BB&T Contributing Editor

Collagen. This relatively simple, rather under-rated but extremely ubiquitous material works much as a medical device because of its many structural medical opportunities and applications. By making up 25% of body mass it is the most abundant protein in the human body.

Collagen molecules possess a triple helix structure assembled into fibers that provide mechanical strength and shape for most organs and tissues. There are at least 27 genetically distinct types of collagen. Type I collagen is the most common type and found in bones skin, tendons and ligaments. Type II is found in cartilage and Type 3 in blood vessels (see Table 6).

Collagen has a long history of clinical use and has found widespread applications in devices used in orthopedics, urology, cardiology, ophthalmology, neurology, general surgery and dentistry. These applications include wound dressings, hemostats, absorbable sutures, dermal fillers, bone grafts, nerve guides, arterial and dural closures, vascular grafts, surgical meshes, corneal shields, tissue bulking agents and for guided tissue regeneration.

The worldwide market for collagen-based biomaterials has been estimated at $279 million in 2005, projected to grow to $290.2 million this year. For the period 2000-2010 period, it is predicted to have a 3.8% compound growth rate and could reach $351.3 million by 2010.

Bovine collagen is composed of 95% Type I and 5% Type II collagen. It is the predominant collagen used in medical products. Collagen can be isolated from tissues in soluble and insoluble forms and can be processed, with and without enzymes to remove non-collagenous proteins and/or portions of the non-helical regions of the collagen molecule, into a variety of physical forms including gels, fibers, films, sponges and tubing. Potential risks of using this bovine collagen are viral contamination, bovine spongiform encephalopathy (BSE, or mad cow disease) and immunogenicity requiring a pretest prior to injection. Alternative animal sources are porcine and ovine (sheep).

Recombinant human collagen

The advantages of recombinant human collagen versus bovine collagen are that it overcomes the concerns of viral contamination, allergic response and the fear of transmitting mad cow disease. Although recombinant human collagen has been produced from yeast and from tobacco plants, there are not yet any commercial sources that are competitively priced against bovine or porcine-derived medical grade collagens.

Following are some of the companies and their products in this sector.

• FibroGen (South San Francisco, California) produces recombinant human collagen Types 1 and 3 from yeast. This production method is costly and the product is sold for research purposes only. The company is developing a dermal filler from Type III recombinant human collagen.

• Meristem Therapeutics (Clermont-Ferrand, France/Cambridge, Massachusetts) does research on the production of proteins in plants as a source of lower-cost pharmaceuticals. The company has produced small quantities of recombinant human collagen, among many other proteins, from whole leaf biomass of the tobacco plant.

• CollPlant (Kiryat Shimona, Israel) is developing a transgenic expression platform in tobacco plants to produce pharmaceutical and cosmetic grades of recombinant human collagen. By targeting the collagen to a specific site in the plant, it has achieved high yields and a system that is expected to be cost effective. The process is based on research conducted at the Hebrew University (Jerusalem).

Orthopedic and dental applications

• DePuy (Warsaw, Indiana), a subsidiary of Johnson & Johnson (J&J; New Brunswick, New Jersey), markets Healos bone graft replacement. It is a resorbable hydroxyapatite-coated collagen microfiber that has a structure and composition similar to bone. The company is exploring the use of a collagen matrix for delivering bone growth factors

• Orthovita (Malvern, Pennsylvania) markets Vitoss, a porous and resorbable bone void filler composed of 80% beta tricalcium phosphate and 20% collagen.

• Kensey Nash (Exton, Pennsylvania) sells Vitoss scaffold foam, a resorbable beta-tricalcium phosphate made by Orthovita, using Kensey Nash collagen technology to form a pliant, compression resistant scaffold as a bone void filler.

• ReGen Biologics (Franklin Lakes, New Jersey/Baar, Switzerland) sells the CMI collagen scaffold for meniscus repair in Europe. The product is not approved for sale in the U.S.

• Implant Innovations (Palm Beach Gardens, Florida), a subsidiary of Biomet (Warsaw, Indiana) sells Ossix collagen membrane for guided tissue regeneration and for restoring bones in the oral cavity. It is licensed from ColBar Lifesciences (Herzliya, Israel), a J&J subsidiary.

• Osteohealth, a division of Luitpold Pharmaceuticals (Shirley, New York), markets Bio-Gide, a resorbable bilayer membrane for guided tissue regeneration and for filling periodontal defects. It is made from purified porcine Types I and II collagen. Bio-Oss is a natural bone grafting material that contains 10% purified porcine collagen and is used as a bone void filler in dental surgery. These products are licensed from Geistlich & Sons (Wolhusen, Switzerland).

