The Controversial Use of Apligraf in the Treatment of Diabetic Foot Ulcers - Research Paper Example

 Discuss the Controversial Use of Apligraf (Graftskin) in the Treatment of Diabetic Foot Ulcers Introduction: Foot complications are major causes of hospital admissions for diabetes, and they often demand surgical procedures and prolonged length of stay. Indeed, diabetic foot complications are major global public health problems in that these foot lesions and amputations represent the most important of all long-term problems associated with the disease of diabetes and have medical, social, and economical implications. Three great pathologies come together in the diabetic foot: neuropathy, ischaemia and infection. Their combined impact is so great that it causes more amputations than any other lower limb disease. As diabetic foot problems quickly reach the point of no return, it is vital to diagnose them early and provide rapid and intensive treatment. Furthermore, it is important to achieve early recognition of the at-risk foot so as to institute prompt preventive measures. The late sequelae of diabetic peripheral neuropathy are recognized to be foot ulceration and Charcot’s neuro-arthropathy. It has been the fact that the risk of developing foot ulceration as a result of end-stage complications of neuropathy and vascular disease in diabetes is much greater than the other end-stage sequelae of diabetes, namely, retinopathy and nephropathy. The prevalence of foot ulceration in the general diabetic population is 4–10%, being lower in young and the highest in older patients. The lifetime risk for foot ulcers in diabetic patients is about 15%. Rothman’s model of causation defines a combination of neuropathy, trauma, and foot deformity to be the commonest pathways to foot ulceration and faulty healing may eventually lead to amputation. Foot ulceration and amputation affect the quality of life for patients and create an economic burden for both the patient and the health care system. Therefore, efforts to identify the patient who is at risk for foot ulceration, prevention and appropriate treatment must, of necessity, become a major priority for healthcare providers. Peripheral neuropathy and vascular disease alone do not cause foot ulceration. It is the combination of many factors that act together in the vast majority of cases. Trauma from either the patient’s shoes or from external causes, and loss of protective sensation and peripheral vascular disease are among the major contributors to foot ulceration in the diabetics. Pathologically, both large and small fibre somatic nerve damage lead to the insensate foot, but it per se does not ulcerate spontaneously. It is the combination of neuropathy with either extrinsic factors or intrinsic factors such as high foot pressures or plantar callus that results in ulceration. Long periods of high pressure due to insensitivity lead to tissue ischaemia, necrosis and ulceration. Additionally autonomic dysfunction results in blunted pressure-induced vasodilation where cutaneous blood flow in response to locally applied pressure is impaired in diabetic patients. The end results of treatments of many diabetic foot ulcerations are very disappointing, and throughout the world, health-care systems, both public and private, have been unsuccessful in managing the overwhelming problems of patients suffering with diabetic foot complications, which often result in amputations (McCabe, Stevenson, and Dolan, 1998, 80-84). Management: Most diabetic foot ulcer guidelines recommend screening and treatment algorithms that are based on an evaluation of neuropathy, skin integrity, ulcer history, deformity and vascular insufficiency. Treatment includes paring of calluses, debridement of infected or nonviable tissue, dressings, and off-loading with patient education and provision of appropriate orthoses and/or footwear. Wound control in the neuropathic and neuro-ischaemic ulcer is centred upon sharp debridement. Debridement is a procedure that is considered to be the most important part of wound control, which involves removal of all calluses surrounding the ulcer and cutting away all slough and nonviable tissues (Dinh and Veves, 2006, 348-355). Debridement is an important step in management of diabetic foot ulcers since it removes callus thus lowering plantar pressures. Moreover, after removal of dead, devitalized, and infected tissue, the true dimensions of the ulcer may be perceived. It also facilitates drainage of exudates and removal of dead tissues, so chances of infections become remote. Persistent infection in diabetics usually worsens the ulcer, and diagnosis and treatment of these infections with appropriate antibiotics improve chances of healing (Lipsky et al., 2004, 885-910). Debridement enables the surgeon to take a deep swab from the wound to be taken for culture. It is also the fact that debridement to healthy freely bleeding would margins allow the growth factors to percolate into the wound, and intact vascularity enhances chances of healing. Debridement can be viewed as restoration of a chronic would to an acute one. It is always assumed that clinicians would uniformly perform surgical debridement as part of a unified approach to the care of chronic wounds. When there is a plantar foot ulcer, it is important to reduce the pressure surrounding the wound, since there is a predilection of the ulcers to occur in the high-pressure areas of the neuropathic foot of the diabetics (Hunt, Hopf, Hussain, 2000, 6-11). As