Background and Significance
It is well documented in the literature that an acute injury to the skin and/or skin structures will go on to heal without issue.1 When comparing acute wounds with chronic wounds, the latter often heal with unpredictable patterns and represent a major challenge for healthcare providers. Billions of dollars are spent each year in the United States treating chronic wounds, so accurate assessment and treatment are critical to ensure positive clinical outcomes.2 The consideration of adjunctive therapies in the treatment of chronic wounds, which includes complementary approaches, should be based on clinical data and evidence to support the use of alternative therapies.
REVIEW OF THE LITERATURE
After an acute injury to the skin, most acute wounds will go on to heal without issue. As people get older, their bodies become compromised by (a) poor blood circulation, (b) diminished inflammatory response, and (c) development of chronic diseases, such as diabetes mellitus, all of which can lead to slower healing and the development of a chronic wound.1 Wound healing has previously been described as a complex cascade of cellular and biochemical events that occurs at the molecular level. The normal wound healing process involves various cell types and includes 3 predicable phases or stages: (a) inflammation, (b) proliferation, and (c) remodeling or maturation.3
Characteristics of an acute wound. During the wounding process, injury that occurs to adjacent blood vessels will eventually lead to the formation of a blood clot. Singer and Clark4 cited that the blood clot serves several key roles in the initiation of the healing process, including (a) provision of key components necessary in the initial formation of the extracellular matrix, (b) creating a barrier against invading microorganisms, and (c) acting as a reservoir of growth factors. In the acute wound, regardless of the etiology, a sequential cascade of cellular and biochemical events occurs that guides the healing process. As previously described, the stages of wound healing are sequential and predictable in nature, which is often characteristic of the acute wound. It is a lack of progression and/or stagnation through these fundamental stages that promotes abnormal healing processes. A smooth progression through the 3 stages of healing will ultimately lead to wound closure and complete healing in a timely manner.
Characteristics of a chronic wound. Chronic wounds remain a major problem for healthcare providers, with billions of dollars spent caring for these complex patients each year in the United States.2 Currently, there are multiple descriptors used when defining a chronic wound; in the literature, however, it appears to be analogous with a wound in which healing is impaired. Many factors have been associated with impaired wound healing, including (a) maceration, (b) ischemia, and (c) infection. Gasbarro5 stated that underlying systemic factors also need to be considered in which (a) chronological age, (b) diabetes mellitus, (c) poor nutrition, and (d) renal impairment have all been implicated in negatively affecting wound healing. Chronic wounds are often the resultant effects of an underlying disease state or display impaired healing due to coexisting disease.4 Examples of chronic wounds would include (a) diabetic foot ulcers, (b) arterial/ischemic lower-extremity ulcers, (c) pressure ulcers, and (d) venous leg ulcers. Despite different etiological factors, chronic wounds all share a common characteristic in which they lack progression through normal stages of healing. Combined with the heterogeneous nature of chronic wounds, the lack of progression through normal healing processes is what makes the selection of wound treatment modalities quite complex.4
The beneficial effects of phytochemicals found in fruits and vegetables are becoming more evident in the literature. Most of the beneficial effects appear to be related to the presence of organic compounds that possess varying degrees of antioxidant and anti-inflammatory activity.6–8 The characterization of biological effects attributed to phytochemicals, particularly the effects on wound healing, has stimulated considerable debate and research regarding their efficacy and utility. Research has extended beyond the profiling of phytochemicals isolated from common fruits and vegetables to the investigating various herbs and spices rooted in traditional herbal medicine.
