Sara S. Abou Zekry, Ahmed Abdellatif and Hassan M. E. Azzazy
Honey, pomegranate peel extract (PPP) and bee venom (BV), were used in combination with polyvinyl alcohol (PVA) to develop a novel nanofibrous wound dressing. Methanolic PPP was prepared and mixed with either manuka honey (MH) or lyophilized multiflora honey powder (LH) together with BV to have a total of three formulas: MH/PPP, MH/PPP/BV and LH/PPP/BV. The formulas were tested for their antibacterial activity, cytotoxicity, and wound healing activity in an excisional wound rat model. Scanning electron microscopy showed that LH fibers had smaller and more uniform diameter than MH fibers. Moderate swelling and higher weight loss capacities were detected when compared to PVA mats. Antibacterial tests showed significant antibacterial activity against S. aureus and E. coli compared to negative controls (P < 0.0001). No cytotoxicity was observed. In vivo wound healing study showed that all treatment groups enhanced wound healing as shown by increased wound closure percentages compared to negative control groups at days 3,5 and 10 (P < 0.0001), and histological examination. In comparison to treatment groups, Medihoney® calcium alginate dressing significantly enhanced healing compared to negative controls at days 3 and 5. However, healing was delayed afterwards. These results indicate that MH/PPP/BV nanofibers are promising for wound healing.
Wounds are considered one of the critical public health problems in the world. In the United States, undertreated wounds and chronic wounds affected 6.5 million patients in 2009, with an annual cost in excess of 25 billion USD. The global market of wound-care products is expected to reach nearly 16,300 million USD by 2023. Therefore, new technologies are essential to address this problem. In the time of the serious increase of antibiotic resistance, natural products might become the last resort in order to deal with wounds. Nanofibrous scaffolds are suggested to have advantageous properties over conventional dressings such as large surface area to volume ratio, high porosity and very small pore size. These properties led to higher exudate absorption compared to other polymer films, better wound permeation and prevention from further infection. The use of honey in wound healing applications has been adopted owing to its remarkable antimicrobial properties. Honey consists of water (20 %), fructose (40 %), glucose (30 %), sucrose (5 %), and other substances (minerals, vitamins, amino acids, and enzymes). Honey was shown to have, antimicrobial, and anti-inflammatory properties. Moreover, honey is acidic therefore it is able to provide fibroblasts with optimal environment for their activity, making it difficult for bacterial survival. Honey was shown to be superior to amniotic membrane dressing, and to silver sulfadiazine in treating partial thickness burns, and to ethoxy-diamino-acridine plus nitrofurazone dressing in pressure ulcer patients. Poly vinyl alcohol (PVA) being a biocompatible, non-toxic, biodegradable polymer with good mechanical properties, has been proposed for various biomedical applications. The combination of honey and PVA seems promising, in comparison to Aquacel Ag ® dressings, honey/PVA based scaffolds had similar wound closure rates while having better biocompatibility. Pomegranate juice together with its peel contain remarkable amounts of polyphenolic compounds such as ellagic acid, ellagic tannins, flavanols, anthocyanins, catechin, procyanidins and gallic acid. Pomegranate peel constitutes 50 % of the pomegranate fruit weight. The peel was shown to have higher amounts of polyphenolic compounds than pomegranate juice and thereby possessing even stronger biological activity with promising wound healing potential. Despite this, the peel is often discarded as waste. Under European regulations, pomegranate peel waste should not be disposed neither on land nor in landfills because it holds a significant risk to watercourses. Therefore, pomegranate peel waste disposal and /or use is turning into a major industrial and scientific area. PPP has shown promising results when used in wound healing as suggested by numerous studies. Another interesting natural product that was included in our study is BV. The venom has been the focus of many research groups for years till date for its powerful therapeutic effect in various pathological conditions ranging from pain, rheumatic arthritis and skin diseases as well as tumors. Also, BV can be considered as a promising candidate for wound healing owing to its powerful antibacterial effect and potent anti-inflammatory properties. In the present study, PPP and BV were loaded within honey/PVA nanofiber scaffolds in order to test their wound healing activity in an animal model of excisional wound. Two types of honey were used, Manuka honey (MH) and Lyophilized multiflora honey powder (LH).
