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Genetic Engineering News Advances in Tissue Engineering Products Click here to go directly to the portion of the article which references PPTI. Tissue engineering appears to have finally hit its stride as a viable area of business 10 years after the National Science Foundation began touting it as a hybrid of biology and engineering aimed at restoring, maintaining and improving tissue functions. Companies in this field are now at various phases of product development, and a few firms are successfully marketing their wares. Yet, in its reliance on emerging technologies, the tissue engineering field "is more evolving than maturing," says Elise T. Wang, a biotech analyst at Paine Webber Inc. (New York City). "The trend is to go toward biologics [traditionally, blood-derived for blood-borne products] and toward the fundamentals as to why these wounds developed in the first place and how you can repair them by regenerating tissue in the natural way," she adds. As a result, companies profiting from non-biologic products are now looking to capitalize on recent discoveries by biologists, particularly in the growth-factor field. Researchers with biologic tools in hand, conversely, are seeking to parlay them into profitable products. Non-Biologics In 1993, 20 years after electron microscopists first noticed similarities between human spongy bone and coral, Interpore Intl. (Irvine, CA) introduced a bone-graft material derived from coral. Dubbed Pro Osteon, it was the first such material approved by the FDA. Pro Osteon is molded into the void created by a serious bone fracture or defect and forms an "osteoconductive" scaffold into which the body's own bone grows. Approved in more than 40 countries, Pro Osteon was responsible for most of Interpore's $9.5 million in orthopedic sales in the first nine months of 1997, according to chief financial officer Richard L. Harrison. He estimates the total worldwide bone-graft market at $800 million, 90% of which uses natural human grafts. Osteoconductive vs. Osteoinductive Unlike osteoconductive materials, whose structure lets bones heal themselves, osteoinductive materials, such as growth factors, actively induce bone growth. "Most doctors would probably say that they prefer a combination of osteoinductive and osteoconductive materials" because it presumably works faster and more thoroughly, according to Harrison. Interpore, consequently, is now collaborating with Quantic Biomedical Inc. (San Rafael, CA) on using concentrated human growth factors to speed up Pro Osteon-stimulated bone growth. A second Interpore collaborator is Sulzer Orthopedics Biologics (Lakewood, CO), which has discovered a bovine-derived bone growth factor called Ne-Osteo. Interpore is also working with scientists at the University of Southern California Medical Center who have engineered a fusion protein that incorporates osteogenin, a human bone growth factor discovered at the National Institutes of Health. By also incorporating a calcium-binding peptide, the fusion protein promotes the binding of osteogenin to calcium-rich Pro Osteon, Interpore is wagering that osteogenin, once bound, will not migrate and thus stimulate bone growth in inappropriate areas of the body. A patent application was filed in 1997 for the fusion protein. The Sulzer and U.S.C. projects "are probably no sooner than five years from the market," notes Harrison. The Quantic collaboration, on the other hand, could move into clinical trials by the end of 1998. Like Interpore, Integra LifeSciences Corp. (Plainsboro, NJ) is already marketing an in vivo, non-biologic regeneration product. Integra Artificial Skin, approved by the FDA in 1996 for the treatment of life-threatening burns, currently brings in revenues of $7.5 million annually, says George W. McKinney, Ph.D., the company's COO. Estimates of the world market for all uses of the product range form $600 million to $1.5 billion, he adds. Integra Artificial Skin is now sold in 19 countries, and the company hopes to win approval shortly for its use in plastic and reconstructive surgery. The artificial skin consists of an inner layer of bovine collagen and a shark-cartilage derivative and an outer layer of silicone. The inner layer induces the patient's dermis to regenerate and is later reabsorbed by the body. The outer layer seals in moisture for two to three weeks, after which a surgeon peels it off and covers the wound with a thin graft of the patient's own epidermis. Intregra's product has been shown to cause significantly less scarring than the traditionally used full-skin graft. "We are trying to stay away from culturing the cells in an ex vivo sense" because it is costly and time-consuming, McKinney says. "What we want to do is to signal the cells to do what they originally did." He elaborates: "What we are doing with all our technologies is developing what look like off-the-shelf products that, when placed in the body, are smart. They recognize that local biology." Regeneration Templates Integra foresees its line of so-called regeneration templates being used eventually to treat bone and cartilage damage, periodontal disease, severed peripheral nerves, tears in the dural membrane of the nervous system and vascular occlusions. "While this may sound like an enormous number of things, it comes from a very small core of technology," McKinney notes. Integra's collaborators include Genetics Institute Inc. (GI; Cambridge, MA) and Sulzer Calcitek (Carlsbad, CA). The regeneration templates are at various stages of development. Thus, in five-year primate studies, neural templates helped close 5-cm gaps in peripheral nerves, and human safety studies have already been done in Europe. Integra just finished a thousand-patient trial of its dural regeneration template and, according to McKinney, expects European approval in 1998. The company is also heeding the growing emphasis on growth factors in the tissue-engineering fields. In clinical trials conducted by GI, one of Integra's regeneration templates is serving as a matrix carrier for GI's proprietary bone morphogenetic protein (BMP). BMPÕs are a family of growth and differentiation factors that stimulate bones and other tissues to grow. Growth Factor GI's big rival in the BMP filed is Creative BioMolecules, Inc. (CBM; Hopkinton, MA), whose proprietary growth factor is BMP-7, or OP-1, as