has been mentioned earlier, for reduction of foot pressures, a number of methods are used, such as, total contact casting, half-shoes, short-leg walkers, or felted dressings of foam. Of these, total contact casting is the most effective means of pressure offloading, since they have been observed to offer highest rate of healing in these ulcers. Edema has been an important hindering factor, and this offloading method effectively counteracts edema, while allowing mobility during treatment. Infection treatment is considered to be a significant step, and all diabetic foot ulcers are considered to be infected unless proved otherwise. The foot of patients with diabetes mellitus is affected by several processes which not only contribute to the development and progression of infection but on occasion alter the appearance of the foot in ways, which may obscure the clinical features of local infection. Finding purulent drainage or two or more signs or symptoms of inflammation such as erythema, induration, pain, tenderness, or warmth is indicative of infection. Clinical signs on occasion belie the significance and severity of infection (Shen and Falanga, 2003, 217-224). Fever in excess of 102°F suggests infection involving deeper spaces in the foot with tissue necrosis and undrained pus, extensive cellulitis, or bacteremia with hematogenous seeding of remote sites. It is important to classify the severity of diabetic foot infections according to the clinical manifestations. There are many classification grids available that can provide a grid to diagnose these infections. Clinically uninfected ulcers should not be cultured. When infection is present, a microbiological diagnosis will usually facilitate subsequent therapy, particularly in the setting of limb-threatening infection or failure of prior antimicrobial therapy. After cleansing the skin and debriding any overlying eschar, specimens for culture should be obtained before initiating therapy by curettage of the necrotic base of the ulcer (Akopian et al., 2006, 307-314). Concurrent antimicrobial therapy may preclude isolation of susceptible organisms during effective therapy; however, resistant organisms missed on the initial cultures can be recovered from these debridement specimens. Thus, it can be stated that the mainstay of treatment of infections in diabetic foot ulcer is debridement of all necrotic tissue and drainage of purulent collections along with antibiotic therapy based preferably on the results of the would culture. This is important to treat with antibiotics, since in many cases, the limb-threatening infections are due to polymicrobial infections. With the exception of cellulitis or lymphangitis arising from an unrecognized portal of entry, infected foot lesions generally require debridement. Debridement should be done surgically rather than by chemical or enzymatic agents. Limb-threatening infection by virtue of extension to deep tissue planes requires surgical debridement (Sweitzer et al., 2006, 197-210). This also highlights the importance of other measures of wound care in diabetic foot ulcers. The goal is to provide a clean, moist, wound-healing environment has been widely accepted. These managements are designed to prevent tissue dehydration and cell necrosis on the one hand, and on the other, such would also promote new vascular proliferation as opposed to the innate vasculopathy of diabetic foot ulcers leading to reversal of blood flow in an ischemic condition. This would also facilitate interaction of the growth factors with the target cells. If the wound dressings are moist, it would produce less discomfort. Wound bed preparation takes the driver's seat, since this ensures a healthy wound bed with maximum chance of healing (Falanga, Saap, & Zonoff, 2006, 383-390). Antibacterial wound products can be used, and use of living skin equivalents would need a meticulous wound bed preparation. In this relation, mention must be made of recombinant platelet-derived growth factors and biologic skin substitutes. Living skin equivalents are currently approved by FDA for use in diabetic foot ulcers (Zaulyanov and Kirsner, 2007, 93-98). Regarding its mechanism of action and real utility, there is considerable debate; however, it is widely believed that it leads to induction of extracellular matrix proteins, with the subsequent induction and expression of growth factors and cytokines necessary for wound healing (Mansbridge, 1998, 803-809). Apligraf: Apligraf is tissue-engineered artificial skin, which is nonimmunogenic. These are laboratory processed skin sourced from neonatal foreskin and bovine type I collagen and can serve as alternative to autologus graft (Ehrenreich and Ruszczak, 2006, 2407-2424). For patients with nonhealing ulcers such as in diabetic foot sores or venous leg ulcers, it can serve as a three-layered biological alternative since like skin; it contains living cells, structural proteins, and growth factors similar to natural skin (Trent and Kirsner, 1998, 408-413). Apligraf has been demonstrated to act as a scaffold on which natural skin can grow, and as long as it is not growing, it can provide a barrier for external infections to invade the nonhealing sore. The most important advantage perhaps is that like other grafts, it is not rejected clinically (Waugh and Sherratt, 2007, 556-565). This has been approved by FDA for use in diabetic foot ulcers and venous stasis ulcers. The living cells in it actively proliferate and lay down extracellular matrix. This active