Human Fibroblast-Derived Dermal Substitute - Dermagraft; Interactive Wound Dressing
Status: withdrawn from the market; recently relaunched
Organizations involved:
Advanced BioHealing, Inc.. – Manuf.; R&D; Tech.; World mark.
Advanced Tissue Sciences Inc. – Former
Smith & Nephew, Inc. – Former
Smith & Nephew plc – Parent; Former
Massachusetts Inst. of Tech. (MIT) – R&D; Tech.
Children’s Medical Center Corp. – R&D; Tech.
Marrow-Tech, Inc. – Former
Cross ref.: See the entry above for Apligraf, a product also involving culture from neonatal foreskin, particularly the Biological section, for further information about skin. See also the other cultured skin products. See the entry (#657) for TransCyte (Derma--graft-TC), which is similar to Dermagraft but contains non-viable cells on a non-biodegradable mesh. See the entry below for MySkin, a product similar to Dermagraft.
Description: Dermagraft is a cryopreserved (frozen) human fibroblast-derived dermal substitute composed of viable (living) fibroblasts (cuºººtach, are further cultured, form human dermal-like tissue, and the sheets are frozen and shipped. The manufacturing method mimics the conditions of the body, so that in a 2-6 week period of time the cells divide and secrete growth factors, natural collagens, and glycosaminoglycans to form a functional dermal construct able to support the migration, growth, and differentiation of the patient’s own keratinocytes (i.e., form an outer epidermal layer).
Dermagraft delivers living fibroblasts along with naturally secreted matrix components to the patient’s wound bed. This provides living, metabolically active human dermal tissue capable of interacting with the wound bed and facilitating tissue repair and healing. Once applied, Dermagraft fibroblast cells produce large amounts of extracellular matrix proteins, vascular endothelial growth factor (VEGF), and other growth factors that induce angiogenesis and endothelialization to facilitate wound healing.
Dermagraft is similar to TransCyte (Dermagraft-TC), which involves fibroblasts seeded onto inert nylon mesh and frozen. However, TransCyte/Dermagraft-TC contains no live cells and is used as a temporary covering for burns, while Dermagraft contains viable cells and is applied permanently for tissue engraftment (e.g., treatment of diabetic foot ulcers).
Dermagraft is supplied frozen in a clear bag containing one piece, approximately 2 x 3 inches (5 x 7.5 cm) for single-use application. Dermagraft is packaged with a saline-based cryo-protectant solution is supplemented with 10% dimethylsulfoxide (DMSO) and bovine serum to facilitate long-term frozen storage of the product.
Biological.: Diabetics can develop deficiencies in their dermis, and their dermis eventually loses its ability to secrete normal skin matrix proteins and growth factors. Skin collagen is abnormal due to non-enzymatic glycosylation of the proteins. The glycosaminoglycans (GAGs) of the dermis are abnormal both in content as well as in structure. Growth factor secretion and response are abnormal due to both early senescence (aging) of the fibroblasts, as well as down-regulation of the growth factor receptors. Dermagraft addresses these diabetes-associated deficiencies in the dermis. Dermagraft delivers normal matrix proteins to the wound bed, including collagens Type I and Type III. Dermagraft delivers normal GAGs, which are important not only for structure, but for also delivering a variety of bound dermal growth factors to the patient’s wound bed, including platelet-derived growth factor (PDGF), tumor growth factor-beta (TGF-beta), and vascular endothelial growth factor (VEGF).
Nomenclature: Skin, Cultured/Dermagraft [BIO]; Human Fibroblast-Derived Dermal Substitute [FDA; since relaunch by ABH; Interactive Wound Dressing [FDA former]; Dermagraft [TR]
Companies.: Dermagraft was developed and originally manufactured through a joint venture of Advanced Tissue Sciences Inc. (ATS; formerly Marrow-Tech, Inc.) with Smith & Nephew. The original 50-50 joint venture was formed in April 1996 for commercialization of Dermagraft for diabetic foot ulcer indications:, with the joint venture also having certain rights to market TransCyte (see entry #657). In Feb. 2000, ATS and Smith & Nephew restructured their joint venture. As restructured, milestone and royalty payments to ATS (except for $10 million in regulatory and reimbursement milestones paid by Smith & Nephew related to development for the Dermagraft foot ulcer indication, which failed to receive FDA approval) came from joint venture earnings exceeding certain levels.
In late 2002, Advanced Tissue Sciences filed for Chapter 11 bankruptcy reorganization, and the company liquidated its primary assets. ATS sold its interest in the Dermagraft joint venture to Smith & Nephew for $12 million, and entered into a manufacturing and supply agreement with Smith & Nephew, which assumed manufacture of ATS’ dermal fibroblast and collagen products for non-wound care indications: (including those in development).
Dermagraft was subsequently marketed by Smith & Nephew in the U.S., U.K., several European countries, and Canada. It was manufactured by ATS in La Jolla, CA.
In Oct. 2005, Smith & Nephew halted manufacture of Dermagraft after it became clear that FDA would not approve it for venous ulcers. See the Status section below for further information.