Recent data suggest that Madhu ghrita and Jatyadi Taila, which are herbal formulations and/or compounds traditionally used in Ayurvedic medicine, have demonstrated positive effects on wound healing.8 In addition, recent research suggests that extracts formulated from several indigenous plants found commonly on the Indian subcontinent, in particular Solanum xanthocarpum, demonstrated increased wound epithelialization and decreased scar formation with topical application.9 It is believed that the phytochemical compounds found in the leaves of S xanthocarpum are responsible for the plant’s positive effects on wound healing activity. Some of the isolated compounds reported, which include (a) glycosides, (b) saponins, (c) tannins, and (d) phenolic compounds, have been previously documented in the literature as having a positive effect on wound healing.10–13
One specific fruit that has been found to possess high levels of phytochemicals is the North American cranberry in which phenolic acids, flavonoids, and ellagic acid are of key interest to researchers.14 Evidence suggests that the phytochemicals found in cranberries have been associated with the prevention of urinary tract infections, the promotion of cardiovascular health, and the prevention of certain stomach ulcers.14,15 Despite the evidence supporting the health benefits of cranberry consumption, little research has been carried out profiling the wound healing effects when ingested or applied topically.
North American cranberry. The North American cranberry (Vaccinium macrocarpon) has long been identified as a folk remedy for treating infections.16 Most of the published data appear to be carried out with the V macrocarpon, although limited data found in the literature do demonstrate similar efficacy with the European variant, Vaccinium oxycoccus.17 The antibacterial effect associated with the Vaccinium species seems to be attributed to the fruit containing high levels of polyphenol compounds, in particular proanthocyanidins (PACs). Data suggest that PACs possess a unique quality in which bacterial adhesion to epithelial cells is inhibited. Primarily, this inhibitory effect has been profiled in the urinary tract, with Escherichia coli being the main pathogen studied. Studies have shown that a correlation exists between the ingestion of cranberries and the prevention of urinary tract infections in females.18–20 The ability of PACs to promote urinary tract health by inhibiting bacterial adhesion of uroepithelial cells has been demonstrated both in vitro and in vivo studies.21 Further in vitro studies have demonstrated that the antiadhesion effects of PACs sourced from cranberry extracts can decrease bacterial adherence not only to urinary tract cells, but also to various other biological materials.18 Cranberry extracts also appear to have similar inhibitory effects on tissue adhesion with other gram-negative bacteria, including (a) Proteus, (b) Klebsiella, (c) Enterobacter, and (d) Pseudomonas.6
The bacterial antiadhesion effect of cranberry extracts has also been profiled in gastric epithelium in which ingestion has been associated with decreased incidence of gastric ulcers and gastric cancer.15 The literature suggests that by preventing adherence of Helicobacter pylori bacteria to gastric tissue, mucosal damage and progressive peptic ulcer disease can be avoided.21–23 With the criterion standard of treatment for H pylori–induced peptic ulcer disease being a multiagent antibiotic regimen, antibiotic resistance should be a major problem if complete eradication of H pylori from the gastric mucosa is a treatment goal.23 A published randomized controlled study based in China demonstrated that drinking two 250-mL juice boxes of cranberry juice per day (over a 90-day period) significantly reduced the incidence of H pylori infection in high-risk populations.21 In addition, Burger et al24 demonstrated in cultured gastric epithelial cells that phytochemicals found in cranberry juice may specifically interfere with a sialyllactose-specific adhesion process that allows the H pylori organism to adhere to gastric mucosa. The study authors conclude that “cranberry juice may also inhibit adhesion of bacteria to the stomach in vivo and may prove useful for the prevention of stomach ulcers that are caused by H pylori.”24
Applications in Wound Healing
Wound infections inherently possess the potential to have an impact on a patient’s quality of life, with the costs being measured both financially and emotionally.25 A study published in the United Kingdom estimated that 1% of the UK population has a chronic wound and carries a cost to the health system of at least £1 billion per year.26 Using traditional criteria, such as the presence of purulent drainage and malodor, may not be a consistent measure to determine a wound infection in all chronic wound types. Using clinical criteria that are not in line with professional consensus or guidance documents may lead to ineffective treatment in which the clinical identification of infection is still dependent on an expert opinion.25 This dependency on expert opinion for consistent diagnoses of wound infections seems to support the notion that an “ounce of prevention is worth a pound of cure.”
