Improving the ability to eliminate wounds and pressure ulcers Damien P. Kuffler, PhD Institute of Neurobiology, University of Puerto Rico, San Juan, Puerto Rico
Reprint requests: Damien P. Kuffler, PhD, Institute of Neurobiology, University of Puerto Rico, 201 Blvd. del Valle, San Juan, Puerto Rico 00901. Tel: 787-721-1235; Fax: 787-7251289; Email: [email protected] Manuscript received: July 8, 2014 Accepted in final form: March 13, 2015 DOI:10.1111/wrr.12284
ABSTRACT Pressure ulcers can be initiated by as little as 2 hours of constant pressure on the ski, that blocks blood circulation causing the skin and underlying tissues to die, leading to an open wound that never heals, but continues to grow in diameter and depth, and frequently jeopardizes patients’ lives. Despite the application of many diverse techniques, pressure ulcers remain exceptionally difficult to heal because many ulcer elimination techniques have minimal effects, and although other techniques may appear to be effective, the evidence supporting their efficacy is weak. However, increasing evidence indicates that other techniques, such as the application of platelet-rich plasma, vacuum assisted closure, electrical stimulation, and hyperbaric oxygen therapy are effective and should be substituted for the older techniques. This review describes different standard and novel techniques that have been tested for eliminating pressure ulcers and discusses the relative efficacy of these techniques.
Ulcers may be initiated with as little as 2 hours of constant localized pressure leading to an occlusion of the microcirculatory blood flow to the skin, and ischemia leading to tissue anoxia and inflammation a downward spiral toward ulceration,1 followed by rapid deterioration of lifestyle and death. This review examines various standard methods used to treat pressure ulcers, and provides insights into newer methods for which evidence is increasingly strong that they induce faster and more reliable ulcer elimination. In the United States, pressure ulcers affect as many as 2% of the general population, and are major sources of morbidity, mortality, and health care costs.2
STANDARD PRESSURE ULCER TREATMENTS The current standard methods of treating pressure ulcer involve eliminating the chronic pressure on the wound, cleaning the wound of necrotic debris, controlling infection, and applying growth factors and various dressings. The general hope is that these approaches will allow the living tissue around the wound to release sufficient quantities of growth factors, cytokines, and other proteins to stimulate chronic wound bed healing. Unfortunately, the standard treatments induce relatively poor wound healing rates in clinical trials.3 The application of growth factors is one approach used for trying to accelerate chronic wound healing.4,5 For animal model and clinical studies, it has been reported that nerve growth factor is more effective in decreasing the size of pressure and diabetic foot ulcers.6,7 The topical application of basic fibroblast growth factor appears to induce enhanced healing of wounds, chronic dermal ulcers, burns, and diabetic ulcers vs. what is seen for untreated wounds, due to inducing the proliferation of reparative cells that are 312
otherwise nonproliferating.8 Applied transforming growth factor-beta (TGF-b) may also promote wound healing by inhibiting proteolytic tissue destruction, and stimulating angiogenesis.9 Although some studies suggest that the topical application of platelet derived growth factor (PDGF) provides wound healing benefits, its efficacy remains controversial.1 However, caution is required in relying on the data from most such studies because they involved small sample sizes, were not randomized control trials, were of brief duration, and had short to no follow-up periods. Further, many of these studies involved their use in manners both consistent and not consistent with existing guidelines, and their levels of evidence remains low.3,10 Therefore, further studies are required to increase the levels of evidence that these techniques prevent/eliminate pressure ulcer. The presence of microbes within wounds can retard and prevent wound healing while the presence of collagen within wound sites is important for promoting all stages of ulcer healing.11,12 The application of alginate dressings, composed primarily of calcium alginate fibers, to pressure sores and infected surgical wounds induces healing.13 Catrix, a collagen-based product, promotes healing of wounds that are unresponsive to conventional treatments by promoting the growth of fibroblasts and keratinocytes within the wound, preventing the loss of fluid from the wound, and protecting wounds from bacterial infections.12 The application of Hydrofiber (ConvaTec Inc., Bridgewater, NJ) combined with a silver dressing leads to tissue granulation and a decrease in wound size14 while the use of hydrogel plus silver-based dressings are beneficial because they maintain the wound environment moist while exerting an antimicrobial influence.15 However, the antibacterial efficacy of different silver-based medications varies greatly,16 and additional larger studies are required to determine the reliability of these techniques. C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 312–317 V
