BBI Contributing Editor

NEW YORK – More than 75 public and private companies made presentations at Techvest's (New York) 3rd annual Healthcare Conference in October. As in prior years, the focus was on regenerative medicine, soft and hard tissue repair and replacement. Regenerative medicine is defined as harnessing the body's inherent ability to repair damage caused by disease, trauma or age. The technologies and products reviewed at this conference encompassed cellular therapies, stem cells, growth factors and biopolymers for both external and implanted applications.

Co.don (Bradenburg, Germany), a sponsor of the Techvest meeting, is a contract development company that uses autologous cultured cells and bioprocessing techniques to produce tissue engineered products for the treatment of cartilage, bone, vascular and cardiothoracic defects. The company also develops minimally invasive surgical instruments to accompany the use of its products. Co.don is currently seeking to obtain FDA approval to market Chondrotransplant autologous cultured chondrocytes. The company is also developing autologous cultured osteoblasts and intervertebral disk chondrocytes.

Colbar R&D Ltd. (Ramat Hasharon, Israel) develops tissue engineered products. It uses proprietary programmed biomatrix technology to create a matrix that has both biological properties and a controlled rate of degradation. Colbar has developed Ossix, a dental membrane that is marketed in the U.S. and Europe by the dental implants company, 3i Implant Innovation (Palm Beach Gardens, Florida). Its product for bone regeneration in dental surgery has received the CE mark and has marketing approval from the FDA. Dermicol, a tissue augmentation product for treating facial wrinkles, is expected to enter a pivotal trial in Europe and a pilot trial in the U.S. early next year. Colbar soon plans to initiate animal trials on tissue engineered products for stress urinary incontinence.

Curis (Cambridge, Massachusetts), created one year ago from the merger of three companies, is seeking to use genomic data and stem cells to develop regenerative therapeutics. The company has developed Chondrogel, autologous chondrocytes in an alginate matrix for treating pediatric vesicoureteral reflux, and expects to file a BLA in the second half of 2002. It is in a Phase I trial for Vascugel, an allogeneic implant of human aortic endothelial cells for preventing thrombosis and intimal hyperplasia, and for use in coronary artery bypass graft (CABG) surgery. Curis is seeking corporate partners for its BMP-7 programs which use specific morphogenic pathways for neurological recovery. It functions by stimulating new synapse formation, enhancing the recovery of memory and motor skills within 72 hours of stroke, and aids in the recovery from acute renal failure when administered within eight hours after ischemia. It also is being developed for treating chronic renal disease caused by diabetes and hypertension.

Isto Technologies (St. Louis, Missouri) is developing a proprietary method of culturing human articular cartilage to form 3-D grafts without the use of scaffold materials. Its initial products are in vitro cultured chondral and osteochondral allografts for the repair and replacement of injured or diseased cartilage of the knee or other joints and a natural surgical adhesive that employs human tissue transglutaminase enzyme to crosslink proteins of adjoining tissues. These chondral grafts have been tested in sheep and rabbits. They offer the advantages over current treatments by eliminating the need for additional surgery to harvest autologous tissue and continuing to secrete hyaline matrix to fill defects. The target market for these grafts is sports medicine. The company is also developing an osteochondral allograft for more severe defects caused by osteoarthritis. Isto is seeking corporate partners to market its products.

Pronova, a subsidiary of Norsk Hydro (Oslo, Norway), and one of only a few companies exhibiting at the Techvest gathering, produces high purity grades of alginates and chitosan. Its alginate is used by Curis as an encapsulant of chondrocytes. Its chitosan is used by West Pharmaceutical Services (Lionville, Pennsylvania) in a nasal delivery system and by 3M (St Paul, Minnesota) in a wound dressing.

ProChon Biotech (Rehovot, Israel) is developing therapeutic agents and cell-based treatments for genetic and acquired skeletal disorders. The company's approach is to modulate fibroblast growth factors (FGF) and their corresponding receptors, the key natural regulators of cellular processes involved in the formation and repair of bone and cartilage. It is focused on inhibiting the abnormally overactive growth factor signaling in short-limbed dwarfism and certain cancers or, alternatively, stimulating the FGF system to promote repair of cartilage and bone.

BioMimetic Pharmaceuticals (Brentwood, Tennessee) is developing recombinant human platelet-derived growth factor (rhPDGF) formulated in an osteoconductive matrix for use in the localized treatment of periodontal and maxillofacial bone defects. When administered systemically, it was found in animal studies to substantially stimulate skeletal bone formation. When administered with Merck's (West Point, Pennsylvania) osteoporosis drug Fosamax, the combination was twice as effective as Fosamax alone.

