Originally Published MDDI May 2005

Biomaterials

The biomaterials market stands on the cusp of technological breakthroughs.

Heather Thompson

The biocompatible materials market is estimated to reach nearly $11.9 billion by 2008.¹Biomaterials are used in every medical device meant for body contact, from orthopedic implants and bone grafts to coronary stents and soluble sutures.

Any device that needs to function in connection with a biological system must display properties of biocompatibility and biodurability, says Jay Goldberg, PhD, director of the healthcare technologies management program at Marquette University (Milwaukee). “There is no such thing as inert in the body,” he says. “Every material will elicit some type of response; the issue is trying to find something that's minimal so it's as close to being inert as possible.”

A biomaterial, which is often made from an alloy, a ceramic, or a polymer, must display traits of biocompatibility, meaning that it does not elicit a negative response. Biomaterials must also display biodurability, meaning that they resist wear or corrosion.
The characteristics of durability and compatibility have long been associated with biomaterials. But recently, manufacturers and researchers have been able to create and market materials that contain a third property: bioactivity. Materials that incorporate bioactivity work in some way to enhance the healing process.

The engineered biomaterials program at the University of Washington (UW; Seattle) promotes the idea that biocompatibility research should address more natural, integrated healing. “The body still sees biomaterials as foreign invaders,” says Buddy Ratner, PhD, a professor of chemical engineering and bioengineering at UW. “Today's biomaterials are sealed into a collagen bag that isolates the material from the body. We ask, for example, if normal, vascularized healing could be induced by biomaterials of the future.”

Of course, says Goldberg, “no material is perfect.” And even with the vast amounts of research being done to find the best material for specific jobs, Goldberg says he is not sure that all advances will appear on the market. “Sometimes companies will avoid using a new material in favor of one that already has regulatory approval, in order to cut down costs.” Such a decision, he says, could hinder innovation.

Nonetheless, researchers continue to make promising advances to improve the use of bioresorbables, natural materials, engineered tissues, and nanotechnology. This article discusses materials currently on the market, and it examines the upcoming trends in biomaterials that could change the industry.

Flexing Alloy Muscles

More than other biomaterials, metals have corrosion issues. As an implant wears, metal ions are introduced to the body. There is some speculation that those ions may have unpredictable results at a molecular level. Getting FDA approval when introducing a new alloy therefore might be more difficult than getting approval for other materials. “That's why alloys are less likely to be used in newer biomaterial devices,” says Goldberg. Even so, Ratner counters, “A metal such as titanium can be every bit as biocompatible as a polymer.”

One alloy has gone far beyond what we think of as traditional metals. Since its initial use in military applications, nitinol has exploded in the medical marketplace, and with good reason. Nitinol belongs to a class of shape-memory
alloys. It contracts when it's heated, whereas standard metals usually expand when heated. It is also super-elastic and produces 100 times greater thermal movement (expansion, contraction) than standard metals.

These properties contribute to nitinol's common use in ballooning stents and catheters, in guidewires, and in orthodontic arch wires for braces, says Alan Pelton, senior research fellow and director of research and development for Nitinol Devices & Components Inc. (NDC; Fremont, CA).

But nitinol offers more than just shape memory, Pelton says. He explains that beyond thermal and mechanical properties, nitinol has magnetic resonance (MR) compatibility. “The magnetic susceptibility of nitinol is closer to that of titanium than of stainless steel,” says Pelton. “Because of this, you can determine the exact dimensions of the device, and it won't interfere with the image of the vessel.” However, he says, not all nitinol devices act the same way; it depends on the geometry of the device.

Even more importantly, Pelton explains that with MR there is a risk that a magnetic response could actually move the device, and nitinol has properties that help resist that movement. He adds that there are ASTM standards that demand all stents have protection against such movements. It may be easier to meet those requirements with nitinol than with stainless steel.

Nitinol manufacturers are taking steps to improve biocompatibility through engineered surface preparation. “You can't just throw nitinol in the body and expect it to perform,” Pelton says. “The nitinol must develop a passive surface layer through mechanical and electrochemical engineering.” Researchers have found that an oxide surface can convince the body that the stent is part of its normal mechanics.

Nitinol does have limits, but suppliers are working to stretch those limits where possible. “A big topic right now is fatigue performance,” says Pelton. “Medical manufacturers are using follow-up studies to see how the devices are behaving.” What happens, explains Pelton, is that owing to bending, extension, compression, and torsion that occurs once a stent is deployed, many stents end up broken. And until now, that possibility had not been considered at the design level. He says that to his knowledge, there have been no adverse effects reported in connection with a fracture. Nonetheless, he says, many designers—not just at NDC—are learning more about these physiological conditions to improve stent durability. “The next generation of nitinol will have a larger threshold,” Pelton says.

