BBI Contributing Writer

WAIKOLOA, Hawaii – The Sixth World Biomaterials Congress, held here in mid-May, showed that the scope of biomaterials research has expanded into the biological and pharmaceutical sciences with emphasis on protein and cellular interfaces and the use of biomaterials for delivery of drugs, growth factors, and genes. The gathering had a record attendance of 2,300 participants from 40 countries, and more than 650 papers and nearly 900 posters were presented.

Although polyurethanes have found application in biomedical implants, they have limitations. Soft polyurethanes degrade after long periods of implantation, and hard polyurethanes are unsuitable for applications that require flexibility. Several new developments on modified polyurethanes were featured. Two companies are developing copolymers that combine the advantages of polysiloxanes and polyurethanes for improved flexibility, elasticity, and biostability, as described below.

Nine papers were presented on Elast-Eon polymers, a family of high-performance, biostable polyurethane-based polymers for use in long-term implantable devices that were developed by Elastomedic Pty (Sydney, Australia) in collaboration with CSIRO (Clayton, Australia). The Elast-Eon material uses a more biostable precursor than other similar polyurethanes. Elastomedic was recently acquired by AorTech International (Bellshill, Scotland), a maker of heart valves. A customized Elast-Eon formulation that is a biostable, flexible, and tear-resistant siloxane-polyurethane copolymer, is used in a trileaflet heart valve that AorTech is developing and currently testing in sheep and other animal models in the United Kingdom at the University of Liverpool and University of Glasgow. The polymeric valve combines the best features of both tissue and mechanical valves. Elast-Eon polymers are being evaluated by more than 10 medical device firms. Some of the potential uses are as a cover for pacemaker and defibrillator leads, in vascular grafts, LVAD sacs, finger joint implants, urological implants (sphincters and penile implants), and indwelling catheters.

The Polymer Technology Group (Berkeley, California) has introduced thermoplastic, high-strength and optically-clear silicone-containing polyurethanes that are biostable and biocompatible. They are available in pelletized or granular forms for use in injection, extrusion, and compression molding. These copolymers are CarboSil silicone-polycarbonate-urethane and PurSil silicone-polyetherurethane, available as aliphatic and aromatic copolymers. They are prepared with surface-modifying end groups of fluorinated hydrocarbons or polyethylene oxide. These copolymers are candidates for use in vascular grafts, cardiac assist devices, heart valves, urological implants, and catheters. The CarboSil and PurSil polymers also have been developed with covalently bound heparin for possible use in cardiopulmonary bypass circuits, catheters, and guidewires. Polymer Technology Group also sells Bionate polycarbonate-urethanes, a family of high-strength thermoplastic polymers that were previously sold under the Corethane trade name for cardiovascular applications, and Elastane, a high-strength polyetherurethane that has properties similar to Pellethane. It was developed in response to Dow Chemical's decision to limit the use of its Pellethane thermoplastic polyurethanes to those medical devices with an implant duration of no more than 30 days. Pellethane has a long history of use in implantable devices such as pacemaker leads, heart valves, intra-aortic balloons, and ventricular-assist devices.

Advanced Polymers (Salem, New Hampshire), an OEM supplier of angioplasty balloons, has developed and patented a crosslinked polyurethane coating containing mica that imparts puncture resistance to the balloon and also increases the friction of coefficient between the stent and the balloon surface, thereby reducing slippage during stent delivery and deployment.

Investigators at the University of Toronto (Toronto, Ontario, Canada) have synthesized a series of polyurethane elastomers containing amino acid-based hydrolyzable chain extenders. The inclusion of specific amino acids residues in the polymer backbone was found to confer susceptibility to enzymatic degradation. It was concluded that it should be possible to selectively design biodegradable polyurethanes with specific enzymatic susceptibility that may be relatively easily modified.