BioTransplant (Charlestown, Massachusetts) is developing therapeutics around its ImmunoCognizance technology to re-educate the body's immune system to accept transplanted cells, tissues and organs by recognizing them as "self." This is intended to overcome the serious side effects associated with organ and cell transplantations used to treat cancer and other life threatening diseases. ImmunoCognizance-based therapies are expected to increase the therapeutic benefit of bone marrow transplants used to treat cancer patients. This approach is based on mixing elements of the donor's immune system with that of the recipient to establish recognition of the donor's tissue. This technology has the potential of reducing or eliminating the need for lifelong anti-rejection immunosuppressive drug therapy and to significantly improve a patient's outcome.

BioTransplant is collaborating with MedImmune (Gaithersburg, Maryland) to develop MEDI-507, a humanized monoclonal antibody designed to treat autoimmune disorders and treat and prevent organ and tissue transplant rejection.

Protein Polymer Technologies (San Diego, California) produces genetically engineered biomaterials that comprise high molecular weight protein polymers and are processed into products with physical and biological characteristics tailored to specific clinical performance requirements. The company is clinically testing a silk-elastin polymer hydrogel for use as a urethral bulking agent for treating female stress urinary incontinence and for tissue augmentation of dermal contour deficiencies. The company also is developing a crosslinked protein polymer solution that is injected into the nucleus of the spinal discs. It is transformed after injection from a liquid into a tough, adhesive hydrogel that seals the inside of the disc. Lower back pain is the fastest-growing major segment of the orthopedic products industry.

FzioMed (San Luis Obispo, California) has developed and patented Oxiplex, an absorbable hydrogel comprised of carboxymethylcellulose and polyethylene oxide. Its primary focus is on the use of Oxiplex for preventing adhesion formation after spinal, abdominal/pelvic and cardiac surgeries. The company is conducting U.S. clinical trials in adhesion prevention and has CE mark approval for Oxiplex in Europe. FzioMed is also developing hemostasis products using Oxiplex to control bleeding tissues during surgery.

Tissue-engineered products enter market

Ortec International (New York), a tissue engineer-ing company, featured OrCel, its recently approved bilayered cellular matrix for healing donor site wounds in burn victims. The company also received FDA approval under a humanitarian device exemption for use of OrCel in victims of epidermolysis bullosa, a rare skin disorder. Ortec is conducting clinical trials using its cellular matrix technology for healing venous and diabetic skin ulcers and says that its platform technology may extend to the development of other human tissue, such as tendons, ligaments, cartilage, bone, muscle and blood vessels. The company is seeking strategic corporate alliances for these applications.

Organogenesis (Canton, Massachusetts) produces the Apligraf bilayered skin substitute that contains living human cells and is the first tissue engineered product to gain FDA approval. It is marketed by Novartis (Basel, Switzerland) for treating venous leg ulcers and diabetic foot ulcers. The company plans to introduce several products by year-end, including its FortaPerm bioengineered tissue support product, FortaGen bioengineered tissue repair product, PuraPly wound dressing and Revitix regenerative skin complex. Its pipeline includes the Vitrix living dermal replacement, a coronary vascular graft and a liver-assist device.

Advanced Tissue Sciences (ATS; La Jolla, California) develops and manufactures human-based products for tissue repair and transplantation. Its Dermagraft product is the first FDA-approved tissue engineered, living dermal substitute that is cryopreserved. It is approved in the U.S. for the treatment of diabetic foot ulcers and has been approved in Canada for use on all chronic wounds. The company has two joint ventures with Smith & Nephew (Hull, UK). One program focuses on the application of ATS' tissue engineering technology for skin wounds which includes the Dermagraft product and Trans-Cyte, a temporary covering of second and third degree burns. A second program is directed at the development of tissue engineered orthopedic cartilage. ATS has a strategic alliance with Inamed (Santa Barbara, California) for the development of human-based, tissue-engineered products such as collagen for aesthetic and reconstructive applications. NouriCel is being developed for skin care and cosmetic markets.

LifeCell (Branchburg, New Jersey) processes human tissue by removing all cells but preserving the essential biochemical and structural components. The company markets three products: AlloDerm for reconstructive, burn and periodontal procedures, Cynetra for non-surgical correction of soft tissue defects, and Repliform for urological and gynecological procedures. The company is using its tissue processing technology to develop small diameter blood vessel grafts and its acellular tissue matrix for regenerating tendons, cartilage and bone. It also is investigating the use of human tissues as carriers for drugs

ReGen Biologics (Franklin Lakes, New Jersey) uses a biologically active collagen matrix for tissue regeneration. The company focuses on the repair and preservation of the knee. Its Collagen Meniscus Implant, a resorbable collagen scaffold for the repair and regeneration of meniscus tissue, has received regulatory approval in Europe and is distributed by Sulzer Medica (Winterthur, Switzerland). It is currently completing enrollment in a pivotal multicenter clinical study in the U.S. ReGen Biologics also has developed the SharpShooter tissue repair system, an inside-out suture used to repair a torn meniscus which is distributed by Linvatec, a subsidiary of Conmed (Utica, New York).

