An MD&DI February 1997 Column
The first medical devices to be produced by means of tissue engineering
are now on the market. The number of artificial-skin and related products
is small but growing rapidly.
On the frontiers of medical device development, the standard concept of a device as an inanimate, mechanical product often does not apply. Nowhere is that more true than in tissue engineering. This new branch of the industry--barely 10 years old--may ultimately produce engineered body tissues that are virtually indistinguishable from their natural counterparts. By contrast, the current array of implantable devices will look primitive at best. While most of these products have yet to be developed, artificial skin and related wound-healing products are already realities.
Synthetic skin products like Apligraf may be used on patients with severe burns or skin ulcers, or those undergoing dermatologic surgery.
Among these products is Integra Artificial Skin, which is composed of bioengineered collagen and shark cartilage. "This materials-based device mimics the body's own extracellular matrix, convincing the body that this is a normal environment and that the body should do its normal thing, which is to replace its own tissue in an organized fashion," says Richard Caruso, PhD, the president, CEO, and chairman of Integra Life Sciences Corp. (Plainsboro, NJ).
Another product is Seprafilm, a membrane made of biopolymers used by surgeons to keep tissues from joining abnormally. Seprafilm is absorbed and excreted by the body within 28 days. "It is dry and looks like a piece of plastic wrap," says Cheryl Greenhouse, spokesperson for Genzyme (Cambridge, MA).
These two devices are each aimed at very different patient populations,one undergoing surgery, the other suffering from open wounds. The wounds are life threatening or chronic. They include severe burns and skin ulcers, such as diabetic foot ulcers and pressure sores. The estimated market for burn treatment is about $100 million worldwide; for treating skin ulcers, it exceeds $1 billion.
Cadaver skin is the gold standard for covering severe burns to prevent infection and fluid loss until skin grafts from healthy parts of the body can be harvested and put in place. Compression dressings--essentially standard cotton-based products held in place by Ace bandages--are used on chronic ulcers. These treatments each have drawbacks that biotech devices promise to overcome.
For patients with deep burns, the artificial skin being manufactured by Integra Life Sciences not only replaces the use of cadaver skin as a dressing, but provides a foundation for the growth of new skin. After several days, the patient's own cells migrate into the bovine collagen and the material is naturally vascularized.
The Integra product eliminates the need to graft full- or partial-thickness skin from a healthy part of the body. Instead, only an ultrathin epidermal layer--about 0.005 in. thick--needs to be grafted to the wound. The silicone membrane on top, which acts as an artificial epidermal layer, is removed to make way for this autograft. "The idea of the thin epidermal autograft is really only to get the epidermal cells, because those cells will migrate and close the wound," Caruso explains.
Since FDA approval of the artificial skin on March 1, 1996, Integra has been training surgeons in its use as well as introducing the product commercially. At present, the only approved use of the product is for the treatment of patients with life-threatening burns.
Whereas Integra Artificial Skin is designed to remain in place permanently, Dermagraft-TC by Advanced Tissue Sciences (ATS; La Jolla, CA) is intended as a temporary covering. "If patients need to be covered for 5, 6, or 10 weeks before they have enough of their skin to autograft, which is the case with a 60 to 80% burn, then our product can stay on for that time," says Gail Naughton, PhD, president and COO of Advanced Tissue Sciences. "Also it shows potential for use in partial-thickness burns to provide a more effective pain-free cover for that population of patients."
Dermagraft-TC is designed to replace cadaver skin, which has several drawbacks, particularly a very short life span, about nine days, once it is on the patient. Skin harvested from cadavers is often difficult to obtain and can cause complications, including rejection by the patient, bleeding, epidermal sloughing, and disease transmission. On November 19, 1996, an FDA advisory panel recommended approval of Dermagraft-TC, which is made of cultured human cells, for treating severe burns.
