Assessing The Role And Impact Of Enzymatic Debridement

By Jonathan Moore, DPM and Pamela Jensen, DPM

Over the last few decades, many technological advances have occurred in the field of wound healing, resulting in a variety of wound dressings, ointments, creams, debriding agents, growth factors and bioengineered skin grafts. While one does not have to be a wound care specialist to treat complicated wounds, it is important to have a basic knowledge of normal wound healing and the etiology of a chronic or nonhealing wound, an understanding of the wound products available, and the ability to adapt to an ever-changing wound. Chronic, delayed or non-healing wounds demonstrate an impaired response due to the presence of bacteria, necrotic tissue, growth factor deficiencies, increased inflammatory cytokines, abnormal matrix metalloproteinase regulation, poor oxygenation of the wound and the development of cellular senescence. Recognizing the involved factor(s) that are preventing the wound from healing is the key to knowing what product to use to optimize the chemical processes that allow for wound bed preparation and facilitate healing. The exudate from chronic wounds affects wound healing in a variety of mechanisms. Exudate inhibits the proliferation and function of key resident cells and contains proteases that break down extracellular matrix proteins.1-3 Extracellular matrix components, including fibronectin, accumulate within the wound for up to a year in the life of a non-healing diabetic foot ulcer.4 With inflammatory wounds, such as venous ulcers, there is enough exudate to interfere with healing or hamper the effectiveness of therapeutic products like growth factors and bioengineered skin. In addition, fibroblasts and keratinocytes may become altered, becoming unresponsive to certain signals, including growth factors.5-9 Studies have shown these cells are not only senescent (aged), but also demonstrate decreased proliferative rates. Understanding The Importance Of Wound Bed Preparation Wound bed preparation has been defined as the global management of the wound to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures.10 This includes the use of sharp, mechanical and enzymatic debridement to convert a chronic wound into an acute wound. When we remove necrotic, devitalized tissue, we are creating an injury response that changes the molecular environment into a healing wound environment. This is the goal of wound bed preparation. Reestablishing a rejuvenation of the cellular response, decreasing bacterial burden and decreasing the amount of growth inhibiting exudate are all necessary to allow the wound to progress to healing. However, despite our best efforts at debridement, one must still address the underlying factors that have caused the chronic wound. (See “Chronic Wound Characteristics” below.) Chronic Wound Characteristics • Necrotic, fibrotic tissue within the wound bed • Poor blood flow • Recurrent tissue/wound breakdown • Degeneration of fibronectin, vitronectin • Lack of granular tissue • Lack of epithelialization • Elevated levels of cytokines • Elevated levels of matrix metalloproteinases (MMPs) • Elevated levels of proteases • Decreased levels of inhibitors for MMPs (TIMPs) • Decreased levels of protease inhibitors • Decreased growth factor activity • Decreased mitotic activity • Increased presence of senescent cells • High levels of bacterial content • High levels of multi-drug resistant organisms • Presence of bio-films • Increased likelihood of osteomyelitis • Increased likelihood of amputation Reviewing The Various Types Of Debridement Debridement certainly remains the critical first step in the process of wound healing. However, there is no specific methodology that one can universally apply to every wound. One must weigh many considerations before selecting the appropriate course of debridement. Surgical (or sharp) debridement involves the acute reduction of necrotic, devitalized tissue with sharp instruments, such as scissors, scalpels, dermatomes or curettes. Although this is the fastest type of debridement, it is invasive, may require anesthesia and/or hospitalization and must be performed with extreme caution when treating those who have peripheral vascular disease. Mechanical debridement may include wet-to-dry gauze dressings, hydrotherapy, irrigation and dextranomer bead therapy. Although it is often used and simple to perform, mechanical debridement does not discriminate between viable and nonviable tissue. Autolytic debridement occurs when the presence of phagocytic cells and endogenous proteolytic enzymes in the wound or wound fluid clear the wound bed of devitalized tissue and cellular debris. While autolytic debridement is effective, it is not predictable and may involve lengthy healing times. Chemical (enzymatic) debridement involves applying topical enzymatic agents that chemically disrupt or digest devitalized extracellular proteins in the wound. Enzymatic debridement is faster than autolytic debridement and far more conservative than sharp debridement. Papain and collagenase are the two most common proteolytic enzymes currently used for the chronic wound. Although papain (used with urea) and collagenase are both enzymatic agents with similar activity, these two preparations differ considerably with regard to acting agents, specificity and effect (see “Understanding The Differences Between Papain-Urea and Collagenase-Based Debriding Agents” below). A Closer Look At Enzymatic Debridement Options Papain-urea–based combinations. Papain is purified from the carica papaya fruit. The most commonly used papain-urea based product is Accuzyme® (Healthpoint). The mechanism of papain is attaching and breaking down any proteins containing cysteine residues. This process is nonselective as most proteins, including growth factors, contain cysteine residues. Collagen contains no cysteine residues and is therefore unaffected by papain.11 The urea component also attaches to a wide variety of proteins. However, urea’s key role in this combination is to change the three-dimensional structure of a protein. The urea disrupts the hydrogen bonds and disulfide bridges, resulting in an increased exposure of the papain to the cysteine residues. This makes the combination of products twice as effective.12,13 It is important to note that other commonly used treatments and agents for chronic wounds, such as silver sulfadiazine, gentamicin, alcohol-based products and hydrogen peroxide, can block the effects of papain-urea preparations. The primary use of a papain-urea product is for nonspecific bulk debridement with a broad pH range (3 to 12). Also keep in mind that a prominent inflammatory response and significant pain have been associated with using Accuzyme in chronic wounds. To address the significant inflammatory response and resulting pain, the papain-urea combination was modified with the addition