Cook Biotech, a subsidiary of Cook Surgical (Bloomington, Indiana), has developed a range of grafts and dressings based on small intestinal submucosa (SIS) derived from the porcine small intestine. They include the Surgisis soft tissue graft for use as a mesh in tissue reinforcement, Surgisis Gold hernia repair graft, Oasis burn dressing and a range of vascular grafts. Cook Biotech uses the extracellular matrix of SIS for tissue engineering development, an example being its vivoSIS, which has a 3-D architecture and is marketed for cell culture applications.

Stem Cells: Core technology

Stem cell technology is a cornerstone of regenerative medicine which has as its goal the restoration of organ function lost to chronic degenerative diseases or injury. The therapeutic value of stem cells derives from their ability to renew and become the cell types characteristic of the organ into which they are transplanted. Because stem cells have the capability of integrating and generating new cells within an organ, they are considered prime candidates as vehicles for delivering gene therapy. Human embryonic stem cells can develop and differentiate into all cell types in the body.

StemCells (Palo Alto, California) is engaged in the discovery and commercialization of stem cells and is focused on the repair or repopulation of neural, liver and pancreatic tissues for treating diseases of the central nervous system, liver and pancreas, respectively. StemCells is the first company to identify and isolate human neural stem cells from brain tissue for therapeutic use. It has been shown that human neural stem cells engraft and become the cell types characteristic of the sites within the brain into which they are transplanted and that they continue the process of forming new neurons. The company also has demonstrated the differentiation of adult blood-forming cells into mature liver cells.

Stem Cell Pharmaceuticals (Seattle, Washington) presented a rationale for developing compounds that stimulate the in vivo proliferation of autologous adult stem cells as an alternative to the transplantation of stem cells. This approach was described as overcoming the scientific problems (age of cells and culturing of cells), regulatory and ethical problems (source of cells – adult vs. fetal, and uniformity of drug product). Support for the hypothesis of drug-induced stem cell activation and injured tissue repair was generated in studies of the human protein gfa50 in rat models for Parkinson's disease.

Stem Cell Sciences (Victoria, Australia) seeks to realize the potential of embryonic stem cells in human medicine. Embryonic stem cells offer an advantage for patient treatment over stem cells obtained from fetal tissues, umbilical cord blood and adult tissue which are restricted in the types of cells they can produce, and are difficult to grow in the laboratory. The company's strategy is to partner with pharmaceutical companies for its stem cell discovery platform. Its major academic partner, the Center for Genome Research at Edinburgh University (Edinburgh, Scotland), has identified and patented the first two embryonic stem cell essential genes. Stem Cell Sciences has exclusive rights to technology capable of purifying any cell type on the basis of any differentially expressed gene. It also has established a high-throughput embryonic stem cell-based screening platform to identify key stem cell growth factors needed to deliver a range of embryonic stem cells.

Geron (Menlo Park, California) is developing products based on three patented core technologies: human embryonic stem cells, telomerase and nuclear transfer. The company intends to combine all three technologies to develop transplantable tissue-matched cells in therapeutic quantities that would not trigger rejection by the patient's immune system. Telomerase is an enzyme that restores telomere length and rewinds the molecular "clock," thereby extending the cell's ability to multiply or replicate. The activation of telomerase increases the lifespan of normal cells which have aged and the inhibition of telomerase will kill cancer cells where telomerase is abnormally expressed. Geron is developing customized adenoviruses that will infect and kill cancer cells which express telomerase. Nuclear transfer is a technology for generating cells or whole animals from genetic materials derived from the nucleus of a single donor cell. Using nuclear transfer, it may be possible to produce genetically modified pigs to be used as sources for multiple transplantable organs such as hearts, kidneys and pancreases without causing acute immune rejection.

TEI Biosciences (Boston, Massachusetts) is initiating research programs based on the discovery of a family of signaling complexes each member of which has the capacity to induce stem cells to express a particular tissue or organ phenotype. Its current work centers on the development of spinal orthopedic and cardiovascular products for Medtronic (Minneapolis, Minnesota), its corporate partner, which also has rights to Durepair, a dural tissue replacement. The company also is developing hernia repair tissue for regeneration of body wall muscle and a skin replacement product which will soon enter clinical trials in Europe.

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