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Genetic Engineering News Cost Competitiveness
Issues Driving Biopolymer Research and Development Click here to go directly to the portion of the article which references PPTI. Biopolymers are gaining currency as new materials for medical devices and as a subject of research at companies, universities and research laboratories for a broad range of industries throughout the world. Researchers are finding that some biopolymers offer advantages that inorganic substances may lack, including, for medical devices, compatibility with the body and the ability to be absorbed when their work is complete. By synthesizing these polymers, commercial-scale quantities can be made more readily available. Much of the research, according to Robert Wetegrove, Ph.D., corporate research associate, Nalco Chemical Company (Naperville, IL), is a reaction to the environmental movement. But the need for cost-competitive products is causing scientists to focus on ways to make the molecules more efficient. Although companies talk about a host of projects in development, they are tending to keep any results that can be analyzed quiet-ostensibly because of complex webs of research and confidentiality agreements. Hyaluronate At BioMatrix (Ridgefield, NJ), a pioneer in this field, the focus is upon visoelastics made by cross-linking the hyaluronan molecule, which resulted in a high-elastic, viscous and pseudoplastic polysaccharide (Hylan A), and a water-insoluble polysaccharide that, when hydrated, forms transparent gels with high elasticity (Hylan B). Such properties make them ideal as therapeutic agents. Endre Balazs, M.D., CEO and chief scientific officer, said. The firm has a strong international presence. In 1995, BioMatrix received regulatory approvals for four products -- including Synvisc for arthritic pain, and Hylaform for tissue viscoaugmentation -- in the European Economic Community; Gelvisc Vet, a viscosupplementation product for arthritis in animals, in Sweden; and Hylashield for an ophthalmic viscoelastic surgical shield in Canada. Approvals are expected in France and Italy later this year for Gelvisc Vet and in Italy for Hylashield and Synvisc. Six other products are in late-stage development, according to Dr. Balazs. Clinical studies have begun for Hylagel Vasc to treat percutaneous embolization of arteriovenous malformations; for Hylasol for ophthalmic viscosurgery; and Hylagel Eye for ophthalmic viscosupplementation. Preclinical studies have been completed for Hylagel for the postsurgical prevention of adhesions and excessive scar formation; for Hylagel Uro to treat urinary incontinence; and for Hylasine to prevent postoperative scarring and the development of mucous membrane adhesions. Clinical trials will begin both in Europe and in the U.S. this year. Additionally, new, modified forms of hylans are being developed for use as membranes, molecular sponges and tubes. BioMatrix also is working with several biotechnology companies to develop vascoelastic hylans as drug delivery matrices. Currently, products are being sold in Canada and Sweden for osteoarthritis, arthritis in animals and viscoprotection of the eye surface during surgery. Nine products for cosmetics are being sold in the U.S., Europe and Japan. Synvisc, Gelvisc Vet and the Hylashield product line are obtaining regulatory approval in South America, South Africa, Australia, New Zealand, the U.S., Japan and Italy. The firm has 21 patents internationally and more than 90 patents pending internationally. Cataract Surgery At Lifecore Biomedical, Inc. (Chaska, MN), the hyaluronate division concentrates on developing components in ophthalmic surgical solutions for cataract surgery. Applications to prevent post-surgical adhesions in general surgery, catheter coating for cardiovascular sues, drug delivery and treatments for traumatic arthritis, interstitial cystis, and, in veterinary medicine, the storage of fertilized embryos and for orthopedics are being developed with a variety of corporate partners. So far, alliances have been formed with Alcon, Ethicon, Chiron Vision Corp. (Claremont, CA) and Storz Ophthalmics, Inc. (OÕFallon, MO). The most promising potential application, however, is the use in post-surgical adhesion prevention. The company is focusing on abdominal procedures performed annually in the U. S., the reported incidence of adhesions ranges from 35-90%, according to Lifecore. Clinical trials for Lubricoat 0.5% Ferric Hyaluronate Gel began in May 1995 and involved 25 patients. Lifecore reported that it reduced the number, extent and severity of adhesions when compared to controls. Although the actual statistics have not yet been mad public, vice president of new business development Brian Kane said they were sufficiently promising for Lifecore to begin larger, Phase II multi-center trials this spring in Europe and the U.S. The patent for Lubricoat Gel now is allowed in the U.S., Australia, Canada and Greece. Work to commercialize Caprogel Topical Aminocaproic Acid, in cooperation with Orphan Medical (Hopkins, NM) is ongoing, but it remains in the early-trial stage, Kane said, despite the Phase I trials that were begun in 1994 by Orphan Medical (before Lifecore became involved with the product). Caprogel is designed to control ocular bleeding. Additionally, Lifecore received investigational device exemption (IDE) approval for Lurocoat Ophthalmic Solutions for use during cataract surgery and is preparing an IDE application with Storz for an ophthalmic gel for use during refractive surgery. Lifecore estimates a global market of about $160 million per year for hyaluronate for cataract surgery. Currently, hyaluronate is used during ophthalmic surgery to coat and lubricate the anterior chamber of the eye during the implantation of an intraocular lens. Protein Polymer Technologies (San Diego) is developing protein-based biopolymers for use as adhesives to replace or augment the sutures and staples currently used to close wounds and surgical incisions. The U.S. Markets for wound closure products is estimated at $1.5 to $2 billion annually, according to company reports. Currently, the company is designing polymers that set quickly, provide high bond strength and are later absorbed by the body. These high molecular weight protein polymers "...reproduce and amplify selected activities of natural proteins, combine properties of different natural proteins, eliminate undesirable properties of natural proteins and act as precisely defined polymer platforms to chemically combine protein and synthetic materials properties," notes a company spokesman. They can be produced as gels, sponges, films and fibers. "We are conducting demonstrations and are in discussions with several different groups. We haven't published results from our collaborations because of confidentiality agreements," says Protein Polymer Technologies', Gwen B. Como. The company reports that wound-healing
matrices are in animal testing using the name ProLastin. This material
incorporates BetaSilk and mammalian elastin and can be produced as fully
resorbable gels, sponges, films and fibrous sheets. Surgical-adhesion
barriers currently are being made from bioresorbable films in preparation
for clinical trials. These polymers also are being developed as drug delivery
devices. Protein Polymer has teamed with a major medical center to formulate
and test the devices using analgesic drugs for a controlled target release
directly to nerve tissue for the relief of chronic pain.
