SPECIAL REPORT ON MATERIALS

ADVANCEMENTS IN MATERIALS MAY MEAN ADJUSTMENTS FOR DEVICE MANUFACTURERS

From developments in protein engineering to the use of biomaterials for bone repair, materials suppliers are reshaping the medical device industry.

Lori Bryan

New technologies and novel therapies for the treatment of illness and injuries have challenged materials suppliers both to improve their existing materials and to develop new ones. Exciting breakthroughs are being made in areas such as engineered tissues, lipid-resistant polycarbonates, latex alternatives, polyurethanes for vascular grafts, and artificial bone-graft substitutes. For medical device manufacturers seeking a competitive edge, the following products and technologies merit investigation.

Protein Engineering

"There has been a void in terms of materials designed specifically for [medical] applications," explains Joseph Cappello, vice president of R&D at Protein Polymer Technologies (San Diego, CA, USA). In particular, he cites "a complete deficiency of technologies and chemistries that allow you to arrive at a diverse set of properties from a design standpoint." According to Cappello, Protein Polymer Technologies is helping to fill that void by producing biomaterials based on protein engineering.

"We have the ability," says Cappello, "to construct high-molecular-weight proteins composed of units of defined amino acid sequence, which are then repeated in the full-length product that we produce." By manipulating the amino acids within these protein polymers, the company theoretically can recreate selected properties of virtually any protein that has ever been characterized. Product areas that the company has investigated include fibrous applications, potential internal sutures, wound dressings, and scaffolds for tissue engineering.

A bulking material currently in development at the company is designed to solve the problem of urinary incontinence. "In many cases, the tissues in our bodies lose their tension or their ability to constrict certain features or structures," says Cappello. "We can remedy this by injecting an agent into the urethral wall just inside the sphincter muscle that will increase the volume or strength of that tissue. Then, whatever strength the muscle has can be better applied to increasing the luminal constriction that occurs."

The material used in the urinary incontinence project is a silk-elastin engineered protein polymer that forms a gel when injected into the body. While the material may have some disadvantages (bovine-derived collagen has caused allergic reactions in some humans), the possible benefits look promising. "Because our material is a true solution, it retains its entire volume during its solution-to-gel transition and may be a more effective bulking agent at the time of administration," says Cappello. "Moreover, we potentially could increase or change the durability of the material by making it more or less sensitive to the proteases which, in the body, are involved in the normal degradation and replacement of natural proteins." By incorporating silk and elastin units in the right amounts, explains Cappello, the firm can generate materials that, after injection, will be resorbed within a week or remain within the body for one year, possibly longer. "We have the ability to create durable bulking as well as more-temporary agents that might be appropriate for drug-delivery applications."

The company's work in tissue adhesives is somewhat a consequence of the bulking material technology, according to Cappello. The formulation of nonchemically created hydrogels is a self-assembly process that occurs via hydrogen bonding of the subunits within the protein structure.

The firm uses its cross-linking technology to create a chemical bond between the protein elements within the structure. Essentially, a protein solution and a cross-linking agent mix, causing a solidification and a bonding of the matrix to itself. "We have found that we can create very strong bonds that are flexible," says Cappello, "because our protein material is a flexible product." According to Cappello, the company's tissue adhesive far exceeds the bond strength of fibrant sealant and is, in some cases, quite comparable to the bond strength of cyanoacrylate. And unlike cyanoacrylate, the company's proteinaceous material remains flexible after bonding and is ultimately biodegradable.

"We've been exploring the potential applications for our adhesive formulations, especially in the areas of orthopaedic surgical repair," says Cappello. "There is a great need for such products that can be delivered in a minimally invasive way, and their use in cartilage arthroscopic repair seems to have the most immediate potential."

Lipid-Resistant Polycarbonate Resin

When some customers indicated that polycarbonate was the right material for their applications but wished that it performed better when exposed to lipids or alcohol, a materials supplier responded with a significant product improvement. Bayer AG, Plastic Div., (Leverkusen, Germany) created Makrolon DP1-1805, reportedly the first lipid-resistant polycarbonate. The material, which helps to alleviate cracking in high-stress applications where there is contact with IV fluids, can be used in such products as IV components, flow control components, stopcocks, Y-sites, check valves, and filters. Like all of the company's thermoplastic materials, the polycarbonate can be processed by any of the standard techniques including injection moulding, extrusion, and thermoforming.