In June 2006, Advanced BioHealing, Inc. (ABH) acquired from Smith & Nephew all rights and intellectual propertry related to Dermagraft. In Feb. 2007, ABH (re)launched Dermagraft in the U.S. and other markets where it has received approvals (or its marketing does not require this). ABH continues to manufacture Dermagraft in former ATS La Jolla, CA, facilities.
Manufacture: Neonatal foreskin fibroblast cells obtained from circumcised male infants are separated and seeded onto a polyglactin polymeric mesh scaffold. The fibroblasts proliferate, fill the scaffold’s interstices, and secrete human dermal collagen, matrix proteins, growth factors, and cytokines, forming a three-dimensional human dermis-like structure containing metabolically active living cells. Dermagraft does not contain other skin components, e.g., macrophages, lymphocytes, blood vessel, or hair follicles. Unlike Apligraf, the cells do not form a differentiated, multi-layered, skin-like structure.
The fibroblasts are taken from a qualified cell bank, which has been tested for animal viruses, retroviruses, cell morphology, karyology, isoenzymes, and tumorgenicity. Cell banks are tested for the presence of HIV-1, HIV-2, HTLV-1, HTLV-2, hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus types 1 and 2 (HSV-1; HSV-2), Epstein-Barr virus (EBV), adenovirus, Adventitious Viral Contaminants (In Vitro and In Vivo Assay), virus particles by electron microscopy, retroviruses by RT-PCR, bacteria, and fungi. Reagents used in manufacture are tested and free from viruses, retroviruses, endotoxins, and mycloplasma. Dermagraft is manufactured with sterile components under aseptic conditions until the final packaging. manufacture includes use of bovine calf serum (BCS) obtained from a BSE/TSE-free country.
Since freezing does not affect any of the matrix constituents of Dermagraft, primary attention is directed to release of product that will remain metabolically active after thawing. To maintain cell viability, the product is not terminally sterilized. Since there are no release specifications for the viability of such tissue engineered products, standard methods have been adopted for setting device release specifications. A standardized MTT [(3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyl-tetra-zolium bromide); a fluorecent dye indicator] assay is utilized to assess metabolic activity. This is a colorimetric assay using a tetrazolium salt to measure oxidized enzymes within viable cells. Metabolic activity, as assessed by MTT, closely correlates to the number of total cells, as measured by DNA, and growth-associated activity, such as secretion of glycosaminoglycans. This assay is used to check Dermagraft’s viability and metabolic activity both prior to and after cryo-pre-ser-vation (freezing). Dermagraft within the 0.5 to 0.6 mean MTT range has optimal properties for inducing keratinocyte growth in vitro, as well as epithelialization in a pre-clinical model. The product that was utilized in trials had a mean MTT range of 0.58. Tighter MTT specifications have been correlated with good patient healing, and product release specifications are within two standard deviations of this mean. This provides product with stability at -70˚C for up to 6 months, and regain its metabolic activity after implantation.
Prior to release, each lot much pass the USP Sterility (14-day), endotoxin, and mycoplasma tests. Each lot must meet release specification for collagen content, DNA, and cell viability. The mother of the infant’s cells used is tested for evidence of infection with HIV-1, HIV-2, hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, and HTLV-1. During subsequent screening of the fibroblast cell strain at various stages of manufacturing, testing is performed for these viruses and also Epstein-Barr virus (EBV) and HTLV-2.
FDA class: Medical device; PMA
Approvals: Date = 20010928; PMA; Indication = treatment of foot ulcers in patients with diabetes
Indications: [full text of the “Intended Use /indications:” section of product insert/labeling, 2/2007]
Dermagraft is indicated for use in the treatment of full-thickness diabetic foot ulcers greater than 6 weeks duration, which extend through the dermis, but without tendon, muscle, joint capsule, or bone exposure. Dermagraft should be used in conjunction with standard wound care regimens and in patients that have adequate blood supply to the involved foot.
Status: Dermagraft entered a pivotal U.S. trial for treatment of diabetic foot ulcers in early 1995, and FDA granted expedited review status in Nov. 1995. ATS filed a PMA in Dec., 1996. It was accepted for filing in Feb. 1997, and was amended with further confirmatory trial results in Oct. 1997. An FDA advisory committee in Jan. 1998 recommended approval with the condition that the company conduct a post-marketing study. However, the FDA did not follow its advisory committee recommendations and issued a non-approvable letter in June 1998. The company then performed another pivotal Phase III and resubmitted its PMA on Aug. 25, 2000, after announcing the trial had reached the primary endpoint of complete wound healing at 12 weeks (in difficult-to-heal chronic ulcers, with duration greater than six weeks). On Feb. 21, 2001, the company reported that FDA had requested additional information, further delaying approval. Dermagraft was approved on Sept. 28, 2001; approval time = ~6.6 years.
Original development of Dermagraft for venous leg ulcers was discontinued in 1994 after it failed to show advantage over conventional therapy.