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Good patient nutritional status is essential for wound healing, with protein deficiency contributing to poor healing rates with reduced collagen formation and wound dehiscence.17 Skin breakdown resulting in high exudate loss can result in a protein deficit of up to 100 g per day,18 and there is a positive correlation between low serum albumin and body mass index and the development of pressure ulcers.19 There are indications that the topical application of essential fatty acids to the entire body, including potential wound sites, may result in sufficient tissue hydration to prevent the development of pressure ulcers.20 Moderate-strength evidence indicates that pressure ulcer healing in adults is improved by protein supplement administration,2,21 although there is mixed evidence as to whether nutritional interventions prevent the development of pressure ulcers.22 Activated macrophages play a major role in almost all stages of wound healing, and their local application to ulcers may promote healing. However, prior to ulcer application, monocytes/macrophages must be activated to trigger a significant increase in the levels of expression of genes directly involved in macrophage function and wound healing, including the activation of genes involved in macrophage expression of cytokines and receptors.23 This is consistent with the observation that activated macrophages secrete cytokines such as IL-1 and IL-6, as part of the healing process.23 Thus, although macrophages application might contribute to ulcer healing, additional studies are necessary to determine whether this is true. Negative pressure therapy, vacuum-assisted closure (VAC) therapy, is clinically effective on infected surgical wounds, traumatic wounds, pressure ulcers, wounds with exposed bone and hardware, diabetic foot ulcers, and venous stasis ulcers.24 VAC therapy increases wound blood flow, speeds the formation of tissue granulation, decreases the accumulation of fluid and bacteria, accelerates healing, and alters the wound bed cytoskeleton, which triggers a cascade of intracellular signals that increase the rate of cell division and the subsequent formation of tissue granulation. VAC therapy is also rapid and effective in promoting angiogenesis with the subsequent formation of healthy tissue.25 VAC reduces patient hospitalization rates due to wound problems.26 It also results in quicker closure of chronic wounds in patients with diabetic foot and ankle ulcers, and wounds secondary to peripheral vascular disease, diabetes, or peripheral vascular disease,27,28 and significantly increases skin graft success rates when used over freshly skin-grafted wounds.29 Of all the techniques so far mentioned, VAC and the elimination of wound infection appear to be the most effective in inducing pressure ulcer healing. However, it is important to test whether combining these techniques further enhances wound elimination vs. the application each approach alone.
arthritic joints, in an attempt to reduce back and neck pain, inflammation, and induce the healing of nonhealing wounds, such as diabetic foot ulcers, pressure ulcers, venous ulcers, and post chemotherapy against radiation ulcers. The primary wavelengths tested are in the ranges of 635, 730, 810, and 980 nm. In comparative studies, exposing nonhealing chronic pressure ulcers that are unresponsive to standard medical care to wavelengths in the range of 635 and 810 nm results in their healing faster than control wounds.30 However, treatment wavelengths around 730 and 980 nm do not stimulate healing.30,31 Combining 633- and 830-nm wavelength illumination improves blood flow and neovascularization, and is claimed to induce cytokines, chemokines, and macromolecules, resulting in enhanced epithelization via the restoration of the collagen/collagenase balance in wounds,32 although the influences are predominantly associated with 830-nm wavelength illumination.32 Illumination with 470 or 630 nm light also results in a significant increase in blood perfusion, and a significant decrease in wound size, which is ascribed to the release of nitric oxide from nitrosyl complexes with hemoglobin,33 which leads to enhanced epithelialization.34 Wound illumination with 400- and 1,072-nm light induces wound healing by affecting keratin expression33 while illumination by 1,072-nm light results in a significant increase in the level of vascular endothelial growth factor (VEGF) that could lead to an enhanced immune response and faster wound healing.35 Chronic wounds may contain a number of different types of bacteria making the wounds resistant to conventional therapy. LLLT irradiation in the visible and near infrared wavelengths (400 and 1,072 nm) results in a significant reduction in the colony count of several but not all types of bacteria36,37 while illumination with light of 650 nm in