BBI Contributing Editor

This year's annual meeting of the American Academy of Dermatology (AAD; Alexandria, Virginia) in San Francisco, California, featured several symposia on dermal fillers. This product category has gained much attention with the FDA's recent granting of market clearance for human collagen-based CosmoDerm and CosmoPlast from Inamed Aesthetics (Santa Barbara, California), which was launched at the AAD meeting, and from the anticipated approval of the hyaluronic-acid based Restytlane and Perlane fillers from Medicis Pharmaceuticals (Scottsdale, Arizona). Also, the widely publicized application of Botox from Allergan (Irvine, California) for treating facial wrinkles and furrows has stimulated interest in this area among the aging baby boomers. The products are aimed at the 7,000 plastic surgeons, 10,000 ENT-trained facial plastic surgeons and 12,000 dermatologists in the U.S.

Dermal fillers are used for smoothing facial wrinkles, furrows and acne scars, for lip augmentation and for correcting other soft tissue contour deficiencies. Worldwide sales of dermal fillers were $134.8 million in 2002, of which one-third were in the U.S. The demand for facial cosmetic surgery for delaying or reversing the signs of aging is increasing, but many plastic surgeons and dermatologists have become disenchanted with the use of collagen for injections because of its bovine origin, pretest requirement and short duration of action. The American Society for Aesthetic Plastic Surgery (Los Alamitos, California) has reported that 783,458 collagen injections were performed in the U.S. in 2002, representing the third most common non-surgical cosmetic procedure after Botox injections (1,658,667) and microdermabrasions (1,032,417).

CosmoDerm and CosmoPlast use collagen of human origin and do not require pretesting of patients for allergic reaction. They will likely replace Zyderm and Zyplast which have been used for 20 years and are collagen of bovine origin and require a skin sensitivity test prior to use. The test entails a subcutaneous injection and is often repeated after 28 days. After injection, these products are resorbed after three to six months, depending on the degree of mechanical motion at the injection site. Greater motion, such as around the mouth, results in faster resorption. CosmoDerm and CosmoPlast are produced from dermal fibroblasts in foreskins obtained from circumcisions using the same technology that is employed for producing the Dermagraft skin substitute that is sold by Smith & Nephew Wound Management (Largo, Florida), a subsidiary of Smith & Nephew plc (London). CosmoPlast and Zyplast are collagens that are crosslinked with glutaraldehyde and are injected deeper into the skin for treatment of more pronounced scars and furrows.

Dermalogen, an injectable human tissue suspension of collagen, was previously sold as a dermal filler by Collagenesis, which is no longer in existence. Attempts are under way to re-introduce the produce by a startup company, Collagen Matrix Technologies. EnColl (Newark, California) has patents on a process for preparing highly purified bovine and bovine collagen that is claimed to not require testing for an allergic reaction. Collagen obtained from cowhides is comprised of Types 1 and 3 collagens. Type 3 collagen was identified as possibly causing an immunogenic response and is removed by EnColl during the purification process. The company sells collagen-based products in India for use as a hemostat and as a periodontal pocket filler.

Hyaluronic acid (HA) is a viscoelastic material that occurs naturally in the body and is produced commercially by extraction from rooster combs or by a fermentation process. HA is the principal ingredient in many dermal fillers that are sold in Europe, Canada and Australia, but it is not yet approved for this indication in the U.S. However, HA is used commercially in this country as a lubricant in ophthalmic surgery, as a replacement for synovial fluid and as a post-surgical anti-adhesion barrier. Nicholas Lowe, MD, medical director of the Cranley Clinic (London, United Kingdom), reported at the AAD meeting on his evaluation of competing HA injectable dermal gel fillers and concluded that Restylane and Perlane from Q-Med (Stockholm, Sweden) last longer after injection and are the preferred products. Medicis Pharmaceutical (Scottsdale, Arizona) has acquired marketing and distribution rights to these products in the U.S. and Canada.

