BB&T Contributing Editor

AMSTERDAM — The World Biomaterials Congress, held here in early June, drew 3,000 participants from 54 countries with the largest representation from the U.S., followed by the UK and the Netherlands, the host country. This congress convenes every four years and will be held in 2012 in Chengdu, China.

The Dutch Program for Tissue Engineering (DPTE; The Hague) was launched in 2004. It is a consortium of research groups involving most Dutch universities, medical centers and several research institutes.

The program covers three platform technologies stem cells, scaffolds and bioreactors. It aims to standardize procedures in stem cell research since laboratories are currently using stem cells from many different sources, including cord blood, bone marrow, fetal cells from amniotic fluid and fat tissue. It focuses on optimal conditions and signaling pathways invol-ved in the growth and differentiation of stem cells. In the field of scaffolds, collaboration has accelerated the development of optimal carrier materials for cells, often with a mixture of biological and synthetic components.

Bioreactors provide an optimal environment for the growth of tissues. Researchers aim to develop the technology to grow tissue grafts, primarily cardiovascular tissues (heart valves and small vessels) and cartilage. Living cells (myofibroblasts on the inside and endothelial cells on the surface) are seeded on a biodegradable polymer scaffold and grown under conditions of pulsatile mechanical stimulation. In three to four weeks of cultivation within the bioreactor, much of the polymer is degraded and replaced by collagen fibers produced by the myofibroblasts. The architecture of these fibers has a close resemblance to the natural heart valve of a newborn baby.

A company has been started to produce heart valves under GMP conditions and perform pre-clinical testing of the valves in collaboration with Zurich University Hospital in Switzerland and Utrecht University Medical Centre (Utrecht, the Netherlands). The collaboration may yield a new approach in which cells obtained from amniotic fluid may be used to start growing the heart valve upon diagnosis of congenital heart disease after 20 weeks of gestation, so when the baby is born he heart valve would already be available for implantation.

Researchers at DPTE are developing bone from a syringe to be used as an injectable bone substitute, and the engineering of bioceramic scaffolds that may include small bioactive agents within the scaffold, such as growth factors. Progress has been made toward the development of injectable scaffolds that could be used to mend herniated intervertebral discs.

A new electrostatic spray deposition apparatus has been developed to deposit calcium phosphate and biological agents. An electrospinning technique is used to create nanofibers with different properties. The bone-forming properties of polymers can be enhanced by coating them with a layer of bone-like apatite of calcium phosphate ceramic.

Biocompatible polymers for devices

DSM Biomedical, a division of Royal DSM (Heerlen, the Netherlands) has identified biomedical materials as an important growth area and is aiming for $150 million in sales of medical biomaterials by 2012. DSM's Dyneema Purity, made from polyethylene and developed for medical applications, is claimed to be the world's strongest fiber. It is flexible, soft, possesses abrasion resistance and can be bent, twisted or stretched. It is being used in orthopedic sutures.

A new grade of Dyneema Purity with thinner diameters was launched at the conference. It was designed for smaller and lower-profile implants for use in minimally invasive procedures without sacrificing strength and durability.

Consistent with its strategy for growth, DSM acquired the Polymer Technology Group (PTG ; Berkeley, California) which makes synthetic fibers, engineered plastics and resins used in coatings. PTG touted the strength of its thermoplastic polycarbonate-urethane. A paper was presented on the use of this biomaterial with permanently bonded surface-active alkylammonium chloride end groups for imparting antimicrobial surface properties. PTG expects 2008 sales to exceed $40 million, with a projected 20% annual growth over the next three to five years.

PTG has been supplying device makers with biomaterials since 1989. It is collaborating with Bezwada Biomedical (Hilsborough, New Jersey, and Hyderabad, India) in offering synthesis, scale-up and processing of both generic and novel bioresorbable polymers for medical applications. In September 2007, PTG spun out Emergence, a life science incubator that focuses on opportunities in biostable polymers, resorbable polymers and polymers for therapeutic use.

Solvay Advanced Polymers (Alpharetta, Georgia), a division of Solvay (Brussels), and FMC BioPolymer, a division of FMC Corp. (Philadelphia), have also targeted biomaterials for growth of their businesses. This is an area which many companies avoided after Dow Corning (Midland, Michigan) declared bankruptcy under the weight of liabilities from silicone breast implants. Suppliers of implantable materials now have product liability protection offered by the 1998 Biomaterials Access Insurance Act.