association with photosensitive toluidine blue exerts an antibacterial effect on infected skin ulcers.38 These data indicate the importance of determining the type of bacterial within a wound prior to selecting the irradiation wavelength to apply,39 or combining LLLT with the application of the appropriate antibacterial agents. The influences of LLLT on wound healing are explained by LLLT photons being absorbed by mitochondrial cytochrome c in skin causing an increase in adenosine triphosphate nitric oxide release, electron transport, increased blood flow, and the production of low level reactive oxygen species as a first step of photobiomodulation,37,40 and activation of diverse signaling pathways, which lead to wound healing, and prevent tissue necrosis in normal and diabetic rats.30,41 However, although there are strong indications that LLLT is effective in wound healing, there is also conflicting evidence, which means that further studies are required to determine the best wavelength/wavelengths and power parameters that optimize the potential effectiveness of LLLT.42
NEWER TREATMENTS FOR PRESSURE ULCERS
Hyperbaric oxygen therapy
Low level light therapy
Phototherapy/low-level laser therapy (LLLT) and light emitting diode illumination are used on sports injuries, C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 312–317 V
Little evidence suggests that topical oxygen therapy is beneficial in promoting ulcer healing.43,44 However, the administration of systemic hyperbaric oxygen therapy (HBOT) induces both increased collagen production and fibroblast proliferation, which are associated with improved wound healing.45 For diabetic ulcers, HBOT 313
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induces a 4.6-fold decrease in ulcer size in 70% of patients after an average of 2.5 months.27 HBOT is valuable for treating selected cases of hypoxic diabetic foot ulcers by doubling of the rate of ulcers healing, and increasing the number of wounds that are completely healed with longterm follow-up.46 In a small clinical study, combining HOBT with basic fibroblast growth factor induced the elimination of leg skin ulcers refractory to conventional therapy.47,48 The combined therapies that induce the proliferation of connective tissue in ulcers, especially collagen and noncollagenous proteins, suggest that the healing is due to the proliferation of the ulcer lesion granulation tissues.47 Thus, HBOT enhances the healing of ischemic, nonhealing diabetic leg ulcers, and appears to be a valuable adjunct to conventional therapy.49 However, larger studies are required to establish the most efficacious application of HBOT.50 Electrical stimulation
Oxidative stress plays a major role in the pathogenesis of diabetes mellitus with low levels of antioxidants accompanied by raised levels of free radical damage playing a major role in delaying wound healing. Electrical stimulation leads to an enhanced rate of ulcer elimination51 and a reduction of pain from therapy-resistant venous leg ulcers.52,53 Electrical stimulation may promote wound healing in part by stimulating blood flow by the production of nitric oxide, which changes the environment of vascular endothelial cells54 due to ultra-low microcurrents having an antioxidant effect that accelerates wound healing.55 It has been proposed that intermittent electrical stimulation induces contractions of muscles surrounding bony prominences subject to constant pressure, and that each contraction induces a reduction in internal pressure thus allowing brief periods of restoration of blood flow to the tissue56 thus inducing up to a 100% increase in tissue oxygenation of compressed muscles.57 Although different types of currents, including bidirectional currents, have been used to promote healing, there is neither a good analysis of their effects, nor a consensus on the best parameters to use to promote healing. Further, there is a lack of well-designed studies on biphasic and alternating stimulation and there is a need for improving the description of the parameters and in the uniformity of the nomenclature used.58,59 Platelet-rich plasma
As stated earlier, bacterial infection makes pressure ulcers difficult to heal. Clinically, platelet-rich plasma (PRP) assists in eliminating ulcers by acting as an antibacterial agent60 thereby significantly reducing infection rates.61 The antimicrobial action of PRP involves human beta defensin-3, which is released in bactericidal concentrations,62,63 and to functionally active complement.64 The antimicrobial activity of PRP is influenced by how the fibrin sealant65 and thrombin are prepared,66 and on the concentration of thrombin used.67 However, it must be noted that the application of thrombin alone to skin flaps increases their necrosis.68 PRP promotes tissue granulation, synthesis of extracellular matrix, tissue formation, and the inflammatory phase of 314