Dermagraft-TC is produced by culturing human dermal fibroblasts, obtained from neonatal foreskins, onto a nylon mesh, which is bonded to an ultrathin, semipermeable membrane. This membrane forms a synthetic covering whose permeability simulates the skin's epidermis. The nylon mesh acts as a three-dimensional scaffold for the growth of dermal tissue. "The cells attach to it, divide, and then secrete human matrix to actually form this dermal tissue," says Naughton.
ATS submitted a premarket approval (PMA) application to FDA on December 19 for another version of Dermagraft, which is metabolically active. This particular product is designed to be a permanent, living dermal implant. "As the scaffold dissolves, it is replaced by human collagens," Naughton explains. "So with Dermagraft, we are implanting into the patient's body a dermal tissue consisting of the fibroblasts, the collagens, and all the matrix proteins found in the normal dermis."
The device is grown in a bioreactor that looks like a see-through cassette hooked up to pumps and tubes. Before shipping, the tissue is frozen, the tubes are detached and sealed, and the bioreactor is placed on dry ice and used as a shipping container that maintains the controlled environment and sterility. "This is one of our edges in tissue engineering--that we have these systems," Naughton says. Dermagraft must be maintained at -70°C until defrosted for use. Because, by contrast, Dermagraft-TC is nonviable, temperature requirements are not as stringent. Nor are such low temperatures necessary for Integra Artificial Skin, which contains no living cells.
The primary indication for Dermagraft is the treatment of diabetic foot ulcers, but Naughton says that the company will pursue "any basic problem where the patient is missing a dermis."
In April 1996, ATS formed a joint venture with Smith & Nephew plc (London) to commercialize Dermagraft for diabetic ulcers. Dermagraft-TC will be sold directly by ATS through a small sales force concentrating on some 80 key burn centers in the United States.
Several other companies have wound-repair devices in various R&D stages. Life Medical Sciences, Inc. (Princeton, NJ), has developed a proprietary in situ tissue-culturing (ITC) technology designed to create an optimal environment for the growth of the patient's own tissue. Its product, called Cariel, is an ITC-based gel designed for treating wounds such as burns, venous stasis, diabetic ulcers, and pressure sores. Cariel is provided for research in freeze-dried form to enhance stability and lengthen shelf life up to two years. Prior to use, the dried product is reconstituted with a gel provided by the company and then applied directly to the wound.
The first steps toward conducting a clinical trial of Cariel in Europe began last November. A similar trial is scheduled to start this spring in the United States. The studies will measure the efficacy of Cariel in healing stasis ulcers without compression therapy. How the U.S. trials will be organized depends on a yet-to-be-held meeting between the company and FDA. "We have to determine whether Cariel is a device or a drug or a biologic," says Eli Pines, vice president and chief scientific officer at Life Medical. "Once that is done, we will have to put in place the clinical development program to satisfy U.S. regulatory needs."
The research that is being done in Europe, when completed, is expected
to generate data sufficient to support approval for CE marking, according to Robert Hickey, Life Medical's CEO. "Our intention is to use the results of these studies to submit for regulatory approval so we can have this product available throughout Europe probably in the middle part of 1998," Hickey says. "We will still be conducting our studies in the United States at that time."
Organogenesis (Canton, MA) uses living human cells in the development of its Apligraf product, a bilayer synthetic analogue to living skin. "We have a living differentiated epidermis and a living dermis," says Carol Hausner, director of investor relations. "So we truly are a living skin equivalent."
The top layer of the synthetic skin contains human keratinocytes, the most common cell type in human epidermis, and forms a well-differentiated epidermal layer. The other layer of Apligraf, which forms the lower dermal layer, contains a combination of collagen, a structural protein, and fibroblasts.
