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Cover of Skin Substitutes for Treating Chronic WoundsSkin Substitutes for Treating Chronic Wounds

Заменители кожи для лечения хронических ран

Technology Assessment Report

David L Snyder, PhD, Nancy Sullivan, BA, and Karen M Schoelles, MD, SM, FACP.

ECRI Institute EPC

Rockville (MD):Agency for Healthcare Research and Quality (US);2012Dec18.




Wounds – раны

to promote – ускорять

wound closure – закрытиераны

to derive – получать

extent – степень

commonly – обычно

ulcer – язва


environment – окружающаясреда

abrasions – истирание

unwanted – нежелательное

ability to sweat – способность к потоотделению

distinct – различный

outer layer – внешний слой

subcutaneous – подкожный

sweat glands – потовые железы

adipose tissue – жировая ткань

Superficial – поверхностные

abrasions – ссадины

penetration – проникновение

consequences – последствия

lesions - поражения

shear – сдвиг

prominences – выступы

inflammatory – воспалительные

blood clot – кровяной сгусток




A wide variety of wound care products are available for clinicians to choose from when treating chronic wounds. Many of these products are said to mimic or substitute for some aspect of the skin's structure and function to promote healing and wound closure. The materials used to produce these products may be derived from human or animal tissue and may undergo extensive or minimal processing to make the finished product. The extent of processing and the source of the material used in the product also determines what regulatory pathway may be required before the product can be marketed. CMS requested this report on the types of wound care products that are commonly referred to as “skin substitutes” and on the regulatory pathways required for the different types of products. For this report, we have not created a definition for a skin substitute product. Instead we used the products listed under CMS codes Q4101 to Q4122 as a starting point and looked for similar products listed in the U.S. Food and Drug Administration (FDA) product codes to generate a list of products. We included only those products indicated for chronic wounds. We note that FDA does not refer to any product or class of products as “skin substitutes,” and we are not proposing an official classification system.

In addition to identification of the products, a second objective of this review was to begin to characterize the state of the evidence base on skin substitutes as wound care products. To address this objective, we sought to determine the number of RCTs of these products and to assess the efficacy of skin substitutes under the conditions presented in the trials. Systematically reviewing and analyzing all the clinical research on skin substitutes is beyond the scope of this report.

This report specifically examined the use of skin substitutes for treating the following chronic wound types: diabetic foot ulcers, pressure ulcers, and vascular ulcers (including venous ulcers and arterial ulcers). Treatment of burn wounds with skin substitutes is outside the scope of this report.

Normal Healthy Skin

As the interface between the environment and body, the skin has several distinct functions. It protects the underlying tissues from abrasions, the entry of microbes, unwanted water loss, and ultraviolet light damage. Tactile sensations of touch, pressure, and vibration, thermal sensations of heat and cold, and pain sensations all originate in the skin's nervous system. The body's thermoregulation relies on the skin's ability to sweat and to control the flow of blood to the skin to increase or decrease heat loss. The skin's functions are performed by three distinct tissue layers: a thin outer layer of cells called the epidermis, a thicker middle layer of connective tissue called the dermis, and an inner, subcutaneous layer. The outer layers of the epidermis are composed of flattened, cornified dead keratinocytes that form a barrier to water loss and microbe entry. These cells are derived from a basal layer of constantly dividing keratinocytes that lies next to the dermis. The epidermis does not contain nerves or blood vessels and obtains water and nutrients through diffusion from the dermis. The dermis is composed mostly of collagen fibers and some elastic fibers both produced by fibroblasts and, along with water and large proteoglycan molecules, makes up the extracellular matrix. This layer of the skin provides mechanical strength and a substrate for water and nutrient diffusion; it contains blood vessels, nerves, and cells involved in immune function, growth, and repair. The dermis also contains sweat glands, oil glands, and hair follicles. The subcutaneous layer is composed of adipocytes that form a thick layer of adipose tissue.1

Chronic Wounds

Wounds are breaches in the structure of the skin that compromise skin function. Superficial wounds such as abrasions affect mainly the epidermis and are quickly healed by growth of new keratinocytes to cover the damaged skin. Partial-thickness skin loss involves the epidermis and dermis and requires more extensive healing, especially if the wound is large. Full-thickness skin loss involves penetration through the epidermis and dermis into the subcutaneous tissue and may expose muscle and bone.

