A Closer Look At Topical Therapies In Wound Care

Given the increasing numbers of diabetic wounds among the populace and the complex environment of wounds, it is crucial to have a grasp of effective topical treatment options that can facilitate healing. These authors discuss factors that affect wound healing as well as treatment options ranging from hydrogel dressings and calcium alginate to split thickness skin grafts, foams and biologics. In the year 2030, diabetes is projected to affect 4.4 percent of the population worldwide.1 It has been estimated that upward of 15 percent of those diagnosed with diabetes will develop a foot ulceration in their lifetime.2    Therefore, having an understanding of wound healing as well as a comprehensive knowledge of common topical wound care therapies is of great importance. Having this knowledge allows one to facilitate the optimal wound healing environment based upon the type of diabetic foot ulcer (DFU) that is present. Accordingly, let us review the wound healing phases, key factors that affect wound healing and lastly common topical wound care therapies clinicians may use in the treatment of DFUs.    Wound healing is a dynamic process composed of four distinct but continuous phases. These phases are rapid hemostasis, inflammation, proliferation and remodeling.3    The rapid hemostasis phase consists of vasoconstriction and fibrin clot formation. The fibrin clot releases well-known pro-inflammatory cytokines and growth factors, such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF). These cytokines and growth factors promote chemotaxis of neutrophils, macrophages and lymphocytes.4 As these cells are stimulated, the inflammatory phase begins.    Neutrophils are the first responders during the inflammatory phase. These cells help remove invading bacteria and cellular debris. Macrophages have a similar role but subsequently go on to a phenotypic transition that stimulates and attracts cells like fibroblasts and keratinocytes. Researchers have noted that macrophages aid in the initiation of angiogenesis.5 While their role is entirely known, lymphocytes such as t-lymphocytes also hold an important role in the inflammatory phase. They are believed to release important cytokines for cell-to-cell communication, thereby helping to defend the wound from pathogens and also assist in the process of regulating inflammation. As such, this allows the proliferative phase to peak.3-6    The proliferative phase is characterized by the migration and maturation of fibroblasts and endothelial cells. These cells are necessary for wound healing as they promote collagen formation, support capillary growth and establish the foundation for granulation tissue. Fibroblasts are also extremely important in the formation of the extracellular matrix as these cells are known to produce collagen, glycosaminoglycans and proteoglycans. The proliferative phase is quite robust but eventually ceases, leading the way to the long-term phase of remodeling.    Remodeling is the last and final phase of wound healing. During this phase, the extracellular matrix is remodeled in order to support the architecture of normal tissues. Perhaps the most obvious sign of remodeling is the physical wound contraction, which occurs with the help of myofibroblasts.6 The remodeling phase is well known to be a slow process, often lasting years.

Key Factors That Have A Negative Impact On Wound Healing

Any disruption to the aforementioned wound healing phases will lead to delayed healing or chronic wounds. Some of the most common interruptions to wound healing include ischemia, sensory neuropathy and infection.    Ischemia. Oxygen is essential to all phases of wound healing as it is necessary for cellular metabolism and production of energy in the form of adenosine triphosphate. Adequate tissue oxygenation promotes angiogenesis, prevents infection and induces keratinocyte and fibroblast maturation and proliferation. This leads to re-epithelialization and formation of collagen, which aids in wound contraction.7 Ischemia in the form of peripheral vascular disease is a common complication of those afflicted with diabetes mellitus. Microvascular changes are apparent in the way of capillary size reduction and basement membrane thickening.8 This poor oxygen environment or hypoxic state often clinically appears as a dry or necrotic wound.    Peripheral sensory neuropathy. Peripheral sensory neuropathy is another contributor to a chronic DFU. In one study that looked at the causal pathway of DFUs, researchers estimated that in 78 percent of the cases, peripheral sensory neuropathy was present.9 The thinking is that peripheral sensory neuropathy initiates the development of the DFU, beginning with the patient being unable to sense pain. This leads to repetitive trauma in areas of peak pressures, disrupting normal tissues or making existing ulcerations progressively worse.10    This propagates a vicious cycle that often goes unrecognized until significant clinical changes are visible in the DFUs. Researchers have noted a decrease in important chemotactic neuropeptides (nerve growth factor, substance P and calcitonin gene-related peptide) in patients with peripheral sensory neuropathy.3 In addition, authors have shown that patients with peripheral sensory neuropathy also have deceased levels of lymphocyte infiltration.11 As such, these wounds often get “trapped” in the inflammatory phase, leading to exudative types of wounds.    Infection. After any injury or break in the skin, microorganisms can easily access deeper tissues. It is important to classify the wound into one of four categories: colonized, contaminated, with local infection or with deep infection. The large, irregular heel ulceration at left should raise concern for the potential of deep infection. Recognizing the stage of bacterial invasion helps the physician choose the proper therapy for management of infection.    If one does not adequately remove the microorganisms from the wound, the bacteria and endotoxins produced will lead to a prolonged inflammatory phase. This also often leads to increased production of inflammatory cytokines, proteases and metalloproteases that, when unregulated, will lead to degradation of the extracellular matrix.12 Other concerns include the formation of biofilms, aggregates of bacteria that often produce an extracellular polysaccharide matrix, which protects the bacteria from traditional antibiotic topical and systemic therapies.13    While we have described only a few factors that affect wound healing, one should understand there are countless causes of delayed wound healing. These factors do not act independently but rather in tandem. This makes wound healing a complex challenge. One should emphasize having a strong understanding of the underlying pathology of the DFU and perform a good clinical examination of the wound as well.