On October 4, 1995, Organogenesis submitted a PMA application for Apligraf specifically for the treatment of venous stasis ulcers. In January 1996 Sandoz Ltd., which has since merged with Ciba-Geigy to form Novartis, struck an agreement with Organogenesis to license the manufactured skin product. Under the terms of the agreement, Novartis will have exclusive worldwide marketing rights to Apligraf; Organogenesis will supply the product. The technology might ultimately be used on patients suffering from severe burns or skin ulcers, as well as those undergoing dermatologic surgery for such conditions as removal of skin cancers and birthmarks.
Ortec International, Inc. (New York City), is developing Composite Cultured Skin (CCS), a bilayer product composed of a bioengineered bovine collagen composite matrix seeded with keratinocytes for epidermal growth and fibroblasts for dermal growth. Both types of cells are obtained from neonatal foreskin.
The device is engineered specifically for patients with deep second-degree burns--not third-degree burns that have destroyed the underlying dermis. "We are really looking at what is more representative of the burn population," says Suzanne Schwartz, MD, Ortec medical director. "Most burns are classified as second-degree injuries." In such injuries, CCS may be the final solution. The device is designed so that grafts of the patent's own skin will not be necessary to close the wound.
Ortec is now evaluating CCS for the treatment of burns and epidermolysis bullosa, which is characterized by painful ulceration and scarring. Like other such biotechnologies, CCS may have possible applications in reconstructive and cosmetic surgery, as well as skin ulcers. The clinical trial now going on for burns will require about two years to complete.
Antiadhesives are biotech devices that keep tissues from abnormally joining together following surgery. These abnormal unions, called adhesions, may form between an incision in the abdominal wall and the small bowel after abdominal surgery, leading to chronic pain or even bowel obstruction. Adhesions also occur following gynecologic surgery, resulting in fibrous scarring that may involve the uterus, bladder, bowel, or ovaries and fallopian tubes, and that can, in the worst case, lead to infertility.
Several companies have developed bioresorbable membranes that promise to serve as temporary physical barriers between the surfaces of different tissues at the surgical site. Published literature suggests that adhesions occur in up to 93% of abdominal surgeries. The removal of such adhesions from the lower abdomen resulted in $1.2 billion of inpatient treatment charges in 1988 in the United States alone. Between 55 and 100% of gynecologic operations also result in the formation of adhesions.
Some experience has been gained with a product called Interceed, which has been marketed in the United States by Johnson & Johnson (Arlington, TX) since 1989. The bioresorbable membranes, composed of oxidized regenerated cellulose, are limited to use in gynecological surgery. The biotech membranes are applied at the end of the operation, just before the surgeon closes the patient. Once implanted, they dissolve within days.
Genzyme's Seprafilm, which was approved by FDA in August 1996 for use in open abdominal and pelvic surgery, turns into a gel two days after application. By the seventh day, the gel is absorbed by the body. Less than a month after surgery, the biopolymer that originally formed the membrane has been excreted from the body. Genzyme has at least two other antiadhesive products in development.
Genzyme could get some competition from other companies. Life Medical Sciences is developing a bioresorbable polymer technology called Repel. The company has submitted an investigational device exemption application to FDA with the intent of starting U.S. clinical trials of Repel in abdominal and gynecological procedures.
Gliatech, Inc. (Cleveland), is developing a gelatinous line of bioresorbable products, called Adcon, that mimic activity of the basal lamina, a natural barrier against tissue adhesion. In early 1996, the company received approval from the European Union to market Adcon-TN, which is designed to inhibit postsurgical adhesions around tendons and peripheral nerves. Just months earlier, the company had received a CE marking for Adcon-L, which has since been launched commercially in Europe as a means for inhibiting peridural fibrosis following lumbar surgery. Adcon-L is now approaching clinical trial in the United States.
The development of these myriad technologies is just the beginning. Richard Caruso of Integra believes that in time these technologies will become more sophisticated and tuned in to the body's normal processes. "This whole flurry of technological activity tells us that medical practice is going to change very rapidly," he says. "The final solution is to enable the body to heal itself."