JULY 2014
Topical Phytochemicals: Applications for Wound Healing C M E 1 AMA PRA Category 1 CreditTM
ANCC 2.0 Contact Hours
Edward W. Walton, DHSc, APN-C, NP-C & Graduate Director and Assistant Professor of Nursing School of Health Sciences: Nursing Program & The Richard Stockton College of New Jersey & Galloway, New Jersey Dr Walton has disclosed that his employer, The Richard Stockton College of New Jersey, currently has a provisional patent application in process regarding the isolation and use of phytochemical compounds for wound healing purposes. All staff, faculty, and planners, including spouses/partners (if any), in any position to control the content of this CME activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity. To earn CME credit, you must read the CME article and complete the quiz and evaluation on the enclosed answer form, answering at least 13 of the 18 questions correctly. This continuing educational activity will expire for physicians on July 31, 2015.
PURPOSE: To enhance the learner’s competence with knowledge about studies that examined phytochemical use for assisting the body’s healing processes. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to: 1. Identify the normal healing process and problems with this process that lead to the development of chronic wounds. 2. Summarize study findings that examined the healing properties of phytochemicals.
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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
ABSTRACT To maximize the effectiveness of any complementary therapy in treating chronic wounds, the clinician must fully appreciate the scientific basis in which this treatment modality influences wound healing. The biological changes influenced by phytochemical compounds can have a positive effect on wound healing, which often depends on extract selection and clinical application. A sound understanding of the physiological changes that are associated with phytochemical compounds will help the clinician to make an appropriate extract selection and guide treatment decisions. Tissue adhesion has long been considered a key step in determining a bacterium’s pathogenicity. The process of preventing infections by decreasing bacterial-tissue adhesion has been reported in the literature, with particular focus on the antibacterial effects of ingested cranberry juice. Cranberry juice has been studied primarily as a ‘‘home remedy’’ in the treatment of urinary tract infection with its antiadhesion and/or antibacterial effects in a chronic wound needing further investigation. KEYWORDS: phytochemicals, plant extracts and wound healing, chronic wounds, complementary therapy
Wound Classification 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
ADV SKIN WOUND CARE 2014;27:328–32; quiz 333–4.
INTRODUCTION 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 Wound Healing 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
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Phytochemicals
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 highrisk 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
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 antiinflammatory 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 ADVANCES IN SKIN & WOUND CARE & VOL. 27 NO. 7
DISCUSSION 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 U1 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.’’ 330
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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.
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 bacterialtissue 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
PRACTICE PEARLS & 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.
CONCLUSIONS 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 WWW.WOUNDCAREJOURNAL.COM
REFERENCES 1. Becker DL, Thrasivoulou C, Phillips AR. Connexins in wound healing; perspectives in diabetic patients. Biochim Biophysic Acta 2012;1818:2068-75. 2. Fonder MA, Lazarus GS, Cowan DA, Aronson-Cook B, Kohli AR, Mamelak AJ. Treating the chronic wound: a practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol 2008;58:185-206. 3. Komarcevc A. The modern approach to wound treatment. Med Pregl 2000;53:363-8. 4. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med 1999;341:738-46. 5. Gasbarro R. Negative pressure wound therapy: a clinical review. Wounds 2007;19(Suppl 12):2-7.
