EDITORIAL
The use of dermal substitutes in burn surgery: Acute phase
I rise to applaud the excellent review by Shahrokhi, Arno, and Jeschke on the use of dermal substitutes.1 The authors provide a very concise and complete review on the current state of dermal substitutes for the treatment of acute burns. Clearly, there has been a great deal of research along with a great deal of money spent on the development of these products. I have to disagree with their comment that “[d]ermal substitutes are becoming more and more an essential part of burn care.” They are not. The progress on all skin substitutes has not advanced significantly in the past 15 years. Although I feel that skin substitutes could make a huge impact on burn care, we have a long way to go. The publication by Shahrokhi et al., however, has sparked my desire to write a somewhat melancholy commentary on dermal, and for that matter, any skin substitute. I have been a burn surgeon for 25 years, and my research has focused, at least partially, on wound healing and scar formation. I was extremely excited when skin substitute research really started in the late 1970s and early 1980s. Yes, over 30 years ago! There was a huge interest in creating skin substitutes during those early times as the ability to grow cells in culture had become routine. It is a very simple concept to perform a biopsy, grow a patient’s skin cells, and then use this artificial skin to replace the burn. At that time (and unfortunately currently), burn patients needed to undergo skin grafting to survive a major burn. One can only cover a small area when there are limited donor sites. After harvesting a splitthickness skin graft, one had to wait 2–3 weeks before usable skin was available for reharvest. To cover a patient with 90% total body surface area (TBSA) burn would require multiple harvests, and typically, if the patient did not die of sepsis, this process would lead to a hospital length of stay of at least 1 day per percent burn (90 days). The scarring was severe, and most patients did not survive. Then in 1984, Gallico et al. published their landmark paper2 that described the survival of patients with massive burns (>90% TBSA) by growing their epithelial cells (keratinocytes) and covering their wounds with these cells— how miraculous! There was instant excitement that we could grow cells to cover people with massive burns and rapidly improve their outcomes. Soon, however, it became apparent that cultured epithelial autografts were not the panacea that was expected. First of all, the original protocol for placing these grafts was to perform a “fascial excision” which means to remove all of the fat and place the grafts on the fascia surrounding the muscle. The loss of fat led to spindly appearing extremities with large “step-offs” where normal fat existed. In addition, all cultured cells (and dermal substitutes) have little resistance to infection, so take was often very poor. Even more importantly is the fact that epithelial grafts have little resistance to shearing, so even grafts that had “taken” would be prone to blistering and shearing. We learned that we need both an epidermis and dermis, with the dermis providing the “strength and durability” of skin. Although one can currently obtain commercially processed cultured epithelial Wound Rep Reg (2014) 22 1–2 © 2014 by the Wound Healing Society
autografts, they are not used very often 30 years after the first publication of their use. When we learned that a dermis is required, many excellent investigators worked on developing dermal substitutes. Like the cultured epithelial autografts, this work was performed over 30 years ago.3 The first publication of the multicenter trial to test the efficacy of the dermal substitute “Integra” (Integra LifeSciences, Plainsboro, NJ) was published in 1986.4 As described in Dr. Shahrokhi’s review, this dermal matrix of type 1 collagen/chondroitin-6-sulfate covered by silicone rapidly became a popular substitute that would vascularize in 3–4 weeks. After the period of vascularization, the silicone “epithelium” could be peeled away, and an ultra-thin autograft could be placed on it. This was a great advance as the thinner autografts could lead to more rapid healing of donor sites and reduced chances for scarring. In addition, many Integra users even suggested that the dermal substitute would “eliminate scarring.” Although Integra is still being used with good results, it has not been a total replacement for a thick sheet autograft.5 There are still higher risks for infection with Integra that can, on occasion, lead to total loss of the product. The most important need for Integra is in the massively burned patient where infection can still be a problem. A second issue is that Integra does not “take” cultured epithelial autografts very well. Although it is a good product that has its role in burn care, it has not been as revolutionary as initially expected. There is no product that eliminates scarring. Dr. Shahrokhi et al. also describe other pure dermal products that are available around the world, most of them are either still in development or not available in the US. One of the earlier products (Alloderm, Lifecell Corporation, Bridgewater, NJ) is now rarely used in acute burn care as it acted as a barrier to the diffusion of nutrients to the autograft. It has found other roles such as a material for closure of hernias or for supporting breast reconstruction. The group also describes products that incorporate cells (especially fibroblasts), but they are mainly used to treat chronic wounds as they release growth factors. The major problem is that these products are made with allogeneic cells and therefore are eventually rejected by the host’s cells. There is no advantage for a burn patient to have a temporary dermal substitute when skin banks exist. The substitutes are significantly more expensive. It is obvious what is needed is a “composite skin substitute” that is derived from the patient’s own cells. This concept is also not a new one. Research has been done on this concept for more than 30 years. An excellent example of using composite skin substitutes has been demonstrated in many publications from the group in Cincinnati.6 Their protocol involves taking a biopsy from a massively burned patient, growing the keratinocytes, placing their fibroblasts in a dermal substitute, and putting it all together as an autologous composite skin substitute. They clearly show that this technique improves length of stay and likely survival in children with major burns. I have been fortunate to be able to use the skin in some of my patients, and it really works well. Again, my frustrations rise 1