Solvay Advanced Polymers markets Solviva biomaterials, a family of polymers launched late last year that are used in implantable medical devices for both short-term and long-term applications. They include PEEK (polyetheretherketone), self-reinforced poly-phenylene, polyphenylsulfone and polysulfone. It recently launched Ixef polyacrylamide, which can be sterilized by gamma radiation and still maintains its mechanical and chemical resistance properties. It is intended for use in disposable instruments.

Polymers, ceramics for orthopedic use

Ceremed (Los Angeles) markets Ostene, an alkylene oxide copolymer that is a water-soluble bone hemostasis material and is pressed into the bone to stop bleeding. It dissolves in 48 hours, does not swell and is not metabolized. To date, Ceremed has sold over 125,000 units in the U.S. for sternal closure after coronary bypass graft surgery and is currently developing its international markets. Ostene is an alternative to the controversial bone wax which is made from beeswax.

AOC, another version of alkylene oxide copolymer, is a carrier system for drugs or biologics such as antibiotics, bone morphogenic protein and demineralized bone matrix, as well as other pharmaceuticals. The company has developed a porous polyethylene (PPE) coated with AOC for ease of insertion due to tissue grab, and for use in augmenting or reconstructing the cranio-maxillofacial skeleton. It also can be applied as a coating on other medical devices for ease of insertion or to carry an antibiotic to fight infections.

Orteq Bioengineering (London) is awaiting CE-mark approval for Avtifit, a polyurethane-e-caprolactone copolymer foam for use after meniscectomy. This biodegradable meniscal implant has 80% porosity, is sutured in place and serves as a scaffold. Blood cells enter the pores and meniscus-like tissue is regenerated. The company completed a 52-patient clinical trial in Europe with 12-month follow up in which arthroscopic procedures were performed on patients with irreparable meniscus tears. U.S. clinical trials are planned for the last quarter of this year.

Oxford Performance Materials (Enfield, Connecticut) markets OXPEKK (polyetherketoneketone) thermoplastic polymers for use in long-term implantable devices. It is used by PINA Medizintechnik (Neuhausen, Switzerland) and Orthopaedic & Spine Development (Avignon, France) in spinal fusion cages. PEEK is widely used in cages and spacers for cervical spine fusion applications.

The company claims that OXPEKK has a wider processing window than PEEK for injection molding. Also, unlike PEEK, it is available in an amorphous form that is not quenched or alloyed, and can be steam sterilized without altering its crystalline structure.

Promimic (Gothenburg, Sweden) is working in the field of bioactive nanotechnology to produce hydroxyapatite with the same structure and shape as it exists naturally in the human body. The material can be applied onto various substrates including metals, ceramics and some polymers. Promimic HAnano was shown in in vivo studies to increase bone-to-implant contact after only a few weeks and to increase osseointegration.

CAM Implants (Leiden, the Netherlands) is a supplier of custom-made bioceramic powders and granules for orthopedic and dental applications as bone substitutes and as coatings on orthopedic prostheses and dental implants. The materials are hydroxyapatite alone or in combination with tricalcium phosphate usually in a 60/40 ratio. Other ratios of the combined materials will result in different densities and particle sizes.

Other bone replacement materials that were exhibited include:

• Clacibon, a synthetic bone substitute comprising a calcium phosphate paste sold in Europe by Biomet (Warsaw, Indiana).

• Mozaik from Integra LifeSciences (Plainsboro, New Jersey), an osteoconductive scaffold used as a bone void filler, comprising 80% tricalcium phosphate and 20% Type 1 collagen.

• OsSatura TCP, a bone void filler composed of pure tricalcium phosphate, and OsSatura BCP, made with biphasic tricalcium phosphate, which has a slower resorption rate, from IsoTis OrthoBiologics (Irvine California), a subsidiary of Integra LifeSciences.

• chronOS from Synthes (Solothurn, Switzerland), a synthetic bone graft substitute that serves as an osteoconductive scaffold and is made from beta tricalcium phosphate.

Vivoxid (Turku, Finland) displayed its BonAlive bioactive silicon oxide glass that is use in orthopedic and cranio-maxillofacial applications. It was shown in clinical trials to have better bone-growth promoting properties than Bioglass.

BonAlive granules are bioactive and resorbable. MetAlive is in development for use as a coating for metals, ceramics and polymers. It possesses osteoconductivity and provides a safe attachment to soft tissue, reducing inflammatory reactions while speeding up the healing response. It is being evaluated in two clinical trials for use in dental implants and in a bone-anchored hearing aid.

