Putting Implants to the Test

Many tools and processes are used to check implant safety and performance.

Like other products, implantable medical devices are tested to determine whether and how well they perform their
intended functions. But unlike other products, medical implants are also tested to see if they can somehow cause
harm during long-term residence in the human body.

To satisfy government agencies and standard-setting organizations, implants undergo many different safety tests
spanning a variety of technologies and requiring widely varying amounts of time and money. How best to meet this
testing challenge? The answer depends on a number of factors, including the implant maker’s in-house capabilities,
testing workload, and confidentiality concerns.

R&D Testing

For critical information on how well implants will work in the body, manufacturers test their products during the
research and development process. For example, consider typical breast implants, which consist of an inner barrier
layer between two outer layers. In R&D testing, measurements of breast implants are normally taken with
micrometers. Manufacturers “measure the total thickness of the implant and then make some assumptions,” notes
Steve Heveron-Smith, vice president of sales and marketing for Lumetrics Inc. (West Henrietta, NY), which makes
gauging systems for industrial applications.

According to Heveron-Smith, the assumptions made involve the thickness of each layer—and even whether or not all
the layers are present in the implant. These assumptions can be erroneous, he says, resulting in the production of
implants with missing layers or layers that are too thin to prevent leakage.

To prevent these problems, Lumetrics offers the OptiGauge, which takes measurements using infrared light directed
at a surface. Used during R&D testing of breast implants, the OptiGauge probe shines IR light through an implant.
The light reflects off the interfaces of the different materials in the implant and travels back to the device, which uses
algorithms to determine the thickness of each layer of the implant. The probe can be mounted on the end of a robot
arm that moves the OptiGauge to different places around the outside of the implant, allowing it to take a number of
thickness measurements.

For the OptiGauge to take a reading, the probe must be oriented at a 90-degree angle to the implant surface. In
addition, the implant material must be translucent so light from the device can penetrate it.

“With our device, there are no assumptions,” says Heveron-Smith. “You know that the total thickness is correct and
that each layer is the correct thickness. You also know that all three layers are there. So the implant will pass the
quality tests that have to be done.”

But these benefits don’t come cheap. The basic OptiGauge device costs about $60,000, with the price rising as high
as $85,000 for a system that includes special fixturing, according to Heveron-Smith.

Safety Tests

To address the FDA’s main concern, much of the testing done on new products seeks to evaluate their safety. Some
of this safety testing provides information about critical mechanical properties of products. Such properties include
the radial strength and stiffness of stents, which must be measured to meet FDA requirements. These measurements
can be made by the RX550/650, a device produced by Machine Solutions Inc. (Flagstaff, AZ), which offers stent
testing products and services.

The RX550/650 measures the amount of outward force a stent will exert on the inner wall of a vessel, as well as the
amount of force required to collapse the stent. By doing so, the device “makes sure a stent is strong enough to hold
its position in the body, but not so strong that it’s going to damage a vessel,” explains Melissa Lachowitzer, the
company’s testing product manager.

The system includes a chamber in the shape of a 12-sided polygon, which holds the stent to be tested. The shape of
the chamber allows it to compress the stent at 12 points equally spaced around its perimeter, while the system
measures the amount of force required to compress the stent. Then, as the chamber opens up again, the system
measures the force exerted on it by the stent.

The RX550/650 can test stents at body temperature but not in liquid, so users can’t determine how the forces in
question will be impacted when a stent is exposed to body fluids. “We’re not sure how much [this limitation] affects the
test results, but I think it’s fairly minimal,” Lachowitzer says.

The average selling price of the RX550/650 is about $50,000. In addition to selling the system, Machine Solutions
also uses it to do contract testing for medical firms. The company charges about $3000 to test 20 devices and
produce a report of the results.

This stent testing “is generally done in-house by major manufacturers,” Lachowitzer reports. “Some of the smaller
ones farm it out. They’ll use our services for a time as they’re getting their first device onto the market. But once they
have an approved device, most of them will purchase the equipment.”

Evaluating Biocompatibility

For guidance on many other types of safety testing, implant makers turn to ISO 10993, which contains a series of
standards for evaluating the biocompatibility of a medical device. This job includes the chemical characterization of
materials, which is covered in  Part 18 of 10993. When characterizing an implant material, “it’s not enough to analyze
the surface. You have to know what’s going to leach out of the material into the tissue environment,” notes Anne
Schuler, quality assurance manager for LexaMed Ltd. (Toledo, OH), which provides laboratory services to the
medical device industry.

To find out what will leach out of an implant material, Schuler explains, lab personnel perform physical chemical tests
from the United States Pharmacopeia. The first step is to expose the material to an environment similar to that inside
the body for an extended period of time. So the material is soaked in a solvent (for example, water or alcohol) or a
lipid that simulates body fat at 37ºC, which is normal body temperature.

Then a variety of chemical tests are run on the so-called “extract” from the soaking process, which includes whatever
substances leached out of the material. The chemical procedures include gas chromatography and high-
performance liquid chromatography tests, as well as the inductively coupled plasma assay. These tests identify the
specific organic and inorganic materials in the extract.

Once this information has been obtained, Schuler says, the medical device manufacturer must determine whether
the amounts of the substances found in the extract are at acceptable levels. This is done by performing a risk
assessment that includes a search of the available literature on the material in question. A key factor in assessing
risk is how the implant material will be used in the body, she notes.

The equipment needed to perform tests such as gas chromatography and high-performance liquid chromatography
can cost hundreds of thousands of dollars. Rather than buying this equipment, Schuler says, “it’s probably more cost
effective for manufacturers to farm out chemical testing to contract research organizations, especially if they’re only
making one or two devices that require it.”

