Skin Substitutes for Treating Chronic Wounds

CMS evidence review | evidence_type=Technology Assessment | record_type=technology_assessment | document_id=109 | year=2020

Normal Skin Normal healthy skin has several distinct functions. It protects underlying tissues from abrasions, 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 control blood flow 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 keratinocytes in the basal layer, which lies above the dermis, and are responsible for skin reepithelization. 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 (ECM). This skin layer provides mechanical strength and a substrate for water and nutrient diffusion; it contains blood vessels, nerves, sweat glands, hair follicles, and cells involved in immune function, growth, and repair. The subcutaneous layer is composed of adipocytes that form a thick layer of adipose tissue. Chronic Wounds Wounds are disruptions of the skin’s structural and functional integrity. Wounds normally transition through four distinct phases—hemostasis, inflammation, proliferation, and remodeling—until the skin’s structure and function are restored. Chronic wounds have failed to pass through the normal healing process in an orderly and timely manner and often remain in the inflammation phase. A wound may be considered chronic if it has not entered the proliferation phase after 4 weeks of therapy. Repeated tissue injury, microorganisms, and ECM fragments attract inflammatory immune cells and prolong the inflammatory phase. Elevated matrix metalloproteases (MMP) in chronic wounds may break down growth factors and other agents responsible for stimulating native fibroblasts to produce granulation tissue in the wound bed, a key step in wound healing. MMPs include collagenase and gelatinase. In addition, the fibroblasts in chronic wounds appear senescent and unresponsive to growth factor signals. The increased MMP levels result in ECM breakdown that prevents the wound from moving into the proliferative phase. Chronic wounds may also have deficient and defective mesenchymal stem cells (MSCs). MSCs synthesize growth factors and cytokines that affect the proliferation and remodeling phases of wound repair. Recruiting MSC into a wound may be an essential part of the wound healing process. Patients with chronic wounds experience loss of function, wound recurrence, and significant morbidity, and care of these patients is a major challenge in the United States. The majority of chronic wounds are pressure ulcers, diabetic foot ulcers, and venous leg ulcers, all of which may need specific interventions to restart the healing process. Complete healing of chronic wounds is marked by epidermis reepithelization and dermis repair. Successful healing of chronic wounds depends on critical factors, such as proper blood flow and nutrition to ensure tissue growth, infection control, maintenance of a moist environment, and removal of dead tissue to allow space for new cells and tissue to fill the wound void. According to the International Diabetes Federation Diabetes Atlas 8th edition, about 30.2 million people had diabetes in the United States in 2017. Annually, between 1 to 4 percent of individuals with diabetes will develop a foot ulcer. Among Medicare Parts A and B fee-for-service beneficiaries with diabetes, the annual incidence of diabetic foot ulcer is about 6 percent and of lower-extremity amputation about 0.5 percent. In the United States, the lifetime incidence of foot ulcers has been estimated at between 19 percent and 34 percent of those with diabetes. Recurrence of diabetic foot ulcers is high: about 40 percent of patients at 1 year and almost 60 percent within 3 years. Diabetic foot ulcers are particularly burdensome and associated with markedly increased morbidity and mortality. These wounds are associated with a high risk of limb amputation, with about 20 percent of moderate to severe diabetic foot ulcer infections leading to amputation. Mortality after amputation exceeds 70 percent at 5 years. Active or healed venous leg ulcers occur in about 1 percent of the general population; however, the prevalence, functional impact, and financial burden are greater in the elderly. Using data from the General Practice Research Database, Margolis et al. (2002) estimated the annual prevalence of venous leg ulcers among the elderly (aged 65 years or older) was 1.69 (95% CI, 1.65, 1.74), and the overall incidence rate was 0.76 (95% CI, 0.71, 0.83) per 100 person-years for men and 1.42 (95% CI, 1.35, 1.48) for women. Individuals with venous leg ulcers have a reduced quality of life due to pain, which in turn