-2, only conventional dressing was done. Under aseptic conditions, dressings were done on alternate days.

Debridement was done when needed and appropriate wound care was given in both groups.

Outcome

Wound condition was evaluated on admission, 4^th and 8^th week of admission for size, presence of slough, and development of granulation tissue in both the groups.

Statistical analysis

The data was entered in Microsoft Excel and analyzed using Jamovi v 2.3.28 software. The data was presented as frequencies and proportions for categorical variables and mean (SD) for continuous variables. Mann-Whitney U Test and Chi-square test were employed to determine the efficacy of treatment modalities among the two groups. The probability value (p-value)of less than 0.05 was determined to be statistically significant.

Among the study population, 53% (n=32) and 47% (n=28) were male and female respectively. The overall mean age of the study population was found to be 49.5 (12.3) years and the distribution among the two groups was 50 (12.3) years and 48.3 (12.5) years respectively. Table 1 depicts the age group distribution among the silver nanogel and normal saline groups. The maximum proportion of patients were in the age group of 36-50 years.

Table 1: Age group distribution among the study population

More than half of the patients in the study (n=32, 53%) were under oral hypoglycaemic agents for diabetic management, else were using insulin. The mean (SD) HbA1C of the study population was found to be 7.98 (1.09). Table 2 depicts the distribution of HbA1C levels among the study population. The mean (SD) of HbA1C among Group A and Group B were 7.98 (0.99) and 7.99 (1.20) respectively. There is no significant difference between HbA1C levels among the two groups (p-value =0.972).

Table 2: HbA1C levels among the study population

Table 3 shows the prevalence of wound stage among the silver nanogel and normal saline group. There is no significant difference between the two groups whenaboutthe distribution of wound stage (p-value = 0.301).

Table 3 Prevalence of wound stage among the silver nano gel and normal saline

From Table 4,it is evident that there is no significant difference in wound size between the two groups on admission, but wound size was reduced in group A inthe 4^th and 8^th week of admission which is statistically significant with a p-value of 0.001. Figure 1 depicts the rate of reduction in wound size between the two groups across the course of treatment.

Table 4 Wound size among the study population

Figure 1 Wound size between the two groups across the course of treatment

Through Table 5, it is evident that there is a significant difference in the formation of granulation tissue between the two groups at 4^th and 8^th week of admission.There is no significant difference in the presence of granulation tissue at the time of admission, but healthy granulation tissue was noted in seventy percent of the patients in group A, whereas only fifty-five percent in group B.

Table 5 Growth of granulation tissue among the two groups

Through Table 6 it is observed that the occurrence of the slough was reduced in group A at the 4^th and 8^th week of admission, with p-values of 0.010 and 0.012 respectively, which were statistically significant.

Table 6Occurrence of slough among the two groups

From the study, it has been evident that dressing with silver nano gel had led to a significant reduction in wound size in comparison with the conventional method of dressing, which can be supported by the similar findings of (5), where it has been found that usage of nanosilver gel in the management of diabetic foot ulceration resulted in more percentage reduction in wound size and early would healing with better efficacy when compared to traditional betadine dressing.

Nanoparticles could be used as an ideal vehicle in would management, due to their properties such as antimicrobial activity, electrical conductivity, higher surface-to-volume ratio, swelling, and contraction flexibility. They hasten the process of wound healing through their antimicrobial, antioxidant, anti-inflammatory, enhanced cell-proliferation, and improved remodeling of skin. (6)

Also, the proliferation of granulation tissue was more among the patients managed with the application of silver nano gel when compared to normal saline dressing, which is similar to the findings reported by (7),where they demonstrated the rapid healing rate with the use of nanocrystalline for dressing along with the development of bright red and healthy granulation tissue, which was statistically significant.

Due to their high surface area, silver nanoparticles are capable of dispensing Ag+ ions more quickly than bulk silver. A prior study found that using a more recent, generally less harmful antiseptic has advantages compared to topical antibiotics, particularly when the drugs are available for systemic use. (8).

The antibacterial activity was shown by silver nano gelthrough the release of silver ions from the silver nanoparticles that would bind with the thiol groups of protein and enzymes present on the surface of cells, leading to the destabilization of the cellular membrane and breaking the ATP synthesis pathway. Also, it adheres to the membrane wall, leading to the formation of pores, through which they penetrate the bacteria and interact with intracellular components. Further, other mechanisms suggest that reactive oxygen species (ROS), such as singlet oxygen, are produced at the cell membrane, leading to irreversible damage to DNA replication affecting metabolic processes and cell division.(9-11).