Wound healing problem represent an increasing economic burden on health care systems especially in developing countries. The current study is an attempt to develop an effective and safe nanofibrous wound dressings which meets the demands and fights against bacterial infections. Pomegranate is an interesting fruit known for its superior antioxidant and antibacterial effects. The fruit’s peel is usually discarded as waste. In the present study, methanol was used for the extraction of pomegranate peel powder. According to Chidambara et al., methanol extracted the highest amount of antioxidant poly phenolic compounds from pomegranate peel in comparison to ethyl acetate and water. Pomegranate (PPP) was investigated in enhancing wound healing in several research projects. One study demonstrated that the methanolic extract of the fruit’s peel contained a high content of phenolic compounds as well as other constituents. The study further aimed at preparing a 10 % (wt/wt) gel and investigated its efficacy on Wistar rats’ excision wounds. The results showed that rats that received 5.0 % gel treatment showed complete healing after 10 days compared to 12 days in those rats treated with 2.5 % and 16–18 days in the rats that received a blank gel. In 2011, Hayouni et al., investigated the efficacy 5 % (w/w) of the methanolic extract of a pomegranate peel based-ointment on guinea pigs. The results demonstrated that the PPP ointment significantly promoted wound contraction as well as the period of epithelialization as assessed by the biochemical, mechanical and histopathological characteristics. Another study evaluated the activity of PPP gel in cutaneous wounds in diabetic rat models. The results showed that the gel significantly shortened healing time as shown by histological examination as its use promoted in collagen regeneration, fibroblast infiltration, vascularization, and epithelialization. However, PPP was not loaded before into nanofibers. In our study, 2.5 % concentration was used based on previous data suggesting that standardized PPP (5 and 2.5 %) increased incision wounds’ tensile strength in a rat model and had superior results over ellagic acid (pomegranate peel extract main anti-oxidant component) in increasing the synthesis of collagen and inhibition of the infiltration of neutrophils. In the present work, we report that honey-based nanofibers showed strong antibacterial activity against both gram positive and gram-negative organisms tested. Previous studies using higher concentration (40 %) of honey, demonstrated that honey/chitosan nanofibers showed pronounced antibacterial activity against S. aureus, and moderate activity against E. coli [8]. The use of MH can possibly explain the differences with the current study as a strong antibacterial effect of MH against E. coli was demonstrated previously [22]. In our hands, MH mats were more effective than those with LH against E. coli. However, since a good antibacterial effect was also observed in LH mats, we suggest a possible synergistic effect between honey and PPP that led to a strong antibacterial effect against E. coli. Previously, the antibacterial effect of PPP has been demonstrated against wide range of bacteria including S. aureus and E. coli. Unlike other honey types, MH is able to retain its antimicrobial activity in the presence of catalase enzyme which is commonly present in the wound tissue. MH has been famous with its non-peroxide antimicrobial effect owing to the presence of methylglyoxal (MGO) which was discovered in 2008. MGO is responsible for most of the manuka honey’s antimicrobial activity. In addition to its non-peroxide antimicrobial activity, it was suggested that MH has a role in modulating the initial inflammatory response by promoting the production of cytokines that regulate the production and the angiogenesis of fibroblasts. MH was shown to help in stimulating toll-like receptor 4 on monocytes which in turn leads to the stimulation of the production of interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha from monocytes which are important in tissue repair and regeneration. Other effects that aid in the healing process were mentioned such as lowering the pH of wound area. It was reported that MH decreased pH of cutaneous wounds. Raising pH of the wound towards acidic was suggested to have many effects starting from including a shift to the right to what is called the oxygen–hemoglobin dissociation curve, leading to an increase in oxygen release, decreased toxicity of end products of bacteria such as ammonia, decreased protease activity, activated destruction of abnormal collagen, activated angiogenesis, enhanced fibroblast and macrophage activity as well as controlled the enzyme activity.
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