A diabetic wound is a major complication of diabetes, and a major component of the diabetic foot. It occurs in 15% of all patients with diabetes and precedes 84% of all lower leg amputations.1 A US study in 1999 estimated the average outpatient cost of treating one diabetic foot ulcer (DFU) episode as $28,000 over a two-year period.2,3 In Europe, the authors estimated that costs associated with treatment of DFUs might be as high as 10 billion euros per year.4
Major increases in mortality among patients with diabetes, observed over the past 20 years, are thought to be due to the development of macro- and microvascular complications, including failure of the wound healing process.5 Wound healing refers to the portion of tissue that is destroyed in any open or closed injury to the skin. Being a natural phenomenon, wound healing is usually taken care of by the body's innate mechanism of action, which works reliably most of the time. A key feature of wound healing is stepwise repair of lost extracellular matrix (ECM) that forms the largest component of the dermal skin layer.5 Therefore, controlled and accurate rebuilding becomes essential, so as to avoid under- or overhealing that may lead to various abnormalities.5 However, in some patients, certain disorders or physiological insults disturb the wound healing process. Diabetes is one such metabolic disorder that impedes the normal steps of the wound healing process. Many histopathological studies show a prolonged inflammatory phase in diabetic wounds, which causes delays in the formation of mature granulation tissue, and a parallel reduction in wound tensile strength.6
Hard-to-heal diabetic ulcers are often treated with ECM replacement therapy. It is common, in diabetic foot care, to use advanced, moist wound therapy, bioengineered tissue or skin substitutes for growth factor, and negative pressure wound therapy.7 No therapy is completely perfect, as each type has its own disadvantages. Moist wound therapy is known to promote fibroblast and keratinocyte proliferation and migration, collagen synthesis, early angiogenesis and wound contraction.7
There are various categories of moist dressings available, such as an adhesive-backing film silicone-coated form, hydrogels and hydrocolloids. Unfortunately, all moist dressings cause fluid retention; most of them require a secondary dressing, and hence are not the best choice for exuding wounds.8 Furthermore, moist dressings with topical antimicrobial agents containing silver are used to prevent or manage infection in a wide range of wounds.9
Silver has a proven antimicrobial activity against many species of bacteria, fungus, yeast and antibiotic-resistant bacteria, such as meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin–resistant enterococci (VRE).9,10 Its role as an antimicrobial agent is particularly attractive because of its broad spectrum of antimicrobial activity,10,11 with minimal toxicity toward mammalian cells at low concentrations.10,12 It also has a smaller tendency than antibiotics to induce resistance, due to its activity at multiple bacterial target sites.10,13 Many diabetic ulcers present with cavities, tracks or a combination of these. It is important to ensure that the dressing is in contact with the majority of the cavity, and that the dead space is reduced.14
A new silver dressing (BluRibbon, Novatec Healthcare Co., Ltd., Thailand), a biocellulose with blue nanosilver dressing, has the ability to contour around and be packed into cavities as well as areas of undermining or tunnels, while conforming to the irregular surface of a wound bed. It can also absorb minimal-to-moderate quantities of exudate. This product has a composition of silver 0.4mg/100cm2, with blue silver nanoplates that have a higher (than normal silver) surface area per mass, thus allowing a large amount of silver ion interaction with bacteria and fungi. It demonstrates broad antimicrobial activities against Gram-negative and Gram-positive bacteria, with minimal development of bacterial resistance. The shape of the blue silver nanoplate is a truncated, triangular plate, and it has demonstrated greater antibacterial activity than other shapes.15 Therefore, these products may improve healing rates, as well as offering improved comfort to the patient, while reducing dressing times.
Aim
To evaluate the efficacy of biocellulose with blue nanosilver, compared with silver sulfadiazine cream in the treatment of hard-to-heal diabetic ulcers.
Methods
A prospective, randomised control trial was conducted at the Division of Plastic Surgery, Department of Surgery, Prince of Songkla University, Songklanagarind Hospital between July 2012 and July 2014. The study was approved and monitored by the ethical committee of Songklanagarind Hospital (REC: 56-080-10-4-3).
Patients with hard-to-heal diabetic ulcers who were treated as outpatients were included in the study. Hard-to-heal diabetic wounds were classified according to the University of Texas wound classification system.14,16
Inclusion criteria were: age >18, diabetic wound for >1 month, available for study. Exclusion criteria were: connective tissue disease, silver and sulfadiazine allergy, patient receiving steroids, radiation therapy or chemotherapy, serious illness, severe renal and hepatic disease, osteomyelitis, alcohol being used. Patients were enrolled in the study, after obtaining written informed consent.
