Skin Substitutes and Wound Healing: Current Status and Challenge
Skin Substitutes and Wound Healing: Current Status and Challenge
Bioengineered skin substitutes have emerged over the past 20 years as the most carefully studied and proven of the advanced wound management technologies. While the initial impetus for their development was to replace autograft, allograft, and xenograft in burn applications, they have found even wider application in the treatment of chronic venous and chronic diabetic ulcers. The current review addresses the history of skin substitutes, surveys the landscape of existing Food and Drug Administration-approved products and other promising innovations that appear close to market, and discusses the reasoning and controversies associated with design of these products. While acellular biologic constructs are discussed, the authors focus on products that include autologous or allogeneic cells. The various clinical trials supporting the use of skin substitutes for different wound healing indications are reviewed. The preponderance of literature supports the cost effectiveness of using skin substitutes in healing burn, autograft donor site, diabetic, and venous wounds. In addition, better methods for early identification of diabetic and venous ulcers that may not heal well with standard treatment should improve the process of triaging candidates for skin substitute therapy. In the future, attaining a more detailed understanding of the mechanisms by which skin substitutes induce accelerated healing, including a better appreciation of the roles of cytokines and cell scaffolds, may lead to product enhancements that increase efficacy. Ongoing progress toward overcoming issues, such as abbreviated shelf life and distribution difficulties, as well as high manufacturing costs, should enable broader implementation of skin substitutes in acute and chronic wound therapy.
In the 1980s, the emergence of tissue engineered skin substitutes and cultured skin cells ("cell-based wound therapy") for use as experimental wound healing therapies was motivated primarily by the critical need for early coverage of extensive burn injuries in patients with insufficient sources of autologous skin for grafting. Since then, skin substitutes have been widely used to address the prevalent problem of chronic wounds associated with non-burn etiologies. The treatment of such hard-to-heal, chronic, open wounds has assumed increasing importance as the aged segment of the population in the United States and the rest of the industrialized world has increased and as the incidence of comorbid states, such as diabetes mellitus and atherosclerosis, has increased. To put these wound healing indications into quantitative perspective, the annual incidence of serious burns in the United States is estimated at 70,000; the prevalence of venous leg ulcers is between 600,000 and 1,500,000; and 15 to 20 percent of people with diabetes eventually suffer a chronic foot wound. The direct cost, in the US, of dressings alone for all these conditions has been estimated at over $5 billion per year.
Concurrent with the increasing socioeconomic importance of wound management, an infusion of scientific understanding of the cellular and biochemical steps involved in wound repair has spawned multiple new advanced technologies that may be applied to treat nonhealing wounds. The old paradigm for wound management was essentially passive: to remove impediments to wound healing (e.g., uncontrolled diabetes mellitus, infection, and ischemia) and allow nature to take its course. The contemporary approach, while not ignoring these basics, seeks to more actively intervene and improve upon natural healing using such modalities as hyperbaric oxygen, electrical stimulation, skin surface negative pressure, exogenous growth factors and bioengineered skin substitutes. Thus, a "one-size-fits-all" approach, whereby a clinician would use his favorite dressing on most wounds, has given way to individualization of therapy based upon the physiology of each particular patient and wound. The current challenge for clinicians is to understand the relative merits and roles of each available technology. One objective of this review will be to compare and contrast various commercial or nearly-commercial skin substitutes and cell-based wound therapies, and illustrate their roles in wound management.
A variety of acellular matrices that are used to promote regenerative skin wound healing, such as Alloderm (LifeCell Corporation, Branchburg, New Jersey), Oasis (Healthpoint Ltd., Fort Worth, Texas), Integra Dermal Regeneration Template (Integra Life Sciences Holding Co., South Plainfield, New Jersey) and Biobrane (Bertek Pharmaceuticals, Sugarland, Texas) are generally included in the skin substitute category; these have been reviewed elsewhere and will be mentioned briefly here, but will not be the focus of this discussion. Cultured epithelial autografts, acellular dermal matrices, as well as composite dermal/epidermal cultured autografts, can act as autograft alternatives to provide life-saving skin replacement. Many recent reviews have summarized the history and current status of skin substitutes made with acellular matrices or with autologous cells. Other authors have provided encyclopedic overviews of the landscape of biological skin substitutes. The authors of this review aim not to repeat a detailed summary of all available skin substitute and cell-based wound therapy devices, but rather to consider current advances and challenges within this field and to use particular products to exemplify various concepts. Also, while many centers have reported limited experience with "home-grown" cell-based wound therapies, most of which are technical variations on the platform of cultured autologous keratinocytes, alone or in combination with a dermal layer, the authors will focus primarily on cellular, mostly allogeneic, commercial devices that already have achieved or appear to be nearing Food and Drug Administration (FDA) approval.
