Human Fibroblast-Derived Temporary Skin Substitute - TransCyte; Dermagraft-TC
Status: abandoned, then relaunched in 2007
Organizations involved:
Organogenesis, Inc. – Manuf.; R&d; Tech.; World mark.
Advanced BioHealing, Inc. – Forrmer
Shire plc - Parent; Former
Advanced Tissue Sciences Inc. – Former
Smith & Nephew, Inc. – Former
Smith & Nephew plc - Parent; Former
Massachusetts Inst. of Technology – R&D; Tech.
Marrow-Tech, Inc. – Former
Cross ref: See the entry for Dermagraft (#652), similar to this product but containing cultured live human fibroblasts. See also the Apligraf entry (#651), particularly the Biological section, for further information about skin.
Description: Human Fibroblast-Derived Temporary Skin Substitute or TransCyte, original trade name Dermagraft-TC [TC for transitional covering], is a transparent bi-layered membrane with an outer silicone polymer layer bonded to an inner layer of nylon mesh containing cultured but non-viable (dead) neonatal human fibroblast cells. Prior to cell culture, nylon mesh is coated with porcine (pig) dermal collagen and bonded to a silicone polymer membrane.
For manufacture, human fibroblast cells from neonatal foreskin tissue are cultured in the nylon mesh scaffold of the layered membrane, forming a layer of human dermal tissue equivalent adhering to the nylon fibers. As fibroblasts proliferate within the nylon mesh, they secrete human dermal collagen, matrix proteins, and growth factors (much like normal human skin). The water-resistant outer covering and the inner dermal-like layer of human cells simulate the bi-layered structure of human skin. TransCyte is frozen at cryogenic temperatures (e.g., -90˚F), killing any living cells, and shipped to burn specialists for use as a temporary (transitional) covering for serious (second and third-degree) burns.
TransCyte is sold in cassettes of two 13 cm x 19 cm (5 inch x 7.5 inch) sheets. No metabolic activity remains after freezing of the product, but the human tissue matrix and bound growth factors remain intact. The product was stored frozen at between -70°C and -20°C, with a shelf life of 18 months. This requirement for cryogenic storage tended to limit physician use of the product.
TransCyte is the first human-based, bioengineered temporary skin substitute for the treatment of burns to be approved by FDA. TransCyte provides a protective alternative to cadaver skin for patients with third-degree burns, and to silver sulfadiazine (SSD) dressings for patients with second-degree burns. After application to the burn wound, TransCyte provides a temporary covering to protect the wound from fluid loss and reduce the risk of infection.
Note, a different product, Dermagraft [without ‘TC’ designation], from the same company, is also available (entry #652). Dermagraft is similar to Transcyte (originally known a Dermagraft-TC), except that it contains live human fibroblast cells (i.e., is not cryogenically killed by freezing) for engraftment and subsequent growth in wounds.
Nomenclature: Skin/TransCyte [BIO]; TransCyte [TR]; -Human Fibroblast-Derived Temporary Skin Substitute [FDA]; Dermagraft-TC [TR former]
TransCyte was originally known as Dermagraft-TC (Dermagraft-Transitional Covering). With the transfer of the product to the join venture of Advanced Tissue Sciences and Smith & Nephew, the trade name was renamed TransCyte (more descriptive of its transitional transparent cover function, and to differentiate it from Dermagraft which contains living cells for engraftment).
Companies.: Transcyte was developed and originally manufactured by Advanced Tissue Sciences Inc. (formerly Marrow-Tech, Inc.), in collaboration with Smith & Nephew PLC (London, U.K.). Smith & Nephew was responsible for U.S. and worldwide sales and marketing of the joint venture’s products. Smith & Nephew’s Wound Management Division had over a hundred sales and education specialists addressing the U.S. wound care market. The product is now manufactured and marketed by Advanced BioHealing, Inc.