the company calls it. Besides bone, OP-1 induces the formation of cartilage, kidney, brain and teeth. To commercialize the effect on bone, CBM has long been in partnership with Stryker Corp. (Kalamazoo, MI), which, in turn, formed Stryker Biotech (Natick, MA) to market the anticipated products. A year ago, Biogen, Inc. (Cambridge, MA) and CBM agreed to collaborate on developing the use of OP-1 in treating renal failure. BiogenÕs investment could top $122 million. CBM and Stryker have developed an osteoinductive bone-regeneration product that combines OP-1 with a collagen matrix. A recent 122-patient study found the product was equivalent to a human autograft, the "gold standard" therapy, according to Marc F. Charette, Ph.D., CBM's senior director of R&D. Stryker is, accordingly, filing a PMA application with the FDA. In November, CBM announced that intravinous injections of OP-q preserved kidney function in rats in which acute renal failure was induced by ischemia. Other studies have found that OP-1 stabilizes kidney function when 5/6 of a rat's kidneys are removed, a standard model of chronic renal failure. Dr. Charette notes that in the U.S. about 300,000 people are on dialysis and another 700,000 show some renal insufficiency. Some 250,000 Americans wee diagnosed with acute kidney failure in 1995. The idea driving CBMs neurological program, Dr. Charette says, is that "OP-1 might be able to enhance [the brain's] natural, endogenous plasticity" after a stroke. When strokes are induced in rats, they recover motor skills much more quickly and completely if OP-1. These findings, in turn, tally with the way the OP-1 gene was discovered. Dr. Charette recalls that it was cloned from a hippocampal cDNA library after "we started probing everything that we had" in the race to isolate BMPs. Under a 1996 agreement with GI intended to avoid lengthy patent litigation, CBM and Stryker reserved exclusive rights to OP-1 and two related BMPs, while GI gained rights to BMP-2 and a related BMP. This deal has given CBM the green light to start studying BMPs besides OP-1. "There is a whole wealth of biology and other therapeutic applications that this family of proteins could potentially afford the company," says Dr. Charette. GI, meanwhile, is conducting a Phase II clinical trial in the U.S. to study the use of BMP-2 in oral/maxillofacial surgery. Stem Cells BMPs act by binding to receptors on stem cells, among others, thereby causing the cells to differentiate. Taking a different approach than that taken by CBM, MorphoGen Pharmaceuticals, Inc. (New York City) has isolated the stem cells targeted by growth factors rather than the factors themselves. In stem-cell research, says Lawrence M. Rifkin, the company's acting president, "what people have been focused on so far is the blood cell-forming units. What they're starting to realize now is that there's so much more in terms of tissue repair." Last October, the PTO allowed a patent covering MorphoGen's pluripotent mesenchymal stem cells (PPM-SCs) and the means of isolating them. According to FACS analysis, PPMSCs differentiate in vitro into the kinds of cells comprising bone, cartilage, tendon, ligament, the three types of muscle, fat and endothelium. While undifferentiated, PPMSCs divide over 110 times, compared to about 50 for the average human cell. But Rifkin emphasizes that the cells never form cancerous teratomas. MorphoGen's roster of scientists now includes only its three founders, Cato T. Laurencin, M.D., Ph.D., Paul A. Lucas, Ph.D,. and Henry E. Young, Ph.D., who still work in their respective academic institutions. Although the researchers are now focusing on cultured human cells, Rifkin hopes the company will be conducting clinical trials by 1999. Stem Cell Transplants' Mechanism of Action In practice, stem-cell transplants might work as follows: Through a skin or muscle-punch biopsy, tissue would be withdrawn from a patient and sent to MorphoGen. In two weeks' time, PPMSCs would be isolated from the sample, cultured and seeded into a polymer molded to fit an injured area, for instance, damaged knee cartilage. A surgeon would then insert the polymer into the patient when the cells were still undifferentiated. Responding to locally acting endogenous factors, they would differentiate appropriately and form the correct tissue structures. Unlike stem-cell transplants, autografts are fully differentiated tissues transplanted from one area of the body to another. So far, bone and skin have been used, but fat, which is far more easily harvested, could join their ranks if the plans of CellSource Inc. (Pittsburgh, PA) pan out. "Fat is one of those things that everybody has looked at as something you don't want," says CEO John M. Johnson. "All of a sudden, there's a school of thought that says, maybe we do want fat tissue." After liposuction, fat might be reinjected into the body to enlarge breasts (thereby replacing silicone and saline implants), treat vocal-cord atrophy, provide prosthetic padding in amputees and alleviate urinary incontinence. The problem is that fat transplants tend to resorb or necrose, so their final volume is unpredictable. "What [the mature fat cell] seems to be missing is the ability to quickly lay down enough vascular structure to support itself over a period of time," says Johnson. "So it ends up dying." In the past year, CellSource has been working with a few scientists on promoting fat angiogenesis. Johnson will not disclose any findings yet, but his firm is already turning fat into revenue: It sells the Tulip syringe system used in liposuction. If transplanted fat is still a problematic treatment for incontinence, Protein Polymer Technologies, Inc. (PPTI; San Diego) has another solution to this condition estimated to affect 10 million American women. PPTI's recombinant protein polymer forms a pliable, long-lasting hydrogel when injected into the urethra. The gel enables the sphincter, the muscular valve controlling urine flow, to close fully. Human safety testing should begin in 1998 or early 1999. Joseph Cappello, Ph.D., VP of R&D, says of PPTI's polymers: "What we're trying to do is build new biomaterials -- materials that can be used inside the body -- that will provide the physical and mechanical robustness" of the natural tissue whose properties the company is trying to duplicate.
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