|Year : 2018 | Volume
| Issue : 1 | Page : 29-37
Nanocrystalline silver gel versus conventional silver sulfadiazine cream as topical dressing for second-degree burn wound: A clinicopathological comparison
Gouranga Dutta1, Nandini Das2, Abhishek Adhya3, Kinkar Munian4, Bijay Kumar Majumdar3
1 Department of Plastic Surgery, R G Kar Medical College, Kolkata, West Bengal, India
2 Department of Pathology, Medical College, Kolkata, West Bengal, India
3 Department of Plastic Surgery, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
4 Department of Plastic Surgery, Calcutta National Medical College, Kolkata, West Bengal, India
|Date of Web Publication||11-Mar-2019|
Dr. Gouranga Dutta
113 Ashutosh Road, Ward No. 1, P.O. Mathabhanga, Coochbehar - 736 146, West Bengal
Source of Support: None, Conflict of Interest: None
Background: The use of topical chemotherapy is fundamental to prevent infections thereby reducing local inflammation, pain and early healing in superficial, and deep dermal burns. Among the whole gamut, choice of topical agents became an important decisive factor. Silver sulfadiazine (SSD) cream has been an important part of burns management for many years. The major complications attributed to silver compounds are due to the complex or anion sulfadiazine, not the silver itself. With better understanding of the physical and chemical properties, nanocrystalline silver particles have emerged as the most studied material for burn wound dressing recently. Having in mind the difficulties experienced, the aim of the present study is to compare SSD with nanosilver (nano-Ag) gel dressing to treat second-degree burn wounds.
Materials and Methods: Over a period of 24 months, a total of 90 cases were studied. 45 patients randomly included in each group, further divided into two subgroups depending on depth (superficial and deep) and involvement of total body surface area (10%–20% and >20%–30%) to minimize bias. Clinical, microbiological, and histological parameters were analyzed.
Results: In NS group, significantly less pain observed throughout the study period in both superficial and deep dermal burn patient. Pseudomonas was the predominant flora. Nano-Ag gel was effective in controlling most of the microorganisms except Klebsiella and Proteus sp. Healthy granulation tissue appeared faster (P = 0.0009) in deep dermal burns in nano-Ag group and confirmed histologically. Overall wound healing was more satisfactory in nano-Ag group for both superficial and deep dermal wounds, clinically as well as by histological examination.
Conclusions: Clinical and histological studies showed that nano-Ag gel has a positive impact on overall healing process of the patients and proved more beneficial for the management of partial thickness burn as compared to SSD.
Keywords: Burn wound dressing, histological study, nanosilver gel, silver sulfadiazine cream
|How to cite this article:|
Dutta G, Das N, Adhya A, Munian K, Majumdar BK. Nanocrystalline silver gel versus conventional silver sulfadiazine cream as topical dressing for second-degree burn wound: A clinicopathological comparison. Indian J Burns 2018;26:29-37
|How to cite this URL:|
Dutta G, Das N, Adhya A, Munian K, Majumdar BK. Nanocrystalline silver gel versus conventional silver sulfadiazine cream as topical dressing for second-degree burn wound: A clinicopathological comparison. Indian J Burns [serial online] 2018 [cited 2019 May 25];26:29-37. Available from: http://www.ijburns.com/text.asp?2018/26/1/29/253861
| Introduction|| |
Burns is a global public health problem, accounting for an estimated 180,000 deaths annually. The majority of these occur in low- and middle-income countries and almost two-thirds occur in the WHO African and Southeast Asia Region. Over 10 lakh people are moderately or severely burnt every year in India. Second degree or partial thickness burn patients are targeted as nonfatal burns are the leading cause of morbidity and prolonged hospitalization. Burns are among the leading causes of disability-adjusted life years (DALYs) lost in low-income and middle-income countries. Apart from the cost of treatment indirect costs, such as lost wages, prolonged care for scars and deformities, emotional trauma, and commitment of family resources, also contribute to the socioeconomic impact.
The final aim of burn management and therapy is to minimize pain and thereby reducing the chance of anxiety and depression, to prevent infection, to promote early epithelialization as well as healing of wound and betterment of functional and esthetic after effects. The use of topical agent has been fundamental in that regard and has helped to improve the survival of patients with major burns and to minimize the incidence of burn wound sepsis, a leading cause of mortality and morbidity in these patients. One of the strategies that have gained attention is the use of noble metal antimicrobials, the most prevalent of which is silver. The delivery systems available, often in the form of a salt, have been the limiting factor to the successful biological use of this noble metal.