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20. Tempera G, Corsello S, Genovese C, Caruso FE, Nicolosi D. Inhibitory activity of cranberry extract on the bacterial adhesiveness in the urine of women: an ex-vivo study. Int J Immunopathol Pharmacol 2010;23:611-8. 21. Howell AB, Reed JD, Krueger CG, Winterbottom R, Cunningham DG, Leah M. A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry 2005;66:2281-91. 22. Zhang L, Ma J, Pan K, Go VL, Chen J, You WC. Efficacy of cranberry juice on Helicobacter pylori infection: a double-blind, randomized placebo-controlled trial. Helicobacter 2005;10: 139-45. 23. Lin YT, Kwon YI, Labbe RG, Shetty K. Inhibition of Helicobacter pylori and associated urease by oregano and cranberry phytochemical synergies. Appl Environ Microbiol 2005;71: 8558-64. 24. Burger O, Weiss E, Sharon N, Tabak M, Neeman I, Ofek I. Inhibition of Helicobacter pylori adhesion to human gastric mucus by a high-molecular-weight constituent of cranberry juice. Crit Rev Food Sci Nutr 2002;42(Suppl 3):279-84. 25. Rondas AA, Schols JM, Stobberingh EE, Price PE. Definition of infection in chronic wounds by Dutch nursing home physicians. Int Wound J 2009;6:267-74. 26. Thomas DW, Harding KG. Wound healing. Br J Surg 2002;89:1203-5. 27. Hsu S. Green tea and the skin. J Am Acad Dermatol 2005;52:1049-59. 28. Shivananda Nayak B, Dan Ramdath D, Marshall JR, Isitor G, Xue S, Shi J. Wound-healing properties of the oils of Vitis vinifera and Vaccinium macrocarpon. Phytother Res 2011;25: 1201-8. 29. Khanna S, Venojarvi M, Roy S, et al. Dermal wound healing properties of redox-active grape seed proanthocyanidins. Free Radic Biol Med 2002;33:1089-96. 30. Sen CK, Khanna S, Gordillo G, Bagchi D, Bagchi M, Roy S. Oxygen, oxidants, and antioxidants in wound healing: an emerging paradigm. Ann N Y Acad Sci 2002;957:239-49. 31. Greener B, Hughes AA, Bannister N P, Douglass J. Proteases and pH in chronic wounds. J Wound Care 2005;14(2):59-61.
6. Schmidt DR, Sobota AE. An examination of the anti-adherence activity of cranberry juice on urinary and nonurinary bacterial isolates. Microbios 1988;55(224-225):173-81. 7. Belobrajdic D, Bird A. The potential role of phytochemicals in wholegrain cereals for the prevention of type-2 diabetes. Nutr J 2013;12:62. 8. Shailajan S, Menon S, Pednekar S, Singh A. Wound healing efficacy of Jatyadi Taila: in vivo evaluation in rat using excision wound model. J Ethnopharmacol 2011;138:99-104. 9. Dewangan H, Bais M, Jaiswal V, Verma VK. Potential wound healing activity of the ethanolic extract of Solanum xanthocarpum schrad and wendl leaves. Pak J Pharm Sci 2012;25(1):189-94. 10. Stevenson P, Simmonds MS, Sampson J, Houghton PJ, Grice P. Wound healing activity of acylated iridoid glycosides from Scrophularia nodosa. Phytother Res 2002;16:33-5. 11. Kim YS, Cho IH, Jeong MJ. Therapeutic effect of total ginseng saponin on skin wound healing. J Ginseng Res 2011;35:360-7. 12. Li K, Diao Y, Zhang H. Tannin extracts from immature fruits of Terminalia chebula Fructus Retz. promote cutaneous wound healing in rats. BMC Complement Altern Med 2011;11:86. 13. Murthy KN, Reddy V, Viegas J, Murthy U. Study on wound healing activity of Punica granatum peel. J Med Food 2004;7:256-9. 14. Vattem DA, Ghaedian R, Shetty K. Enhancing health benefits of berries through phenolic antioxidant enrichment: focus on cranberry. Asia Pac J Clin Nutr 2005;14:120-30. 15. Biswas N, Balac P, Narlakanti SK, Haque E, Hassan M. Identification of phenolic compounds in processed cranberries by HPLC Method. J Nutr Food Sci 2013;3:181. 16. Nowack R. Cranberry juiceVa well-characterized folk-remedy against bacterial urinary tract infection. Wien Med Wochenschr 2007;157(13-14):325-30. 17. Kontiokari T, Laitinen J, Jrvi L, Pokka T, Sundqvist K, Uhari M. Dietary factors protecting women from urinary tract infection. Am J C Nutr 2003;77:600-4. 18. Kontiokari T, Salo J, Eerola E, Uhari, M. Cranberry juice and bacterial colonization in childrenV placebo-controlled randomized trial. Clin Nutr 2005;24:1065-72. 19. Carson CF, Riley TV. Non-antibiotic therapies for infectious diseases. Commun Dis Intell Q Rep 2003;27(Suppl):S143-6.
For more than 116 additional continuing education articles related to skin and wound care topics, go to NursingCenter.com/CE.