"The lipid-resistant material is important to manufacturers that sell components into this market because, quite frankly, people are using more lipids," says Douglas Powell, medical industry manager at Bayer. Because a lot of new drug therapies don't dissolve in water, stresses Powell, materials suppliers and device manufacturers must devise products for successfully introducing them into the patient. Today, lipids are used in applications ranging from drug delivery and anaesthesia procedures to the parenteral feeding of infants.

According to James P. Roma, senior materials engineer for B. Braun Medical Inc. (Melsungen, Germany), lipid resistance was a key factor in specifying the polycarbonate for its Safsite needle-free IV system (pictured). The product is designed for the injection, aspiration, or infusion of fluids and medications without needles. "Offering our IV system in a lipid-resistant material was a breakthrough," says Roma. "The increased chemical resistance in a polycarbonate material is an added value we can offer our customers." The polycarbonate resin also can be solvent bonded and sterilized via radiation, EtO, and steam autoclaving.

"B. Braun Medical started to evaluate the lipid-resistant Makrolon grade as well as some other materials because they saw what others have also seen in the marketplace—more use of lipids and more issues related to cracking, leakage, and things of that nature," explains Powell. "The polycarbonate was a product they already knew how to handle, and ours offered them the additional benefit of lipid resistance. They were able to improve their product by making very little change to it."

Latex Alternatives

Because of an incidence of human allergic reactions to latex, materials suppliers and medical device manufacturers are faced with the task of modifying their products or creating suitable replacement materials.

International Medical Products B.V. (Zutphen, Netherlands), a manufacturer of all types of medical disposables, began dipping a variety of latex products about 12 years ago. Allergic reactions to latex and to the powder used in the production of latex caused the firm to look for an alternative material with the same or similar characteristics.

As a result, the firm has developed an aqueous-based polyurethane for its product range (pictured). The same production methods employed in latex dipping, explains product manager Harry te Winkel, are used to produce the polyurethane. However, the company did have to segregate the production unit because the powder that is used to prevent latex from becoming sticky can cause pinholes in the polyurethane.

"The aqueous polyurethane has, more or less, the same characteristics as latex," says te Winkel. "It's elastic and very strong." In fact, the material is half as thick as latex and even stronger, according to te Winkel. "We use the polyurethane to make protective covers for ultrasound transducers in thicknesses of about 20 µm and down to even 12 or 13 µm, depending on how many times we dip."

According to te Winkel, the aqueous polyurethane could potentially be used in the manufacture of catheter balloons. "With more and more end-users becoming aware of the problems with latex," says te Winkel, "they will continue to look for alternative latex-free materials."

Thermoplastic vulcanizate elastomers (TPVs) are another viable option for device manufacturers, according to Suresh Swaminathan of Teknor Apex International (Pawtucket, RI, USA), a supplier of custom and standard compounds for world markets with local representation in several European countries. "[Within industry], there is concern that the origin of natural rubber is basically latex," says Swaminathan. "Natural rubber is slowly being targeted for replacement, and the closest thing to replacing natural rubber is a TPV."

The company's Uniprene 7010 TPV compounds, which can be used to produce syringe seals like the black component pictured, are easier to process than thermoset rubber, according to Swaminathan. Compared to most other thermoplastic elastomers, he says, TPVs exhibit greater elastic recovery as measured by tests for compression set, especially at elevated temperatures. This is particularly important in such applications as resuscitator bellows, tubing, filters, and seals. "TPVs marry the advantages of a thermoplastic rubber under actual process conditions with the advantages of a thermoset under use conditions," he says.

Uniprene TPVs are available for injection and blow moulding and extrusion applications and are provided in a range of durometers from 55 Shore A to 50 Shore D. Because the CE-marked materials are nonhygroscopic, they do not have to be dried prior to moulding or extrusion.