Over the past 40 years, silver sulfadiazine (SSD) has become a very popular antimicrobial silver delivery system. All kinds of combinations of sulfa drugs with silver were tested in vitro, but SSD appeared to be the most effective  and therefore used as a conventional dressing agent in burn wounds. However, development of bacterial resistance and impaired reepithelialization has been described. Bone marrow toxicity observed with SSDs primarily due to the propylene glycol component. Other side effects include argyria, hepatic, and renal toxicity.,,, These adverse effects demand a new therapy options for better burn wound management.
Advances in the field of nanotechnology helped us to provide a new form of silver delivery system and have markedly improved the biologic value of silver. Nanosilver particles have no local or systemic toxicity and do not impair healing. Smaller the particle size of silver, greater contact with wound surface area, thus increasing bioactivity and silver solubility. These advances in crystal chemistry will likely have a dramatic impact on the microbiology, as well as the biology of wound healing and control of inflammation.
The aim of this study is to compare the overall effect (clinical, microbiological, and histological) of topical application of 1% SSD and nanocrystalline silver gel dressing in second-degree burn patients.
| Materials and Methods|| |
The study was carried out in a tertiary care burn unit, in Kolkata, from January 2013 to December 2014. The study was approved by the Institutional Ethical Committee. A total of 90 patients aged between 10 and 60 years were selected for the study. 45 patients assigned for each nanocrystalline-silver (nano-Ag) and 1% SSD group randomly.
Inclusion criteria – Patients with second-degree thermal burn injury involving 10%–30% of the total body surface area (TBSA) involvement attending within 24 h and those patients who gave an informed consent. Exclusion criteria – Patients who refused to participate in the study or not fulfilling the inclusion criteria, pregnants, or those suffering from other medical illnesses.
In outpatient department or after hospitalization, patients are subjected to clinical assessments regarding degree ,, and extent of burn. Written informed consent obtained and clinical photographs taken from those who meet the inclusion criteria. Initial burn management was started according to the principles of ABCDEF – It denotes A-Airway control, B-Breathing, C-Circulation, D-Neurological Disability, E-Environment control, F-Fluid Resuscitation.
As the wound healing time, depends on TBSA burnt and depth of tissue injury, we distributed the patients in two groups on TBSA burnt (10%-20% and >20%-30%). We further divided them into subgroups on depth of involvement (second-degree superficial and deep dermal burn).
After exposing the burn wound, the involved and its adjacent area washed properly with normal saline to remove all dirt, soot, debris, following which all blisters were deroofed, dead epithelium was removed as far as possible. Now, a dilute povidone-iodine solution was applied and finally, washed again with sterile normal saline solution. Having selected randomly SSD cream and nano-Ag gel applied over the control group and test group, respectively. We assumed all acute burn wound are sterile. Systemic broad-spectrum antibiotics given to all on day 0 and changed according to pus culture report which was sent on 3rd postadmission day; bacterial culture and sensitivity determinations were made from the swabs taken from the surface of the wounds; hemoglobin, nutrition, hydration, and dyselectrolytemia was corrected, and hence, optimization of internal environment and external environment kept equal for all patients.
Nano-Ag gel applied in the test group and covered by sterile gauze (inner layer), and gamjee (outer layer) and dressings were changed every alternate day until the wound is healed. SSD cream was applied in the control group and then covered with sterile dressing, and the frequency of dressing change was kept the same for the two groups until the wound was healed. The involved and surrounding area of wound was photographed at regular interval.
A histological study was done only in deep dermal burn cases, as these wounds granulates and heals with scarring. Only, clinically deep dermal burn patients were biopsied on day 3 of burn injury, for the proper assessment of depth of injury. Initially, by clinical estimation of depth, biopsy was done in 59 patients, of those only 48 cases who fulfilled the criteria of deep dermal burn were included (SSD and nano-Ag applied in 25 and 23 patients, respectively) for further histological study. Tissues were also taken on day 15, from granulation tissue and after 12 weeks, from the healed wound in both the groups. All tissues were taken under local anesthesia. Biopsies were taken from at least three representative areas of the wound surface to include 3 mm depth of the wound and a 3 mm area of normal skin. All of them were fixed in buffered formalin, sectioned, and stained with hematoxylin and eosin. The sections were viewed and photographed at ×40, ×100, and ×400 magnifications.