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Topical Phytochemicals: Applications for Wound Healing C M E 1 AMA PRA Category 1 CreditTM
ANCC 2.0 Contact Hours
Edward W. Walton, DHSc, APN-C, NP-C & Graduate Director and Assistant Professor of Nursing School of Health Sciences: Nursing Program & The Richard Stockton College of New Jersey & Galloway, New Jersey Dr Walton has disclosed that his employer, The Richard Stockton College of New Jersey, currently has a provisional patent application in process regarding the isolation and use of phytochemical compounds for wound healing purposes. All staff, faculty, and planners, including spouses/partners (if any), in any position to control the content of this CME activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity. To earn CME credit, you must read the CME article and complete the quiz and evaluation on the enclosed answer form, answering at least 13 of the 18 questions correctly. This continuing educational activity will expire for physicians on July 31, 2015.
PURPOSE: To enhance the learner’s competence with knowledge about studies that examined phytochemical use for assisting the body’s healing processes. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to: 1. Identify the normal healing process and problems with this process that lead to the development of chronic wounds. 2. Summarize study findings that examined the healing properties of phytochemicals.
ADVANCES IN SKIN & WOUND CARE & VOL. 27 NO. 7
328
WWW.WOUNDCAREJOURNAL.COM
Copyright © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
ABSTRACT To maximize the effectiveness of any complementary therapy in treating chronic wounds, the clinician must fully appreciate the scientific basis in which this treatment modality influences wound healing. The biological changes influenced by phytochemical compounds can have a positive effect on wound healing, which often depends on extract selection and clinical application. A sound understanding of the physiological changes that are associated with phytochemical compounds will help the clinician to make an appropriate extract selection and guide treatment decisions. Tissue adhesion has long been considered a key step in determining a bacterium’s pathogenicity. The process of preventing infections by decreasing bacterial-tissue adhesion has been reported in the literature, with particular focus on the antibacterial effects of ingested cranberry juice. Cranberry juice has been studied primarily as a ‘‘home remedy’’ in the treatment of urinary tract infection with its antiadhesion and/or antibacterial effects in a chronic wound needing further investigation. KEYWORDS: phytochemicals, plant extracts and wound healing, chronic wounds, complementary therapy
Wound Classification 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
ADV SKIN WOUND CARE 2014;27:328–32; quiz 333–4.
INTRODUCTION 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 Wound Healing 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
WWW.WOUNDCAREJOURNAL.COM
329
ADVANCES IN SKIN & WOUND CARE & JULY 2014
Copyright © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Phytochemicals
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 highrisk 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
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 antiinflammatory 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 ADVANCES IN SKIN & WOUND CARE & VOL. 27 NO. 7
DISCUSSION 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 U1 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.’’ 330
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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.
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 bacterialtissue 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
PRACTICE PEARLS & 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.
CONCLUSIONS 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 WWW.WOUNDCAREJOURNAL.COM
REFERENCES 1. Becker DL, Thrasivoulou C, Phillips AR. Connexins in wound healing; perspectives in diabetic patients. Biochim Biophysic Acta 2012;1818:2068-75. 2. Fonder MA, Lazarus GS, Cowan DA, Aronson-Cook B, Kohli AR, Mamelak AJ. Treating the chronic wound: a practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol 2008;58:185-206. 3. Komarcevc A. The modern approach to wound treatment. Med Pregl 2000;53:363-8. 4. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med 1999;341:738-46. 5. Gasbarro R. Negative pressure wound therapy: a clinical review. Wounds 2007;19(Suppl 12):2-7.