Abstract and Introduction
Abstract
Bioengineered skin substitutes have emerged over the past 20 years as the most carefully studied and proven of the advanced wound management technologies. While the initial impetus for their development was to replace autograft, allograft, and xenograft in burn applications, they have found even wider application in the treatment of chronic venous and chronic diabetic ulcers. The current review addresses the history of skin substitutes, surveys the landscape of existing Food and Drug Administration-approved products and other promising innovations that appear close to market, and discusses the reasoning and controversies associated with design of these products. While acellular biologic constructs are discussed, the authors focus on products that include autologous or allogeneic cells. The various clinical trials supporting the use of skin substitutes for different wound healing indications are reviewed. The preponderance of literature supports the cost effectiveness of using skin substitutes in healing burn, autograft donor site, diabetic, and venous wounds. In addition, better methods for early identification of diabetic and venous ulcers that may not heal well with standard treatment should improve the process of triaging candidates for skin substitute therapy. In the future, attaining a more detailed understanding of the mechanisms by which skin substitutes induce accelerated healing, including a better appreciation of the roles of cytokines and cell scaffolds, may lead to product enhancements that increase efficacy. Ongoing progress toward overcoming issues, such as abbreviated shelf life and distribution difficulties, as well as high manufacturing costs, should enable broader implementation of skin substitutes in acute and chronic wound therapy.
Introduction
In the 1980s, the emergence of tissue engineered skin substitutes and cultured skin cells ("cell-based wound therapy") for use as experimental wound healing therapies was motivated primarily by the critical need for early coverage of extensive burn injuries in patients with insufficient sources of autologous skin for grafting. Since then, skin substitutes have been widely used to address the prevalent problem of chronic wounds associated with non-burn etiologies. The treatment of such hard-to-heal, chronic, open wounds has assumed increasing importance as the aged segment of the population in the United States and the rest of the industrialized world has increased and as the incidence of comorbid states, such as diabetes mellitus and atherosclerosis, has increased. To put these wound healing indications into quantitative perspective, the annual incidence of serious burns in the United States is estimated at 70,000; the prevalence of venous leg ulcers is between 600,000 and 1,500,000; and 15 to 20 percent of people with diabetes eventually suffer a chronic foot wound. The direct cost, in the US, of dressings alone for all these conditions has been estimated at over $5 billion per year.
Concurrent with the increasing socioeconomic importance of wound management, an infusion of scientific understanding of the cellular and biochemical steps involved in wound repair has spawned multiple new advanced technologies that may be applied to treat nonhealing wounds. The old paradigm for wound management was essentially passive: to remove impediments to wound healing (e.g., uncontrolled diabetes mellitus, infection, and ischemia) and allow nature to take its course. The contemporary approach, while not ignoring these basics, seeks to more actively intervene and improve upon natural healing using such modalities as hyperbaric oxygen, electrical stimulation, skin surface negative pressure, exogenous growth factors and bioengineered skin substitutes. Thus, a "one-size-fits-all" approach, whereby a clinician would use his favorite dressing on most wounds, has given way to individualization of therapy based upon the physiology of each particular patient and wound. The current challenge for clinicians is to understand the relative merits and roles of each available technology. One objective of this review will be to compare and contrast various commercial or nearly-commercial skin substitutes and cell-based wound therapies, and illustrate their roles in wound management.
A variety of acellular matrices that are used to promote regenerative skin wound healing, such as Alloderm (LifeCell Corporation, Branchburg, New Jersey), Oasis (Healthpoint Ltd., Fort Worth, Texas), Integra Dermal Regeneration Template (Integra Life Sciences Holding Co., South Plainfield, New Jersey) and Biobrane (Bertek Pharmaceuticals, Sugarland, Texas) are generally included in the skin substitute category; these have been reviewed elsewhere and will be mentioned briefly here, but will not be the focus of this discussion. Cultured epithelial autografts, acellular dermal matrices, as well as composite dermal/epidermal cultured autografts, can act as autograft alternatives to provide life-saving skin replacement. Many recent reviews have summarized the history and current status of skin substitutes made with acellular matrices or with autologous cells. Other authors have provided encyclopedic overviews of the landscape of biological skin substitutes. The authors of this review aim not to repeat a detailed summary of all available skin substitute and cell-based wound therapy devices, but rather to consider current advances and challenges within this field and to use particular products to exemplify various concepts. Also, while many centers have reported limited experience with "home-grown" cell-based wound therapies, most of which are technical variations on the platform of cultured autologous keratinocytes, alone or in combination with a dermal layer, the authors will focus primarily on cellular, mostly allogeneic, commercial devices that already have achieved or appear to be nearing Food and Drug Administration (FDA) approval.