MARKET WATCH
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A polymer from Micromuscle can release controlled substances through the application of voltage.
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The Influence of Nitinol
Metal alloys, the first widely used biomaterials, are no longer specified solely for their strength in orthopaedic applications; they also play an active role in treating disease. The invention of the coronary stent in 1969 made implantable metal a vital tool for cardiology applications, and has ultimately led to the popularization of an alloy with a relatively short history of use for medical applications—nitinol. After improved manufacturing techniques were developed in the 1970s and 1980s, the nickel-titanium alloy gained a prominent place in modern medicine.
Nitinol’s popularity is largely a result of its shape-memory property, which enables it to change shape within the body. Exposed to high temperatures to achieve the desired shape for a given application, the alloy can be reformed at low temperatures and implanted in the body, where it will return to its original geometry. In the case of stents, this property is exploited to expand blood vessels.
Examples of orthopaedic applications include bone clips that contract slightly when implanted, applying constant pressure to pull fractured bones together. Other applications that benefit from nitinol’s ability to provide gradual directed force include scoliosis correction rods and bone suture anchors, which are used to reattach tendons to bone.
Nitinol’s shape memory and biocompatibility are the result of the bonds between its nickel and titanium atoms. Unlike simple alloys, “nitinol is an intermetallic compound alloy. It is not simply a mixture of base metals,” explains Jochen Ulmer from Euroflex (Pforzheim, Germany). “Nitinol’s nickel and titanium atoms are bonded in an atomic lattice.” The alloy’s atomic structure provides chemical stability and high corrosion resistance.
Although nitinol is biocompatible, like other foreign materials in the body it generally requires some form of surface treatment before implantation. Thin polymeric films that biologically interact with cells are a development in this area. “Metal implants have typically been designed to be noninteractive, but there has been a recent trend to modify metals to make them more functional,” explains Kevin Healy, professor of bioengineering and material science at the University of California at Berkeley (UCB). “Because of the biological interaction with the cells, the body recognizes implants coated with these polymers as a natural part of the body.” For instance, polyethylene glycol coatings can be engineered to control specific cell adhesion to optimize an implant’s integration in the body and minimize the patient’s recuperation time.
Functional Polymers
Like metals, polymers also have a long history as biomaterials. The potential biocompatibility of polymers was discovered during World War II, when pilots occasionally fell victim to shards of polymethyl methacrylate from shattered aircraft canopies. Physicians treating the soldiers found that the accidentally implanted polymer was well tolerated by the pilots. Now the largest segment of the biomaterials market, polymers’ success in medical applications is a result of their relatively low cost and their functionality.
“One of the major advantages of polymers is that they can be formulated to meet determined characteristics,” explains Dow Corning (Midland, MI, USA) spokeswoman Amy Rosborough. For instance, polymers can be produced that resist bacterial infection, that biodegrade, and that deliver drugs. “They have fewer limitations than metals or ceramics. With the right chemistry set and a commitment to innovation, a scientist can design almost anything with polymers,” notes Rosborough.
“Silicone polymers are one example of a family of polymers that may be suitable materials for various healthcare applications such as urological catheters and wound drains,” states Eric Luftig, global healthcare marketing director of GE Advanced Materials (Bergen op Zoom, Netherlands). As a result of their biocompatibility and mechanical properties, materials such as GE’s LSR 4000, LSR 4800, and LIM 6000–series liquid silicones have been found to be excellent candidate materials for use in injection moulding of various device components. Elastomers can be extruded into tubing sections, enabling design freedom for OEMs and fabricators. Combined with these substrates, liquid silicone coatings such as GE’s LSR Topcoat can be applied where reduced friction is desired.
With increased focus on innovative device solutions, customization of materials is also becoming a preferred approach to help customers meet specific application requirements. For example, the incorporation of radiopaque additives into silicone elastomers enables the detection of devices under x-ray. Formulation optimization, allowing for a specific look and feel of material, is another consideration. Special adhesion-promotion packages can be incorporated into silicones, allowing these materials to be bonded to a variety of plastic and metal substrates.
One company specializing in biomaterials has developed electroactive polymers that expand when subjected to a small amount of voltage. When the voltage is removed or reversed, the polymers contract to their original proportions. Available from Micromuscle (Linköping, Sweden), the micro- and millimetre-sized electroactive polymer components can generate movement and exert force, providing functionality for medical device applications. “We want to establish electroactive polymers as the next-generation materials for development of active and controllable medical devices,” says Micromuscle development engineer Daniel Carlsson.