What About Enzymatic Debridement?

When it comes to topical therapy treatment of DFUs, it is helpful to categorize wounds into one of three categories: dry/necrotic, exudative or infected. Depending on the type of wound, the clinician can choose appropriate topical therapy. Topical therapies ideally should be comfortable, provide protection to the wound itself and create an optimal wound healing environment.14    Debridement of DFUs is one of the most important aspects of initial diabetic wound management.15 Often, clinicians can perform debridement quickly in the office with a scalpel or in the operating room if required for cases involving deep infection or those requiring anesthesia.    However, when a wound has a large amount of nonviable tissue, one may employ topical enzymatic debridement therapies. Diabetic foot ulcers that require frequent debridement of necrotic tissues also may benefit from more frequent enzymatic therapy application.    Collagenase (Santyl, Healthpoint Biotherapeutics) is a well known enzymatic debridement agent that works by breaking up the peptide bonds specific to collagen, therefore promoting healthy granular tissue.16 Researchers have also shown that collagenase is safe and effective for necrotic wounds as well as wounds with higher bioburden.17

Pertinent Insights On Non-Adherent, Hydrogel And Hydrocolloid Dressings

Diabetic foot ulcers that appear dry with little to no exudate, such as the ulcer in the photo at right, often have surrounding hyperkeratosis or necrotic debris within the wound. One must properly remove this nonviable material from the wound before any topical treatment can be effective. Clinicians can often accomplish this with sharp debridement in the office. Once there is adequate wound bed preparation and a healthy granular base is present, the physician can select from several topical therapies for appropriate management.    It is well known that maintaining a moist environment facilitates wound healing with several actions. These actions include: prevention of tissue dehydration and cell death; accelerating angiogenesis; increasing breakdown of necrotic tissue or fibrin; and providing an environment for optimal transport of cytokines and growth factors, allowing appropriate target cell stimulation.18 Topical therapies that help support a moist environment include non-adherents, hydrocolloids and hydrogels.    Non-adherents or low adherent dressings have been regarded as the standard treatment for most DFUs.15 These are relatively simple dressings that are designed to be atraumatic and provide a somewhat moist environment. Structurally, they consist of fine mesh-type gauze that is typically impregnated with vaseline or petroleum.19 Other benefits to traditional non-adherent dressings include low cost, their relatively hypoallergenic properties and the ability to use them in conjunction with other topical therapies, making them extremely versatile. Common commercial non-adherent dressings include Adaptic (Systagenix), Xeroform (Covidien) and Telfa (Covidien).    Hydrocolloids, with the most popular one being Duoderm (ConvaTec), are characterized as being occlusive to wound exudate, absorbent and adherent. These types of topical therapies are structurally, cross-linked dispersions of gelatin, pectin and carboxymethylcellulose along with other complex polymers and adhesives.15 The polysaccharides and polymers absorb wound exudate, expanding and creating the adherent barrier to provide a moist wound environment. While a meta-analysis has shown that there is no significant difference between using a traditional non-adherent and a hydrocolloid, authors have recommended that the clinician choose an appropriate topical therapy based on wound exudate or the lack thereof.20    Hydrogels are similar to hydrocolloids in composition and function. They are composed of polymers of hydrophilic chains. Available brand products include Tegagel (3M) and Curasol Hydrogel Saturated Dressing (Healthpoint Biotherapeutics). Accordingly, the benefits of hydrogels include absorbency, moisture support and aid in autolysis.21 Accordingly, hydrogels provide a similar environment to hydrocolloids but without the adhesive and occlusive properties. Like most of the limited research on topical wound care therapies, studies have failed to show that the use of hydrogels is superior when it comes to the treatment of diabetic wounds.22