Q-Med is the leading supplier of dermal fillers outside the U.S., with sales of $57 million in 2002 and a 40% to 60% market share in the 60 countries in which Restylane and Perlane are sold. They are partially crosslinked HA, differ in gel particle size and viscosity and are made by a microbiological process. They are sold in Canada and have overtaken Zyderm and Zyplast as the leading dermal fillers. Other HA-based products sold in Europe are DermaLive and DermaDeep from France's DermaTech, Hyal Rofilan Gel from Rofil Medical International in the Netherlands and AcHyal from Spain's Tedec Meji Farma.

Although some plastic surgeons and dermatologists still use liquid injectable silicone as a permanent treatment for wrinkles and acne scars, its use was banned by the FDA in 1992. Silicone oil is approved for ophthalmic use in retinal reattachment. RJ Development (Peabody, Massachusetts) markets such a product and is investigating the use of purified silicone oils, SilSkin and Silikon 1000, as permanent facial soft tissue fillers.

Permanent tubular implants produced from expanded polytetrafluoroethylene (ePTFE) are used in nasolabial folds to reduce smile and frown lines and for lip augmentation. These products are sold in the U.S. and internationally by W.L. Gore and Associates (Flagstaff, Arizona), Atrium Medical (Hudson, New Hampshire) and Tissue Technologies (San Francisco, California).

LifeCell (Branchburg, New Jersey) markets Cymetra, injectable particles of micronized AlloDerm, for the correction of soft tissue defects. AlloDerm is acellular human tissue that is prepared using tissue matrix technology for removing cells from human tissue without damaging the essential biochemical and structural components needed for normal tissue regeneration. Cymetra does not require sensitivity testing and is claimed to last for three to nine months.

Fascia Biosystems (Los Angeles, California) markets Fascian and Fasciablast dermal implants in the U.S. and Europe. They are preserved and compressed fascia particles that are prepared from the fascia of cadavers. They do not require pretesting for allergic reaction.

Uroplasty (Minneapolis, Minnesota) sells Bioplastique in Europe, an injectable facial implant fabricated from polydimethylsiloxane (vulcanized rubber) for use in reconstruction and for filling defects, but not for smoothing wrinkles. It is not approved for sale in the U.S.

PlastiQ (San Jose, California) was recently founded to develop injectable bioabsorable polymer gel implants for the plastic and reconstructive surgery market. The bioabsorbable implant is a polylactide-polycaprolactone copolymer. It can be formed in situ by injecting a liquid polymer that solidifies after injection upon contact with cellular fluids. Potential applications include soft tissue augmentation, interstitial bulking agent, body cavity filler and use as a supporting member to suspend prolapsed body organs. A 510(k) application has been submitted to the FDA for Contour-Q for tissue augmentation.

Aquamer (Seattle, Washington) is developing injectable polymers based on polyvinyl pyrrolidone. These include AquaDerm for treating deep wrinkles and facial scars and for cosmetic plastic surgery procedures such as lip augmentation. The corrective effects of this treatment are claimed to be long-term. Additional PVP-based products being developed are AquaFlux as a treatment for chronic heartburn or gastroesophageal reflux disease and AquaGen for use as a bulking agent for treating stress urinary incontinence.

Many companies are developing products to enter the U.S. injectable dermal fillers market and are profiled below.

Dermik Laboratories (Berwyn, Pennsylvania), a division of Aventis Pharmaceuticals (Bridegwater, New Jersey), acquired New-Fill, a polylactic acid implant from Biotech Industry in Luxembourg, for treating facial lines and wrinkles. The product has been used in more than 100,000 patients in Europe, South America and Australia. Clinicians in Europe claim that New-Fill lasts 12 to 18 months and does not require a pretest prior to treatment. Dermik seeks to obtain FDA market clearance for New-Fill.