Polymers for drug delivery, devices

Purac Biomaterials (Gorinchen, the Netherlands), a supplier of monomers and resorbable polymers, is the world's largest producer of lactic acid and lactide and polylactide derivatives. Purasorb polymers are used in controlled drug delivery systems and in soft tissue fixation devices such as screws, pins, anchors and tacks in knee and shoulder surgeries. A new product is a copolymer of L-lactide and e-caprolactone, a flexible and resorbable material that is used in a composite with ceramics for spinal fusion applications. It also is being used in tissue-engineered scaffolds.

Boehringer Ingelheim (Ingelheim, Germany) markets an extensive line of Resomer polylactide/polyglycolide copolymers which biodegrade by hydrolysis after implantation or injection. Varying degradation rates and degrees of mechanical stability can be achieved by modifying the molecular weight and copolymer composition. The company's newest product is thermoplastic polydioxanone for use in medical implants.

Durect (Cupertino, California) displayed its Lactel absorbable polymers fabricated from polylactide/polyglycolide copolymes for use in drug delivery applications and implanted medical devices. Ortec (Piedmont, South Carolina) featured its glycolide and lactide monmers. Innocore (Groningen, the Netherlands) gave a presentation on its SynBiosys family of multiblock polymers for use as a biodegradable drug delivery system which is currently in clinical trials for use as a coating on coronary stents, and as microspheres for subcutaneous drug delivery applications

Chitosan and collagen products

NovaMatrix, a business unit of FMC BioPolymer, markets alginate foam and ultrapure chitosan. It featured Novatach peptide-coupled alginates for enhancing cell attachment, and the Novafect series of highly deacetylated low molar mass chitosan, which is being evaluated for non-viral gene/oligonucleotide delivery.

Pharming (Leiden, the Netherlands) has produced large quantities of recombinant human procollagen. Several variants of collagen will be prepared from this procollagen.

CollPlant (Rehovot, Israel) is developing rh-collagen that is produced from transgenic tobacco plants. iGen (Taipei) has a collagen matrix implant that serves as a biodegradable scaffold for use in ophthalmic surgery. It improves the remodeling of the regenerating tissue and prevents scar formation.

Syntacoll, a division of Innocoll Pharmaceuticals (Ashburn, Virginia), produces CollaRx, a resorbable collagen sponge or membrane implant for use in drug delivery. Collatamp G is its gentamicin-impreganted collagen implant that is used following surgical debridement for the treatment of bone infection.

CollTech Australia (West Perth) supplies OviColl, collagen of ovine (sheep) origin, and Devro (Chryston, Scotland) supplies Apcoll, bovine collagen.

Therapeutic and diagnostic Aapplications

TiGenix (Belgium) is developing products for the treatment of articular cartilage defects. ChondroCelect, its lead product, is a cell-based therapy focusing on durable repair of cartilage defects of the knee and has completed a randomized Phase III trial. The product is used in combination with autologous chondrocytes for implantation. The aim is for ChondroCelect to aid in the durable repair of cartilage defects and postpone the onset of osteoarthritis.

Biocompatibles (Farnham, UK) has entered into a new business area with CelLuminate, nanoparticles that are able to enter and deliver a payload into any cell with active endocytosis. It can deliver an encapsulated fluorophore to fluorescently track cells in 2-D and 3-D environments for extended periods. It has been tested on stromal, epithelial and endothelial cells.

3D Biotek (North Brunswick, New Jersey) is engaged in the research and development of 3-D porous devices for stem cell culture, stem cell delivery and tissue engineering applications. Its first product line is 3D Insert, a series of 3-dimensional porous scaffolds for use with multi-well cell culture plates. They are made from both biodegradable and non-degradable polymers and are composed of struts/filaments that are joined together to form a porous structure. They are available in polycaprolactone and polylactide/polyglycolide. A polystyrene scaffold will be the next product.

Biological vascular graft

Arterion (Gothenburg, Sweden) is developing biosynthetic vascular grafts suitable for human applications that are made from microbially derived cellulose using Acetobacter xylinum. Vessels can be made with an internal diameter of less than 6 mm. They are produced by electrospinning of nanofibers, a proprietary process developed by Professor Paul Gatenholm at Chalmers University of Technology (Gothenburg) that was the subject of several posters.

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