proliferation is unique in comparison to other available artificial graft materials (Karr, 2007, 270-275), since these are produced by laboratory culture of human fibroblasts in a three-dimensional scaffold, and this extracellular matrix generate papillary dermis like device that has angiogenic, growth factor, and cell adhesion properties which all combine to enhance the healing of these recalcitrant ulcers (Wong, McGrath, and Navsaria, 2007, 1149-1155). Based on these principles, this can have use in other acute conditions where skin debridement is an important parameter of the condition, including injury, burns, and other desquamating skin conditions (Curran and Plosker, 2002, 439-455). Moreover, in plastic reconstruction of the skin, effective donor site coverage could be possible with the use of Apligraf. Despite these advantages, there are several disadvantages of this product (Espensen et al., 2002, 395-397). The mechanism of action of this not agreed upon universally, although most have agreed that these engineered products can deliver important growth factors and extracellular matrix components to the wound. In many cases, graft take does not occur so readily, indicating failure (Streit and Braathen, 2000, 831-833). Moreover, these products being engineered would not have a specific match with the treatment modality justified for a particular condition. Thus the clinical effect of not outstanding, hence there would be issues with cost effectiveness, although there are quite a number of studies that calculate cost effectiveness of use of such materials from the point of view of future complications such as amputations. The question of cost effectiveness in cases of failure of this product to achieve would coverage has been raised and remain unanswered (Redekop et al., 2003, 1171-1183). Based on this information, there are questions as to the utility, and there is a perceived need for research, and the most pragmatic step would be to advocate better foot care, education, and glycemic control, rather than advocating Apligraf (Lazareth, 2002, 157-163). This is worth stressing that there are studies which advocate that majority of chronic wounds even in the diabetics would respond to conventional would care, and they have acceptable results if they are treated early in the course if treated with topical growth factors instead of Apligraf. This indicates there is debate, and literature can be examined to find evidence and reach the truth about the management of chronic ulcers such as diabetic foot ulcers. In the following section, a critical review of this literature will be presented. Literature Review: Biologic and synthetic dressings or temporary skin substitutes are available in different forms for use on chronic would beds mainly to serve as barriers. Tissue-engineered skin products are better than these due to the fact that they contain living cells and perform like human skin as opposed to these. Eaglstein and Falanga (1997, p. 895) describes the rationale of usage of these equivalents in cases where there are problems with use of autografts and allograft. Some of these problems are unavailability, discomfort, ethical issues, and chances of rejection. The authors review in detail the technique of cultured autologus keratinocyte grafts and mention several variables that determine the success. Although there are advantages of this method and the appliance, from the list of these factors, it is conceivable that there is considerable risk of failure of this grafting method. While describing the advantages, the authors did a justice in mentioning the drawbacks of this graft, such as, short-term stability, 50 to 60% short-term take, and others. Apligraf in that sense contains both viable dermis and epidermis that can reproduce cells making it morphologically, biologically and metabolically similar to human skin in terms of organized morphology and proliferation kinetics of a functionally differentiated epidermis. The authors report trial series where the clinical experience with the use of Apligraf had been analyzed. This data indicate success in a small series of 15 patients, limiting generalizability and there had been no randomization, limiting its validity. Although success rates were as high as 80%, the wound contracture took place in 10 to 15% of the patients. There were no rejections or adverse events. Although details are not available, this study also reports the results of a Falanga et al study that can prove to be promising, although the followup period was only 6 months, which appear to be inadequate given the chronic nature of these wounds. Human skin equivalents for closure of chronic skin wounds have several advantages with explicable rationale, but from these studies, it would be too early to comment on its recommended routine use in all cases of skin loss, acute or chronic. This study is further limited by the fact that the authors have been sponsored by one of the manufacturers (Eaglstein and Falanga, 1997, p. 894-905). Apligraf can be a very suitable medium for investigation of events surrounding application of different substances on the skin and can serve as an in vitro model of assessment of irritant potential of any substance that can be a potential content of skin applications. Medina et al., (2000, p. 38-45) investigates Apligraf as a predictive model of testing human skin products before actual application to human skin. The authors performed a double blind, randomized, vehicle controlled within subject study with