• Collagen Matrix (Franklin Lakes, New Jersey) sells a resorbable collagen membrane for guided tissue regeneration and in ridge augmentation procedures, porous collagen used for wound healing after oral surgery and a fibrillar collagen dental dressing used in areas that are not easily accessible such as extraction sites. At the recent meeting of the North American Spinal Society (LaGrange, Illinois), it presented a porous and resorbable collagen-mineral composite bone graft that is available in strip, pad and granular forms, and a resorbable and conformable collagen protective sheet used for bone healing.

• Zimmer (Warsaw, Indiana) sells, under license from Integra LifeSciences (Plainsboro, New Jersey), BioMend, an absorbable collagen membrane for guided tissue regeneration, and CollaCote, CollaTape and CollaPlug absorbable wound dressings used in dental surgery.

• EnColl (Newark, California) markets dental and orthopedic products outside the U.S. made from its ultrapure bovine collagen. They are: Healiguide, a collagen membrane for guided tissue regeneration; Osseograft, a demineralized bone-derived collagen; and Osseomold, a mixture of calcium sulfate and bioresorbable collagen, bone void fillers, and Periodontal Plus AB, resorbable collagen fibrils containing tetracycline for treating gum disease. The company also sells Enco Skin, a topical collagen cream for use on wrinkles and photodamaged skin, and collagen-coated multiwell plates for use in accelerating cell culture processes.

• Angiotech Pharmaceuticals (Vancouver, Canada) acquired NeuColl (Los Gatos, California) which is developing Collagraft, a synthetic bone substitute comprised of collagen, hydroxyapatite and tricalcium phosphate. It currently is sold in Europe.

Sealant, graft, neural and urological applicatons

Collagen is used as an arterial puncture sealant to close the wound created in the femoral artery for inserting a catheter in catheterization procedures, including balloon angioplasty, diagnostic angiogrpahy and for inserting coronary stents.

Among these products are On-Site and VasoSeal sold by Datascope (Montvale, new Jersey) and AngioSeal that is sold by St. Jude Medical (St. Paul, Minnesota), under license from Kensey Nash (Exton, Pennsylvania). Datascope also sells the InterGard line of collagen-coated knitted and woven vascular grats and patches for reconstructive vascular and cardiovascular surgery.

• Devro (Chryston, Scotland/Bathurst, New South Wales, Australia) obtains collagen that is produced from a disease-free cattle herd. It is used as a hemostat and in vascular grafts. Its Protocoll K soluble collagen solution is used in skin moisturizing applications. Devro is a leading supplier of collagen as an edible casing for the meat products industry.

• Medtronic (St. Paul, Minnesota) sells Durepair, a collagen membrane for the repair of the dura, the connective tissue membrane that surrounds the brain and spinal cord. It is sold under license from TEI Biosciences (Boston).

• Integra LifeSciences (Plainsboro, New Jersey) markets several neurological products that utilize bovine-derived Type I collagen. These include DuraGen, an absorbable dural graft matrix for the repair of dura mater, NeuraGen nerve guide, an absorbable collagen tube used for the repair of severed peripheral nerves, and NeuraWrap nerve protector that provides an interface between the nerve and surrounding tissue.

Integra produces VitaCuff, a silver nitrate impregnated collagen matrix ring which is placed over a catheter to provide protection against infection. It is sold by Bard Access Systems (Salt Lake City), Arrow International (Reading, Pennsylvania) and Quinton (Bothell, Washington).

• Collagen Matrix develops bovine collagen-based products that it licenses to other companies for distribution. Its neurological products are DuraMatrix, a resorbable membrane used for the repair of dura mater. Neuroflex and NeuroMatrix are collagen nerve cuff products that are resorbable, flexible and semi-permeable tubular matrix and provide protection during peripheral nerve repair. All products are distributed by Stryker.

Collagen Matrix has under development collagen of porcine origin and the following collagen-based products: coil and a template for the treatment of cerebral aneurysms, peripheral vascular endoprosthesis, extracellular matrices for tissue engineering, ligament template for ACL reconstruction, and a tubular collagen dressing for endoscopic repair of urethral strictures.

• CR Bard’s Urological Division (Covington, Georgia) has for many year marketed Contigen as a bulking agent for the sphincter muscle in women with stress urinary incontinence. Sales of Contigen have been declining because its short-use life due to resorption.

• Uroplasty (Minnetonka, Minnesota) is seeking to enter this market with its silicone-based Macroplastique implant which recently received an approvable letter from the FDA for its premarket application.

• CollTech (Subiaco, Western Australia) has developed a patented process for extracting collagen from sheep (ovine) skins using a closed, veterinary-controlled and disease-free herd.