Following parameters are evaluated to assess the efficacy of nano-Ag gel dressing over SSD cream dressing:
- Pain perception assessed using visual analog scale  on day 7, 14, and 21
- Assessment of microbial flora
- Antimicrobial efficacy of the agents to prevent colonization
- Degree of wound discharge (Amount of exudates)
- Appearance of healthy granulation for deep dermal burn
- 50% reepithelialization and probability of complete reepithelialization by 2 and 4 weeks depending on the depth of burn
- Actual duration of wound healing
- Histological assessment.
The study was a prospective study. Sample randomization was done by computer software. SSD 1% cream used was supplied by hospital store. Nano-Ag gel was prepared aseptically and packed in sterile container [Figure 1] in the departmental laboratory.
|Figure 1: Nano-Ag gel with container as prepared in the departmental laboratory|
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All the data gathered summarized and statistical analysis has been done by GraphPad Prism version 5 (Developer: GraphPad Software, Inc., California, USA). The analysis was two-tailed and P < 0.05 was considered statistically significant.
| Results|| |
A total of 90 patients were recruited for the study purpose. Demographic and average age distribution of the patients for the study is depicted in [Table 1] and [Table 2], respectively. There was no statistically significant difference between both the groups in respect of age, gender, and extent of TBSA involvement.
The intensity of pain is observed more in the cases of deep dermal burns and in initial week. Results were compared using two-way ANOVA test which showed the intensity of pain felt is significantly lesser in nano-Ag group than in patients of SSD dressing group throughout 1st, 2nd and 3rd week in both superficial [Figure 2]a and deep dermal burn patients [Figure 2]b.
|Figure 2: (a) Bar diagram showing comparison of average pain score and P < 0.05 in superficial dermal burn on 7th, 14th, and 21st days (two-way ANOVA test). (b) Bar diagram showing comparison of average pain score and P < 0.05 in deep dermal burn on 7th, 14th, and 21st days (two-way ANOVA test)|
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In superficial dermal burn patients, majority of the patients had small amount of exudates, whereas none of them had heavy exudates. However, in deep dermal group, 13 patients (52%) in the SSD group had heavy exudates whereas similar percentage in the nano-Ag group had small exudates [Table 3].
|Table 3: Amount of exudates is compared in this table in both dressing groups|
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Out of 90 patients, 48 were culture positive and mostly in deep dermal burns. Nano-Ag group showed less number of culture-positive cases, and it is statistically significant (P = 0.0369) as shown in [Table 4]. Among 48 positive cases, 84 colonies were present. More than 50% of cases are positive for Pseudomonas. [Figure 3] shows all types of microorganisms are more effectively killed in nano-Ag group compared to the SSD group except for Klebsiella and Proteus.
|Figure 3: Using a bar diagram, distribution of the microorganisms and effectiveness of both the dressing compared for each organism|
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Usually, superficial dermal burn does not need the formation of granulation for healing unless complicated by patients immunity profile. The appearance of healthy granulation tissue in respect of days was only studied in deep dermal burns and showed significant less time (P = 0.0009) in nano-Ag group (21.69 ± 7.16) compared to SSD (29.80 ± 9.04) [Figure 4].
|Figure 4: Scatter diagram showing distribution of the patients according to number of days to appear healthy granulation tissue in both arms. Mean and standard deviation shown with horizontal bars (blue: nanosilver, rver sulfadiazine)|
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In deep dermal burn, statistically significant number of patients in nano-Ag group achieved 50% epithelialization by 4 weeks (P = 0.020), on the other hand, majority of the patients could not achieve complete epithelialization by 4 weeks in both study arms and are not statistically significant (P = 0.06) [Table 5]. When Log-ranked, Kaplan–Meier plots depict [Figure 5] statistically significant result in the time trend (in the two study arms) toward the probability of 50% epithelialization (P = 0.0018) and probability of complete epithelialization (P = 0.0380).