affects sleep and overall well-being. They also experience impaired physical function and reduced mobility, which often lead to loss of work and isolation. Rice et al. (2014) investigated the financial burden of venous leg ulcers in the United States using two insurance claims databases, a random sample of Medicare beneficiaries aged 65 or older, and a privately insured population aged 18 to 65. The average annual incidence rate of venous leg ulcers was 2.2 percent in Medicare patients and 0.5 percent in those with private insurance. Patients with venous leg ulcers used more medical resources and had more days missed from work, resulting in higher work-loss costs compared with patients who did not have venous leg ulcers. Using these data, the estimated annual U.S. payer burden is $14.9 billion. The incidence of pressure ulcers is increasing due to an aging population with decreased mobility and increases in morbidity associated with obesity and cardiovascular disease. Each year, more than 2.5 million people in the United States develop pressure ulcers. Two percent to 28 percent of nursing home residents have pressure ulcers. Special wound care is needed in 35 percent of nursing home residents with stage 2 or higher pressure ulcers. Once developed, pressure ulcers typically need a lengthy course of treatment, with an annual cost in the United States near $11 billion, based on data from the Healthcare Cost and Utilization Project for adult hospital stays in 2006. An analysis of the Medicare 5 percent Limited Data Set for calendar year 2014 reported on the cost of care for chronic wounds, including diabetic foot ulcers, venous leg ulcers, and pressure ulcers. In this dataset, the prevalence of infected diabetic foot ulcers was 3.4 percent, infected venous leg ulcers was 2.3 percent, and pressure ulcers was 1.8 percent. Including noninfected and infected wound costs, the estimated cost of care for diabetic foot ulcers ranged from $6.2 billion to $18.7 billion, for venous leg ulcers the range was $0.7 billion to $1.5 billion, and for pressure ulcers the range was $3.9 billion to $22 billion. The low-range estimate counted only Medicare provider payments when a wound was the claim’s primary diagnosis. The high-range estimate counted Medicare provider payments when a wound was either the primary or secondary diagnosis.

Issue: Normal Skin Normal healthy skin has several distinct functions. It protects underlying tissues from abrasions, 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 control blood flow 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 keratinocytes in the basal layer, which lies above the dermis, and are responsible for skin reepithelization. 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 (ECM). This skin layer provides mechanical strength and a substrate for water and nutrient diffusion; it contains blood vessels, nerves, sweat glands, hair follicles, and cells involved in immune function, growth, and repair. The subcutaneous layer is composed of adipocytes that form a thick layer of adipose tissue. Chronic Wounds Wounds are disruptions of the skin’s structural and functional integrity. Wounds normally transition through four distinct phases—hemostasis, inflammation, proliferation, and remodeling—until the skin’s structure and function are restored. Chronic wounds have failed to pass through the normal healing process in an orderly and timely manner and often remain in the inflammation phase. A wound may be considered chronic if it has not entered the proliferation phase after 4 weeks of therapy. Repeated tissue injury, microorganisms, and ECM fragments attract inflammatory immune cells and prolong the inflammatory phase. Elevated matrix metalloproteases (MMP) in chronic wounds may break down growth factors and other agents responsible for stimulating native fibroblasts to produce granulation tissue in the wound bed, a key step in wound healing. MMPs include collagenase and gelatinase. In addition, the fibroblasts in chronic wounds appear senescent and unresponsive to growth factor signals. The increased MMP levels result in ECM breakdown that prevents the wound from moving into the proliferative phase. Chronic wounds may also have deficient and defective mesenchymal stem cells (MSCs). MSCs synthesize growth factors and cytokines that affect the proliferation and remodeling phases of wound repair. Recruiting MSC into a wound may be an essential part of the wound healing process. Patients with chronic wounds experience loss of function, wound recurrence, and significant morbidity, and care of these patients is a major challenge in the United