Currently, the primary applications of the electroactive polymers are angioplasty and other vascular applications involving guidewires and catheters. Using electroactive polymers, vascular devices can be accurately steered through narrow and tortuous blood vessels. Components also can be designed to deliver drugs and hold and release objects such as wires. To date, the company has mainly targeted segments within interventional cardiology and percutaneous transluminal coronary angioplasty. Additional product opportunities have been identified in such market segments as cardiac rhythm management, neuro intervention, drug delivery, and vascular surgery.
The electroactive polymers are the product of almost 20 years of research. In 2000, Alan Heeger, Alan MacDiarmid, and Hideki Shirakawa were awarded the Nobel Prize for the discovery of electroactive polymers.
Bioceramics and Autologous Tissue
Since they are bioinert, implantable ceramics are well tolerated by the body and are used for a variety of orthopaedic applications and for ceramic drug-delivery devices. In some cases, porous ceramics provide a dissolvable framework that is replaced by natural bone tissue. Hydroxyapatite ceramic, which is generally porous, can be used to form composite materials that closely mimic natural bone. One example of such a composite, the Collagraft bone graft substitute from NeuColl (Campbell, CA, USA), unites hydroxyapatite with tricalcium phosphate and collagen. It performed as well as autologous bone in a study involving more than 400 subjects.
Traditionally limited by their brittleness, modern ceramics are often durable enough to be suited for joint-replacement procedures. “The design of artificial ceramic joints has improved considerably in recent years,” says Wolfram Mittelmeier, the director of the Orthopaedic Hospital at the University of Rostock, Germany. “With conventional treatments, especially with metals, synthetic materials, and bone cement, particles eventually accumulate with wear that can strain the body.” By contrast, ceramics show hundreds or even thousands of times less linear wear than polyethylene. “Today, there are ceramic-based implants with extremely high wear resistance, which for young and active patients, represent a low-risk alternative to frequent revisions often necessitated by implants made of other materials,” Mittelmeier explains. “Contemporary ceramic implants give a patient a much better likelihood of having a long-lasting prosthesis,”
In March, US FDA approved a ceramic spinal spacer system for use in the thoracic-lumbar region of the spine. The implant can replace collapsed, damaged, or unstable vertebrae in case of trauma or degenerative disease. Made by Amedica (Salt Lake City, UT, USA), the ceramic implant combines strength with the ability to bind with bone. According to Amedica president and CEO Ashok Khandkar, the product is the first ceramic spinal implant cleared for use in humans. Offering an alternative to other synthetic and allograft bone implants, the ceramic-based implant combines strength, radioactive imaging clarity, and biomimetic characteristics. The company is working on developing ceramic implants for femoral heads used in hip-replacement surgery, knee replacement, and spinal-disc-replacement surgery, and spinal-fixation implants that mimic bone.
Peptide and Stem-Cell Hydrogels
Biologically engineered cell grafts are limited to primarily orthopaedic applications, because other tissues must be connected to nerves and vasculature. Unless the tissue is enervated, it will die from lack of oxygen. Researchers at UCB are working on hydrogels that become stiff after injection into the body, trying to match the biological modulus of the area. Once in the body, the gel forms a collagen matrix that can serve as a carrier for cells or drugs. For instance, hydrogels carrying peptides and stem cells committed to cardiac tissue could be used to treat heart defects. Through the use of stem cells, the longevity of cardiac cells can be increased. Other hydrogels containing peptides can also be used to stabilize heart tissue at the border of damaged areas after myocardial infarction. Here, cells in the region can stabilize the area, stimulating new blood vessel formation and alleviating stress at the injured area of the heart. The procedure could prove to be a powerful method of treating congestive heart failure. According to UCB’s Healy, the technology may be in clinical trials in three to five years.
Nanotechnology Enhances Alloy’s Mechanical Properties
A company specializes in the production of biocompatible alloys with high purity and corrosion resistance. Available from Sandvik Bioline (Sandviken, Sweden), the products can be supplied quench annealed or cold worked in order to provide required mechanical properties for medical applications. They are suitable for medical implants, coronary stents, and orthopaedic applications.