Artes Medical (San Diego, California) received in February a recommendation of approval for its Artecoll injectable implant for facial wrinkles, scars and soft tissue contour deficiencies from the FDA's Plastic and Reconstructive Surgery panel. Artecoll is a permanent implant that is comprised of polymethylmethacrylate microspheres that are suspended in a water-based carrier gel containing bovine collagen and the analgesic, lidocaine. The non-biodegradable microspheres remain permanently implanted as the bovine collagen is gradually resorbed. The product requires patient testing for allergic response prior to use. Artecoll has been sold outside the U.S. for the past decade. In Canada, it is sold by Canderm (Montreal, Quebec) and in Europe by Rofil Medical International in the Netherlands. Rofil also markets its own dermal filler, Resoplast, a bovine collagen implant. Sales of Artecoll were $12.1 million in 2002. It will be marketed in the U.S. under the Artefill name.

Isolagen (Houston, Texas) processes a patient's own cells to produces autologous collagen. The patented process uses collagen-producing cells that are obtained by a punch biopsy behind a patient's ear and are sent to Isolagen for propagating by in vitro culture into new autologous fibroblast living cells. About six weeks after initiating the cell culture, a small specimen is sent to a physician for injection into the patient's forearm to test for an allergic reaction although a reduced allergic response is expected because the dermal filler uses the patient's own cells. Two weeks later, the cultured cells are ready for injection into the patient to stimulate the natural production of collagen.

Autologous implants are expected to last longer because the immune system recognizes the patient's cells and does nor resorb them as it does with foreign materials, such as bovine collagen. Isolagen's autologous collagen has been sold in the U.K. since late 2002 and will soon be introduced in Australia. Isolagen has started a pivotal clinical trial in the U.S. to prepare for a biological license application. Anticipated uses are for the treatment of wrinkles, scars from acne and for minor trauma.

Protein Polymer Technologies (San Diego, California) is evaluating in a pilot clinical trial an injectable silk-elastin block copolymer for use in correcting facial lines, wrinkles and scars. The polymer segment is encoded with the crystalline structure of silk and is combined with a segment encoded with mammalian elastin to provide both strength and flexibility. After injection, the solution transforms into a pliable hydrogel for permanent tissue augmentation. A corporate partner is sought for sponsoring this program.

Biosyntech (Laval, Quebec) is conducting a clinical trial in France on BST-Fill, an injectable soft tissue filler having a long residence time for cosmetic and reconstructive surgery applications. It is a chitosan-based thermosensitive gel which is injected as a liquid and solidifies into a hydrogel at body temperature, providing a mechanical support to surrounding soft tissue. BST-Fill is expected to be initially approved in Europe and to be licensed to a marketing partner.

Adipose-derived stem cells are being investigated for potential use as dermal fillers. Artecel Sciences (Durham, North Carolina) is collaborating with Duke University (also Durham) in developing stem cells obtained by liposuction for soft tissue cosmesis (i.e., repairing wrinkles) and hematopoietic support. The stem cells are programmed to become adipocytes and their degree of differentiation is controlled. If cells are fully differentiated, then they will not grow after injection into the wrinkles. The cells are expected to age at the same rate as other adipose tissue and should therefore last for a year after injection. Preclinical toxicology studies were started with the intent of filing an investigational new drug application. StemSource (Thousand Oaks, California) was acquired recently by MacroPore Biosurgery (San Diego, California) and also is working on differentiating cells derived from adipose tissue into more fat cells as well as other cell types, including muscle, cartilage and bone cells.

An alternative to commercial dermal fillers is use of a patient's own fat for tissue augmentation. This technique has been used for many years. The fat is extracted by liposuction from the patient's abdomen, thighs or buttocks and centrifuged to separate fat cells from collagen. The process of autologous fat transplantation, or lipoinjection, is effective for deep skin indentations, furrows and scars. It is not suitable for treating fine wrinkles because the substance being injected is too thick to pass through thin needles. This method has not gained much popularity mainly because of its short duration (resorbs in as little as six weeks) and the need to perform liposuction.

Miller Medical (Mesa, Arizona) promotes its FAMI (Fat Autograft Muscle Injection) bloodless technique that avoids the facial vasculature and transplants the autologous fat into the facial muscles to provide long-lasting results. Specially designed catheters are used to insert the fat autograft into the vascular facial muscle bed.