Novel surface treatments to impart bioactivity

Hydromer (Branchburg, New Jersey) has developed a biostatic coating for infection control. This patented material comprises hexetidine covalently bound (non-leachable) to a hydrophilic polymer of polyvinylpyrrolidone (PVP)/polyurethane. It is being evaluated for use in central venous access catheters, urinary catheters and trachea tubes. Hydromer's Aquatrix II hydrogels, composed of PVP and chitosan or PVP and polyethyleneimine, were developed as a replacement for hyaluronic acid or collagen for use in ocular and cosmetic surgery and as a wound dressing. It is licensed to Imed Pharma (Montreal, Quebec, Canada). Hydromer also has developed a radio-opaque polymeric coating that will be clinically tested by Symbiotech (Quebec City, Quebec, Canada) in a vascular stent.

Healthshield Technologies (Wakefield, Massachusetts) uses silver ions to impart antimicrobial properties to polymers and metals. The silver is compounded into polymers and is not a surface treatment. It is being used commercially for a range of medical, consumer, and industrial applications. Medical applications include urological catheters, semi-occlusive wound dressings, absorbent pads, and pressure-sensitive adhesives. Pryor Products (Oceanside, California) is using Healthshield's antimicrobial system in medical stands, carts, I.V. poles, and accessories. It also has found use in toothbrush heads and bristles, baby bottles, and garbage pails.

Surface Solutions Laboratories (Carlisle, Massachusetts) is a technology development and licensing company that is working on the attachment of bioactive agents to the surface of materials for controlled release. Ongoing programs are directed at the prevention of restenosis, tumor management, stimulation of bone growth, and wound-healing. The company's development of heparin bonded to a stent to prevent restenosis will be on the market by the end of this year. Bonded heparin is also under development for use in indwelling hemodialysis devices. Other bonded bioactive materials being investigated are DNA and phospholipids.

New biomaterials and surface modifications

Researchers from Ethicon (Somerville, New Jersey), a Johnson & Johnson subsidiary, are studying polyoxaesters, a new class of synthetic absorbable polyesters that are hydrophilic and may find application as drug delivery matrices, coatings, and lubricants. They are made by polycondensation, and have molecular design flexibility by changing the diacid and diol components. These polymers differ from commercial synthetic absorbable polymers that are somewhat hydrophobic in nature.

Victrex (Lancashire, United Kingdom) has developed PEEK (polyaryletheretherketone)-Optima LT, a replacement for titanium or stainless steel in orthopedic and dental implants. This high-performance, thermoplastic, biocompatible polymer is radiotranslucent and can be custom-tailored to the same modulus as bone. The company anticipates receiving FDA clearance by the end of this year. PEEK-Optima LT will be sold as pellets or rods.

STS Biopolymers (Henrietta, New York) has developed Graft-Coat, a reversed-phase graft polymerization technology that allows for polymer layers to be permanently bonded to polymeric surfaces such as silicone, latex, polyethylene, and Teflon. STS' Echo-Coat is applied as a reflective echogenic coating on ultrasound needles used in imaging to enhance their detection.

Spire (Bedford, Massachusetts) has developed a hydroxyapatite coating for fixation of metal implants. It is being tested on spinal cages, hip stems, and titanium posts of dental implants.

Halosource (Seattle, Washington) has licensed technology for producing antimicrobial rubber that was developed by Professor Shelby Worley at Auburn University (Auburn, Alabama). The material is produced by introducing N-halamine into polystyrene molecules present in synthetic rubbers. The pathogen is killed when it comes in contact with the surface of the rubber and is exposed to the chlorine constituent. Tests have shown the antimicrobial rubber to be effective against Staphylococcus aureus and other sources of hospital infection. It can potentially be used in surgical gowns, aprons, and catheters.

Artimplant (Gothenburg, Sweden) has developed a biodegradable implant that is derived from polyurethane urea and stimulates healing of a ruptured anterior cruciate ligament. It serves as a scaffold between the damaged ends of the ligament and degrades over a period of 12 months, allowing cells to regenerate supporting tissue. The company hopes to prove in a 200-patient, multi-center study that the implant can be used as a prosthesis, eliminating the need for a ligament tissue graft. The polymer can be made with variable strength, elasticity, and rate of resorption, suggesting applications in wound healing and drug delivery.

Scientists at Boston Scientific (Natick, Massachusetts) reported work on a polyisobutylene-based thermoplastic elastomer that exhibited great hardness and biostability. It is believed to be well-suited for use in long-term implant applications such as porous vascular grafts, endoluminal grafts and pacer lead insulators.