Ceramics on the Verge

All-ceramic orthopedic implants are used widely in Europe and Japan, but not so in the United States. The material is at a premium, and a single implant procedure using ceramics can cost between $10,000 and $15,000. Ceramic also has something of an image problem. Since the 1990s, FDA has required that ceramic heads be used with polyethylene cups, although recently ceramic-on-ceramic devices have been approved in some applications. The FDA requirement was implemented because ceramic is very brittle. “Ceramic materials tend not to wear, but they can fracture,” says Goldberg. And if a ceramic fractures in the body, it can be a very involved process to remove the shattered pieces.

But ceramics may also hold enormous potential for orthopedic implants. And the advent of better quality control, new processing techniques, and improved chemistry has alleviated much of the risk of fracture in ceramics. Newer material compounds could also offer increased benefits for ceramic implants.

Ian Clarke, PhD, a professor of orthopedic research and director of the Howard and Irene Peterson Implant Tribology Laboratory at Loma Linda University School of Medicine (LLUSM; Loma Linda, CA), has done extensive work on alumina implants that demonstrate ceramics' benefits for orthopedics. Research from LLUSM has shown that alumina-on-alumina bearings can run in serum for 20 million cycles, the equivalent of 20 years in a patient. He maintains that ceramic-on-ceramic is the best option for hip and knee replacement. “Alumina-on-alumina is more than 1000 times more wear resistant than the polyethylene bearings,” he says.

Clarke explains that alumina-based ceramics were not as advanced when they were first introduced in the 1970s, but the technology has since gotten much better. For example, he says, grain size has been reduced. “You used to have grain size up to 40 µm; that's a very large grain.” Today's alumina ceramics are engineered to have grains that are between 1 and 4 µm.
Another reason Clarke says ceramics are better today is because of quality control. Batch samples used to be destruct-tested. Now each part is proof-tested to twice the pressure it would need to withstand in the human body.

Ceramics manufacturers also employ hot isostatic pressing processes that close the pores to reduce brittleness. According to Clarke, because of these improvements, none of the ceramic-on-ceramic implants that have been implanted during the last six years have fractured.

LLUSM is also running studies on a 75% alumina and 24% zirconia compound. “Zirconia is about twice as strong as alumina,” Clarke says, adding that it can withstand 50,000-lb loads, but has caused some problems when processed incorrectly. “In 1999, a company changed its manufacturing process from a batch furnace to a continuous conveyor furnace,” Clarke says. The change exposed weaknesses in zirconia's chemical structure, making it more susceptible to fracture. But Clarke maintains that by combining it with alumina, those weaknesses are alleviated, and the resulting compound is very strong and wear resistant.

Another ceramic product that is available is an implant made of an oxygen-enriched composite material of zirconium metal with a zirconia ceramic surface. The ceramic surface, says Clarke, is 5 µm thick. Introduced by Smith & Nephew (Memphis), Oxinium oxidized zirconium is a metallic alloy with a ceramic surface that provides wear resistance without brittleness. The company claims it combines the best properties of metal and ceramics. It is a metal with fracture toughness to match cobalt chrome, but it also has a ceramic surface for wear resistance.

Besides structural applications, ceramics manufacturers also make use of the materials' electrical resistivity. Morgan Advanced Ceramics (MAC), whose North American offices are in Fairfield, NJ, uses ceramics for feed-through applications for implantable pacemakers, defibrillators, and nerve stimulators. According to business development manager Keith Ferguson, “The ceramic serves to electrically insulate the wires delivering power or sensing signals in and out of the device.”

Ferguson says that MAC is also exploring additional process capabilities like ceramic-injection molding (CIM) to produce shapes that are not readily available by traditional processes. New processing techniques could allow more- complex shapes, and more importantly, encourage more economical use of the ceramic. “CIM offers maximum material utilization,” says Ferguson.

Polymers and Tissue Engineering

Because polymers are popular with device manufacturers, their suppliers get the lion's share of the biomaterials market. In 2003, polymer sales accounted for more than $7 billion, almost 88% of the entire market for that year.

The reasons for such popularity are obvious. Polymers are cheap—especially when compared with alloys and ceramics. They are also more flexible. Polymers can pretty much be built to accommodate whatever trait the manufacturer needs. Certain polymers exhibit toughness but also maintain the elasticity of a plastic. They can also be designed to have increased lubricity.