Medical-grade steel alloy 1RK91 is engineered at the molecular level to provide strength and ductility. It also withstands repeated sterilization. The material’s strength is achieved through age hardening; it is formed in soft condition prior to developing the final and desired strength. Shown to be noncytotoxic through in vitro testing, the alloy can safely be used in applications involving contact with blood, body fluids, and human tissue. It is available in strip, bar, rod, and seamless tubing form.
Comprehensive Biocompatibility Testing Services Offered
In vivo and genetic toxicology and microbiology testing services are provided by a contract research organization that specializes in analytical chemistry services. Toxikon (Leuven, Belgium) conducts tests in compliance with US FDA, EU, and Japanese regulations. The company, which is certified to ISO 9001 and EN 45001, has laboratories in Belgium and the United States, and agents in Japan.
Devices can be tested for acute, subchronic, or chronic toxicity. In vivo mutagenicity, carcinogenicity, and geno- and reproductive toxicity tests are available for implantable materials. The firm’s professional and scientific expertise coupled with its strong R&D support activities for new materials and products enable it to effectively troubleshoot problems in existing products. Testing programmes for finished products are designed according to type and duration of contact with the body. Raw material testing programmes are designed to specifically address client concerns involving compounds used in formulating materials and the potential interaction of those compounds.
Alloy Features Resistance to Pitting and Corrosion
A nickel-free austenitic stainless-steel alloy has a high nitrogen content, which allows it to maintain its austenitic structure. Produced by Carpenter Technology (Reading, PA, USA), the BioDur 108 alloy resists pitting and corrosion, and has high levels of tensile and fatigue strength compared with nickel alloys. The material’s pitting and crevice corrosion resistance is superior to that of Type 316L stainless steel, according to the firm. BioDur 108 is noncytotoxic and meets the requirements of the ISO 10993 elution test.
Fabricated by means of the electroslag remelting process, the nonmagnetic metal exhibits high microstructural integrity. Suitable for applications requiring high strength and corrosion resistance, the alloy can be used to manufacture bone plates, bone screws, spinal-fixation components, hip and knee implants, and related medical components and instruments.
PC Film Withstands Gamma and E-Beam Radiation
A special additive prevents a polycarbonate film from turning yellow when exposed to high-energy radiation. The Makrofol LP 209 film from Bayer Material Science AG (Leverkusen, Germany) is transparent and exhibits high impact strength and stiffness. Extruded from a special grade of polycarbonate, the material satisfies the requirements of ISO 10993-1 and meets the biological compatibility criteria specified in the US Pharmacopeia.
Suitable for devices that come into contact with body fluid or tissue for up to 30 days, the film is also used to manufacture blood-heat exchangers; its transparency enables blood flow to be checked visually. The film is available in thicknesses ranging from 175 to 500 µm; other thicknesses and surface structures can be specified to suit other applications. The top and bottom of the film have a glossy finish.
Plastics for Optical Implantations Are Clear Choice
Polymers for ophthalmic implantation are available from a company that has 15 years of experience producing materials for hydrophilic foldable intraocular lenses. Vista Optics (Widnes, Cheshire, UK) supplies an implantable grade of polymethyl methacrylate (PMMA), which has a US FDA drug master file. Its Vistacryl range is based on a series of polymethacrylate-siloxy formulations designed to meet the exacting standards demanded by regulatory bodies and industry. Available in rod and sheet form, the materials can be processed by means of CNC lathes and laser cutters into a range of custom shapes and sizes. Hydrophobic materials for foldable intraocular lenses and implantable custom acrylic polymers are also available.
Metal Implant Can Replace Smallest Bone in the Body
The smallest bone in the body, the stapes works with auditory ossicles to transfer vibrations generated by sound waves to the inner ear. When the bone is injured, it can be replaced with a titanium or titanium alloy implant. Krämer Engineering (Rendsburg, Germany) has developed metal powder–injection moulding tooling that can be used to fabricate the implant.
CAD surface modelling and a custom production process work in tandem to produce an implant that replicates the bone’s size and shape. The development of the manufacturing process has yielded improvements in the firm’s moulding capabilities, enabling it to fabricate metal parts with wall thicknesses as thin as 280 µm.