All patients were randomly assigned, using a computer-generated randomisation list, to one of two equal-sized groups:
- Treatment with biocellulose with blue nanosilver (experimental group)
- Treatment with silver sulfadiazine cream (control group).
The study period was eight weeks for each patient. Demographic data, 10g monofilament test, ankle–brachial index, wound size calculation from picture, and bacterial wound culture were recorded at the beginning of the study. Laboratory investigations, including complete blood count, serum total protein, serum albumin, blood sugar, blood urea nitrogen and creatinine, were performed at study entry. The wound size was assessed using the ImageJ program.17 Wound beds were cleaned by normal saline solution and covered with silver sulfadiazine cream in the control group, and biocellulose with blue nanosilver in the experimental group. Cotton gauze was used as the secondary dressing in both groups. Dressings were changed twice daily in the control group, and every three days in the experimental group. All patients used an offloading shoe after dressings were applied.
Results
A total of 20 patients from the original 22 recruited to the study were randomly assigned to the study groups (10 patients in each group); two patients were excluded. Each of the 20 patients finished the eight-week study. Mean ages were 63.6 years and 62.3 years in the experimental group and the control group, respectively. The patients in each group had no differences with regard to underlying disease, general medical condition/health, size and duration of the ulcer, antibiotics used and smoking history when these parameters were compared by Fisher's exact test, rank sum test and t-test.
The most common hard-to-heal diabetic ulcers, in both groups, were located on the finger (Table 1). The bacterial study from the experimental group and the control group exhibited the same microbial pathologies, and it was found that they had nosocomial pathogens. The most common pathogens in both groups were Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii. Drug-resistant microbial infections were also found, such as meticillin-resistant Staphylococcus aureus (MRSA) and extended spectrum β-lactamases (ESBL) (Table 2). The distribution of ulcer size was equal in both groups (Fig 1). The median ulcer areas at the start of treatment were 3.6cm2 (range: 3–8.3cm2) in the experimental group and 2.1cm2 (range: 1–3.5cm2) in the control group (p=0.14). The median ulcer areas at week eight were 0.0cm2 (range: 0–0.7cm2) and 0.0cm2 (range: 0–0.9cm2) for the same groups, respectively (p=0.926) (Fig 2). The highest mean wound healing rates, found at week seven, were 91.4% in the experimental group, and 83.9% in the control group (p=0.47) (Fig 3). The University of Texas wound classification system was used to classify hard-to-heal diabetic ulcers for both groups. Most of the ulcers in this study were in the: A0, A1 and A2 groups (no infection or ischaemia and epithelialised, superficial or penetrating just to tendon or capsule, respectively) (Fig 4).
Table 1. Baseline characteristics of patients and ulcers*
| Characteristics | Silver sulfadiazine cream group (n=10) | Biocellulose with blue nanosilver group (n=10) |
|---|---|---|
| Age, years | 63.6±9.7 | 62.3±9.9 |
| Sex, male/female | 4/6 | 7/3 |
| BMI, kg/m2 | 26.1±7.2 | 25.3±3.3 |
| Hct, % | 34.5±3.5 | 34.8±5.6 |
| Blood sugar, mg% (range) | 143.5 (120.2–276.8) | 170.0 (149.0–225.2) |
| HbA1C, % | 9.8±2.9 | 9.0±2.8 |
| Total protein, g% | 7.5±0.7 | 7.5±0.5 |
| Albumin, g% | 4.1±0.6 | 4.2±0.3 |
| ABI index | 1.0±0.1 | 1.1±0.1 |
| BUN, mg% | 20.0±7.8 | 15.0±4.5 |
| Creatinine, mg% | 1.3±0.5 | 1.0±0.5 |
| Onset, day | 120 | 120 |
| Antibiotic, n (%) | 5 (50.0) | 4 (66.7) |
| Smoking, n (%) | 0 | 3 (30.0) |
| CVA, n (%) | 3 (30.0) | 2 (20.0) |
| Hypertension, n (%) | 7 (70.0) | 9 (90.0) |
| Dyslipidaemia, n (%) | 6 (60.0) | 3 (30.0) |
| Smoking, n (%) | 0 | 3 (30.0) |
| Other comorbidity, n (%) | ||
| Chronic renal disease | 3 (30.0) | 2 (20.0) |
| Myocardial ischaemia | 0 | 1 (10.0) |
| PAD | 0 | 1 (10.0) |
| Psoriasis | 1 (10.0) | 0 |
| Location, n (%) | ||
| Forefoot | 3 (30.0) | 3 (30.0) |
| Hindfoot | 1 (10.0) | 0 |
| Finger | 5 (50.0) | 7 (70.0) |
| Other | 1 (10.0) | 0 |
BMI—body mass index; BUN—blood urea nitrogen; CVA—cerebrovascular accident/stroke; Hct—haematocrit; PAD—peripheral arterial disease
Table 2. Wound culture of patients at first visit