Treating Exudative Wounds With Foams And Alginates

Exudate from open wounds can help provide a moist, good wound healing environment. However, in many situations, too much exudate overwhelms and complicates the wound healing process. Other times, the exudate is toxic and prevents proper wound healing by interfering or destroying healthy tissue.23 Exudate itself is mostly composed of water but also contains electrolytes, nutrients, inflammatory mediators, growth factors and many different types of cells involved in the wound healing phases as we previously described.24 Signs that the wound is producing either too much exudate or harmful exudate include periwound skin changes (maceration, denudation), odor, leakage or soiling of the bandage, and delayed healing. Types of topical wound care therapies that may be indicated for highly exudative DFUs include foams and alginates.    Physicians often use foams for these highly exudative wounds. Foams also provide thermal insulation and they can easily conform to the contours of irregular wounds to provide good protection in addition to providing good absorbency.15 Negative effects of foams include the inability to adhere and remove healthy tissue. They also have been reported to cause occasional dermatitis. Patients also describe the dressing as being bulky. A recent meta-analysis compared the use of foam dressings to hydrocolloids and found no significant difference.25    Alginate dressings derive from natural algae and seaweed. Restore Calcium Alginate (Hollister Wound Care) is one example of this type of dressing, which is ideal for highly exudative wounds. In addition to its absorptive properties, calcium alginate reportedly inhibits the growth of Staphylococcus aureus and limits growth of common microorganisms such as Pseudomonas aeruginosa and Streptococcus pyogenes.26 Alginate dressings can also be infused with a silver lining or other bacteriostatic agents, thereby treating wounds with higher bacterial loads. One can treat deep or irregular DFUs that are highly exudative with alginates as they also come in coiled or packable forms. Accordingly, alginate dressings are useful for a variety of different DFUs.

Can Silver And Iodine Preparations Have An Impact For Infected Wounds?

While we can often successfully treat colonized or contaminated wounds with topical antimicrobial therapies, local or deep infections may require additional oral or intravenous agents to maintain a good wound healing environment.13 The photo at right depicts a small plantar heel ulcer with a significant amount of surrounding edema and erythema. One should carefully examine this wound for the possibility of a deep infection. Common topical therapies for infected wounds include silver impregnated dressings and iodine preparations.    Silver impregnated dressings have direct antimicrobial effects. These effects include inducing direct inhibition of cellular respiration, inactivation of intracellular enzymes and alterations to the bacterial cell membrane.27 Other topical therapies include silver nitrate sticks, silver sulfadiazine ointment and other modalities that are impregnated with silver. The literature has shown elemental silver dressings to be more efficacious than silver nitrate sticks or silver ointment.28    Iodine-based preparations are antiseptic in nature with reported in vitro bactericidal rates of 0.1 to 1 percent.29 Physicians often use iodine preparations for locally infected wounds in conjunction with oral or intravenous antibiotics. Iodine preparations come in many forms, including ointments, solutions and moderately absorptive substances, thereby making iodine useful for many types of wounds, including those wounds that are moderately exudative. Commonly used forms of iodine preparations include Iodosorb (Smith & Nephew) and Betadine (Purdue Pharma). Despite the apparent usefulness and diverse utility of iodine, there is much debate as to whether iodine is effective at managing locally infected wounds.30