|Table 5: Comparison of the proportion of deep dermal burn cases showing 50% and complete epithelization by 4 weeks|
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|Figure 5: Kaplan–Meier plots depicting the time trend toward achieving 50% and complete healing for deep dermal burns|
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Similarly, in superficial dermal burn patients, 50% epithelization (P = 0.055) and complete epithelization (P = 0.190) in 2 weeks assessed and it is found that majority of these patients could not achieve complete epithelization by 2 weeks in both the study groups [Table 6]. When log-ranked, Kaplan–Meier plots depict statistically significant result in the time trend (in the two study arms) toward the probability of 50% epithelialization (P = 0.0221); however, the probability of complete epithelialization (P = 0.101) was not significant statistically.
|Table 6: Comparison of the proportion of superficial dermal burn cases showing 50% and complete epithelization by 2 weeks|
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As depicted in [Table 7], complete wound healing time was less in nano-Ag group be it deep dermal or superficial dermal. However, statistically significant results obtained only in deep dermal burns in both 10%–20% TBSA (P = 0.024) group and >20%–30% TBSA (P = 0.029) group. Photographs of a patient with deep dermal burn treated with nano-Ag gel dressing in various stages of wound healing as shown in [Figure 6]a, [Figure 6]b, [Figure 6]c.
|Figure 6: (a) Deep dermal burn involving ankle and dorsum of the foot on the 2nd day after allocation for nanosilver gel dressing, (b) On day 16th showing healthy granulation tissue with areas of epithelialization in the periphery. (c) Complete epithelialization as photographed on day 29th with complete wound healing in peripheral areas of the involved foot|
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On day 3, the biopsied tissue from both the groups showed acute inflammatory exudate intermixed with necrotic debris and red blood cells up to the papillary dermis or both papillary and reticular dermis (depth assessment). On day 15, majority of the samples in the nano-Ag group showed the presence of well-formed granulation tissue without stromal edema, and acute inflammatory cell infiltrate whereas the SSD group showed the presence of both [Figure 7] and [Figure 8]. At the margin of the wound, partial epithelialization was observed in few specimens of nano-Ag group. The nano-Ag group in 12 weeks showed complete epithelialization with normal maturation, normal vascularization in the papillary dermis, and preservation of dermal appendages in varying amount with minimal inflammatory cell infiltration. The SSD group also showed complete healing at 12 weeks with predominantly hyperplastic overlying epidermis, underlying fibrovascular dermal stroma with deposition of thin fibrillary collagen in the papillary and reticular dermis [Figure 9] and [Figure 10]. These histological findings corroborate well with clinical assessment.
|Figure 7: Fifteenth day after silver sulfadiazine treatment showing granulation tissue composed of proliferated capillary blood vessels, fibroblasts and mixed inflammatory cell infiltrates comprising of lymphocytes, plasma cells, eosinophils, and neutrophils. The stroma is edematous (H and E, ×400)|
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|Figure 8: Fifteenth day of nanosilver gel dressing shows granulation tissue composed of proliferated capillaries, fibroblasts, and chronic inflammatory cells (H and E, ×400)|
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|Figure 9: After treatment with silver sulfadiazine, at the end of 12 weeks showing hyperplastic squamous epithelium, scarring of the papillary dermis with deposition of fibrillary collagen of regular thickness (H and E, ×100)|
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|Figure 10: After treatment with nanosilver gel dressing, at the end of 12 weeks showing complete wound healing with normal epithelialization and keratinization of overlying stratified squamous epithelium and underlying fibrocollagenous stroma with few dermal appendages. Inflammation is minimum (H and E, ×40)|
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| Discussion|| |
Silver as a topical antimicrobial agent has been used for many centuries. A wide range of wound dressings that contain elemental silver or a silver-releasing compound has been developed for primary burn management. Dr. Charles Fox introduced SSD cream in 1970, and since then has been an important part of burns management. Among all kinds of sulfa drugs combinations with silver, silver sulfadiazine emerged as  the “gold standard” topical agent for burn wounds. This silver complex acts on the bacterial wall, and its effectiveness can be explained by the relatively strong bonding of silver sulfadiazine to DNA  which differs from that of silver nitrate or other silver salts., However, the use of silver dressings in wound care has recently been faced with considerable challenges as it may slow the process of healing  can develop bacterial resistance ,, and has been reported with bone marrow toxicity.