Smith & Nephew formed its original 50-50 joint venture in April 1996 with Advanced Tissue Sciences for commercialization of Dermagraft (containing live cells, unlike Transcyte) for diabetic foot ulcer indications:, with the joint venture also having rights to market TransCyte for all wound care applications outside the U.S. and for all wound applications except burns in the U.S. The joint venture was expanded in August 1998 to include marketing of TransCyte for burns in the U.S., effective Oct. 1998. 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) come from joint venture earnings exceeding certain levels.
In late 2002, Advanced Tissue Sciences filed for Chapter 11 bankruptcy reorganization, and the company was liquidated. 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 TransCyte, Dermagraft, and those in development).
On Oct. 27, 2005, Smith & Nephew announced its would no longer manufacture or market Dermagraft or Transcyte after receiving an “approvable letter” from FDA regarding a PMA supplement seeking approval of Dermagraft for venous leg ulcers. 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.”
In June 2006, Advanced BioHealing, Inc. (ABH) acquired from Smith & Nephew all rights and intellectual property related to Dermagraft. In Feb. 2007, ABH (re)launched Transcyte and Dermagraft.
In May 2011, Shire plc acquired Advanced BioHealing for $750 million.
In Jan. 2014, Organogenesis, Inc. acquired Dermagraft, not paying anything up front but will pay Shire up to $300 million if it meets sales targets up to 2018. Shire took a $650 million loss on the deal. The acquisition included a 115,000-square-foot manufacturing plant in La Jolla, CA. Shire at the time was constructing a 2nd manufacturing facility, not included the deal, presuming this needed for Dermagraft. But the new owners plan to only use La Jolla for Dermagraft manufacture.
Manufacture: Fibroblast cells derived from circumcised human male neonatal foreskin tissue are seeded onto a three dimensional nylon scaffold mesh membrane in a proprietary closed aseptic bioreactor system that simulates the environment in the body. This three-dimensional cell culture system allows cells to develop and assemble into tissues that more closely resemble their counterparts in the body. The membrane simulates human “stroma” or the living matrix that provides the attachment sites and three-dimensional structure for each organ and produces growth factors that promote the development of organ cells into functioning tissues. The cells attach to the membrane, divide, and secrete extracellular matrix proteins and growth factors, forming human functional tissue. The membranes are harvested, cut to proper size, and cryogenically frozen (-90˚F). Transcyte undergoes extensive viral and bacterial testing procedures to prevent disease transmission.
FDA class: Medical device PMA
Approvals: Date = 19970318; first approval, PMA; Indication = for use as a temporary wound covering for surgically excised full-thickness and deep partial-thickness thermal burn wounds in patients who require a covering prior to autograft placement
Date = 19971000; Indication = for use as a temporary wound cover for partial thickness (second degree) burns
Indications: [full text of the "Indications” section of product insert/labeling]:
TransCyte is indicated for use as a temporary wound covering for surgically excised full-thickness and deep partial-thickness thermal burn wounds in patients who require such a covering prior to autograft placement. TransCyte is also indicated for the treatment of mid-dermal to indeterminate-depth burn wounds that typically require debridement and that may be expected to heal without autografting.
Status: The Premarket Application (PMA; medical device) for TransCyte was approved by FDA on March 18, 1997; approval time of about 3.6 months (~.3 year).
As discussed in the Companies section, Smith & Nephew abandoned the product and it was not manufactured or available for years. However, in Feb. 2007, Advanced BioHealing, Inc., having acquired the product and related assets from Smith & Nephew, relaunched TransCyte.