Of course, not all polymers are approved as biomaterials, but the ones that are used frequently in hip and knee implants—ultra-high-molecular-weight polyethylene, and polyetheretherketone (PEEK), for example—combine toughness for load-bearing or high-impact applications and enough lubricity to reduce wear.

The most recent trend for biomaterials is in tissue engineering. And in this sector, polymers have gotten a lot of attention. Jack E. Lemons, a professor in the biomaterials department at the University of Alabama (Tuscaloosa), says tissue engineering represents a new phase for biomaterials. “A lot of the hardware that has been used, even though it lasts for decades, cannot necessarily be used forever,” says Lemons. “So the dream of tissue engineering or regenerative medicine is to develop treatments that will last a lifetime.”

So far, the dream is being realized with scaffold seeding. The process involves attracting or impaling cells to grow within a biodegradable scaffold material. As the scaffold degrades, the cells are released and take over the structure. The process may speed healing, but more importantly, it eliminates the need for additional surgeries—for implant removal or replacement.

Osteobiologics Inc. (OBI; San Antonio, TX) manufactures bioresorbable tissue-engineered scaffolds for repairing and replacing musculoskeletal tissues. Gabriele Niederauer, PhD, OBI's director of research and development, explains that the company uses well-known biomaterials that have been in medical devices for many years, but combines them in unique ways. For example, the company has intellectual property for its resorbable polymers combined with polyglycolide (PGA) fibers. “The fibers are aligned in a preferential manner, like rebar or concrete, which enhances the mechanical properties,” says Niederauer.

OBI's resorbable implant technology uses polylactide-coglycolide, which is reinforced with the PGA fibers and calcium sulfate. According to the company, the proprietary scaffolds are 75% porous but structurally sound. They are designed to support the biomechanics, but allow healing cells or drugs to be seeded within the structure of the graft. The scaffold also includes ceramic parts. Niederauer says, “Calcium-containing ceramics provide enhancement for bone growth. It provides a calcium-rich reservoir.”

OBI provides the scaffold, but has not considered marketing the product with any particular bioactive agent. Niederauer says there are many possibilities for seeding; however, at this point, she says, “A combination product would require further regulatory activity on our part.”

The company also has a PolyGraft material designed for cartilage repair. It can be fabricated into products such as granules, blocks, wedges, and other preformed shapes. Currently, PolyGraft is only approved for use in Europe.

“Polymers are attractive for resorbable applications because you don't have leftover pieces,” she says. “They serve their function while the tissue is healing, but once the healing is finished, the material goes away.” According to Niederauer, when degradable polymers are used, there is less concern about encapsulation, corrosion, or continuing surgeries.

Surface Modification Changes the Game

Coatings are a panacea for biomaterials; they can help normal materials achieve qualities of biocompatibility, biodurability, and bioactivity. Coatings and surface modifications serve, in some ways, to trick the body into accepting a foreign material, since the body only reacts to the surface of an object. Many manufacturers are attaching chemicals to or changing the shape of the material surface. Even modifying the electric charge on the surface of a biomaterial can convince surrounding tissues to accept an implant. The right surface can impart properties such as lubricity, hemocompatibility, and corrosion and wear resistance. Coatings can also be formulated for drug elution, tissue engineering, and biocompatibility.

“There is a lot of interest in coating to improve biocompatibility,” says Goldberg. A hydrophilic polymer coating, for example, works in several ways. It mimics the structure and function of a cell wall, so water molecules will attach to it. “So when the body sees the device, it sees this layer of water on it, which does not elicit any response because the body is used to seeing things like that,” Goldberg says. “In essence, the body gets tricked into thinking the device is normal.” Hydrophilic polymer also increases lubricity and can be altered to attract albumin or other biologics that encourage cell growth.

Hydrophilic polymer, says Aron Anderson, chief science officer at SurModics (Eden Prairie, MN), may be the most popular coating. “These days,” he says, “it's almost standard.”

Thrombolitic or blood-compatible coatings, such as heparin, are becoming quite common. Anderson also points out that some coatings are cell repelling—in other words, the cells discourage a fibrin buildup around an implant. At the same time, cell-attractive coatings or surface-modification techniques are being used to allow devices to form a closer bond with surrounding tissue. And, of course, drug-delivery coatings can help in a variety of ways by eluting localized pharmaceuticals.

Applying a coating, explains Anderson, is much like painting a wall—although it's a much more involved process. SurModics has developed proprietary coating techniques that include dipping, spraying, and other processes.

Anderson says that the finished coating should be both flexible and strong. It must also have an even thickness and should be able to be processed at near-room temperatures. “The process becomes too difficult when temperatures have to be very high,” he says.

