Originally Published MDDI August 2004

Biocompatibility



In the early years of the modern medical device industry, ensuring biocompatibility was a major challenge. Much progress has been made.

Richard F. Wallin

Once upon a time, there were no standards for medical devices: no regulations, no guidelines, no test methods, not even an MD&DI. Yet there were medical devices of all kinds, made of a variety of metals, plastics, fabrics, composites, and other materials. For the most part, they did their job and served patients well. But there were exceptions. There were clinical failures and adverse reactions. Manufacturers were eager to avoid these problems, but were unsure how. They had no specific direction about how to ensure the safety, or what became known as the biocompatibility, of their products.

Finding the answers was not simple. As I wrote in 1998, “medical devices are unusual articles for toxicologists to deal with. They tend to be solid objects made of plastics, metals, and ceramics held together by screws, clips, adhesives, and heat seals. They are, by definition, healthcare products that do not achieve their intended purposes by chemical action within or on the body or by being metabolized. They do not go into solution very well, they cannot be dosed on a per-kilogram basis, yet they may contain potentially harmful chemicals and may be used in or around the human body for extended periods of time. They require the attention of toxicologists to ensure that their materials are suitable and can be used safely.”¹ This statement is still true.

Early Efforts

Methods for the study of toxic effects of drugs and chemicals were well developed by the time medical devices began to appear. With the realization that components of devices could be the source of toxic chemicals came the need for methods to ensure the safety of these products. Unlike chemicals, however, device components could not simply be placed into solution and administered to cells in culture or to test animals. Methods had to be developed to extract or otherwise deal with solid test articles. Once fluid extracts were prepared, they could be handled in much the same way as chemical and drug substances. Of course, the materials themselves could be implanted in order to observe local tissue effects.

In the 1960s, adverse reactions to new endotracheal catheters set a team of investigators to work. They were searching for a simple method to screen out such reactive materials from medical products. They developed the agar overlay method using mammalian cells in culture that clearly showed the offending catheters to be cytotoxic.² These and other cytotoxicity tests remain in frequent use today.³

Around the same time, concern arose about the possible systemic effects of components in rubber and plastic materials used to make solution containers or solution-delivery systems. The Pharmaceutical Manufacturers Association undertook studies that led to the development of the “biological tests for plastics” described in the United States Pharmacopeia. Variations of these tests had already been proposed in a paper addressing the safety evaluation of disposable medical devices.⁴ The systemic injection, intracutaneous, and intramuscular implant tests that resulted are still described in the USP. They continue to be used for evaluating device materials. 

Blood bags made of plasticized polyvinyl chloride (PVC) caught the attention of researchers in 1975. They reported that patients were receiving a dose of the plasticizer DEHP with every unit of blood delivered. When the bags were filled with blood, DEHP was extracted from the PVC by the lipid components in the blood. Extensive work was done to define the metabolic disposition of DEHP and its biological effects at various doses in a variety of species in both short- and long-term studies. An extensive biocompatibility profile for plasticized PVC was established using variations on classical methods in toxicology.⁵

In the 1970s, both the Health Industry Manufacturers Association (now AdvaMed; Washington, DC) and the Pharmaceutical Manufacturers Association formed committees to develop guidelines for ensuring the biocompatibility of medical devices. These efforts resulted in charts of potential adverse effects and recommended safety tests. These charts were later revised and adopted by regulators in the United States, Canada, and Great Britain as the Tripartite Biocompatibility Guidance. This document was introduced in the United States by FDA 
at a NAMSA-sponsored seminar in Toledo, OH.

Device materials should produce neither adverse local tissue effects nor adverse systemic effects, whether short term or long term. These effects include carcinogenicity and genotoxicity. Early test methods for device materials were relatively simple. They were short-term, qualitative, insensitive, and general in nature. They could screen out most but not all of the serious toxic effects of extractable chemicals. They were often performed on materials thought to be representative of those used in the manufacture of devices. Usually, though, no attempt would be made to characterize the test article to ensure that this was the case. In fact, variations in the composition of materials and the addition of chemicals during the manufacturing process sometimes occurred. This meant that the test article was not at all like actual device materials that reached the patient. In some cases, this oversight led to clinical device failures.