With the advent of nanotechnology (“nano” signifies one-billionth [10−9]) perhaps the most unique form of silver developed for wound dressings is nanocrystalline silver, which differs in both physical and chemical properties from microcrystalline or macrocrystalline silver and from silver salts. This is, in part, related to the increase in grain boundary atoms as a percentage of the total atoms in the material, which is due to the small crystal size. These grain boundaries, according to Birringer, may represent a third state of solid matter. There is a marked increase in surface area for water to reaction with silver in the nanocrystalline form. High surface-to-volume ratio makes silver nanoparticles more effective even at very low concentration, thus reduces the chance of toxicity. Nanocrystalline silver is a metastable, high-energy form of elemental silver. Normal silver placed in water will not dissolve, but nanocrystalline silver in aqueous system may exist in both Ag + and/or Ag 0 forms, whereas other silver sources release only Ag +.,, The nature of the solute also affects the biological activity of silver. In complex organic biological fluids, continuous concentrations of silver >50 ppm and as high as 60.5 ppm  are needed to kill microbes. This difference in the dissolution properties of nanocrystalline silver dressings appears to alter the biological character of the solution including both antimicrobial and anti-inflammatory activities. When the ions in the dressing-wound bed interface are depleted, the equilibrium shifts and more Ag + ion and Ag 0 are released, thus producing a sustained, steady supply of active silver.
Moreover, the use of SSD cream results in the formation of a pseudoeschar and can withdraw fluid from this wound surface. Whereas, nanocrystalline silver delivery maintains moisture layer on the wound surface. Advantages of a moist wound dressing include decrease in surface desiccation and eschar formation, increase in local growth factor production, activation of surface proteases to remove devitalized tissue, decreased surface inflammation, enhanced wound surface immune defenses, increased rate of angiogenesis and fibroblast proliferation, increased proliferation, and migration of epithelial cells along thin water layer.
Typically, the wound repair process involves steps that include inflammation around the site of injury, angiogenesis and the development of granulation tissue, repair of the connective tissue and epithelium, and ultimately remodeling that leads to a healed wound. One event that impedes wound healing is colonization of the wound bed by microorganisms., In addition to the production of a variety of toxins and proteases, the presence of microorganisms in a wound bed may also lead to a prolonged inflammatory response. The host inflammatory response is remarkably effective at eliminating the invading microbial population, but that same process, over time, may also damage the surrounding tissues. This is evidenced by the fact that wounds associated with a heavy bacterial burden often show healing failure.
Nanocrystalline silver dressings have been demonstrated as effective antifungal agents, have a broad antibacterial effect on a range of Gram-negative and Gram-positive bacteria and antibiotic-resistant bacteria strains, thus decrease the incidence of infections that delay wound healing. It also has anti-inflammatory effects  (reduced local matrix metalloproteinase levels and enhanced cellular apoptosis) on wounds and facilitating the early phases of wound healing. Our study also reflects decrease colonization, acceleration of re-epithelialization, and thus reduction of wound healing time corresponding to other studies ,,, and thus indirect evidence of anti-inflammatory effect of nano-Ag dressing.
Pain remains the primary concern to the burn patient which is associated with initial injury and necessary daily care (procedural pain) that follows and remains largely been undertreated.,, In this study, we found that nano-Ag gel is a better alternative as dressing material regarding relieving pain.
In this study, we did not come across any kind of clinically detectable adverse effects in both the groups.
The histological study revealed that pathological process in each of the subgroups was similar but the time frame differs. Nano-Ag gel dressing group achieved early and quick transition of the healing cycle as compared to SSD dressing group owing to decrease microbial load, attenuating inflammatory process. Moreover, clinically, it is seen that prolonged conservative treatment with SSD longer than 3 weeks, especially in younger age group, usually results in healing with hypertrophic or atrophic scars., In this study, we found that the final esthetic outcome of the healed area is far more superior in nano-Ag gel dressing group and also evidenced by histological study.
| Conclusions|| |
In this study, we were able to discover the multifaceted benefits of nanocrystalline silver gel dressings. By eliminating toxic complexes, it decreases pain and reduces bacterial load and thereby local inflammation. It also reduces exudates formation and thereby frequency of pain provoking dressing can be lessened. Overall, it has very much positive effect on wound healing and final outcome, further confirmed by histopathological study. This study reflects that in comparison to SSD, nano-Ag is able to maintain an undisturbed optimum healing environment in second-degree burn wound. Further studies regarding cost effectiveness and long-term follow-up will decide whether it is the appropriate time to consider nano-Ag gel as the “gold standard” dressing material.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]