of chlorophyllin copper complex (Panafil®, Healthpoint) in the 1950s.14 This extra ingredient is an antiagglutinin, and researchers believe its mechanism of action prevents agglutinated erythrocytes. The antiagglutinin may increase thrombus formation and fibrin deposition, resulting in the plugging of capillaries and lymphatic vessels, which, in turn, decreases inflammation and pain.15 In addition, the chlorophyllin copper complex promotes granulation and decreases wound odors. These papain-urea preparations have been used clinically for decades, especially in treating pressure ulcers. The available literature indicates that these debriding systems are effective when they are properly used, especially if one keeps in mind that they cannot substitute for surgical debridement when that is required.16,17Collagenase preparations. Collagenase is a water-soluble proteinase that specifically breaks down collagen into gelatin, allowing less specific enzymes to act. Collagenase is most effective within a narrow pH range of 6 to 8.18,19 The commercially available preparation of collagenase (Collagenase Santyl®, Smith and Nephew, Inc.) is derived from the bacteria Clostridium histolyticum. In addition, there is new evidence that elastin and fibrin are also degraded by collagenase but to a lesser degree.20 Collagenase has been found to be remarkably gentle on viable cells. The selectivity of collagenase for nonviable collagen appears to center around the protective mucopolysaccharide sheaths of viable collagen. Collagenase appears to initiate the cleavage of collagen at the necrotic tissue margins, and enzymatic debridement of tissue anchored at the central aspect of the wound can not occur until the collagen in this location is denatured.20 Making The Right Call On Enzymatic Debridement The decision to initiate the use of an enzymatic debriding agent is dependent upon the type of wound, the wound base components and the characteristics of the debriding agents. Any wound with an eschar, necrotic, fibrotic or liquifactive tissue may be a candidate for this treatment. These wounds include pressure ulcers, vericose and diabetic ulcers, burns and traumatic or infected wounds. Sharp debridement or crosshatching may be necessary to facilitate the process prior to applying enzymatic debriding agents. In order to determine the most appropriate enzymatic product for your wound, one should compare the properties of papain and collagenase, and how they will meet your wound bed preparation goals (see “Understanding The Differences Between Papain-Urea and Collagenase-Based Debriding Agents” above). Both forms of enzymatic agents have a long history of effectiveness in clinical practice, but one should also be cognizant of potential side effects as well. There are some indications that papain-based preparations may work faster but with much more pain, specifically when it comes to debriding split thickness burns. Neuropathic patients, however, tolerate papain-based enzymatic products well due to the loss of sensation. The non-selective properties of papain-based preparations increase the speed and degree of debridement but may not be appropriate for minimally fibrotic wounds. In this case, collagenase properties that debride at a slower rate and are far more selective in their mechanism may be more appropriate for this type of wound. What about maintenance debridement? With every chronic wound, cell death, chronic ischemia and fluctuations in edema result in chronic deposition of fibrotic and necrotic tissue. This necrotic tissue continues to accumulate and a mild, continuous level of debridement is necessary. In these cases that require maintenance debridement, collagenase is ideal due to its slower enzymatic debridement rate and increased selectivity. One may also use Panafil but when it comes to maintenance debridement, it tends to be used more frequently on moderately necrotic wounds. Maintenance debridement continually prepares the wound bed for healing. Both collagenase and papain-urea based preparations can stimulate granulation tissue and possibly angiogenesis. However, only collagenase has been shown to enhance or accelerate reepithelialization. Case Study One: Resolving Two Chronic Ulcerations On The Same Foot Of A Heavy Smoker A 58-year-old patient with type 2 diabetes and scleroderma developed two chronic ulcerations to her left foot. One wound was dorsal to her extensor tendon and the other wound was over her lateral malleoli. She had both wounds for over three months and both were fibrotic with little granular tissue evident. The patient was non-bypassable, smoked heavily at home and had extremely poor skin integrity. She had faintly palpable pulses with previous amputation of the distal tips of her fingers due to her scleroderma, and had poor control of her diabetes. For the lateral fibular wound, we used Panafil for approximately five to six weeks with aggressive debridement until we achieved a granular base. Subsequently, we employed Oasis for approximately two to three weeks along with zinc oxide, which led to the healing of the wound (see first two photos above right). For the dorsal wound, we used Panafil for four to six weeks along with debridement (see third and fourth photos above left). Doing so enabled us to convert the patient’s fibrotic, nonviable wound into a healthy, granular wound, which we were subsequently able to close with the use of adjunctive modalities zinc oxide and Regranex (Johnson and Johnson). Case Study Two: Healing A Diabetic Foot Wound Of An Obese, Noncompliant Patient A 63-year-old patient with uncontrolled type 2 diabetes and neuropathy developed an ulceration on the sub left hallux IPJ due to ambulation without shoewear. The ulceration became infected and the wound bed became soupy and nonviable. After we cleared the infection and controlled the wound drainage, we used Panafil to remove the extensive fibrotic, necrotic tissue from the wound bed (see photos immediately above). Doing so limited the amount of proteases within the wound and facilitated a healthy, granular wound bed. In Conclusion In the treatment of chronic wounds our understanding of their molecular environment has brought about an era of new and advanced wound healing technologies. Debridement is the first step in wound bed preparation, allowing us to prepare the wound for healing and closure by reducing bacterial load, necrotic tissue and decreasing exudate. Many therapeutic agents may be used and the experienced physician who can assess the wound clinically, minimize the factors preventing wound healing and chose the appropriate agent will be successful at managing and healing chronic wounds. Dr. Moore is a former University of Texas Diabetic Foot Fellow who is in private practice in Somerset, Ky. Dr. Jensen is the Director of the Russell County Wound Care Center and works with Dr. Moore in private practice in Somerset, Ky.