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the wound healing process in healthy and healing-impaired animal models and clinical trials.69 For mice, rats and rabbits, the application of PRP and plasma containing fibrin matrix to chronic diabetic foot ulcers, promotes a significant increase in tissue granulation, a decrease in the size of necrotic tissue areas and fibrosis,70 and a faster rate of wound healing, reepithelialization,71 and skin flap retention.72 The application of PRP under and on top of a skin flap 2 days prior to flap elevation further improves flap survival.73 Platelets play an essential role in promoting wound healing by releasing a host of alpha-granule growth factors including PDGF, TGF-b, and VEGF.9 PRP-released TGF-b is a potent regulator of extracellular matrix (ECM) synthesis, enhances gene expression of fibronectin and collagen, inhibits collagen breakdown, and inhibits various matrix metalloproteinase inhibitors. This leads to ECM reinforcement, fibroblast proliferation, and the synthesis and accumulation of collagen, all of which are essential for wound healing.74 For horses, PRP application induces more rapid epithelial differentiation, increasing collagen presence, and collagen matrix contraction,75 causing dense collagen bundles to be oriented parallel to each other and to the overlying epithelium, which is required for wound healing.76 Platelet-released PDGF promotes the chemotaxis of monocytes, neutrophils, and smooth muscle cells into wounds, enhances the expression of alpha-smooth muscle actin protein and the differentiation of dermal fibroblasts into myofibroblasts, which promotes wound contraction.77 In addition, it induces a significant reduction in inflammatory cells.78 PRP increases the number of viable adipocytes68 in part by the release of epidermal growth factor, which acts as a potent mitogen for keratinocytes, dermal fibroblast, macrophage proliferation, and the migration of endothelial cells into acute wounds.79 Finally, PRP improves microcirculation and angiogenesis.78 These influences appear to result from platelet release of VEGF, PDGF, and TGF-b3.72 The influences of PRP are enhanced when it is combined with manuka honey.75 This suggests that combining PRP with other techniques may induce more rapid and extensive ulcer healing. Acting through various mechanisms, the application of PRP to wounds appears to hold a greater promise of promoting wound healing than all the other techniques discussed.75 However, it is important to note that the PRP separated from whole blood by different devices yields PRP with different concentrations of platelets and different ratios of activated vs. unactivated platelets, which makes it difficult to compare the results from different experiments in which PRP was applied to pressure ulcers. Thus, it is critical to determine which blood separation device yields PRP that optimally and consistently induces maximum wound healing, and then to test the influence of PRP when combined with other wound healing techniques.
LIMITATIONS OF MANY STUDIES Instead of looking at how techniques induce pressure ulcers healing, many studies only look at the ultimate outcome of a technique, its ability to induce complete ulcer elimination and wound healing. Thus, it is difficult to compare the results between studies.80 A further limit in interpreting the conclusions of these studies is their limited C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 312–317 V
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analysis of the dangers associated with different treatments, and the possibility that the length of the follow-up periods are not adequate to fully assess the ability of a method to induce complete wound healing.80 Therefore, future studies require using larger sample sizes, more rigorous adherence to methodological standards for clinical trials, having longer follow-up periods, and more standardized and clinically meaningful outcome measures on which to base clinical practice and policy. Of all the techniques discussed, the application of PRP and VAC appear to be the most effective in inducing pressure ulcer healing followed by electrical stimulation of wounds and HBOT. However, the rate and extent of wound healing may be enhanced when PRP is combined with other techniques.
CONCLUSION Although most standard techniques have only a limited influence in promoting the healing of wounds and pressure ulcers, techniques such as the application of PRP, VAC, electrical stimulation, and HBOT show significant promise in promoting more reliable, rapid, and complete healing. Of these techniques, PRP appears to hold the greatest promise. However, further controlled studies are required to test each of these techniques singly and in various combinations to determine which induces the greatest amount of wound healing. Such studies will result in an enormous reduction in the incapacitation and pain suffered by patients with pressure ulcers, as well as yield an enormous savings of healthcare resources currently required to manage patients suffering pressure ulcers.
ACKNOWLEDGMENTS Source of Funding: No grant support was involved in the production of this article. Conflicts of Interest: The author has no conflicts, economic, or otherwise, with this article.