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20. Tempera G, Corsello S, Genovese C, Caruso FE, Nicolosi D. Inhibitory activity of cranberry extract on the bacterial adhesiveness in the urine of women: an ex-vivo study. Int J Immunopathol Pharmacol 2010;23:611-8. 21. Howell AB, Reed JD, Krueger CG, Winterbottom R, Cunningham DG, Leah M. A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry 2005;66:2281-91. 22. Zhang L, Ma J, Pan K, Go VL, Chen J, You WC. Efficacy of cranberry juice on Helicobacter pylori infection: a double-blind, randomized placebo-controlled trial. Helicobacter 2005;10: 139-45. 23. Lin YT, Kwon YI, Labbe RG, Shetty K. Inhibition of Helicobacter pylori and associated urease by oregano and cranberry phytochemical synergies. Appl Environ Microbiol 2005;71: 8558-64. 24. Burger O, Weiss E, Sharon N, Tabak M, Neeman I, Ofek I. Inhibition of Helicobacter pylori adhesion to human gastric mucus by a high-molecular-weight constituent of cranberry juice. Crit Rev Food Sci Nutr 2002;42(Suppl 3):279-84. 25. Rondas AA, Schols JM, Stobberingh EE, Price PE. Definition of infection in chronic wounds by Dutch nursing home physicians. Int Wound J 2009;6:267-74. 26. Thomas DW, Harding KG. Wound healing. Br J Surg 2002;89:1203-5. 27. Hsu S. Green tea and the skin. J Am Acad Dermatol 2005;52:1049-59. 28. Shivananda Nayak B, Dan Ramdath D, Marshall JR, Isitor G, Xue S, Shi J. Wound-healing properties of the oils of Vitis vinifera and Vaccinium macrocarpon. Phytother Res 2011;25: 1201-8. 29. Khanna S, Venojarvi M, Roy S, et al. Dermal wound healing properties of redox-active grape seed proanthocyanidins. Free Radic Biol Med 2002;33:1089-96. 30. Sen CK, Khanna S, Gordillo G, Bagchi D, Bagchi M, Roy S. Oxygen, oxidants, and antioxidants in wound healing: an emerging paradigm. Ann N Y Acad Sci 2002;957:239-49. 31. Greener B, Hughes AA, Bannister N P, Douglass J. Proteases and pH in chronic wounds. J Wound Care 2005;14(2):59-61.
6. Schmidt DR, Sobota AE. An examination of the anti-adherence activity of cranberry juice on urinary and nonurinary bacterial isolates. Microbios 1988;55(224-225):173-81. 7. Belobrajdic D, Bird A. The potential role of phytochemicals in wholegrain cereals for the prevention of type-2 diabetes. Nutr J 2013;12:62. 8. Shailajan S, Menon S, Pednekar S, Singh A. Wound healing efficacy of Jatyadi Taila: in vivo evaluation in rat using excision wound model. J Ethnopharmacol 2011;138:99-104. 9. Dewangan H, Bais M, Jaiswal V, Verma VK. Potential wound healing activity of the ethanolic extract of Solanum xanthocarpum schrad and wendl leaves. Pak J Pharm Sci 2012;25(1):189-94. 10. Stevenson P, Simmonds MS, Sampson J, Houghton PJ, Grice P. Wound healing activity of acylated iridoid glycosides from Scrophularia nodosa. Phytother Res 2002;16:33-5. 11. Kim YS, Cho IH, Jeong MJ. Therapeutic effect of total ginseng saponin on skin wound healing. J Ginseng Res 2011;35:360-7. 12. Li K, Diao Y, Zhang H. Tannin extracts from immature fruits of Terminalia chebula Fructus Retz. promote cutaneous wound healing in rats. BMC Complement Altern Med 2011;11:86. 13. Murthy KN, Reddy V, Viegas J, Murthy U. Study on wound healing activity of Punica granatum peel. J Med Food 2004;7:256-9. 14. Vattem DA, Ghaedian R, Shetty K. Enhancing health benefits of berries through phenolic antioxidant enrichment: focus on cranberry. Asia Pac J Clin Nutr 2005;14:120-30. 15. Biswas N, Balac P, Narlakanti SK, Haque E, Hassan M. Identification of phenolic compounds in processed cranberries by HPLC Method. J Nutr Food Sci 2013;3:181. 16. Nowack R. Cranberry juiceVa well-characterized folk-remedy against bacterial urinary tract infection. Wien Med Wochenschr 2007;157(13-14):325-30. 17. Kontiokari T, Laitinen J, Jrvi L, Pokka T, Sundqvist K, Uhari M. Dietary factors protecting women from urinary tract infection. Am J C Nutr 2003;77:600-4. 18. Kontiokari T, Salo J, Eerola E, Uhari, M. Cranberry juice and bacterial colonization in childrenV placebo-controlled randomized trial. Clin Nutr 2005;24:1065-72. 19. Carson CF, Riley TV. Non-antibiotic therapies for infectious diseases. Commun Dis Intell Q Rep 2003;27(Suppl):S143-6.
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