Chronic wounds have not completed the process of healing (restoring tissue loss and restoring skin function) in the expected time frame, usually within 30 days;2 have not responded to initial treatment; or persist despite appropriate care.3 These wounds usually do not close without interventions and are sometimes resistant to healing interventions. Diabetic foot ulcers, pressure ulcers or “bed sores,” vascular ulcers, and complications of surgically created sternal wounds commonly become chronic wounds because their etiologies impede healing, and they persist without proper medical care. For this review, we consider chronic wounds to be wounds present for more than 30 days and acute wounds to be those present for fewer than 30 days. Diabetic foot ulcers, venous leg ulcers, and pressure ulcers are the chronic wounds most often treated with a skin substitute.

Chronic wounds of the lower extremity (from hips to feet) affect about 6 million people in the United States, especially the elderly.3

Diabetic Foot Ulcers

http://www.oakleafmedical.com/hv/2013_sp/graphics/wounds.jpgPatients with diabetes often develop foot ulcers due to atherosclerosis that impedes blood flow to the extremities and peripheralneuropathy that prevents the sensation of discomfort associated with mechanical stress on or injury to the feet. Each of these complications of diabetes increases the probability of ulcer formation on pressure-bearing areas of the feet. Neuropathy is present in 60 percent to 70 percent of patients with diabetic foot ulcers, with 15 percent to 20 percent of patients having a combination of neuropathy and vascular problems. Patients with diabetic neuropathy are often not aware of repeated mechanical trauma, and ulcers commonly form under the foot. An estimated 16 million Americans are known to have diabetes. Among patients with diabetes, 15 percent develop a foot ulcer, and 12 percent to 24 percent of individuals with a foot ulcer require amputation.71

Diabetic foot ulcers may be classified using the Wagner Classification System.72 This system is based mainly on wound depth and consists of six wound grades. Grade 0 foot ulcers have intact skin with bony deformities or dry keratinized skin that increases the potential for ulceration, grade 1 involves ulceration of the dermis, grade 2 has ulceration involving tendons and joints, grade 3 extends to the bone and causes osteomyelitis, grade 4 shows localized gangrene, and grade 5 has gangrene involving a major portion of the foot.73 Improved foot care will often help in healing foot ulcers caused by diabetic neuropathy, but ischemic foot ulcers are often difficult to heal unless the underlying vascular problems are corrected.71,74

The major health consequences of diabetic foot ulcers are wound infections, osteomyelitis, and subsequent amputation. Individuals with severe diabetic foot ulcers may be at risk of dying due to concomitant arteriosclerotic disease involving the coronary or renal arteries. Managing diabetic foot ulcers requires appropriate therapeutic footwear, a wound dressing that provides a moist environment, débridement when necessary, antibiotic therapy if osteomyelitis or cellulitis is present, and evaluation and correction of peripheral arterial insufficiency.71,75

Pressure Ulcers

Pressure ulcers, also called “decubitus ulcers,” “bed sores,” or “pressure sores,” are defined as lesions caused by unrelieved pressure or shear resulting in damage of underlying tissue.76 These wounds often occur over bony prominences. Prolonged pressure causes ischemia, which leads to tissue necrosis that typically first occurs in the tissue closest to the bone. Ischemic cell death produces inflammation that results in blood clotting, platelet aggregation, immune complex formation, and the accumulation of inflammatory cells. Patients who are chairbound or bedridden are at increased risk for developing pressure ulcers. The following factors further increase their risk of pressure ulcer development: advanced age, impaired ability to reposition themselves, friction, decreased sensory perception, impaired nutrition, and excessive exposure to moisture (i.e., incontinence, excessive perspiration, wound drainage).77 The exact incidence and prevalence of pressure ulcers are unclear. Reports of pressure ulcer incidence vary widely, from 0.4 percent to 38.0 percent in acute care, from 2.2 percent to 24.0 percent in long-term care, and from 0 percent to 17 percent in home care.78