Editorial
after describing this product as it has never been approved for use in the US by the Food and Drug Administration (FDA). Apparently, there are many regulatory hurdles that have essentially delayed the use of any composite skin autograft for the past 10 years. One can be hopeful that some autogenous skin substitute will be available at some point in the future, but the picture is not very encouraging. The fine products that Shahrokhi et al. describe are really variations on the same products that have been around for decades. Burn surgeons who have to deal with massive burns still have very few choices other than using the “old standard” of harvesting donor skin and waiting for those donor sites to heal. Yes, one can obtain cultured epithelial autografts, but they still have many problems that could be eliminated with the development of a composite skin that is made of both an autologous epidermis and dermis. I hope that soon in the future, the next review on skin substitutes describes an FDA-approved product that will really improve the outcomes of our patients. David G. Greenhalgh, MD1,2,3 Clinical Section Editor, Wound Repair and Regeneration 1. Shriners Hospitals for Children Northern California and Firefighters Regional Burn Center at University of California, 2. Department of Surgery, University of California, Davis, and 3. Burn Surgery, Shriners Hospital for Children, Sacramento, California
2
REFERENCES 1. Shahrokhi S, Arno A, Jeschke MG. The use of dermal substitutes in burn surgery: acute phase. Wound Repair Regen 2014; 22: 14–22. 2. Gallico GG, O’Connner NE, Compton CC, Kehinde O, Green H. Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 1984; 311: 448–511. 3. Yannas IV, Burke JF. Design of an artificial skin. I. Basic design principles. J Biomed Mater Res 1980; 1: 65–81. 4. Heimbach D, Luterman A, Burke J, Cram A, Herndon D, Hunt J, et al. Artificial dermis for major burns. A multi-center randomized clinical trial. Ann Surg 1988; 208: 313–20. 5. Archer SB, Henke A, Greenhalgh DG, Warden GD. The use of sheet autografts to cover patients with extensive burns. J Burn Care Rehabil 1998; 19: 33–8. 6. Boyce ST, Goretsky MJ, Greenhalgh DG, Kagan RJ, Rieman MT, Warden GD. Comparative assessment of cultured skin substitutes and native skin autograft for the treatment of full-thickness burns. Ann Surg 1995; 222: 743–52.
Wound Rep Reg (2014) 22 1–2 © 2014 by the Wound Healing Society
The use of dermal substitutes in burn surgery: Acute phase
I rise to applaud the excellent review by Shahrokhi, Arno, and Jeschke on the use of dermal substitutes.1 The authors provide a very concise and complete review on the current state of dermal substitutes for the treatment of acute burns. Clearly, there has been a great deal of research along with a great deal of money spent on the development of these products. I have to disagree with their comment that “[d]ermal substitutes are becoming more and more an essential part of burn care.” They are not. The progress on all skin substitutes has not advanced significantly in the past 15 years. Although I feel that skin substitutes could make a huge impact on burn care, we have a long way to go. The publication by Shahrokhi et al., however, has sparked my desire to write a somewhat melancholy commentary on dermal, and for that matter, any skin substitute. I have been a burn surgeon for 25 years, and my research has focused, at least partially, on wound healing and scar formation. I was extremely excited when skin substitute research really started in the late 1970s and early 1980s. Yes, over 30 years ago! There was a huge interest in creating skin substitutes during those early times as the ability to grow cells in culture had become routine. It is a very simple concept to perform a biopsy, grow a patient’s skin cells, and then use this artificial skin to replace the burn. At that time (and unfortunately currently), burn patients needed to undergo skin grafting to survive a major burn. One can only cover a small area when there are limited donor sites. After harvesting a splitthickness skin graft, one had to wait 2–3 weeks before usable skin was available for reharvest. To cover a patient with 90% total body surface area (TBSA) burn would require multiple harvests, and typically, if the patient did not die of sepsis, this process would lead to a hospital length of stay of at least 1 day per percent burn (90 days). The scarring was severe, and most patients did not survive. Then in 1984, Gallico et al. published their landmark paper2 that described the survival of patients with massive burns (>90% TBSA) by growing their epithelial cells (keratinocytes) and covering their wounds with these cells— how miraculous! There was instant excitement that we could grow cells to cover people with massive burns and rapidly improve their outcomes. Soon, however, it became apparent that cultured epithelial autografts were not the panacea that was expected. First of all, the original protocol for placing these grafts was to perform a “fascial excision” which means to remove all of the fat and place the grafts on the fascia surrounding the muscle. The loss of fat led to spindly appearing extremities with large “step-offs” where normal fat existed. In addition, all cultured cells (and dermal substitutes) have little resistance to infection, so take was often very poor. Even more importantly is the fact that epithelial grafts have little resistance to shearing, so even grafts that had “taken” would be prone to blistering and shearing. We learned that we need both an epidermis and dermis, with the dermis providing the “strength and durability” of skin. Although one can currently obtain commercially processed cultured epithelial Wound Rep Reg (2014) 22 1–2 © 2014 by the Wound Healing Society