Chitin In the U.S., chitin -- a polymer obtained from crustacean shells and insects and contained in the cell walls of yeast, mushrooms and other fungi -- is finally receiving attention. According to the International Commission on Natural Health Products (ICNHP), "Almost 1000 research papers have been published on chitin and its derivatives worldwide and nearly 200 patents have been issued in the U.S. alone." The research leader in this field, however, seems to be Japan. There, chitin is commonly used as an antibiotic, according to the ICNHP's spokesperson, Wendy Alpine. Japan's Fuji Spinning Co. is blending a chitin derivative, chitosan, with the natural-fiber polynosic to create chitopoly, a fiber that is woven with cotton fibers for use in underwear to limit the growth of bacteria and fungi. U.S. researchers report it also is useful as a natural insecticide as a water-purification treatment, in paper, burnwraps, for drug delivery, bone healing and as a flavor preservative and enhancer. "Most of the (medical) work in the U.S. is in the animal stage," Alpine said. Although raw chitin is plentiful, there is some need to produce synthesized chitin also. One of the benefits of producing chitin in the laboratory is the purity of the product. To obtain the natural, unsynthesized product, according to Peter Wachtel, president of Princeton Polymer Laboratories, (PPL, Princeton, NJ), the pollution created by leaching the chitin from shells is tremendous. "For every kilo of chitin obtained, about one ton of shells must be leached with acid (depending on the type of shell). At PPL, chitin is being developed via vat fermentation so that it is non-alkyline and pure. Because PPL is a contract laboratory, details of its work are proprietary but, Wachtel said, "We're looking at using it as a bone growth hormone matrix and as an implant matrix material." As a bone growth hormone matrix, the hormone would be embedded into the chitosan for a time release. Then, the matrix itself would resolve into bone, further strengthening the site. That work is undergoing bench testing. Another project, also in bench testing, involves developing an optical isomer of chitosan. Biopolymers are being actively investigated for nonmedical applications, also. Nalco Chemical Company, for example, is using the biopolymer dextran to clarify aluminum after it is mined. According to Dr. Wetegrove, "Nalco is investigating the whole spectrum of water treatment," focusing on solid-liquid separations for its biopolymer work. So far, he adds, "It's significantly more expensive on a cost-performance basis-about twice as much, in fact -- to use biopolymers, even if you start with waste raw materials." Nalco is working to increase the efficiency of the biopolymer molecules. At Agracetus, Inc. (Middleton, WI), polymers are being added to cotton. As Ken Barton, Ph.D., co-general manager and vice president of research and development, explained, "Cotton fiber is like a hollow tube of cellulose. We're adding enzymes acetoacetyl CoA reductase and PHB-polymerase from the bacterium Alcaligenes eutrophus that produced polymers like polyhydroxybuterate to make a cellulose/polyester natural fiber." Advantages of this new product include improved dye binding, limited shrinkage and permanent press fibers. "We're in our second year of field trials and are experiencing significant quantities of plastic in the cotton," Dr. Barton said. The cotton is being analyzed for its dye binding, dimensional stability, thermal properties and absorbency. At the U.S. Department of Agriculture, at least 33 projects directly involved biopolymers, the vast majority of which are bench-stage experiments. Some of those include work to create sugar derivatives for use in medicine and specialty chemicals, screening microbes to convert agricultural commodities to viscous polysaccarides, plastics biodegradation, films made from polysacchardies and hydrocolloids to protect foods and the introduction of bacterial polysaccharides in foods to improve the stability and feel of the product. Likewise, university laboratories throughout the country are actively developing biopolymers for the wide range of agricultural, industrial and medical applications.
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