Biological Procedures

Generally speaking, chemical testing is more important in Europe than the U.S., according to Larry Lister, director of
biocompatibility for Toxikon Corp. (Bedford, MA), which provides testing services to the medical device industry. In
the U.S., Lister says, “biological testing is the real safety testing. We want to see if a material is compatible with
tissue. Even if chemical analysis shows that nothing [harmful] is coming out of a material, we want to make sure
biologically that it’s safe.”

Like chemical testing, some biological testing is done using extracts. These are obtained by immersing test materials
in saline (which represents human blood) or vegetable oil (which represents body fat) and baking the materials for
different periods of time at temperatures ranging from 37-121ºC, depending on the material. “The idea is to get
whatever leaches out of the material under those conditions, which are meant to exaggerate the conditions” an
implant will experience in the body, Lister explains.

In some biological tests, animals or cells are exposed to extracts from this process, which include any substances
that leached out of the test material. In others, the material itself is implanted into animals. Biological tests in ISO
10993 include:

• Genotoxicity (10993-3): This testing looks for evidence that substances leaching from an implant can damage cells
involved in reproduction. If a substance can damage the DNA of these cells, it can potentially alter DNA in normal
tissue cells, which can result in cancer, notes Joseph Carraway, director of toxicology for North American Science
Associates Inc. (Northwood, OH). NAMSA specializes in the safety evaluation of medical devices and materials.

The test is performed by exposing different types of cells to extracts. If the cells or cell colonies multiply, that could
indicate the presence of a genotoxic material.

When doing genotoxicity testing, Carraway says, Europeans strictly follow ISO guidelines, which limit the required
tests to in vitro assays. But the FDA subscribes to slightly different guidelines that require inclusion of an in vivo
assay.

• Carcinogenicity (10993-3): Carcinogenicity testing is required when genotoxicity tests yield positive results and
when new materials are used for implants. The procedure is done by implanting the test material in rodents, which
are exposed to 100 times more material per unit body weight than a human would be in order to provide a safety
factor in the testing. Until recently, Carraway says, carcinogenicity testing required lab personnel to study large
numbers of rodents for their entire lives—typically two years or more. But now the test can be performed on
“transgenic” mice that are genetically altered to be more sensitive to carcinogens, which cuts the required testing
time down to six months. At the end of that time, personnel compare the number and type of tumors found in the test
animals to what is found in a control group.

• Hemocompatibility (10993-4): Blood is exposed to extracts or the test material to see if it causes the blood cells to
rupture or changes the way the blood clots.

• In vitro cytotoxicity (10993-5): Cells grown on plates are exposed to an extract to determine whether anything in the
extract is toxic to the cells.

• Implantation (10993-6): Host animals are examined to see if implanted material is having any local effects. Both
gross visual and microscopic examinations are made to determine the reaction at the implant site at different points
in time—for example, at four weeks to see the early reaction, then at three months, and finally at six months to a year
to discover the longer-term reaction. Among the things lab personnel look for: cells attracted to the implanted
material, rejection of the material, and tissue death at the implant site.

• Irritation (10993-10): An extract is injected into the skin of animals to see if it causes irritation.

• Sensitization (10993-10): Guinea pigs are repeatedly exposed to an extract to determine whether it causes an
allergic response. No amount of sensitization is acceptable, Lister notes.

• Systemic toxicity (10993-11): According to Carraway, virtually all implantable devices require this type of testing,
which seeks to determine whether leachables from a device can produce a systemic effect, as opposed to the local
effects checked for during implantation testing. Most implantables require both subchronic (one to three months in
duration) and chronic (six months or longer) assessments, he adds, though one or the other may be avoided
depending on the implant’s duration in the body.

Systemic toxicity testing is usually done by implanting parts of a device in rodents. During the test period, laboratory
personnel look for evidence of illness and weigh the rodents at regular intervals. At the end of the study, blood,
tissues, and organs of the rodents are microscopically checked for damage.

To determine what tests must be run for a certain implant, Lister says, medical device manufacturers consult testing
matrices such as the one in ISO 10993-1. Other matrices are published by the FDA and Japan’s Ministry of Health,
Labour and Welfare. The matrices tell manufacturers what tests to perform based on what an implant contacts inside
the body and how long that contact is maintained, Lister explains.

The cost of  biological testing ranges from several hundred dollars to hundreds of thousands of dollars, depending
on factors such as the duration of the test and the type and number of animals involved. Testing can take anywhere
from a couple of weeks to a couple of years. Fortunately for implant manufacturers, tests that last years are rarely
required, says Gary Swanson, president of Geneva Laboratories Inc. (Elkhorn, WI), which provides testing services
to the medical industry. According to Swanson, the “worst-case” testing scenarios involve implants made of new
materials that are going into the bloodstream.

Who Does the Job?

Most biological testing is done by contract laboratories, according to Carraway, who contends that results from
contract labs may carry more weight with the FDA and other regulatory bodies than results of in-house testing done
by medical device manufacturers. Why? “When the testing is done by an outside party, that party doesn’t have a
vested interest in the outcome of the test,” he notes.

On the other hand, some companies may want to keep biological testing in-house “to keep control of the
information,” says Swanson. “If you have a unique material, this can be an advantage. You know you have control of
the test data if the testing is done in your company-owned facility.”

Lister reports that a number of large medical device manufacturers do biological testing at their own facilities and
send whatever testing work they can’t handle themselves to Toxikon. But it’s a costly proposition to maintain these
facilities, which require a group of scientists, a quality-assurance unit, and an animal-husbandry staff.

“There’s a lot involved in maintaining a GLP [Good Laboratory Practice] animal facility,” Lister notes. “So if your
business is making bone screws, it’s really not cost effective for you to have a whole staff dedicated to animal testing
that’s only required once for a product.”

This article appeared in Medical Device & Diagnostic Industry magazine.