References 1. Bucalo B, Eaglstein WH, Falanga V. Inhibition of cell proliferation by chronic wound fluid. Wound Rep Regen 1993;1:181–6. 2. Trengove NJ, Stacey MC, MacAuley S, et al. Analysis of the acute and chronic wound environments: The role of proteases and their inhibitors. Wound Rep Regen 1999;7:442–52. 3. Raffetto JD, Mendez MV, Marien BJ, et al. Changes in cellular motility and cytoskeletal actin in fibroblasts from patients with chronic venous insufficiency and in neonatal fibroblasts in the presence of chronic wound fluid. J Vasc Surg 2001;33:233–41. 4. Loots MA, Lamme EN, Zeegelaar J, et al. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol 1998;111:850–7. 5. Falanga V. The chronic wound: Failure to heal. In: Falanga V (ed). Cutaneous Wound Healing. London: Martin Dunitz Publishers, 2001:155–64. 6. Stanley A, Osler T. Senescence and the healing rates of venous ulcers. J Vasc Surg 2001;33:1206–11. 7. Stanley AC, Park HY, Phillips TJ, et al. Reduced growth of dermal fibroblasts from chronic venous ulcers can be stimulated with growth factors. J Vasc Surg 1997;26:994–9. 8. Hasan A, Murata H, Falabella A, et al. Dermal fibroblasts from venous ulcers are unresponsive to the action of transforming growth factor-ß 1. J Dermatol Sci 1997;16:59–66. 9. Agren MS, Steenfos HH, Dabelsteen S, et al. Proliferation and mitogenic response to PDGF-BB of fibroblasts isolated from chronic venous leg ulcers is ulcer-age dependent. J Invest Dermatol 1999;112:463–9. 10. Falanga V. Wound bed preparation and the role of enzymes: A case for multiple actions of therapeutic agents. Wounds 2002; 14(2):47-57. 11. Smith B. Expression and regulation of the collagen family in skin. In: Falanga V (ed). Cutaneous Wound Healing. London: Martin Dunitz Publishers, 2001:57–80. 12. Miller JM, Howard F. The interaction of papain, urea, and water-soluble chlorophyll in a proteolytic ointment for infected wounds. Surgery 1958;43:939–48. 13. Silverstein P, Ruzicka FJ, Helmkamp GM, et al. In-vitro evaluations of enzymatic debridement of burn eschar. Surgery 1973;73:15–22. 14. Miller EW. Decubitus ulcers treated with papain-urea-chlorophyllin ointment. NY State J Med 1956;1446–8. 15. Morrison JE, Casali JL. Continuous proteolytic therapy for decubitus ulcers. Am J Surg 1957;93:446–8. 16. Burke JF, Golden T. A clinical evaluation of enzymatic debridement with papain/urea-chlorophyllin ointment. Am J Surg 1958;95:828–42. 17. Alvarez OM, Fernandez-Obregon A, Rogers RS, et al. Chemical debridement of pressure ulcers: A prospective, randomized, comparative trial of collagenase and papain/urea formulations. Wounds 2000;12:15–25. 18. Herman I. Stimulation of human keratinocyte migration and proliferation in vitro: Insights into the cellular responses to injury and wound healing. Wounds 1996;8:33–41. 19. Rao DB, Sane PG, Georgiev EL. Collagenase in the treatment of dermal and decubitus ulcers. J Am Geriatr Soc 1975;XXIII:22–30. 20. Hebda PA, Lo C. The effects of active ingredients of standard debriding agents—papain and collagenase—on digestion of native and denatured collagenous substrates, fibrin and elastin. Wounds 2001;13(5):190–4. 21. Howes EL. Early investigations of the treatment of third degree burns with collagenase. In: Mandl Ines (ed). Collagenase. New York, NY: Gordon and Breach Science Publishers, 1972:123-30.


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