Biomedical Testing Equipment Measures Strain
A system consisting of submersible pneumatic side action grips and a temperature-controlled bath with pneumatic lifting and lowering mechanism is suited for a variety of biomedical testing applications. Testing equipment that evaluates the mechanical properties of biomaterials enables accurate measurements of load and strain in an environment that simulates the human body. The BioPuls submersible pneumatic grips and temperature-controlled bath from Instron (High Wycombe, Bucks, UK) is suited for testing thin films, plastics, thin-walled tubing, fine wires, contact lenses, biological and bioengineered tissues, medical tubing, and plastics.
The temperature-controlled bath allows for accurate simulation of the environmental conditions required for biomedical testing. Distilled water or saline solution is brought to the desired temperature within 30 minutes and the temperature is maintained ±1ÞC through closed-loop controls. The bath has a pneumatic lifting and lowering mechanism that allows for ease of use, increases productivity, and minimizes the risk of spilling fluid on the surrounding test equipment. The bath was specifically designed for compatibility with the company’s video extensometers, allowing for accuracy in strain measurement.
Nitinol and Other Alloys Processed on Custom Basis
Nitinol, stainless steel, magnesium, and cobalt and titanium alloys are processed for medical applications by a firm that manufactures products to customer specifications. Euroflex GmbH (Pforzheim, Germany) fabricates tubing, round wire, sheet material, flat and profiled wire, and components from the materials.
The company’s biocompatible nitinol reportedly has 10 times the elastic ductility of steel and resists buckling. To satisfy OEM demands, the firm has developed a technique that enables the production of large, thin-walled nitinol tubes with extremely narrow ID and OD tolerances.
Firm Expands Medical Elastomers Line
A company that offers biomedical-grade liquid silicone rubber (LSR) for implant applications has expanded its line of materials. The Silastic range from Dow Corning (Midland, MI, USA) now includes the biomedical-grade 7-4870 LSR.
The material can be used to injection mould precise and intricate parts and to fabricate mesh coating. All of Dow Corning’s materials are manufactured, packaged, and tested at the company’s healthcare industries materials site in accordance with GMP guidelines. The firm offers a range of USP Class VI elastomers for the fabrication of devices that can be implanted in humans for 29 days or less.
Company Produces a Range of Custom Biomaterials
A company offering a range of biomaterials produces silicone elastomers suitable for short- and long-term implants. Available from Statice Biomaterials (Besançon, France), the elastomers can be coloured or rendered radiopaque. Biodegradable polymers from the polyglycolic and polylactic families also can be supplied, as well as traditional thermoplastic polymers that can be moulded or extruded for a variety of medical applications.
The firm also processes titanium, stainless steel, shape-memory alloys, and other metals. CNC and laser machining equipment are on-site. In order to improve the mechanical and biological characteristics of implants, surface and thermal treatments can be applied. These include vacuum overhardening, mechanical and electrolytic polishing, electrolytic oxidation, and galvanization. In addition, a range of composite materials can be manufactured to meet customer specifications. The company also can design and manufacture parts made from ceramic, ruby, sapphire, and aluminium oxide materials for medical applications.
Titanium Alloys Provide Strength
A metal fabricator specializes in the production of titanium alloys for medical applications. Dynamet (Brussels) routinely processes titanium for the manufacture of tight-tolerance bar, coil, spools, and hex bars. The material is suited for the fabrication of artificial joints, trauma implants, spinal fixation systems, surgical suture wire and clips, and cardiovascular devices.
Finished bars are available in diameters ranging from 0.508 to 73.00 mm, while finished wire diameters range from 0.127 to 14.22 mm. Hex bar can be supplied in dimensions from 3.17 to 20.62 mm. Materials can be custom engineered to customers’ shape requirements. Titanium in ingot or bloom/ billet form is inspected, pressed, conditioned, and processed in accordance with international standards and customer specifications.
Resins Engineered to Withstand Impact and Sterilization
Biocompatible polycarbonate grades from a global materials supplier have strong flow and release capabilities and are designed to withstand autoclave sterilization. Available from GE Advanced Materials (Bergen op Zoom, Netherlands), the Lexan polycarbonate family has been expanded with the addition of HPX8R and HPX4 resins, which offer strength, mechanical qualities, and clarity consistent with other resins in the product line. The latest materials also mark new improvements in flow and ductility properties, as well as enhanced resistance to impact and autoclave sterilization.