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with platelet-rich plasma in rabbits. J Plast Reconstr Aesthet Surg 2010; 63: e818–22. Mehrannia M, Vaezi M, Yousefshahi F, Rouhipour N. Platelet rich plasma for treatment of nonhealing diabetic foot ulcers: a case report. Can J Diabetes 2014; 38: 5–8. Sonmez TT, Vinogradov A, Zor F, Kweider N, Lippross S, Liehn EA, et al. The effect of platelet rich plasma on angiogenesis in ischemic flaps in VEGFR2-luc mice. Biomaterials 2013; 34: 2674–82. Takikawa M, Sumi Y, Ishihara M, Kishimoto S, Nakamura S, Yanagibayashi S, et al. PRP&F/P MPs improved survival of dorsal paired pedicle skin flaps in rats. J Surg Res 2011; 170: e189–96. Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res 2010; 89: 219–29. Sell SA, Wolfe PS, Spence AJ, Rodriguez IA, McCool JM, Petrella RL, et al. A preliminary study on the potential of manuka honey and platelet-rich plasma in wound healing. Int J Biomater 2012; 2012: 313781. DeRossi R, Coelho AC, Mello GS, Frazilio FO, Leal CR, Facco GG, et al. Effects of platelet-rich plasma gel on skin healing in surgical wound in horses. Acta Cir Bras 2009; 24: 276–81. Notodihardjo FZ, Kakudo N, Kushida S, Suzuki K, Kusumoto K. Bone regeneration with BMP-2 and hydroxyapatite in critical-size calvarial defects in rats. J Craniomaxillofac Surg 2012; 40: 287–91. Li W, Enomoto M, Ukegawa M, Hirai T, Sotome S, Wakabayashi Y, et al. Subcutaneous injections of plateletrich plasma into skin flaps modulate proangiogenic gene expression and improve survival rates. Plast Reconstr Surg 2012; 129: 858–66. Bertrand-Duchesne MP, Grenier D, Gagnon G. Epidermal growth factor released from platelet-rich plasma promotes endothelial cell proliferation in vitro. J Periodontal Res 2010; 45: 87–93. Saha S, Smith MEB, Totten A, Fu R, Wasson N, Rahman B, Motu’apuaka M, Hickam D. H. Pressure Ulcer Treatment Strategies: Comparative Effectiveness. Washington, D.C.: Effective Healthcare Program, Comparative Effectiveness Reviews, No. 90, USDHHS, Agency for Healthcare Research and Quality, 2013.
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Reprint requests: Damien P. Kuffler, PhD, Institute of Neurobiology, University of Puerto Rico, 201 Blvd. del Valle, San Juan, Puerto Rico 00901. Tel: 787-721-1235; Fax: 787-7251289; Email: [email protected] Manuscript received: July 8, 2014 Accepted in final form: March 13, 2015 DOI:10.1111/wrr.12284
ABSTRACT Pressure ulcers can be initiated by as little as 2 hours of constant pressure on the ski, that blocks blood circulation causing the skin and underlying tissues to die, leading to an open wound that never heals, but continues to grow in diameter and depth, and frequently jeopardizes patients’ lives. Despite the application of many diverse techniques, pressure ulcers remain exceptionally difficult to heal because many ulcer elimination techniques have minimal effects, and although other techniques may appear to be effective, the evidence supporting their efficacy is weak. However, increasing evidence indicates that other techniques, such as the application of platelet-rich plasma, vacuum assisted closure, electrical stimulation, and hyperbaric oxygen therapy are effective and should be substituted for the older techniques. This review describes different standard and novel techniques that have been tested for eliminating pressure ulcers and discusses the relative efficacy of these techniques.
Ulcers may be initiated with as little as 2 hours of constant localized pressure leading to an occlusion of the microcirculatory blood flow to the skin, and ischemia leading to tissue anoxia and inflammation a downward spiral toward ulceration,1 followed by rapid deterioration of lifestyle and death. This review examines various standard methods used to treat pressure ulcers, and provides insights into newer methods for which evidence is increasingly strong that they induce faster and more reliable ulcer elimination. In the United States, pressure ulcers affect as many as 2% of the general population, and are major sources of morbidity, mortality, and health care costs.2
STANDARD PRESSURE ULCER TREATMENTS The current standard methods of treating pressure ulcer involve eliminating the chronic pressure on the wound, cleaning the wound of necrotic debris, controlling infection, and applying growth factors and various dressings. The general hope is that these approaches will allow the living tissue around the wound to release sufficient quantities of growth factors, cytokines, and other proteins to stimulate chronic wound bed healing. Unfortunately, the standard treatments induce relatively poor wound healing rates in clinical trials.3 The application of growth factors is one approach used for trying to accelerate chronic wound healing.4,5 For animal model and clinical studies, it has been reported that nerve growth factor is more effective in decreasing the size of pressure and diabetic foot ulcers.6,7 The topical application of basic fibroblast growth factor appears to induce enhanced healing of wounds, chronic dermal ulcers, burns, and diabetic ulcers vs. what is seen for untreated wounds, due to inducing the proliferation of reparative cells that are 312