autografts, they are not used very often 30 years after the first publication of their use. When we learned that a dermis is required, many excellent investigators worked on developing dermal substitutes. Like the cultured epithelial autografts, this work was performed over 30 years ago.3 The first publication of the multicenter trial to test the efficacy of the dermal substitute “Integra” (Integra LifeSciences, Plainsboro, NJ) was published in 1986.4 As described in Dr. Shahrokhi’s review, this dermal matrix of type 1 collagen/chondroitin-6-sulfate covered by silicone rapidly became a popular substitute that would vascularize in 3–4 weeks. After the period of vascularization, the silicone “epithelium” could be peeled away, and an ultra-thin autograft could be placed on it. This was a great advance as the thinner autografts could lead to more rapid healing of donor sites and reduced chances for scarring. In addition, many Integra users even suggested that the dermal substitute would “eliminate scarring.” Although Integra is still being used with good results, it has not been a total replacement for a thick sheet autograft.5 There are still higher risks for infection with Integra that can, on occasion, lead to total loss of the product. The most important need for Integra is in the massively burned patient where infection can still be a problem. A second issue is that Integra does not “take” cultured epithelial autografts very well. Although it is a good product that has its role in burn care, it has not been as revolutionary as initially expected. There is no product that eliminates scarring. Dr. Shahrokhi et al. also describe other pure dermal products that are available around the world, most of them are either still in development or not available in the US. One of the earlier products (Alloderm, Lifecell Corporation, Bridgewater, NJ) is now rarely used in acute burn care as it acted as a barrier to the diffusion of nutrients to the autograft. It has found other roles such as a material for closure of hernias or for supporting breast reconstruction. The group also describes products that incorporate cells (especially fibroblasts), but they are mainly used to treat chronic wounds as they release growth factors. The major problem is that these products are made with allogeneic cells and therefore are eventually rejected by the host’s cells. There is no advantage for a burn patient to have a temporary dermal substitute when skin banks exist. The substitutes are significantly more expensive. It is obvious what is needed is a “composite skin substitute” that is derived from the patient’s own cells. This concept is also not a new one. Research has been done on this concept for more than 30 years. An excellent example of using composite skin substitutes has been demonstrated in many publications from the group in Cincinnati.6 Their protocol involves taking a biopsy from a massively burned patient, growing the keratinocytes, placing their fibroblasts in a dermal substitute, and putting it all together as an autologous composite skin substitute. They clearly show that this technique improves length of stay and likely survival in children with major burns. I have been fortunate to be able to use the skin in some of my patients, and it really works well. Again, my frustrations rise 1
Editorial
after describing this product as it has never been approved for use in the US by the Food and Drug Administration (FDA). Apparently, there are many regulatory hurdles that have essentially delayed the use of any composite skin autograft for the past 10 years. One can be hopeful that some autogenous skin substitute will be available at some point in the future, but the picture is not very encouraging. The fine products that Shahrokhi et al. describe are really variations on the same products that have been around for decades. Burn surgeons who have to deal with massive burns still have very few choices other than using the “old standard” of harvesting donor skin and waiting for those donor sites to heal. Yes, one can obtain cultured epithelial autografts, but they still have many problems that could be eliminated with the development of a composite skin that is made of both an autologous epidermis and dermis. I hope that soon in the future, the next review on skin substitutes describes an FDA-approved product that will really improve the outcomes of our patients. David G. Greenhalgh, MD1,2,3 Clinical Section Editor, Wound Repair and Regeneration 1. Shriners Hospitals for Children Northern California and Firefighters Regional Burn Center at University of California, 2. Department of Surgery, University of California, Davis, and 3. Burn Surgery, Shriners Hospital for Children, Sacramento, California
2
REFERENCES 1. Shahrokhi S, Arno A, Jeschke MG. The use of dermal substitutes in burn surgery: acute phase. Wound Repair Regen 2014; 22: 14–22. 2. Gallico GG, O’Connner NE, Compton CC, Kehinde O, Green H. Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 1984; 311: 448–511. 3. Yannas IV, Burke JF. Design of an artificial skin. I. Basic design principles. J Biomed Mater Res 1980; 1: 65–81. 4. Heimbach D, Luterman A, Burke J, Cram A, Herndon D, Hunt J, et al. Artificial dermis for major burns. A multi-center randomized clinical trial. Ann Surg 1988; 208: 313–20. 5. Archer SB, Henke A, Greenhalgh DG, Warden GD. The use of sheet autografts to cover patients with extensive burns. J Burn Care Rehabil 1998; 19: 33–8. 6. Boyce ST, Goretsky MJ, Greenhalgh DG, Kagan RJ, Rieman MT, Warden GD. Comparative assessment of cultured skin substitutes and native skin autograft for the treatment of full-thickness burns. Ann Surg 1995; 222: 743–52.
Wound Rep Reg (2014) 22 1–2 © 2014 by the Wound Healing Society