Dermagraft received its first approval in the U.K. for diabetic foot ulcers, and was launched in October 1997. Approval was granted in Canada in August 1997. Dermagraft is also approved and marketed in some other European countries, Australia, and New Zealand. No centralized EU approval has been granted.
In Oct. 2005, Smith & Nephew announced it would no longer manufacture or market Dermagraft after receiving an “approvable letter” from FDA regarding a PMA supplement seeking approval of Dermagraft for venous leg ulcers. FDA indicated that further clinical tests would be required. Between delaying approval by 18-24 months, the expenditures required for additional trials, the risk of not receiving approval or for a narrow indication, and with Dermagraft not being a major product in terms of sales, the company decided to abandon it. The company noted, “On a global basis the lack of clear regulatory frameworks for tissue engineered products has resulted in delays that have become commercially unacceptable,” Smith & Nephew expected supplies of Dermagraft to no longer be available after June 2006. The company took a 15.5 million pound ($27.54 million) asset impairment charge (write-off) in third quarter of 2005 and a 25 million pound (~$44 million) charge in the fourth quarter to cover the cash cost of exiting the market and closing down Dermagraft operations.
Advanced BioHealing, after reacquiring the product, (re)launched Dermagraft in the U.S. and other markets in Feb. 2007.
Tech. transfer: Patents covering aspects of Dermagraft include U.S. 4,963,489 and 5,032,508 (and other recent related patents with the same title), Naughton, et al., July 16, 1991, “Three-dimensional cell and tissue culture system,” assigned to Marrow-Tech (now ATS), with claims including culture of fibroblasts in a polyglycolic acid matrix.
ATS has also licensed patents from the Massachusetts Institute of Technology (MIT), presumably including U.S. 5,759,830, “Three-dimensional fibrous scaffold containing attached cells for producing vascularized tissue in vivo,” Va-can-ti, J.P. and Langer, R.S.,; and perhaps 5,770,193, “Preparation of three-dimensional fibrous scaffold for attaching cells to produce vascularized tissue in vivo,” with the same inventors and assignees. These MIT patents, both coassigned to Children’s Medical Center Corp., include claims for use of a polyglycolic acid scaffold for three-dimensional cell culture.
Disease: See the Apligraf entry (#651), particularly the Disease and Market sections, for further information about diabetic foot/leg ulcers. See the Insulin Products entry (#630) for information about the epidemiology of diabetes. About 15% of persons with diabetes develop foot ulcers during their lifetime. Ulcers can become infected, leading to infection of deeper soft tissue, osteomyelitis and limb amputation. The risk for leg amputation is 15-40 times greater for a diabetic than an otherwise healthy patient.
Medical: Dermagraft dermal replacement is used for the treatment of full thickness diabetic foot ulcers.
Market: The 2007 Average Wholesale Price (AWP) is 1,400.00/2” x 3” sheet ($670.00 in 2005; $638.00 in 2004) (Red Book, 2007).
The average cost for Dermagraft dermal replacement in the U.K. in late 1997 was $3,240 per patient for an 8-week course of treatment. The estimated hospital cost incurred by the U.K. national health system for healing a skin ulcer with Dermagraft was $5,630 (3,475 Pounds), while the hospital cost for healing an ulcer without Dermagraft was $7,010 (4,327 Pounds).
Besides competition from conventional treatments, Dermagraft competes with Apligraf and several other skin replacement products (see related entries).
R&D: In various European and Asian Pacific region countries, Clinical Cell Culture Ltd. (Perth, Australia) is developing CellSpray and CellSpray XP, sprayed-on solutions of autologous (patient’s own) cultured epithelial cells, and EpiGrow autologous epidermal cell-derived fluid for treatment of chronic wounds. ReCell from Clinical Cell Culture is an autologous epithelial cell harvesting kit and culturing service available in some European countries for subsequent cell culture and treatment of small burns, pigment loss and scars is already sold in various international markets. These products are manufactured for the company by Cambrex Bio Science Verviers Sprl (Belgium;. merged into Lonza in mid-2006).
Companies involvement:
Full monograph
652 Skin, Cultured/Dermagraft
Nomenclature:
Skin, Cultured/Dermagraft [10]
Interactive Wound Dressing [FDA]
Dermagraft [TR]
skin, cultured [SY]
FDA Class: PMA medical device
Year of approval (FDA) = 2001
Date of 1st FDA approval = 20010928
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
human materials used<!-- humansource -->
skin replacements
2150-2-3, Saccharomyces cerevisiae (yeast) strain
cells, human <!-- humancellculture -->
fibroblasts, human
human fibroblast cells
human neonatal foreskins
human tissues
mammalian cell culture
MRC5 cellular proteins
polygeline
polygeline
serum, fetal calf
stroma
tetracycline
tissue culture, three-dimensional
vesicular stomatitis virus (VSV)
collagen, porcine dermal
dimethylsulfoxide (DMSO)
nylon mesh
polygeline
polygeline
polymer membrane matrix
porcine dermal collagen
silicone polymer membranes
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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