In addition to this, there has been a significant reduction in slough production from the ulcer in patients managed with silver nanogel, which reemphasizes the antimicrobial properties of the silver nanogel. When it comes to treating diabetic foot, nano-silver offers many advantages over other antibacterial dressings, such as a broad-spectrum effect, a wide and safe application, and a long post-treatment action period.(12)

The study's conclusions make it unambiguous that employing nano-silver gel for the management of diabetic foot ulcers was much more effective than using conventional dressing techniques. Patients treated with the nano-silver gel had substantially greater overall efficacy and a much faster pace of healing. Hence silver nano-gel can be a novel approach for the management of patients with diabetic foot ulceration.  Future research with a larger sample size and extended duration would be recommended to refute the present findings and provide a more definitive picture.

1. Anjana, R. M., Unnikrishnan, R., Deepa, M., Pradeepa, R., Tandon, N., Das, A. K., ... & Ghosh, S. (2023). Metabolic non-communicable disease health report of India: the ICMR-INDIAB national cross-sectional study (ICMR-INDIAB-17). The Lancet Diabetes & Endocrinology, 11(7), 474-489.
2. Aravindakshan, V. N., Arun, V. A., Roshni, T. S., & Anjali, V. A. (2020). A comparative study on the wound healing effectiveness of with normal saline and ionized nano-crystalline silver dressing among chronic diabetic foot ulcer patients. International Surgery Journal, 7(12), 3935-3938.
3. Barras, F., Aussel, L., & Ezraty, B. (2018). Silver and antibiotic, new facts to an old story. Antibiotics, 7(3), 79.
4. Choudhury, H., Pandey, M., Lim, Y. Q., Low, C. Y., Lee, C. T., Marilyn, T. C. L., ... & Gorain, B. (2020). Silver nanoparticles: Advanced and promising technology in diabetic wound therapy. Materials Science and Engineering: C, 112, 110925.
5. Huang, C., Wang, R., & Yan, Z. (2021). Silver dressing in the treatment of diabetic foot: A protocol for systematic review and meta-analysis. Medicine, 100(7), e24876.
6. Ivask, A., ElBadawy, A., Kaweeteerawat, C., Boren, D., Fischer, H., Ji, Z., ... & Godwin, H. A. (2014). Toxicity mechanisms in Escherichia coli vary for silver nanoparticles and differ from ionic silver. ACS nano, 8(1), 374-386.
7. Lin, H., BoLatai, A., & Wu, N. (2021). Application progress of nano silver dressing in the treatment of diabetic foot. Diabetes, Metabolic Syndrome and Obesity, 4145-4154.
8. Lipsky, B. A., & Hoey, C. (2009). Topical antimicrobial therapy for treating chronic wounds. Clinical infectious diseases, 49(10), 1541-1549.
9. Palza, H. (2015). Antimicrobial polymers with metal nanoparticles. International journal of molecular sciences, 16(1), 2099-2116.
10. Pickwell, K. M., Siersma, V. D., Kars, M., Holstein, P. E., Schaper, N. C., & Eurodiale Consortium. (2013). Diabetic foot disease: impact of ulcer location on ulcer healing. Diabetes/Metabolism Research and Reviews, 29(5), 377-383.
11. Singh, B., Kapoor, S., & Gupta, A. K. (2020). Comparing the efficacy of nano crystalline silver dressing versus betadine dressing in management of diabetic foot ulcer. International Surgery Journal, 7(5), 1424-1430.
12. Vimbela, G. V., Ngo, S. M., Fraze, C., Yang, L., & Stout, D. A. (2017). Antibacterial properties and toxicity from metallic nanomaterials. International journal of nanomedicine, 3941-3965.
13. Wagner Jr, F. W. (1981). The dysvascular foot: a system for diagnosis and treatment. Foot & ankle, 2(2), 64-122.
14. Wang, X., Yuan, C. X., Xu, B., & Yu, Z. (2022). Diabetic foot ulcers: Classification, risk factors and management. World journal of diabetes, 13(12), 1049.
15. World Health Organization. (n.d.). Diabetes. World Health Organization. Retrieved March 23, 2024, from https://www.who.int/news-room/fact-sheets/detail/diabetes
16. World Health Organization. (2020). HEARTS D: Diagnosis and management of type 2 diabetes (WHO/UCN/NCD/20.1). World Health Organization. https://iris.who.int/bitstream/handle/10665/331710/WHO-UCN-NCD-20.1-eng.pdf?sequence=1
17. World Health Organization. (n.d.). Diabetes. World Health Organization. Retrieved September 19, 2024, from https://www.who.int/health-topics/diabetes
18. Wu, L., Norman, G., Dumville, J. C., O'Meara, S., & Bell‐Syer, S. E. (2015). Dressings for treating foot ulcers in people with diabetes: an overview of systematic reviews. Cochrane Database of Systematic Reviews, (7).
19. Zhang, W., Li, Y., Niu, J., & Chen, Y. (2013). Photogeneration of reactive oxygen species on uncoated silver, gold, nickel, and silicon nanoparticles and their antibacterial effects. Langmuir, 29(15), 4647-4651.