http://img.webmd.com/dtmcms/live/webmd/consumer_assets/site_images/media/medical/hw/h9991533_002.jpgPressure ulcers are classified in stages according to the degree of tissue damage. Stage 1 pressure ulcers are distinguished by non-blanchable redness of intact skin, stage 2 by superficial skin loss (partial-thickness skin loss of the epidermis and dermis), stage 3 by subcutaneous tissue loss (full-thickness skin loss penetrating through the epidermis and dermis into the subcutaneous tissue), and stage 4 by tissue loss that extends into the underlying muscle, tendon, or bone.77 The health consequences of pressure ulcers include local infection, sepsis, osteomyelitis, and pain.79 Local infection of pressure wounds is common and is usually controlled by débridement and antibiotics. Osteomyelitis is a risk in pressure ulcer patients because these ulcers develop over bony prominences.

Treatment of pressure ulcers centers on the following interventions: managing tissue load (i.e., pressure, friction, shearing), nutritional support, ulcer care, and managing bacterial colonization and infection.77 Usual care for pressure ulcers depends on the ulcer stage and usually includes pressure relief and skin protection to prevent progression of the ulcer to advanced stages, débridement of necrotic tissue in stage 3 and 4 ulcers, wound cleansing, and dressings that promote a moist wound environment and absorb exudate.

Vascular Leg Ulcers

Vascular leg ulcers are the result of chronic venous insufficiency (venous leg ulcers, 80 percent to 95 percent of vascular ulcers), or arterial insufficiency (arterial leg ulcers, 5 percent to 10 percent). Between 10 percent and 35 percent of the U.S. population has some type of venous disease, and lower extremity skin ulcers are reported in 1 percent to 22 percent of individuals older than age 60.80

The underlying problem in venous leg ulcers is venous hypertension in the deep and superficial venous system caused by incompetent valves and the incomplete removal of blood from the venous system. The disorder may be due to a previous blood clot that destroys the valves, a comorbid medical problem (arterial disease), or a hereditary absence of the valves in the venous system. The venous hypertension dilates capillaries and increases capillary filtration, causing edema followed by subcutaneoustissue destruction and ulcer formation. Wounds caused by venous insufficiency are hard to heal and often recur.80

Venous leg ulcers, if left untreated, may remain for years and lead to depression, anxiety, reduced activity, and a reduction in the patient's quality of life.81,82 Pain may be experienced by as many as 80 percent of venous leg ulcer patients.83 Edema of the leg is frequently associated with venous leg ulcers. The edema may be the result of the venous insufficiency, inflammation, compromised lymphatic system associated with the wound, or systemic disorders such as heart failure.84 Contact dermatitis is also common in patients with venous leg ulcers, and allergic reactions to wound dressings, topical ointments, and bandage material may hinder wound healing.

Treating venous leg ulcers involves cleaning and protecting the wound, facilitating the healing process, and providing hemodynamic support to control the underlying disorder responsible for the ulcer.80 Wound cleaning can be performed with sterile or nonsterile water or saline and gauze compresses to remove loose slough and eschar from the wound. When necessary, débridement can be performed with application of enzymes or sharp débridement procedures (forceps, scissors, lasers) before applying the dressing and compression bandages. Hemodynamic support is provided by compression bandages that counter the venous hypertension responsible for ulcer development. Compression bandages are a vital part of treating venous leg ulcers.Therapeutic compression stockings with compression of 30-40 mm Hg will counteract the capillary pressure in the tissues. Restoring blood flow through the skin reduces edema, increases oxygen and carbon dioxide exchange, and increases nutrient flow into the tissues. Compression may be applied using a single-component (a stocking or single type of bandage) or a multi-component system using several layers of material. A systematic review from 2009 examined the evidence for compressiontreatment of venous leg ulcers. According to the authors, venous ulcers heal more rapidly with compression than without and multi-component systems achieve better healing outcomes than single-component compression.85

Arterial ulcers are caused by blood-flow restriction in an artery, resulting in ischemia and ulcer development.86 Necrotic tissue with minimum exudate is common in this type of ulcer. Treatment is based on restoring perfusion to the affected tissue either through surgery or medication. Compression bandages are not typically used to treat arterial ulcers because they may increase the ischemia and the risk of amputation.87