Biodurable Polyurethanes for Vascular Grafts

CardioTech International Ltd. (Tarvin, Cheshire, UK) uses proprietary biodurable polyurethane materials in the development of small-bore vascular graft devices for the treatment of cardiovascular disorders. "Polyurethanes are the synthetic polymer of choice for our vascular grafts," says president and CEO Michael Szycher, "because they offer unsurpassed blood compatibility and possess physical properties that mimic the biomechanical properties of arterial tissues." Applications of the grafts include replacing, bypassing, or creating new lining for blocked, damaged, dilated, or diseased arteries, as well as providing access to the bloodstreams of haemodialysis patients. Clinical investigation of the grafts is being carried out at several sites throughout Europe including France, Holland, Germany, and Sweden.

According to Szycher, the company's scientists have developed a unique, polycarbonate-based polyurethane that has proven to be biodurable in long-term in vivo studies. "Biodurability is a property that differentiates our polyurethane-based vascular grafts from others currently undergoing clinical trials," say Szycher. Technologies developed by the firm also include a nonkinking artificial artery that could be used in place of a patient's own saphenous vein to bypass a blocked leg artery, and a small-bore (4–6-mm) polyurethane coronary artery bypass graft (CABG). The company has received a European patent for its CABG design, as well as several European patents for the manufacturing process involved in producing microporous grafts.

In addition to producing polyurethanes for its own vascular grafts, the company supplies medical-grade polyurethanes to manufacturers of implantable devices. "Several Fortune 500 companies are using our polyurethanes in FDA-sanctioned long-term implantables," says Szycher. Device manufacturers, he says, may take advantage of such an opportunity to gain approval for their most complex implantable devices in extremely short periods of time. Among the products available are the company's ChronoFlex AL ether-free polyurethane elastomers. Unlike ether-based polyurethane elastomers that can become weakened by surface microfissures, these materials reportedly are biodurable and not susceptible to biologically induced stress cracking. They are supplied in hardnesses ranging from 80 Shore A to 75 Shore D. Also offered are ChronoFlex AR/LT polyurethanes designed for use in solvent casting and dipping applications; potential applications include artificial heart diaphragms or vascular grafts.

"Increasingly biomaterials are being used in longer-term implants," says Szycher, "and in miniaturized devices designed to reach some of the more tortuous and deep structures of the body." Device manufacturers, he says, must adapt to these changes in order to stay competitive and prosper in the years ahead.

Biomaterials for Bone Repair

In the interest of building better bones, Interpore International (Irvine, CA, USA) produces a bone graft substitute, Pro Osteon, taken from large heads of sea coral and chemically converted to hydroxyapatite. The implant, which is radiation sterilized and ready for use off the shelf, can be configured to fill bone defects of various shapes.

"In the first days of implantation," says Ed Shors, vice president for research and new technology at Interpore, "blood vessels begin to grow into the pores of the hydroxyapatite. They can go anywhere throughout [the implant] to provide support for healing tissue." Unlike a permanent bone plate or hip and knee prosthesis, says Shors, the hydroxyapatite implant is designed to function temporarily. "It's really the bone that grows into the pores that has the tremendous mechanical properties—the ability to remodel and regenerate new bone."

While the implant acts as a temporary osteoconductive trellis, it is often regarded as permanent from a clinical perspective because it is visible on an x-ray for a long period of time, according to Shors. To address this, the company has modified production of the material to create a new, totally resorbable implant—a technology available in Europe and awaiting approval in the United States. "Instead of converting the entire implant to hydroxyapatite," he says, "only a very thin layer of the hydroxyapatite material lines the inner surface of the calcium carbonate pores." This is crucial, says Shors, because the thickness of the hydroxyapatite layer that will stall the rate of resorption is only approximately 4 µm or about one-half the thickness of a cell.

On an experimental basis, the company has also been working with growth factors that could be added to its implants to increase the predictability of bone incorporation. Eventually, says Shors, "we will be able to preinoculate the implants with cells that can help jump-start the process."

Conclusion

A new generation of materials promises to change the way medical device manufacturers do business. While some device manufacturers will need to replace latex used in their products or seek materials compatible with new drug therapies and treatments for illness, others may find their products rendered obsolete by emerging technologies. In the future, manufacturers of orthopaedic implants may find waning customer demand for their products as patients opt for synthetic bone-graft materials. Tissue adhesives administered in a minimally invasive procedure may replace stapling and suturing. In this evolving industry, medical device manufacturers must not only stay current, but also keep an eye on tomorrow to remain competitive.