Collagenesis (Beverly, Massachusetts) has patented a method for producing a human tissue collagen matrix for use in replacing or augmenting deficient or damaged structural tissues. Urogen and DuraDerm are being sold for use as a bladder neck sling to treat incontinence and also have application for pelvic floor reconstruction. Dermaplant is being sold for tissue augmentation. The company continues to develop collagen-based products for applications in ophthalmology, orthopedics, and drug delivery.

Delivery of drugs, genes, and cells

EnColl (Newark, California) has developed a proprietary process for preparing highly purified bovine collagen that would eliminate hypoallergenic reactions. It also has developed phosphorylated collagen for enhanced solubility and bioactivity for potential use in delivering epidermal growth factor.

EnColl's Collagen PRO Coat is a thin coating of collagen for enhancing cell attachment and propagation. It is sold in the U.S. for research applications.

EnColl's Collatrix is a DNA-infused gel of modified collagen for use as a delivery matrix in gene therapy and for the delivery of cytokines. The company sells several collagen-based products in India for use as a hemostat, as a periodontal pocket filler, and in membrane and fibrillar forms in wound dressings.

Biosyntech (Montreal, Quebec, Canada) has developed Cargel, an injectable self-forming polymer. It forms new cartilage-like tissue for possible use in the arthroscopic delivery of cell therapy to a joint. Biosyntech's biodegradable gel matrix, BST-GEL, is a hydrogel crosslinked with chitosan. It is licensed to Viragen (Plantation, Florida) for delivery of Omniferon, a second-generation human white blood cell-derived natural interferon, and to Biomet (Warsaw, Indiana) for bone repair.

Pronova Biomedical (Oslo, Norway), a division of Norsk Hydro, manufactures high-purity grades of sodium alginate and chitosan for use in biomedical and pharmaceutical applications. A primary use for the alginate is as an encapsulant for living cells. A new application is an alginate plug in a spring-loaded retractable safety syringe for which the company is seeking a marketing partner. Chitosan is being developed for use as a drug delivery vehicle.

Researchers at the University of Pennsylvania (Philadelphia, Pennsylvania) have developed novel bioactive and bioresorbable composite microspheres for bone tissue engineering and regeneration. These microspheres were prepared by incorporating a bioactive (osteoconductive) glass powder into a biodegradable polylactic acid matrix using a solid-in-oil-in-water emulsion solvent removal method. The microspheres were shown to induce hydroxyapatite formation on their surfaces.

This program is indicative of the multidisciplinary nature of biomaterials research and was a collaborative effort of scientists from the university's departments of bioengineering, orthopedic research, and mechanical engineering and applied mechanics.

In situ formation of polymer matrices

Tissuemed (Leeds, United Kingdom) has developed Tissuebond, a photocured hemostat and sealant composed of a naturally occurring protein, albumin, and a chromophore (dye) for use as a hemostat and sealant. The chromophore converts light energy to heat which solidifies the matrix to form a material that is analogous to a natural tissue scab but without the fibrin components. The matrix changes from blue to clear as the chromophore absorbs energy and serves as an indicator that the matrix has been activated.

Confluent Surgical (Boston, Massachusetts) has developed sprayable biocompatible hydrogels for use in preventing post-surgical adhesions and as an occlusive liquid that can redirect blood flow to correct anomalies in the vascular system. In situ polymerization is achieved by combining two streams of fluids, delivered into the body via catheter to the disease site. Almost instantaneous transformation of the aqueous solutions into solid polymers is achieved. The solid polymers can be customized to meet specific therapeutic needs and can potentially serve as carriers for the localized delivery of drugs. SprayGel, a sprayable barrier against post-surgical adhesions, is in clinical trials in Europe and is expected to be introduced by the end of this year.

Researchers at the University of Zurich Institute for Biomedical Engineering and Department of Biomaterials reported on the development of a plasmin-degradable, in situ, photocross-linkable, protein-co-polyethylene glycol hydrogel for peripheral nerve regeneration. The matrix mimics fibrin by displaying some of the functional domains needed for nerve regeneration. The mechanical, cell adhesive and degradation properties of the matrix are controllable via the crosslinking site, adhesion site and degradation site density, respectively.

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