Cultured Epidermal Autograft - Epicel; Cultured -Autologous Keratinocytes Service; CEA
Status: approved; marketed
Organizations involved:
Genzyme Biosurgery – Manuf.; R&D; Tech.; World mark.
Genzyme Corp. – Parent co.
BioSurface Technology, Inc. – R&D; Tech.; Former
Harvard Medical School – R&D; Tech.
Cross ref.: See the entry for Apligraf (#651), e.g., the Biological section, for further information about skin. See also the other cultured skin products.
Description: Epicel is both a cultured skin product and a service involving cell culture for each patient. Epicel is composed of sheets of live proliferative cultured autologous (patient’s own) keratinocytes, ranging from 2-8 cell layers thick, formed from the coalescence of cultured keratinocyte colonies, attached to a petrolatum gauze backing (surgical dressing). Autologous skin (keratinocyte) cells from a small biopsy are expanded in culture, harvested, attached to the dressing, and about 16 days later engrafted back onto the patient’s skin for treatment of severe burns or other wounds. Epicel is applied topically in direct contact with the prepared burn wound bed.
Each cultured epidermal autograft is approximately 30 cm2 in size and is individually packaged with a small amount of buffered, serum-free, nutrient medium. Trace amounts of antibiotics from culture media may adhere to each Epicel graft. A 48-hour shelf life allows these grafts to be delivered anywhere in the U.S., Europe or Japan from Genzyme Bio-surgery’s facilities in Cambridge, MA. Epicel is delivered in a cooled shipping container. This should remain closed and kept at cool room temperature (13-23˚C; 55-73˚F) until used.
Companies.: Genzyme Biosurgery. CBER/FDA est. no. 1659, formerly Genzyme Tissue Repair (est. no. 1233), manufactures and markets Epicel CEA. The product/service was originally developed by BioSurface Technology, which was acquired by Genzyme in July 1994. Genzyme Tissue Repair was the first company in the world to successfully provide cultured tissue technology, such as Epicel, as a commercial service, delivering therapeutically viable cells to patients on a reproducible basis. Epicel remains the only skin replacement product that can permanently close a burn wound, and Genzyme Bio-surgery continues to be the only company capable of providing such a product on a worldwide scale.
Nomenclature: Skin, Cultured/Epicel [BIO]; Epicel [TR]; Cultured Autologous Keratinocytes Service [used by company]; cultured epidermal autografts [SY]; CEA [SY]
Biological.: Clinical studies have shown that CEA grafts applied to wound beds composed of non-infected, well-vascularized tissue (deep dermis, vascularized fat, granulation tissue, muscle fascia) generate a permanent epidermis. When brought into contact with the wound bed, the cultured epidermal cells begin the process of attachment, replication, and differentiation. Over time, this process results in a tightly adherent, durable epidermis with a complete anchoring system.
Manufacture: Epicel is made available through an Epidermal Cell Culturing Agreement between the health care provider and Genzyme Biosurgery.
Keratinocytes are cultured in buffered, serum-free, nutrient medium containing 0.1 mg/mL streptomycin/penicillin and/or 0.04 mg/mL gentamicin. Starting with a biopsy of healthy skin about the size of a postage stamp, Genzyme Bio-surgery can grow enough skin to cover a patient’s entire body surface. Autologous keratinocytes are processed to isolate and propagate specific cell types for transplantation back onto the donor in the form of cultured epidermal autografts (CEA). Keratinocytes from the biopsy of healthy skin are isolated, placed into culture in individual flasks with a layer of irradiated murine (mouse) 3T3 feeder cells, nutritionally supported, and allowed to grow together to form sheets of tissue about the size of playing cards. The cells fully differentiate in about 6 days into a multilayered epidermis that appears clinically as a flat, shiny, smooth membrane. Once the culturing process has been completed, the skin membrane is attached to a piece of surgical dressing material (petrolatum gauze) and delivered to the burn center or clinic where it can be engrafted onto the patient. The manufacturing process takes as little as 16 days.
The following components are used during the manufacture of Epicel: anti-infective agents such as vancomycin, amikacin or amphotericin B; bovine serum; culture media supplements such as insulin, triiodothyronine, hydrocortisone, cholera enterotoxin, and epidermal growth factor; and proliferation-arrested murine fibroblasts.
FDA class: Medical Device; HDE
CBER class: xenotransplantation
Approvals: Date = 19870000; first introduction of the Epicel Cultured Epidermal Autograft service (then not requiring a formal approval)
Date = 20071029; Humanitarian Device Exemption (HDE)
Indications: [full text of the " indications: FOR USE" section of product insert/labeling, 8/26/2008]:
Epicel is indicated for use in patients who have deep dermal or full thickness burns comprising a total body surface area of greater than or equal to 30%. It may be used in conjunction with split-thickness autografts, or alone in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns.
