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Genetic Engineering News Tissue-Engineered Product Update Click here to go directly to the portion of the article which references PPTI. The field of tissue engineering is growing rapidly as academic and industrial researchers recognize its potential to provide new, effective therapies for many varied medical conditions. Tissue-engineered products currently in development include skin substitutes, vascular grafts, implants to replace or enhance the function of the pancreas or liver, cartilage and bone replacements and cell therapies for the treatment of neurodegenerative diseases, among others. "Name just about any problem in the body and I can name a tissue-engineering solution," says Chris Tihansky of Genesis Merchant Group Securities (San Francisco), an investment analyst with an interest in tissue-engineering companies. Tutogen Medical, Inc. (Parsippany, NJ) has a proprietary process called Tutoplast® for processing allograft and xenograft tissues, which they market as scaffolds for tissue-engineering applications. Karl Meister, CEO, says, "What distinguishes us from the others in the field is that weĠre working with natural matrices rather than synthetic ones. We think that the characteristics of these natural substrates are far better than any material that can be fabricated in the lab." Tutogen provides both hard (bone) and soft (dura mater, pericardium, and fascia lata) tissue to their clients. "We've been working mainly with neurosurgeons and maxillofacial surgeons," explains Mister, "and recently our biggest market has become urogenital surgery." Tutogen has a collaboration with Mentor Corp. (Goleta, CA) to use Tutoplast-processed fascia lata in urological and gynecological indications. Protein Polymer Technologies, Inc. (San Diego, CA) is developing technologies to engineer structural proteins that mimic the properties of collagen, elastin, silk and keratin, the four basic structural proteins in nature. "We think there is a need for new and novel materials," explains Joseph Cappello, Ph.D., Vice President of Research and Development. "If you need a material with properties that differ even a little from those of the polylactides, collagen or hyaluronic acid, you're out of luck. We hope that our products will provide the strength, durability and resorptive properties of natural materials." The product furthest along in the pipeline at Protein Polymer is a silk/elastin solution that gels in the body for use in soft tissue augmentation. "The material is biodegradable, and we can adjust the durability by adjusting the silk and elastin content," explains Dr. Cappello. "We've made material that persists for one week and some that lasts one year." The first indication for the use of this product will be the treatment of urinary incontinence. Once they have gelled, the silk/elastin copolymers can be freeze-dried to form sponges. The pore size and continuity can be varied to control the final durability of the sponge and the amount of tissue ingrowth that will occur. Applications for these sponges include wound healing, topical wound dressings, surgical plugs and organ fillers or patches. Researchers at Protein Polymer are also working on silk/elastin copolymers that will participate in the chemistry of the body, for example, by cross-linking once exposed to certain exzymes. "We have embedded the site responsible for the cross-linking of fibrin in our copolymer and found that the proteins cross-link when exposed to the factor XIII enzyme," says Cappello. "This process will further stabilize the structure, making a stronger gel." This product could be used in sealants and adhesives for surgical repair. Scaffolds for tissue-engineered products are also being developed at Molecular Geodesics, Inc. (MGI; Cambridge, MA) through the use of a biomimetic technology. Researchers at MGI have developed a proprietary computer-aided design/computer-aided engineering (CAD/CAE) technology that allows them to precisely define the microstructure of a material in order to mimic the microstructure of living tissues. Applications for this technology include stents, bone grafts and dental applications. "We have developed algorithms that allow us to anticipate the mechanical performance of materials or designs," explains, A.J. Meuse, Ph.D., Director of Operations. "We use the computer to cull through our database of designs, matching performance standards with materials and designs, to weed out all things that won't work." According to Dr. Meuse, this ability to anticipate the design performance of the finished product or sub-assembly even before it is built, will considerably shorten the product development time and get products to the market quicker. "Biomimicry has opened up whole new areas in biomedical design and will revolutionize the way people think about materials," says Jim Sherblom, President of Seaflower Associates (Waltham, MA). "Nature has spent billions of years making things flexible and strong -- we can learn from nature." Vascular Grafts "We're using our biodurable, microporous polyurethane vascular graft, Myolink®, as a scaffold for the ingrowth of new tissue," says Mike Szycher, Ph.D., Chairman of CardioTech International, Inc. (Woburn, MA). "In addition, we're seeding the grafts with endothelial cells to provide a biological function, prevention of thrombosis." Maintaining patency of vascular grafts that are used in low-flow situations (e.g., below the knee) has proved to be difficult, but the researchers at CardioTech have shown that vascular grafts seeded with autologous endothelial cells remain patent in dogs for at least one year. In a clinical trial scheduled for this fall, endothelial cells will be isolated from the patient's own fatty tissue and seeded onto the grafts, which will be implanted into the patient's leg the same day. The clinical trial will be conducted at the Royal Free Hospital in London, where researchers will provide the expertise for isolation, clean-up, and seeding of the endothelial cells. "If this technology is successful, we'll apply it to coronary artery bypass, which is an even smaller graft," says Dr. Szycher. The peripheral artery graft is 4mm in diameter, while the coronary artery graft is 3mm. "There's only a 1mm difference in diameter," explains Dr. Szycher, "but that's a huge difference in terms of blood flow, because flow is inversely proportional to the radius to the fourth power. This makes the biological contribution of the endothelial cells even more important." Inhale Therapeutics is developing dry powder aerosol delivery of insulin