| Group | Patient number | First visit culture | |
|---|---|---|---|
| Silver sulfadiazine cream group | 16 | Staphylococcus aureus (MRSA) | Numerous |
| 2, 8 | Enterococcus coli | Numerous | |
| 19 | Pseudomonas aeruginosa | Numerous | |
| 8, 20 | Acinetobacter baumannii | Moderate | |
| 13 | Staphylococcus epidermidis | Moderate | |
| 12 | Enterococcus faecalis | Moderate | |
| 9 | Staphylococcus aureus | Numerous | |
| 4 | No growth | ||
| 5 | Enterococcus coli (ESBL) | Numerous | |
| Biocellulose with blue nanosilver group | 3, 17 | Pseudomonas aeruginosa | Moderate |
| 6, 11 | Klebsiella pneumoniae | Numerous, Rare | |
| 10 | Acinetobacter baumannii | Moderate | |
| 1, 7, 15 | Staphylococcus aureus | Numerous | |
| 14 | Trichosporon beigelii | Rare | |
| 18 | Staphylococcus epidermidis | Few | |
MRSA—meticillin-resistant Staphylococcus aureus
The estimated cost of the treatment was $516 USD per patient in the experimental group and $893 USD per patient in the control group (p=0.009). There were no complications or adverse events from the treatment were reported in either group.
Discussion
Hard-to-heal diabetic ulcers are a common problem worldwide. Diabetes is a chronic, diffuse endocrine disease. Diabetic ulcers are frequent complications of diabetes, with the lifetime risk for foot ulceration in people with diabetes being 15–25%.18 In the UK, it has been estimated that 5–7% of people with diabetes have or have had a DFU.19,20 In Europe, the annual amputation rate for people with diabetes has been cited as 0.5–0.8%,21,22 while in the US it has been reported that around 85% of lower extremity amputations, due to diabetes, begin with a foot ulceration.23,24 Recognising the importance of starting treatment early may allow practitioners to prevent progression to severe, limb-threatening infections, therefore potentially halting the pathway to amputation.25 The ‘TIME framework’ is an acronym that was developed in 2002, by a group of wound care experts, as a practical guide for use when managing patients with wounds. It comprises four main components: T tissue; I infection/inflammation; M moisture imbalance; and E edge.26 (This has since been updated to TIMERS, to include R regeneration and S social factors.27
The conventional dressing method for hard-to-heal diabetic ulcers in our hospital is cleansing the wound with normal saline and dressing with silver sulfadiazine cream over the wound surface twice daily. It is time-consuming for the care team or relatives applying the dressings. Many new silver dressings containing different products have come on to the market. Biocellulose with blue nanosilver dressing is a new ionic silver dressing. It is composed of biocellulose with engineered nanosilver technology. In vitro testing has demonstrated rapid and sustained effectiveness against a wide range of microbes and efficacy of nanosilver is not changed when used with normal saline.26 It is soft and has the ability to both contour around and conform to irregular surfaces of a wound bed. This suits those with hard-to-heal diabetic ulcers, which present with cavities, tracks or a combination of both. From the results of this study, biocellulose with blue nanosilver could enhance wound healing in ulcers, more so than silver sulfadiazine cream. There were no significant microbial pathologies in the first week in either group. There was a significant difference between the groups with regard to cost, due to the frequency of applying dressings, travel costs to and from, and stoppages of work due to, medical visits.
Limitations
The main limitation of this study is the small sample size. Another weakness is in wound size calculation: if the photographs were not clear then the ImageJ program could not calculate wound area.
Conclusion
Biocellulose with blue nanosilver could be one of the choices for hard-to-heal diabetic ulcer treatment, because of its good healing rates and minimal care requirements. Our study indicates that biocellulose with blue nanosilver can be used for hard-to-heal diabetic ulcer treatment, with good healing rates and minimal care requirements. It also has better cost-effectiveness compared to silver sulfadiazine cream.
Reflective questions
- What is the most suitable dressing in diabetic wound care?
- How can bacterial load be reduced in diabetic wounds?
- What is the best shape for nanosilver particles in order to reduce bacterial load?