Assessing The Roles Of Split Thickness Skin Grafts And Biologics

The aforementioned topical therapies for the most part are cost-effective. Clinicians can apply them quickly to the affected area and patients can perform these dressing changes on their own with proper education.13 That being said, there are certain scenarios when the physician can and should employ split thickness skin grafts (STSG) and advanced topical therapies or biologics. Biologics are composed of living cells or substitutes.31    Split thickness skin grafts. Autologous split thickness skin grafts require a wound that has a good, well perfused granular base.32 Split thickness skin grafts also require a wound free of infection and it is best to utilize them in non-weightbearing areas of the foot. Common donor sites for a STSG are the ipsilateral thigh or calf. Split thickness skin grafts involve harvesting the epidermis and varying levels of thickness of the dermis with an electric dermatome. After securing the STSG to the affected site with sutures or staples, one would traditionally bolster it down with a negative pressure wound therapy device (NPWT). Researchers have demonstrated successful use of STSGs over free local flaps and muscle flaps, and most importantly, STSGs remain the gold standard for the reconstruction of diabetic foot wounds.31,32    Xenografts and allografts. Advanced biologics are similar to STSGs in that they require an infection-free, healthy, granular-based wound. Advantages to using advanced biologics over STSGs include not having to take the patient to the operating room and the lack of donor site morbidity.    Xenografts such as Oasis (Healthpoint Biotherapeutics) are derived from porcine products and contain varying thickness of dermal tissue. Researchers have shown that this modality heals chronic leg ulcers faster than compression therapy alone.33 Similarly, commonly used allografts include Apligraf (Organogenesis) and Dermagraft (Shire Regenerative Medicine), both of which contain neonatal fibroblasts as part of their wound healing components. Both products are widely used and researchers have shown them to have successful wound healing potential.34-35 Similarly, EpiFix (MiMedx) is an amniotic membrane allograft, which contains a myriad of growth factors such as EGF, PDGF and FGF, and has shown potential in healing DFUs.36    While there are many new and upcoming advanced biologics similar to the aforementioned products, more research is needed to prove the success of most of these products.