and other macromolecules. In their process, a critical amount of water is removed from a protein, the protein strands immobilize one another, and a state of highly enhanced chemical stability of protein results. Inhale reports it has produced 1µm to 5µm particles without significant degradation of protein therapeutic, developed proprietary methods to fill non-flowing powders into unit dose blister packs and designed an efficient, mechanical inhaler device. Skin Substitutes Skin substitutes are among the furthest along of the tissue-engineered products, with three companies having products on the market: Organogenesis, Inc. (Canton, MA), Integra Life Sciences (Plainsboro, NJ), and Advanced Tissue Sciences (ATS; La Jolla, CA). ATS was recently awarded U.S. patent no. 5,785,964 covering three-dimensional tissue products made with genetically modified cells for gene therapy applications. With the patented technology, genetically modified tissues can be grown on a biocompatible scaffold using genetically engineered stromal cells, genetically engineered parenchymal cells or both. Genetically modified tissue products may provide a safe and unique delivery vehicle for therapeutic proteins, according to ATS. Ortek International is a small, development-stage company based in New York City that has a good chance of successfully competing in the skin-substitute market, according to Tihansky. Ortek's product, Composite Cultured Skin (CCS), was developed through technology licensed from Mark Eisenberg, M.D., in Sydney, Australia. CCS is similar to Organogenesis' product in that it consists of a collagen matrix seeded with keratinocytes and fibroblasts derived from human foreskin. "There are two main differences between our product and Organogenesis' product," says Ron Lipstein, Chief Financial Officer at Orteck. "The matrix in the Organogenesis product is a dense gel, while the matrix in CCS is a porous bovine collagen that allows for more neovascularization of the graft and proliferation of the cells." The cells in CCS are not fully differentiated and they are less densely seeded onto the matrix than are the cells in Organogenesis' product, continues Lipstein. Once that graft is in place, the cells produce growth factors, stimulating the body's own wound-healing processes. "The mix of growth factors produced by the different cell types in the graft is critical for the functioning of the graft," Lipstein explains. At the American Burn Association meeting in 1997, Ortek reported good results from a small clinical trial testing CCS in burn patients. Ortek has received approval to begin a clinical trial at the end of August testing CCS on donor skin sites, and the next several months will begin trials using CCS for chronic dermal ulcers and deep partial-thickness burns without the use of autografts. Ortek is also working on process development and hopes to be able to cryopreserve CCS, which would extend the shelf-life of the product and make distribution to wound-healing clinics easier. Endocrine Tissues Perhaps one of the oldest areas of research in the field of tissue engineering is transplantation of pancreatic tissue to treat diabetes. Several companies, including BioHybrid Technologies (Shrewsbury, MA), Betagene (Dallas), Neocrin (Irvine, CA) and VivoRx (Santa Monica, CA) have been trying to solve the basic, yet difficult, cell biology problems involved in procuring insulin-producing tissue and then regulating insulin release from the cells. Desmos, a San Diego-based company, is developing products for use in the regulation of adhesion, migration and proliferation of cells used in cell therapies, and may have an answer to some of these problems. Desmos recently received a patent for the purification of the extracellular matrix protein laminin-5, and has entered into a collaboration with YoKo Mullen, M.D., Ph.D., Director of Islet Transplantation at UCLA School of Medicine, to study the use of laminin-5 as a substrate for the growth of human pancreatic islet cells. Researchers at Desmos have shown that, with their proprietary technologies, they can expand, cause to reaggregate, and restore partial function to procine islet cells. The collaboration with Dr. Mullen is designed to extend these methodologies to human cells. "Our research group, led by Ivan Todorov, Ph.D., has made incredible progress in the past 18 months in terms of expansion of the islet cultures and expression of insulin," claims Mary Harper, Ph.D., Vice President of Research and Development. "We're using laminin-5 to coat the surface of tissue culture dishes, which causes the cells to reaggregate into 'pseudo-islets,' which stain for insulin, glucagon and somatostatin." Laminin-5 is Desmos' lead product, but several others are in the pipeline, explains Dr. Harper. The technology being developed at Desmos is versatile, and is being taken in three main directions: (1) tissue culture applications for use with cell therapies, as the islet cells; (2) direct therapeutics, such as using laminin-5 to treat periodontal disease, which will be their first product in the clinic; and (3) biocoatings. "Our coatings can enhance the biocompatibility and functionality of existing medical devices," says Dr. Harper. "We just signed an agreement with Baxter Healthcare (Deerfield, IL) to use laminin-5 to coat catheters for intraperitoneal dialysis. This will make a tighter seal between the catheter and the skin, which should enhance healing and decrease the rate of infection." According to Tihansky, tissue-engineering companies are beginning to be recognized by the investment community and by large pharmaceutical and medical device companies as wise investment options. "Medical device companies are going to have to shift from metals and plastics to biological materials, including those that release bioactive products and those that interact with the body to encourage a biological response, if they're going to continue to be successful." There are approximately 22 publicly-traded tissue-engineering companies, several dozen privately-held companies, and a few big companies with tissue-engineering programs, says Tihansky. But that will soon change. "Big companies that didn't historically have an interest in tissue engineering are beginning to make deals with tissue-engineering companies," says Tihansky, "and we're going to see more acquisitions, licensing deals, and technology transfer in the near future. The small companies are beginning to develop from the incubator/development stage to commercial entities with products that are earning money."
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