otherwise nonproliferating.8 Applied transforming growth factor-beta (TGF-b) may also promote wound healing by inhibiting proteolytic tissue destruction, and stimulating angiogenesis.9 Although some studies suggest that the topical application of platelet derived growth factor (PDGF) provides wound healing benefits, its efficacy remains controversial.1 However, caution is required in relying on the data from most such studies because they involved small sample sizes, were not randomized control trials, were of brief duration, and had short to no follow-up periods. Further, many of these studies involved their use in manners both consistent and not consistent with existing guidelines, and their levels of evidence remains low.3,10 Therefore, further studies are required to increase the levels of evidence that these techniques prevent/eliminate pressure ulcer. The presence of microbes within wounds can retard and prevent wound healing while the presence of collagen within wound sites is important for promoting all stages of ulcer healing.11,12 The application of alginate dressings, composed primarily of calcium alginate fibers, to pressure sores and infected surgical wounds induces healing.13 Catrix, a collagen-based product, promotes healing of wounds that are unresponsive to conventional treatments by promoting the growth of fibroblasts and keratinocytes within the wound, preventing the loss of fluid from the wound, and protecting wounds from bacterial infections.12 The application of Hydrofiber (ConvaTec Inc., Bridgewater, NJ) combined with a silver dressing leads to tissue granulation and a decrease in wound size14 while the use of hydrogel plus silver-based dressings are beneficial because they maintain the wound environment moist while exerting an antimicrobial influence.15 However, the antibacterial efficacy of different silver-based medications varies greatly,16 and additional larger studies are required to determine the reliability of these techniques. C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 312–317 V
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Good patient nutritional status is essential for wound healing, with protein deficiency contributing to poor healing rates with reduced collagen formation and wound dehiscence.17 Skin breakdown resulting in high exudate loss can result in a protein deficit of up to 100 g per day,18 and there is a positive correlation between low serum albumin and body mass index and the development of pressure ulcers.19 There are indications that the topical application of essential fatty acids to the entire body, including potential wound sites, may result in sufficient tissue hydration to prevent the development of pressure ulcers.20 Moderate-strength evidence indicates that pressure ulcer healing in adults is improved by protein supplement administration,2,21 although there is mixed evidence as to whether nutritional interventions prevent the development of pressure ulcers.22 Activated macrophages play a major role in almost all stages of wound healing, and their local application to ulcers may promote healing. However, prior to ulcer application, monocytes/macrophages must be activated to trigger a significant increase in the levels of expression of genes directly involved in macrophage function and wound healing, including the activation of genes involved in macrophage expression of cytokines and receptors.23 This is consistent with the observation that activated macrophages secrete cytokines such as IL-1 and IL-6, as part of the healing process.23 Thus, although macrophages application might contribute to ulcer healing, additional studies are necessary to determine whether this is true. Negative pressure therapy, vacuum-assisted closure (VAC) therapy, is clinically effective on infected surgical wounds, traumatic wounds, pressure ulcers, wounds with exposed bone and hardware, diabetic foot ulcers, and venous stasis ulcers.24 VAC therapy increases wound blood flow, speeds the formation of tissue granulation, decreases the accumulation of fluid and bacteria, accelerates healing, and alters the wound bed cytoskeleton, which triggers a cascade of intracellular signals that increase the rate of cell division and the subsequent formation of tissue granulation. VAC therapy is also rapid and effective in promoting angiogenesis with the subsequent formation of healthy tissue.25 VAC reduces patient hospitalization rates due to wound problems.26 It also results in quicker closure of chronic wounds in patients with diabetic foot and ankle ulcers, and wounds secondary to peripheral vascular disease, diabetes, or peripheral vascular disease,27,28 and significantly increases skin graft success rates when used over freshly skin-grafted wounds.29 Of all the techniques so far mentioned, VAC and the elimination of wound infection appear to be the most effective in inducing pressure ulcer healing. However, it is important to test whether combining these techniques further enhances wound elimination vs. the application each approach alone.