States. The majority of chronic wounds are pressure ulcers, diabetic foot ulcers, and venous leg ulcers, all of which may need specific interventions to restart the healing process. Complete healing of chronic wounds is marked by epidermis reepithelization and dermis repair. Successful healing of chronic wounds depends on critical factors, such as proper blood flow and nutrition to ensure tissue growth, infection control, maintenance of a moist environment, and removal of dead tissue to allow space for new cells and tissue to fill the wound void. According to the International Diabetes Federation Diabetes Atlas 8th edition, about 30.2 million people had diabetes in the United States in 2017. Annually, between 1 to 4 percent of individuals with diabetes will develop a foot ulcer. Among Medicare Parts A and B fee-for-service beneficiaries with diabetes, the annual incidence of diabetic foot ulcer is about 6 percent and of lower-extremity amputation about 0.5 percent. In the United States, the lifetime incidence of foot ulcers has been estimated at between 19 percent and 34 percent of those with diabetes. Recurrence of diabetic foot ulcers is high: about 40 percent of patients at 1 year and almost 60 percent within 3 years. Diabetic foot ulcers are particularly burdensome and associated with markedly increased morbidity and mortality. These wounds are associated with a high risk of limb amputation, with about 20 percent of moderate to severe diabetic foot ulcer infections leading to amputation. Mortality after amputation exceeds 70 percent at 5 years. Active or healed venous leg ulcers occur in about 1 percent of the general population; however, the prevalence, functional impact, and financial burden are greater in the elderly. Using data from the General Practice Research Database, Margolis et al. (2002) estimated the annual prevalence of venous leg ulcers among the elderly (aged 65 years or older) was 1.69 (95% CI, 1.65, 1.74), and the overall incidence rate was 0.76 (95% CI, 0.71, 0.83) per 100 person-years for men and 1.42 (95% CI, 1.35, 1.48) for women. Individuals with venous leg ulcers have a reduced quality of life due to pain, which in turn affects sleep and overall well-being. They also experience impaired physical function and reduced mobility, which often lead to loss of work and isolation. Rice et al. (2014) investigated the financial burden of venous leg ulcers in the United States using two insurance claims databases, a random sample of Medicare beneficiaries aged 65 or older, and a privately insured population aged 18 to 65. The average annual incidence rate of venous leg ulcers was 2.2 percent in Medicare patients and 0.5 percent in those with private insurance. Patients with venous leg ulcers used more medical resources and had more days missed from work, resulting in higher work-loss costs compared with patients who did not have venous leg ulcers. Using these data, the estimated annual U.S. payer burden is $14.9 billion. The incidence of pressure ulcers is increasing due to an aging population with decreased mobility and increases in morbidity associated with obesity and cardiovascular disease. Each year, more than 2.5 million people in the United States develop pressure ulcers. Two percent to 28 percent of nursing home residents have pressure ulcers. Special wound care is needed in 35 percent of nursing home residents with stage 2 or higher pressure ulcers. Once developed, pressure ulcers typically need a lengthy course of treatment, with an annual cost in the United States near $11 billion, based on data from the Healthcare Cost and Utilization Project for adult hospital stays in 2006. An analysis of the Medicare 5 percent Limited Data Set for calendar year 2014 reported on the cost of care for chronic wounds, including diabetic foot ulcers, venous leg ulcers, and pressure ulcers. In this dataset, the prevalence of infected diabetic foot ulcers was 3.4 percent, infected venous leg ulcers was 2.3 percent, and pressure ulcers was 1.8 percent. Including noninfected and infected wound costs, the estimated cost of care for diabetic foot ulcers ranged from $6.2 billion to $18.7 billion, for venous leg ulcers the range was $0.7 billion to $1.5 billion, and for pressure ulcers the range was $3.9 billion to $22 billion. The low-range estimate counted only Medicare provider payments when a wound was the claim’s primary diagnosis. The high-range estimate counted Medicare provider payments when a wound was either the primary or secondary diagnosis. Other Material: Other Material 1 Questions: Questions Technology Assessment: Download technology assessment .