The HPX8R and HPX4 resins employ a new formulation based on a proprietary technology that offers better flow performance when compared with conventional polycarbonates. The resins have been developed without additives to address industry concerns about additive migration and the loss of surface additives during cleaning operations. The resins join the company’s established line of tough and virtually unbreakable Lexan resins that feature resistance to gamma, EtO, and steam sterilization, lipids and other chemicals, and high heat.
Biocompatible Polymers Are Suited for Long- and Short-Term Use
A company offers biocompatible polymers that are suitable for long- and short-term blood or tissue contact. Available from Invibio (Thornton Cleveleys, Lancs, UK), the company’s PEEK-Optima polymer is suited for implantable medical devices and pharmaceutical applications involving blood or tissue contact for more than 30 days. Formulated to meet exacting in vivo criteria, PEEK-Optima is a stable polymer. It is available in a range of forms that offer virtually unlimited design possibilities. It can be processed via injection moulding, extrusion, or compression moulding, and is available in standard-, medium-, and low-viscosity grades. Applications include spinal cages, suture anchors, spiked washers, surgical screws, femoral implants, dental healing caps, balloons, intracardiac pumps, and heart valves.
The company’s PEEK-Classix polymer is a biocompatible thermoplastic used in the development of medical device applications requiring blood or tissue contact of less than 30 days. The polymer is said to be one of the most chemically resistant polymers available. It can be repeatedly sterilized using conventional methods without experiencing a degradation of its mechanical properties. Like the Optima material, the Classix polymer is offered in standard-, medium-, and low-viscosity grades. Applications include catheter tubing, drug-delivery products, blood management systems, laparoscopes, surgical instruments, endoscopes, and analytical equipment.
Biocompatible Coatings Feature Drug Elution Properties
Medical device coatings that can be engineered to release drugs are based on inorganic composites that enhance their biocompatibility. Blue Membranes (Wiesbaden, Germany) has developed coatings for combination devices such as drug-eluting stents as well as orthopaedic implants.
The microporous, mesoporous, and macroporous coatings feature good mechanical properties and high drug-loading capacities. They will not cause inflammation, and have tailored release properties that are not restricted to any particular class of drug. Macroporous coatings for drug-eluting stents exhibit good engraftment properties owing to their bioactive carbon–based tissue-like surface structures. Hydrophilic or hydrophobic qualities can be imparted to the materials, and they can be customized with covalently or noncovalently absorbed functional compounds such as antibodies, peptides, or lipoproteins. Stress-resistant coatings with drug-delivery properties for orthopaedic implants are also available.
Firm Specializes in Alloys for Medical Applications
Providing semifinished materials as well as engineered components to the medical device market, a company engineers finished components using proprietary wire, strip, and seamless tubing. Founded in 1983, Memry (Bethel, CT, USA) specializes in the processing of nitinol and other alloys used by medical device OEMs. The firm also offers laser machining, welding, and electropolishing services.
A proprietary alloy, Flexium is a metastable titanium molybdenum–based material that is suitable for orthopaedic and other medical applications. Exhibiting low modulus and high flexibility, the alloy exhibits pseudoelasticity in the annealed state and good strain recovery. Cold-worked Flexium has a modulus around 7.5 Msi (50 GPa) and exhibits linear superelasticity, whereby a recoverable strain as high as 3.0% can be achieved. The material is nickel-free, and has good corrosion resistance. The alloy can be cast or wrought.
Biocompatible Implantable Polymer Is Suited for Long-Term Applications
A company markets versatile, medical-grade polyurethane that is the product of a decade of research at the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Melbourne, Australia. Known as Elast-Eon, the biocompatible polymer from AorTech Biomaterials (Melbourne, Australia) exhibits many of the mechanical properties of silicone rubber and polyurethane elastomers.
The material can be extruded, moulded, solvent cast, and vacuum formed; it is suitable for long-term implantable life-supporting devices in the fields of orthopaedics, plastic surgery, cardiovascular surgery, interventional cardiology, drug-eluting stents, and cardiac rhythm management. The product is available in a variety of formulations, ranging from very flexible to rigid. In addition, the density and mechanical properties of the materials can be refined to meet the requirements of clinicians and medical device designers.