arthritic joints, in an attempt to reduce back and neck pain, inflammation, and induce the healing of nonhealing wounds, such as diabetic foot ulcers, pressure ulcers, venous ulcers, and post chemotherapy against radiation ulcers. The primary wavelengths tested are in the ranges of 635, 730, 810, and 980 nm. In comparative studies, exposing nonhealing chronic pressure ulcers that are unresponsive to standard medical care to wavelengths in the range of 635 and 810 nm results in their healing faster than control wounds.30 However, treatment wavelengths around 730 and 980 nm do not stimulate healing.30,31 Combining 633- and 830-nm wavelength illumination improves blood flow and neovascularization, and is claimed to induce cytokines, chemokines, and macromolecules, resulting in enhanced epithelization via the restoration of the collagen/collagenase balance in wounds,32 although the influences are predominantly associated with 830-nm wavelength illumination.32 Illumination with 470 or 630 nm light also results in a significant increase in blood perfusion, and a significant decrease in wound size, which is ascribed to the release of nitric oxide from nitrosyl complexes with hemoglobin,33 which leads to enhanced epithelialization.34 Wound illumination with 400- and 1,072-nm light induces wound healing by affecting keratin expression33 while illumination by 1,072-nm light results in a significant increase in the level of vascular endothelial growth factor (VEGF) that could lead to an enhanced immune response and faster wound healing.35 Chronic wounds may contain a number of different types of bacteria making the wounds resistant to conventional therapy. LLLT irradiation in the visible and near infrared wavelengths (400 and 1,072 nm) results in a significant reduction in the colony count of several but not all types of bacteria36,37 while illumination with light of 650 nm in association with photosensitive toluidine blue exerts an antibacterial effect on infected skin ulcers.38 These data indicate the importance of determining the type of bacterial within a wound prior to selecting the irradiation wavelength to apply,39 or combining LLLT with the application of the appropriate antibacterial agents. The influences of LLLT on wound healing are explained by LLLT photons being absorbed by mitochondrial cytochrome c in skin causing an increase in adenosine triphosphate nitric oxide release, electron transport, increased blood flow, and the production of low level reactive oxygen species as a first step of photobiomodulation,37,40 and activation of diverse signaling pathways, which lead to wound healing, and prevent tissue necrosis in normal and diabetic rats.30,41 However, although there are strong indications that LLLT is effective in wound healing, there is also conflicting evidence, which means that further studies are required to determine the best wavelength/wavelengths and power parameters that optimize the potential effectiveness of LLLT.42
NEWER TREATMENTS FOR PRESSURE ULCERS
Hyperbaric oxygen therapy
Low level light therapy
Phototherapy/low-level laser therapy (LLLT) and light emitting diode illumination are used on sports injuries, C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 312–317 V
Little evidence suggests that topical oxygen therapy is beneficial in promoting ulcer healing.43,44 However, the administration of systemic hyperbaric oxygen therapy (HBOT) induces both increased collagen production and fibroblast proliferation, which are associated with improved wound healing.45 For diabetic ulcers, HBOT 313
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induces a 4.6-fold decrease in ulcer size in 70% of patients after an average of 2.5 months.27 HBOT is valuable for treating selected cases of hypoxic diabetic foot ulcers by doubling of the rate of ulcers healing, and increasing the number of wounds that are completely healed with longterm follow-up.46 In a small clinical study, combining HOBT with basic fibroblast growth factor induced the elimination of leg skin ulcers refractory to conventional therapy.47,48 The combined therapies that induce the proliferation of connective tissue in ulcers, especially collagen and noncollagenous proteins, suggest that the healing is due to the proliferation of the ulcer lesion granulation tissues.47 Thus, HBOT enhances the healing of ischemic, nonhealing diabetic leg ulcers, and appears to be a valuable adjunct to conventional therapy.49 However, larger studies are required to establish the most efficacious application of HBOT.50 Electrical stimulation
Oxidative stress plays a major role in the pathogenesis of diabetes mellitus with low levels of antioxidants accompanied by raised levels of free radical damage playing a major role in delaying wound healing. Electrical stimulation leads to an enhanced rate of ulcer elimination51 and a reduction of pain from therapy-resistant venous leg ulcers.52,53 Electrical stimulation may promote wound healing in part by stimulating blood flow by the production of nitric oxide, which changes the environment of vascular endothelial cells54 due to ultra-low microcurrents having an antioxidant effect that accelerates wound healing.55 It has been proposed that intermittent electrical stimulation induces contractions of muscles surrounding bony prominences subject to constant pressure, and that each contraction induces a reduction in internal pressure thus allowing brief periods of restoration of blood flow to the tissue56 thus inducing up to a 100% increase in tissue oxygenation of compressed muscles.57 Although different types of currents, including bidirectional currents, have been used to promote healing, there is neither a good analysis of their effects, nor a consensus on the best parameters to use to promote healing. Further, there is a lack of well-designed studies on biphasic and alternating stimulation and there is a need for improving the description of the parameters and in the uniformity of the nomenclature used.58,59 Platelet-rich plasma