Anderson says the good thing about coatings is that they can be defined independently. That is, the same device can be used in a different way depending on the coating applied. “What people have found over time is that it's very difficult to get desired physical properties and biological properties in one material. So you either have to sacrifice the physical properties, or you have to sacrifice the surface properties. But if you can put a coating on something, then you can get both.”

Of course, not all surface modifications are coating processes. Etching and chemical manipulation can also introduce beneficial properties to a device.

According to Gordon Hunter, who is senior research project manager at Smith & Nephew, Oxinium components are made by transforming the original metal surface. In other words, their surface is not a coating; the metal device is chemically altered to form a different material. Hunter explains that the company uses a diffusion process that creates a uniform zirconium-oxide ceramic after it becomes saturated with oxygen. The diffusional gradient under the oxide creates a gradual transition in mechanical properties from the oxide to the metal. “Unlike the abrupt change in strain behavior characteristics of overlay coatings,” he says, “this transition zone along with the nanostructural nature of the oxide enhances oxide adherence.” Each component is oxidized to produce a ceramic surface approximately 5 µm thick and then burnished to produce an articular surface. “It's at least as smooth as that of a cobalt-chrome component,” Hunter says.

Nanotechnology Is Here . . . Sort of

Contrary to popular belief, nanotechnology is not just a dream for the future. According to Ratner, “Modern biomaterials science makes excellent use of nanotechnology and has done so for 30 or more years.” Today's biomaterials involve control of surface structures and immobilized biomolecules at the nanometer scale. Surface modifications, such as aligning molecules on a scaffold to better attract healing cells in the body, are already a nanoscale process.

Thoratec Inc. (Pleasanton, CA), for example, has a left ventricular assist system (LVAS) that has a nanoscale-textured surface to discourage blood clotting. Both the HeartMate IP LVAS and the HeartMate VE LVAS incorporate proprietary textured blood-contacting surfaces to reduce the risk of thromboembolic complications. According to the company, sintered titanium microspheres line the titanium side of the blood chamber while custom-molded Cardioflex polyurethane provides a similarly irregular surface to the diaphragm. These features attract circulating cells to these blood-contacting surfaces.

The lure of nanotechnology lies in its flexibility. “By going down to a nanoscale, you can improve the properties, make them smoother, more wear resistant, or more like the tissues surrounding the area,” says Lemons.

Nanotech applications that are currently on the market or have been demonstrated in the lab are very exciting. Goldberg describes a current practice of putting silver particles into burn dressings because of silver's antimicrobial properties. He also says titanium nanoparticles have been used in sunscreens. And gold nanoprobes may soon be used as DNA markers.
However, those who expect a fully rendered nanodevice or implant may have a long wait ahead. Goldberg says, “So far, there are very few commercial nanotechnology applications.”

The Bionic Boomers

Of course, there is always the chance that a new, and possibly more-effective, material may never be introduced in the market. And there are several good reasons why. For one, there are strict regulatory requirements when introducing a new product. New materials must be thoroughly assayed for safety, according to FDA. Meeting FDA demands often means spending thousands of dollars on clinical and preclinical trials—and that's just for the material. After the material is approved, there are still device studies that must be conducted.

In explaining Oxinium's road to the market, for example, Hunter noted that Smith & Nephew invested heavily in laboratory trials and manufacturing implementation. “There is a risk with any new technology until it is proven clinically,” says Hunter. “Oxidized zirconium was a new material for the orthopedic industry, and it had to be specifically developed for this application.” From the initial invention to general commercial release, Oxinium was in process for more than 11 years, says Hunter.

Because of the expense and time, Goldberg says that many superior materials are simply never used. Companies may be more inclined to use a material that is already on the market, even if it is inferior. “The thinking on the part of the industry is, ‘the old stuff works well enough, so why go through all the expense of these new studies,'” he says.

Even so, if a new material or coating has the potential to vastly improve the healing process or patient quality of life, the benefits for manufacturers often outweigh the risks. Lemons says that the growing aging population will drive companies to take chances on introducing superior materials. He also says that there is quite a bit of money to be made. “The baby boomer population is very demanding,” he says. “They want to remain active, and they want to look good. That [means] a phenomenal amount of resources funneled into quality of life.”

Reference

1. RB-072N Biocompatible Materials for the Human Body [on-line] (Norwalk, CT: Business Communications Company, Inc., July 2003); available from Internet: www.bccresearch.com/press

Heather Thompson is associate editor of MD&DI.

Copyright ©2005 Medical Device & Diagnostic Industry