On Thursday, December 4 at BIOMEDevice San Jose, Thor Rollins, in vivo biocompatibility section leader at Nelson Laboratories Inc. (Salt Lake City, UT), will speak on "Materials Selection and Sampling Techniques for Biocompatibility (ISO 10993)." Some of the themes that he will present at the conference are addressed in the following Q&A.

MPMN: Please go into ISO 10993-1 and why cytotoxicity testing is used for screening medical device materials.

Rollins: Cytotoxicity testing is used for screening materials because it is sensitive. In the body, body systems help protect against cytotoxins, protect the cells to wash away any pH imbalances, or even deal with some of the concentration issues or pressures that the cells cannot handle by themselves. Thus, to determine the potential impact of cytotoxicity testing, we take the device and put it right on the cells and then bombard the cells with pH, particulates, and osmotic issues. Thus, during testing, cells are subjected to substances that may not exhibit toxicity in the patient or that could only have a toxic effect if they are present in the body in large quantities.

Good examples of this phenomenon are nickel and copper. These metals are cytotoxic based on how the cell membrane functions. However, in the body, large quantities of these metals are required to cause toxicity issues because the body can deal with them. Thus, cytotoxicity testing is very sensitive.

In fact, we at Nelson Labs have looked over our failures in performing biocompatibility testing; about 93% of the time, the failures occurred with cytotoxicity. However, while this type of testing is sensitive, it is also the cheapest and fastest type of testing, so that we can screen devices and materials inexpensively and quickly to help predict the potential final biocompatibility impact.

MPMN: How should a medical device manufacturer decide which tests are most appropriate for a given device?

Rollins: This is the $1 million question for most of the tests that we perform. The easy answer is that we have ISO 10993-1, which contains a table that is also designated as FDA G95-1. This table shows a contact type and duration of contact, while also spelling out the type of testing that is required to market a device or consider it safe.

However, a draft FDA document released in 2013 notes that this table should not be used as a checklist. We don't want people to check boxes without giving any thought to the tests that they have performed. Biological safety should be considered when referring to ISO 10993-1, but the need for testing should be reviewed on a case-by-case basis.

The amount of data required about a material and the depth of the investigation depends on the intended use of the device and the processes used to manufacture it, in addition to its function and how long it will have contact with the patient. Thus, if you have knowledge of the materials that were used to make the device and data about the potential leachable compounds, this information can be used together with a biological safety evaluation to help pool which types of testing are necessary. In other words, you take the history of the history, the processing methods used to create it, and some chemistry analysis and then evaluate all of these endpoints to help decide which testing should be performed to show that the device is safe. Thus, instead of using ISO 10993-1 as a series of checkboxes, you approach the safety assessment of the device scientifically based on several factors.

MPMN: Please explain how chemical characterization can be used for supporting and justifying a material's biocompatibility.

Rollins: A scientific evaluation is used to determine which tests to run in a particular situation, and chemistry can be a great tool in helping to evaluate which biocompatibility tests are needed. To determine the required tests, we perform a chemistry-composition analysis that establishes a kind of fingerprint of the chemicals that leach off the device.

This process involves removing materials from the device using a variety of aggressive extraction fluids under both polar and nonpolar conditions. The objective is to try to remove whatever chemicals can leach from the device in a short period of time. The test results represent chemicals that can leach from the device during a long period of patient contact. In essence, we derive a soup of chemicals representing the device's chemical fingerprint.

Once we have identified and quantified the compounds, we perform a toxicological assessment of each one. This step helps us realize the impact that the device may have when it is subjected to contact with the body. Thus, instead of randomly extracting chemicals from a device, injecting them into an animal, and ascertaining whether or not the animal reacts to them, we know exactly which compounds leach from the device and their potential impact. If the test produces a compound that might cause systemic toxicity, genotoxicity, or carcinogenicity, we know which types of testing are needed to address this issue.

FDA and industry are beginning to embrace this procedure. We are seeing FDA requests for material characterizations of chemistries on many implantable devices because this information enables the agency to assess them.

MPMN: Is it necessary to perform all available tests on all devices?

Rollins: I and many other scientists love to gather data--for example, on the chemicals that can leach from medical devices. But it is also necessary to look at data gathering from a business perspective. Because chemical characterization can be expensive to evaluate for all devices, the full gamut of chemical testing may not necessarily be appropriate for all types of devices that make contact with the patient. For example, such devices as stainless-steel surgical tools have very limited contact with the body and are made from a well-characterized material. Thus, such devices need to undergo only the big three tests: cytotoxicity, sensitization, and irritation.

To run a full chemistry evaluation is expensive. It is therefore necessary to ask whether the cost will add value to the device. You need to know whether testing for a particular chemical is beneficial and whether you've just purchased a Lexus when a Ford will do. In short, it is necessary to be educated about all the biocompatibility approaches in order to come up with the best test outline for the device.

Bob Michaels is senior technical editor at UBM Canon.

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