Status: Until its HDE approval in Oct. 2007, Epicel CEA was loosely regulated (implicitly as a biologic) as a service, involving culture of autologous cells (which, technically, does not require FDA approval), rather than as a product. Although involving the patient’s own cells, Epicel was considered by FDA to fall under xenotrans-plan-tation regulations, due to use of the irradiated mouse 3T3 feeder cells during manufacture. Genzyme has demonstrated that no infectious agents are transferred in the cultured human cells (and Epicel is often cited as a prototype for safety of a xenotrans-plantation-type product).
Genzyme it applied for FDA approval of Epicel in 1999. Epicel, as a product, had been considered a banked human tissue until 1996 when the FDA announced that manipulated autologous cell-based products used for structural repair or reconstruction required regulatory approval. Epicel is defined by the Public Health Service (PHS) Guideline on Infectious Disease Issues in Xenotransplantation and the FDA Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans as a xenotrans plantation product because it is manufactured by co-cultivation with proliferation-arrested mouse, 3T3, fibroblast feeder cells.
On Oct. 29, 2007, Epicel received Humanitarian Device Exemption (HDE) from CBER, FDA, for the treatment of life-threatening wounds resulting from severe burns. Epicel is the first xenotransplantation-classified product to be formally approved in the U.S.
The Epicel product/service is marketed in many European and other countries. But no centralized EU approval has been granted.
Tech. transfer: The keratinocyte membrane cell culturing technology used to produce Epicel skin grafts was developed over 20 years ago by Dr. H. Green (and collaborators), Harvard Medical School, and has been exclusively licensed by Genzyme. U.S. patents covering aspects of Epicel include: 4,016,036; 4,304,866; 4,456,687; 5,040,677; 5,100,676; and 5,145,770. Other relevant patents include Canada (1,083,987; 1,159,777); France (76-34,110); Germany (P2651685.8-09); Japan (1,134,191) and United Kingdom (1,514,629).
Medical: Many burn victims are treated with a procedure known as autografting, in which a physician replaces a patient’s damaged skin with a thin layer of healthy skin from another part of the body. In the case of severe and extensive burns, however, a physician may determine that there is not enough healthy skin available to cover the affected area. People with severe burns over a large area of the body often die within days after sustaining this injury. A severe burn can destroy both the epidermis and dermis, leaving the skin unable to regenerate on its own to cover the wound, protect it from infection, and protect the underlying muscle and organs. When treating patients with severe burns, the injured area must be covered quickly with a skin replacement to retain the body’s fluids and prevent infection. Epicel cultured epidermal autografts are the only form of permanent skin replacement available for patients with such life-threatening burns.
Experience with pediatric burn patients receiving CEA grafts has revealed that the dermoepidermal junction is reformed in 3 to 4 weeks. Hemidesmosomes, basal lamina, and anchoring fibrils are re-established along the attachment face of the CEA, as they are in the interstices of meshed split-thickness skin autografts (meshed grafts). Full maturation of anchoring fibrils of an epidermis generated from CEA requires more than a year. Langerhans cells begin to repopulate the grafted area within 1 week, reaching normal densities within 2-6 months, and exceeding normal skin density by 2-3 fold in graft sites older than 1 year. Melanocytes are present in the CEA, but may not be fully functional for an extended period of time. The subjacent connective tissue initially resembles normal scar tissue, but remodels over the ensuing 4-5 years to resemble a vascularized dermis with distinct papillary and reticular layers containing elastic fibers. The regenerated skin remains devoid of sweat glands, hair follicles and sebaceous glands, as do the interstices of meshed grafts.
Market: The Average Wholesale Price (AWP) is not available (not in 20007, 2005 or 2004 Red Book).
Epicel is a very minor product with negligible sales for Genzyme Biosurgery. The company has reported in recent years that it provided Epicel for about 75 burn patients a year, with only 600 patients worldwide having received the Epicel service since it was introduced in 1987 (averaging <100 patients/year). Total Epicel revenues for 1999 were $5.1 million, and $6.0 million in 1998.
Epicel skin grafts are used at major burn centers in the U.S,, France, and Germany. The product has also been used in Japan and Canada.
Companies involvement:
Full monograph
653 Skin, Cultured/Epicel
Nomenclature:
Skin, Cultured/Epicel [BIO]
Epicel [TR]
Cultured Autologous Keratinocytes Service [used by company]
cultured epidermal autografts (CEA) [SY]
CEA [SY]
FDA Class: Device HDE
Year of approval (FDA) = 2007
Date of 1st FDA approval = 20071028
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
human materials used<!-- humansource -->
murine (mouse) materials used
skin replacements
3-beta-D-ribosyl(1-1)ribitol(5-phosphate)-PRP
bovine serum
cells, human <!-- humancellculture -->
chlortetracycline
enzymes, fibrinolytic/thrombolytic
gentamicin (gentamycin)
human keratinocytes
hydrocortisone
insulin, bovine
keratinocytes, human
mammalian cell culture
media, serum-free
murine feeder cells
penicillin
streptomycin
triiodothyronine
vaginitis
amidolysis assays
amphotericin B
gentamicin (gentamycin)
petrolatum gauze
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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