repeated 24-hour topical applications. This study thus provides a pathway to investigate the potential of irritant substances outside human body, where Apligraf can serve as a testing ground simulating the results that could have happened in actual skin. This study also reveals the potential mechanism of injury to the skin, where the study parameters were cell viability indicated by lactate dehydrogenase leakage, release, and mRNA expression of the proinflammatory cytokines, IL-1 alpha and IL-8. Biophysical methods such as transepidermal water loss, chromametry, and blood flow all may indicate tissue death. The Apligraf being a live skin-identical application, can be a specific and sensitive method to monitor cytotoxicity, proinflammatory cytokines, and morphological changes. Apligraf can serve as an experimental model for investigating a new skin agent (Medina et al., 2000, 38-45). Brem et al. (2000, p. 627) based on their hypothesis that early intervention with biological therapy of diabetic foot and pressure ulcers would result in arrest of progression and hence in rapid healing of these chronic wounds, designed a prospective nonrandomized case study series, where human skin equivalent was used post debridement. They examined the evidence in 23 consecutive patients who had cumulatively 41 wounds ranging between 1.0 to 7.5 cm after excisional debridement, who were treated with human skin equivalents. Along with this, all patients with pressure ulcers received alternating air therapy with zero-pressure alternating air mattresses. As main outcome measures, time to 100% heal indicated by epithelialization and absence of drainage. This study indicated high efficacy of human skin equivalents to lead to complete healing in 70% of the patients, although the sample size was too small to comment on the efficacy conclusively. Although the authors highlight the success of the human skin equivalents, the results must be interpreted with caution in both the series of diabetic foot ulcers and pressure sores. The average day of healing in these were 42 days and 29 days respectively, it would be pertinent to say that this does not provide conclusive evidence as to the reduction of healing time due to absence of controls, despite the fact that failure of healing may be due to several reasons. Some recommendations however emanated from the data analysis that can be useful in clinical practice. It is clear that human skin equivalents can at least serve as the reservoir of growth factors that are lacking in a chronic wound, and these may serve as a stimulus for epithelialization and wound contraction. It may not entirely cause healing, but aggressive early therapy with antibiotics, off-loading, and biological therapy may be effective in combination, in that they can stop their progression (Brem et al., 2000, 627-634). Edmonds et al. (2000, p. S51) present their findings from review on recently introduced products dedicated to wound care. The author present here the encouraging findings from one series that support the previous finding of reduction of healing time of diabetic ulcers to 42.5 days as compared to 91 days in the control group, with this finding being statistically significant. In conclusions the authors support the promise shown by these products, but regular use should follow a guideline that would depend on further studies (Edmonds et al., 2000, p. S51-S54). Lee (2000, p. 774) presents an overview of what is known about tissue engineered skin substitutes while discussing different technical aspects of their manufacturing and utility. In the section of Apligraf, he provides information that has been discussed earlier in this assignment. The important thing to note is that he mentions a study involving 275 patients randomized to get Apligraf treatment (146) and compression treatment (129). The final result, although details of data analysis and study design were not available, demonstrated that 63% of the Apligraf cases as opposed to 49% of the compression treated cases demonstrated complete healing at 6 months. The inference was that Apligraf application led to significantly faster healing, with most prominent effect demonstrable in recalcitrant venous ulcers with no rejection despite the need of multiple applications. In the present status that commercially available Apligraf can have a single application. Although a small series, this demonstrated equal efficacy in acute wounds such as in skin wounds of excision sites of skin cancers. There is also a possibility that these may serve as a vehicle of gene therapy in future through virus transfection (Lee, 2000, 774-778). Osborne and Schmid (2002, p. 26-31) attempt to provide the experimental explanation of the success of Apligraf in these chronic ulcers from the point of view of skin biology. They hypothesize that matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) interact to develop, repair, and maintain skin health. Keratinocytes, the main cell population of the skin are regulated by MMP-2 and MMP-9. They designed an experimental study to examine the equivalence of Apligraf in terms of these proteinases and dermal-epidermal reactions. With an appropriate experimental design they demonstrated that after application to a wound, Apligraf expressed MMP-2 and MMP-9 like healthy skin in the epidermis, and TIMP was also detectable in the dermal component. Since most chronic wounds represent an imbalance between matrix production and degradation, coexpresssion of TIMP and Fibronectin in the