Tech. transfer: U.S. 4,963,489, “Three-Dimensional Cell and Tissue Culture System,” Naughton, G.K. (now CEO, ATS) and Naughton, B.A., issued Oct. 16, 1990, assigned to Marrow-Tech, Inc. (now ATS), covers aspects of TransCyte. The exemplary claim (no. 1) is, “A living stromal tissue prepared in vitro, comprising stromal cells and connective tissue proteins naturally secreted by the stromal cells attached to and substantially enveloping a framework composed of a biocom-patible, non-living material formed into a three dimensional structure having interstitial spaces bridged by the stromal cells.” Further claims identify the stromal cells as fibroblasts; the living stromal tissue as a combination of fibroblasts and endothelial cells, pericytes, macrophages, monocytes, leukocytes, plasma cells, mast cells, or adipocytes; the non-biodegradable material is a polymer/plastic; and the framework is a mesh pre-coated with collagen. A critical part of the invention was the use of the inert mesh framework with fibroblast stromal matrix which provides the support, growth factors, and regulatory factors necessary to sustain long-term active proliferation of the cells in culture. When grown in this three-dimensional system, the proliferating cells mature and segregate properly to form components analogous to normal skin.
Trials: TransCyte demonstrated significantly faster healing and less inflammation than conventional silver sulfadiazine (SSD) dressings in a controlled randomized clinical trial for treatment of second-degree burns. The typical one-time application of TransCyte avoided the frequent, painful dressing changes generally required with SSD. A study reported in April 1999 showed that Transcyte reduced the length of hospital stays by 53% (when severity of burns were taken into account), and decreased hospital costs by $6,650 per patient, compared to the standard of care.
Medical: TransCyte is applied to cover burned tissue, usually simply stapled in place, and is left covering the wound until a sufficient amount of the patient’s own skin is available for grafting (in the case of third-degree burns), or until the patient’s own skin heals (in the case of second-degree burns). The product is easily applied and removed. Transcyte is transparent and allowed visual monitoring of the burn wound bed onto which it has been placed.
Disease: The potential U.S. market for Transcyte included about 1,500 third-degree burn patients annually requiring extensive autografts and 30,000-40,000 second-degree burn patients. The product has been in clinical trials for treatment of chronic pressure sores, affecting >200,000 patients annually.
Market: Advanced Tissue Sciences (ATS) reported sales of $1.6 million for the six months ending July 30, 2000 (equiv. to $3.2 million/year). ATS reported 1999 TransCyte sales of $2.2 million, up from $1.4 million in 1998. TransCyte marketing and sales in the U.S, were transferred to the Smith & Nephew/ATS joint venture in October 1998.
The 2007 Average Wholesale Price (AWP) is $1,688.00/10” x 15” sheet (Red Book, 2007; unchagned since 2005, or earlier). TransCyte was sold in the U.S. in cassettes of two 5 x 7 inch sheets listing for $1,350 as of Oct. 1997.
Competition: Alternatives to Transcyte for treatment of third-degree burns primarily involve covering the wound with skin taken from a cadaver (dead body). The cadaver skin is usually rejected by the patient’s immune system after a few weeks and needs to be replaced (requiring further surgery). There are also risks of transmitting disease when using cadaver skin. Alternatives to Transcyte for treatment of second-degree burns primarily involve use of silver sulfadiazine (SSD) or other antimicrobial dressings/bandages, requiring frequent (laborious), often painful, changing of the dressings.
Companies involvement:
Full monograph
657 Skin, Cultured/TransCyte
Nomenclature:
Skin, Cultured/TransCyte [BIO]
TransCyte [TR]
Human Fibroblast-Derived Temporary Skin Substitute [FDA]
Dermagraft-TC [TR former]
FDA Class: Medical device PMA
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19970318
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
human materials used<!-- humansource -->
porcine source materials
skin replacements
collagen, porcine dermal
fibroblasts, human
human neonatal foreskins
mammalian cell culture
porcine dermal collagen
stroma
tissue culture, three-dimensional
collagen, porcine dermal
nylon mesh
polygeline
polygeline
polymer membrane matrix
porcine dermal collagen
silicone polymer membranes
vesicular stomatitis virus (VSV)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
EU011 Approved Formerly in EU/withdrawn
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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