Preventing infections by inhibiting bacterial-tissue adherence is not a new concept and would be a welcomed attribute to any emerging wound care products. As previously described, the North American cranberry possesses the ability to decrease bacterial-tissue adhesion, which correlates with the inherent ability to decrease rates of urinary tract infections in females caused by certain species of bacteria.18 If the ability to prevent bacterial adhesion and subsequent infection was facilitated through the topical application of a treatment or dressing, this would be viewed as a welcomed attribute to most wound care professionals.
The antimicrobial properties of phytochemical compounds and the biologic effects of natural extracts on the wound healing process have been described in the literature.27 Specifically, the wound healing effects of grape (Vitis vinifera) and cranberry extracts were studied in a rodent model in which they were compared with a passive (petrolatum) and active (mupirocin) controls.28 Shivananda et al28 determined the extent of wound healing by the following 2 measures: rate of wound contraction and hydroxyproline content. The authors reported that the wounds treated with cranberry or grape extracts exhibited a significant reduction in surface area and a higher level of hydroxyproline content in excised granulation tissue.28 These data seem to suggest that topical photochemical compounds from cranberry and/or grape origins have a positive influence on wound healing dynamics. In addition, phytochemicals extracted from grape seeds potently up-regulate vascular endothelial growth factor (VEGF) expression in cultured human keratinocytes. The VEGF is believed to be the most abundant and bioactive substance that stimulates angiogenesis in a wound.29,30
Considering the previously described antimicrobial characteristics and biologic effects of phytochemical compounds, one could hypothesize that these attributes would collectively offer a positive effect in a chronic wound. With that said, the potential to exploit the natural acidic nature of fruit extracts may also provide a positive effect in the chronic wound by way of pH modulation and acidification of wound fluid. In vitro data published by Greener et al31 suggest that protein degradation in a chronic wound is modulated by changes in wound pH. An alkaline wound environment supports destructive protease activity in which topical acidification would attenuate protease hyperactivity.31
Despite the lack of well-constructed clinical trials supporting the use of phytochemicals in wound care, data from small in vitro studies suggest that phytochemicals can exert a positive effect on (a) VEGF expression, (b) wound contraction, and (c) overall granulation tissue formation. The phytochemicals known to be found in the North American cranberry and grape variants warrant further exploration, in particular their effects on wound healing and wound pathogens. With considerable evidence supporting the cranberry’s effects on bacterial survival and tissue, most of the research has been conducted on urinary and gastrointestinal pathogens. At this time, little is known about the wound healing applications of phytochemical compounds commonly isolated from cranberry extracts.
The economic impact of healing a chronic wound speaks for itself, and the continued pursuit of cost-effective therapies needs to be explored. The wound healing effects of topically applied phytochemical compounds need further exploration, in particular, phytochemicals derived from the North American cranberry and grape. Additional research is needed to effectively profile the biochemical changes that occur in the wound bed with topical phytochemical application. Once this mechanism is better understood, robust clinical data can be sought if topically applied phytochemicals are to be accepted for widespread use.
* Chronic wounds continue to represent a major challenge for healthcare providers in which billions of dollars are spent each year in the United States treating chronic wounds.
* Adjunctive therapies in the treatment of chronic wounds, which include complementary approaches, should be based on clinical data and evidence to support the use of alternative therapies.
* The beneficial effects of phytochemicals found in fruits and vegetables are becoming more evident in the literature.
* Most of the beneficial effects appear to be related to the presence of organic compounds that possess varying degrees of antioxidant and anti-inflammatory activity.
* Data seem to suggest that topical photochemical compounds from cranberry and/or grape origins may have a positive influence on wound healing dynamics. Additional research is needed to effectively profile the biochemical changes that occur in the wound bed with topical phytochemical application if topically applied phytochemicals are to be accepted for widespread use.
* Once this mechanism is better understood, robust clinical data can be sought.
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