Apligraf indicating suppression of epidermal gelatinase activity, may support epithelialization of the wound (Osborne and Schmid, 2002, 26-31). Veves et al. (2001, p. 290-295) designed a randomized prospective multicentric trial involving 24 centers in the USA with 208 patients to explore the effectiveness of Graftskin in the treatment of noninfected chronic plantar foot ulcers without any vascular compromise, where the patients were randomized into two groups, recipients of Graftskin 112 patients and other contemporary treatments 96. The last group served as the control group. Both the groups received standard surgical debridement, foot offloading, and repeated Graftskin was applied right from the beginning into 4 weeks or less depending on healing. An intention to treat analysis of the outcome was done with the end point being complete would healing at 12-week followup visit. At analysis, 56% of the Graftskin group achieved complete wound healing as opposed to 38% of the control group with a statistically significant difference (Dinh and Veves, 2006, 152S). Statistical calculation revealed that Kaplan-Meier median time for complete closure for the Graftskin group was 65 days as opposed to 90 days in the control group, which was significantly higher. The odds ratio also correlated with the complete healing with a 95% confidence interval of 1.23 to 3.74, indicating a 2.14 times more chances of complete healing with the use of Graftskin with similar adverse reactions in two groups and considerably less incidence of osteomyelitis and amputations in Graftskin group, which insures higher healing rate, and so is a useful adjunct to currently available care (Veves et al., 2001, 290-295). Martson (2004, p. 21-31) presents a review of studies involving Dermagraft, and in the section of controlled randomized trials, it is evident that Dermagraft produces better would healing in comparison to controls. In a phase III prospective single-blinded randomized controlled trial involving 314 patients, it demonstrated 1.7 times more chances of complete healing in comparison to control groups. In case of diabetic foot ulcers, initial ulcer size, infection, and glycemic control appeared to be risk factors that determined ulcer healing rate. For diabetic foot ulcers it can be concluded from the available studies that conventional treatment provide unacceptably poor results in comparison to Dermagraft or Apligraf (Martson, 2004, 21-31). Ho et al., (2005, p. 1-73) based on accumulating evidence review in detail numerous literature suggest that these bioengineered skin grafts promote wound closure effectively leading to rapid healing of diabetic foot ulcers in comparison to standard therapy within a period of 11 to 12 weeks. This benefit is more prominent in venous ulcers, and thus the treatment guidelines would favor it for the management of diabetic foot ulcers without significant adverse events such as infection, cellulitis, or osteomyelitis. This can be recommended despite initial costs since there is net cost saving at the end of one year. This may create controversy since trials that follow these patients for a period of 1 year are rare (Ho et al., 2005, 1-73). Other studies although small in volume and lacking a design rigor have preliminarily proved the efficacy of this agent in effective coverage of donor site wounds (Hu et al., 2006, 427-433) and in the surgical skin closure operations (Shealy, Jr, and DeLoach, 2006, 310-322). Conclusion: Despite disputes whether really effective in the long term, diabetic foot ulcers, as evidence from literature suggests can now be effectively treated by tissue engineered skin grafts since they provide growth factors, promote vascularization and epithelialization in a chronic nonhealing wound in diabetes especially in the foot. These behave like skin and reacts biologically to the appropriately prepared wound bed which has no infection. The chances of skin coverage with these materials are better with other general managements of diabetic foot ulcer and with glycemic control. Randomized controlled trials demonstrated that they hasten skin coverage if applied early in the disease with repeated applications within 12 weeks with less chances of complications such as amputation and osteomyelitis. Although initial costs are more, in the long run the cost effectiveness is acceptable. Many of these studies lack rigor of design, many have appropriate methodology, and on the whole despite difference in opinion, all agree that more long-term studies are necessary to establish these as mandatory for management of diabetic foot ulcers. Reference List Akopian, G., Nunnery, SP., Piangenti, J., Rankin, P., Rinoie, C., Lee, E., Alexander, M., (2006). Outcomes of conventional wound treatment in a comprehensive wound center. American Surgeons; 72(4): 314-7. Brem, H., Balledux, J., Bloom, T., Kerstein, MD., Hollier, L., (2000). Healing of Diabetic Foot Ulcers and Pressure Ulcers With Human Skin Equivalent: A New Paradigm in Wound Healing. Archive of Surgery; 135:627-634. 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Wound Repair and Regeneration; 15: 556–565 Wong, T., McGrath, JA., and Navsaria, H., (2007). The role of fibroblasts in tissue engineering and regeneration. British Journal of Dermatology;156: 1149–1155. Zaulyanov, L. and Kirsner, RS., (2007). A review of a bi-layered living cell treatment (Apligraf) in the treatment of venous leg ulcers and diabetic foot ulcers. Clinical Interventions in Aging; 2(1): 93-8. Read More