In Conclusion

The underlying pathophysiology of DFUs and their associated chronicity are very complex. It is essential that the clinician recognize the potential underlying causes (both systemic and local in nature) of the DFU and manages these causes appropriately. A good clinical examination of the DFU is of the greatest importance as this will help guide the physician toward the most appropriate topical therapy and promoting an optimal wound healing environment.    There are many available topical wound care products including products for dry/necrotic wounds, exudative wounds and wounds that are infected. Split thickness skin grafts and advanced biologics are also available for use in the appropriate situation. While the literature has shown success for the use of STSG and advanced therapies, there is little to no evidence supporting the use of one topical product over another topical product. Regardless, it is widely agreed upon that the clinician should choose a therapy based on the type of wound and its exudate.20,25    Dr. Giurini is the Chief of the Division of Podiatric Medicine and Surgery at Beth Israel Deaconess Medical Center. He is an Associate Professor in Surgery at Harvard Medical School. Dr. Giurini is a Past President and Fellow of the American College of Foot and Ankle Surgeons.    Dr. Berglund is the Chief Resident in the Division of Podiatric Medicine and Surgery at Beth Israel Deaconess Medical Center. She is a Clinical Fellow in Surgery at Harvard Medical School. References 1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004; 27(5):1047–1053. 2. Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest. 2007;117(5):1219–1222. 3. Guo S and DiPietro LA. Factors affecting wound healing. J Den Res. 2010; 89(3):219-229. 4. Broughton G, 2nd, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg. 2006; 117(7):12-34. 5. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8(12):958-969. 6. Gosain A, DiPietro LA. Aging and wound healing. World J Surg. 2004; 28(3):321-326. 7. Rodriguez PG, Felix FN, Woodley DT, Shim EK. The role of oxygen in wound healing: a review of the literature. Dermatol Surg. 2008; 34(9):1159-1169. 8. Jaap AJ, Shore AC, Stockman AJ, Tooke JE. Skin capillary density in subjects with impaired glucose tolerance and patients with type 2 diabetes. Diabet Med. 1996; 13(2):160-164. 9. Reiber GE, Vileikyte, L, Boyko EJ, et al. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care. 1999; 22(1):157-62. 10. Dinh T, Veves A. A review of the mechanisms implicated in the pathogenesis of the diabetic foot. Int J Low Extrem Wounds. 2005; 3(4):154-159. 11. Galkowska H, Olszewski WL, Wojewodzka U, Rosinski G, Karnafel W. Neurogenic factors in the impaired healing of diabetic foot ulcers. J Surg Res. 2006; 134(2):252-258. 12. Menke NB, Ward KR, Witten TM, Bonchev DG, Diegelmann RF. Impaired wound healing. Clin Dermatol. 2007; 25(1):19-25. 13. Edwards R, Harding KG. Bacteria and wound healing. Curr Opin Infect Dis. 2004; 17(2):91-96. 14. Hilton JR, Williams DT, Beuker B, Miller DR, Harding KG. Wound dressings in diabetic foot disease. Clin Infect Dis. 2004; 39(2):100-103. 15. Mulder G, Armstrong D, Seasman S. Standard, appropriate, and advanced care and medical-legal considerations: Part one – diabetic foot ulcerations. Wounds. 2003; 15(4):92-106. 16. Riley KN and Herman IM. Collagenase promotes the cellular response to injury and wound healing in vivo. J Burns Wounds. 2005; 4:e8. 17. Payne WG, Salas RE, Ko F, Naidu DK, Donate G, Wright TE, Robson MC. Enzymatic debriding agents are safe in wound with high bacterial bioburdens and stimulate healing. Eplasty. 2008; 8:e17. 18. Field CK, Kerstein MD. Overview of wound healing in a moist environment. Am J Surg. 1994; 167(1):S2-S6. 19. Moon CH, Crabtree TG. New wound dressing techniques to accelerate healing. Curr Treat Options Infect Dis. 2003; 5(3):251-260. 20. Dumville JC, Deshpande S, O’Meara S, Speak K. Hydrocolloid dressings for healing diabetic foot ulcers. Cochrane Database of Systematic Reviews. 2012; 2(2):CD009099. 21. Zhu J and Marchant RE. Design properties of hydrogel tissue-engineering scaffolds. Expert Rev Med Devices. 2011; 8(5):607-626. 22. Dumville JC, Omeara S, Deshpande S, Speak K. Hydrogel dressings for healing diabetic foot ulcers. Cochrane Database Sys Rev. 2011; 7(9):CD009101. 23. Romanelli M, Vowden K, Weir D. Exudative management made easy. Wounds Inter. 2010; 1(2). 24. Cutting KF: Exudate: Composition and functions. In: White R (ed): Trends in Wound Care: Volume III, Quay Books, London, 2004; pp. 41-49. 25. Dumville JC, Deshpande S, OMeara S, Speak K. Foam dressings for healing diabetic foot ulcers. Cochrane Database Sys Rev. 2001; 7(9):CD009111. 26. Cazzaniga AL, Marshall DA, Mertz PM. Proceedings of the 5th annual Symposium on Advanced Wound Care (New Orleans). The effect of calcium alginate dressing on the multiplication of bacterial pathogens in vitro, 1992, p. 139. 27. Russell AD, Hugo WB. Antimicrobial activity and action of silver. Prog Med Chem. 1994; 31:351-70. 28. Wright JB, Lam K, Burrell RE. Wound management in an era of increasing bacterial antibiotic resistance: a role for topical silver treatment. Am J Infect Control. 1998; 26(6):572-7. 29. Gordon J. Clinical significance of MRSA in UK hospitals and the relevance of povidone-iodine in their control. Postgrad Med J. 1993; 69(Suppl 3):106-16. 30. Mertz PM, Alvarez O, Smerbeck RV, Eaglstein WH. A new in vivo model for the evaluation of topical antiseptics on superficial wounds: the effect of 70% alcohol and povidone-iodine. Arch Dermatol. 1984; 120(1):58-62. 31. Gomez JH, Schumacher J, Lauten SD, Sartin EA, Hathcock TL, Swaim SF. Effects of 3 biologics dressings on healing cutaneous wounds on the limbs of horses. Can J Vet Res. 2004; 68(1):49-55. 32. Ramanujam CL, Zgonis T. An overview of autologous skin grafts and advanced biologics for the diabetic foot. Clin Podiatr Med Surg. 2012; 29(3):435-441. 33. Mostow EN, Haraway GD, Dalsing M, et al. Oasis venous ulcer study group. Effectiveness of an extracellular matrix graft (OASIS Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial. J Vasc Surg. 2005; 41(5):837-43. 34. Veves A. Falanga V, Armstrong DG, et al. Apligraf diabetic foot ulcer study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinic trial. Diabetes Care. 2001; 24(2):290-5. 35. Kirsner R, Warriner R, Michaela M, Stasik L, Freeman K. Advanced biological therapies for diabetic foot ulcers. Arch Dermatol. 2010; 146(8):857-862. 36. O’Donnell E. Epifix human amniotic membrane allograft use in the treatment of chronic diabetic wounds. Clinical Symposium on Advances in Skin and Wound Care. Kissimmee, Fla. September 29, 2010-October 2, 2010.    For further reading, see “A Comprehensive Review Of Topical Agents” in the July 2012 issue of Podiatry Today.