As stated earlier, bacterial infection makes pressure ulcers difficult to heal. Clinically, platelet-rich plasma (PRP) assists in eliminating ulcers by acting as an antibacterial agent60 thereby significantly reducing infection rates.61 The antimicrobial action of PRP involves human beta defensin-3, which is released in bactericidal concentrations,62,63 and to functionally active complement.64 The antimicrobial activity of PRP is influenced by how the fibrin sealant65 and thrombin are prepared,66 and on the concentration of thrombin used.67 However, it must be noted that the application of thrombin alone to skin flaps increases their necrosis.68 PRP promotes tissue granulation, synthesis of extracellular matrix, tissue formation, and the inflammatory phase of 314
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the wound healing process in healthy and healing-impaired animal models and clinical trials.69 For mice, rats and rabbits, the application of PRP and plasma containing fibrin matrix to chronic diabetic foot ulcers, promotes a significant increase in tissue granulation, a decrease in the size of necrotic tissue areas and fibrosis,70 and a faster rate of wound healing, reepithelialization,71 and skin flap retention.72 The application of PRP under and on top of a skin flap 2 days prior to flap elevation further improves flap survival.73 Platelets play an essential role in promoting wound healing by releasing a host of alpha-granule growth factors including PDGF, TGF-b, and VEGF.9 PRP-released TGF-b is a potent regulator of extracellular matrix (ECM) synthesis, enhances gene expression of fibronectin and collagen, inhibits collagen breakdown, and inhibits various matrix metalloproteinase inhibitors. This leads to ECM reinforcement, fibroblast proliferation, and the synthesis and accumulation of collagen, all of which are essential for wound healing.74 For horses, PRP application induces more rapid epithelial differentiation, increasing collagen presence, and collagen matrix contraction,75 causing dense collagen bundles to be oriented parallel to each other and to the overlying epithelium, which is required for wound healing.76 Platelet-released PDGF promotes the chemotaxis of monocytes, neutrophils, and smooth muscle cells into wounds, enhances the expression of alpha-smooth muscle actin protein and the differentiation of dermal fibroblasts into myofibroblasts, which promotes wound contraction.77 In addition, it induces a significant reduction in inflammatory cells.78 PRP increases the number of viable adipocytes68 in part by the release of epidermal growth factor, which acts as a potent mitogen for keratinocytes, dermal fibroblast, macrophage proliferation, and the migration of endothelial cells into acute wounds.79 Finally, PRP improves microcirculation and angiogenesis.78 These influences appear to result from platelet release of VEGF, PDGF, and TGF-b3.72 The influences of PRP are enhanced when it is combined with manuka honey.75 This suggests that combining PRP with other techniques may induce more rapid and extensive ulcer healing. Acting through various mechanisms, the application of PRP to wounds appears to hold a greater promise of promoting wound healing than all the other techniques discussed.75 However, it is important to note that the PRP separated from whole blood by different devices yields PRP with different concentrations of platelets and different ratios of activated vs. unactivated platelets, which makes it difficult to compare the results from different experiments in which PRP was applied to pressure ulcers. Thus, it is critical to determine which blood separation device yields PRP that optimally and consistently induces maximum wound healing, and then to test the influence of PRP when combined with other wound healing techniques.
LIMITATIONS OF MANY STUDIES Instead of looking at how techniques induce pressure ulcers healing, many studies only look at the ultimate outcome of a technique, its ability to induce complete ulcer elimination and wound healing. Thus, it is difficult to compare the results between studies.80 A further limit in interpreting the conclusions of these studies is their limited C 2015 by the Wound Healing Society Wound Rep Reg (2015) 23 312–317 V
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analysis of the dangers associated with different treatments, and the possibility that the length of the follow-up periods are not adequate to fully assess the ability of a method to induce complete wound healing.80 Therefore, future studies require using larger sample sizes, more rigorous adherence to methodological standards for clinical trials, having longer follow-up periods, and more standardized and clinically meaningful outcome measures on which to base clinical practice and policy. Of all the techniques discussed, the application of PRP and VAC appear to be the most effective in inducing pressure ulcer healing followed by electrical stimulation of wounds and HBOT. However, the rate and extent of wound healing may be enhanced when PRP is combined with other techniques.
CONCLUSION Although most standard techniques have only a limited influence in promoting the healing of wounds and pressure ulcers, techniques such as the application of PRP, VAC, electrical stimulation, and HBOT show significant promise in promoting more reliable, rapid, and complete healing. Of these techniques, PRP appears to hold the greatest promise. However, further controlled studies are required to test each of these techniques singly and in various combinations to determine which induces the greatest amount of wound healing. Such studies will result in an enormous reduction in the incapacitation and pain suffered by patients with pressure ulcers, as well as yield an enormous savings of healthcare resources currently required to manage patients suffering pressure ulcers.
ACKNOWLEDGMENTS Source of Funding: No grant support was involved in the production of this article. Conflicts of Interest: The author has no conflicts, economic, or otherwise, with this article.
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