International Standards

The 1980s marked the start of a large-scale international effort to develop specific, detailed, harmonized guidance for biocompatibility testing. These standards, grouped under the ISO 10993 banner, went far beyond the early, general test procedures. They adopted many of the methods used in classical toxicology for application to device materials. The standards dealt with cytotoxicity, based on the first methods published in the 1960s; irritation and sensitization; systemic effects, both short and long term; implant effects at the macroscopic and microscopic levels; genotoxicity (concerning changes in DNA structure); blood compatibility; carcinogenicity; and methods for characterizing materials to confirm their composition and identify potentially toxic extractables. MD&DI reviewed these standards in a series of articles beginning January 1998.^6-17

Over the past quarter century, biocompatibility test methods have evolved significantly. In the early years, simple test methods, originally intended for closures in intravenous solution containers, were used along with cell culture to screen out potentially harmful materials. In a few cases, classical methods in toxicology were used in detailed studies of extractables such as DEHP. Along the way, a variety of groups issued other standards. These groups included the British Standards Institution, The American National Standards Institute, the American Society for Testing and Materials, the Association for the Advancement of Medical Instrumentation, the American Dental Association, the Canadian Standards Association, the Deutsches Institut für Normung (DIN) e. V., the Association Française de Normalisation (AFNOR), and the Japanese Ministry of Health and Welfare. Except for a few tests and methods of sample preparation, the approaches in these standards have been built into the ISO 10993 standards.

Testing Today

Once simple, short-term, and qualitative, biocompatibility testing today is systematic, detailed, and quantitative. Materials characterization is much more common. This process takes advantage of the chemical composition of a material and its extractables, then applies the substantial world literature on toxic substances. In some cases, it can eliminate the need for further biological testing. Today, there is less emphasis on testing in laboratory animals. If in vitro methods and risk assessment can be used instead, they are. At the same time, though, as implantable devices become ever more sophisticated, there is greater emphasis placed on implanting these devices in larger animals to evaluate their performance and safety in situ. 

Innovation in materials and medical devices, and the methods of ensuring their safety, have been truly phenomenal. One can only imagine what the next 25 years will produce. 

MD&DI has played a significant part, publishing hundreds of articles on materials, devices, testing, standards, regulations, and all the other factors that contribute to the success of the medical device industry. One can expect MD&DI to maintain this role in the next 25 years.

References

1.RF Wallin, “Current Problems in Device Evaluations: Some Solutions,” Journal of the American College of Toxicology 7 (1988): 491–497.
2.WL Guess et al., “Agar Diffusion Method for Toxicity Screening of Plastics on Cultured Cell Monolayers,” Journal of Pharmaceutical Sciences 54 (1965): 1545– 1547.
3.RE Wilsnack, RJ Meyer, and JG Smith, “Human Cell Culture Toxicity Testing of Medical Devices and Correlation to Animal Tests,” Biomaterials, Medical Devices, and Artificial Organs 1 (1973): 543–562.
4.Journal of Pharmaceutical Sciences 49 (1960): 652.
5.JA Thomas et al., “A Review of the Biological Effects of Di-(2-Ethylhexyl) 
Phthalate,” Journal of Toxicology & Applied Pharmaceuticals 45 (1978): 1–27.
6.R Wallin, “A Practical Guide to ISO 10993: Part 1—Introduction to the Standards,” MD&DI 20, no. 1 (1998): 121.
7.DE Albert, “A Practical Guide to ISO 10993-14: Materials Characterization,” MD&DI 20, no. 2 (1998): 96–99.
8.R Wallin, “A Practical Guide to ISO 10993-5: Cytotoxicity,” MD&DI 20, no. 4 (1998): 96–97.
9.R Wallin, “A Practical Guide to ISO 10993-10: Sensitization,” MD&DI 20, no. 5 (1998): 122–124.
10.R Wallin, “A Practical Guide to ISO 10993-10: Irritation,” MD&DI 20, no. 6 (1998): 97–98.
11.R Wallin, “A Practical Guide to ISO 10993-11: Systemic Effects,” MD&DI 20, no. 7 (1998): 98–101.
12.R Wallin, “A Practical Guide to ISO 10993-6: Implant Effects,” MD&DI 20, no. 8 (1998): 102–105.
13.LE Sendelbach, “A Practical Guide to ISO 10993-11: Designing Subchronic and Chronic Systemic Toxicity Tests,” MD&DI 20, no. 9 (1998): 102–105.
14.G Johnson, “A Practical Guide to ISO 10993-3: Genotoxicity,” MD&DI 20, no. 10 (1998): 93–94.
15.JM Buchanan, “A Practical Guide to ISO 10993-4: Hemocompatibility,” MD&DI 20, no. 11 (1998): 79–80.
16.T Jansen, “A Practical Guide to ISO 10993-12: Sample Preparation and Reference Materials,” MD&DI 20, no. 12 (1998): 61–62.
17.P Upman, “A Practical Guide to ISO 10993-3: Carcinogenicity,” MD&DI 21, no. 1 (1999): 186–190. 
 

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