Safety of implantable medical devices: Antioxidant breakdown products classified

Antioxidants in polymeric medical implants

Medical devices that are intended for transplant into the human body must be inert to protect the patient for years to come during the lifetime of the implant. This might be easier to achieve for metal devices, like artificial joints, than it is for those made out of plastic. There are likely to be more trace chemicals in plastics due to the additives that must be added to the polymer during the manufacturing and moulding process and there is a danger that they might leak into the body.

One of these additives might be an antioxidant, blended with the polymer before moulding. During the subsequent γ-irradiation step which is carried out to strengthen the polymer by crosslinking, the antioxidant will mop up any free radicals that are formed to prevent them from attacking and destabilising the polymer, reducing its useful lifetime. However, the irradiation step can also break down the antioxidant itself to produce unwanted products.

This degradation has been examined by scientists in the US, who looked specifically at commercial polymeric orthopaedic knee inserts. Gyorgy Vas and colleagues from Johnson & Johnson L.L.C., Raritan, NJ, and DePuy Orthopeadics Inc., Warsaw, IN, wanted to see if the antioxidant added during manufacture broke down during the γ-irradiation step. They devised a thermal desorption GC/MS procedure to identify and measure the breakdown products.

The particular antioxidant used in the inserts was the lengthily named pentaerythritol tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate] (PBHP). Under radiation, it can break down into various phenol and quinone derivatives which could be harmful if they leaked into the body from an implanted insert. The products were analysed by GC/MS following extraction by stir bar sorptive extraction (SBSE), a technique reported for the first time for leachable components in a polymeric medical device.

Leaching out breakdown products

Orthopaedic tibial knee inserts made from ultrahigh-molecular-weight polyethylene were tested. In an initial step, they were extracted by Soxhlet extraction, accelerated solvent extraction and dynamic headspace extraction to identify the full range or potential extractable components. The two solvent-based extractions proved to be poor choices because many of the components were lost during the solvent-reduction step, even though relatively mild temperatures and reduced pressures were employed.

The headspace technique was not without its problems too, namely the appearance of many interfering compounds derived from the polymer matrix in the total ion chromatogram. However, the application of a deconvolution step to filter the chromatograms reduced these interferences, allowing 16 leachable components to be detected by GC/MS. They were confirmed by three steps, according to the best practice recommended by the Product Quality Research Institute (PQRI), a collaboration involving the Center for Drug Evaluation and Research of the FDA, industry and academia.

Firstly, they were matched to the NIST Mass Spectral Library. Then tandem mass spectra were recorded and the fragment ions assigned to structures of individual peaks. Finally, exact mass data generated by isotope pattern matching were examined. As an additional step, the researchers compared the spectra to those of commercial standards, where available.

Following the establishment of the range of extractable components, an SBSE method was designed for their analysis. SBSE was selected because it eliminates the need for a preconcentration step and can be applied to whole medical devices, as well as being recommended by regulatory authorities to eliminate sampling errors, as specified in an ISO method.

The implants were soaked in 10% acetone in water for 24 hours or 30 days then a stir bar coated with polydimethylsiloxane was added to the liquid to trap the compounds that leached out. The bar was blotted dry and placed in the desorption unit for thermal desorption GC/MS analysis, using multiple reaction monitoring to identify and measure the compounds.

Leaky knee inserts

Under the optimum conditions, which were derived from a combination of ISO recommendations and lab-based testing, the detection limits of the leachable compounds were in the region of 200-400 pg/device, or 8-16 pg/mL. The other analytical data were also deemed to be satisfactory.

Using a thermal desorption unit is also advantageous as it allows for the analysis of semi-volatile compounds as well as volatiles. Five leached compounds were identified as 2,6-di-tert-butyl-1,4-benzoquinone (BHT), BHT quinone, BHT aldehyde, 2-tert-butyl-6-(prop-1-en-2-yl)phenol and methyl 3,5-di-tert-butyl-4-hydroxybenzenepropanoic acid, also known as Metilox or Irganox 1300, an antioxidant in its own right.

After an extraction period of 24 hours, the amounts of four of the five compounds were below the safety concern threshold of 150 ng/day set by PQRI. The fifth, 2-tert-butyl-6-(prop-1-en-2-yl)phenol, was above this threshold but Vas argued that its genotoxic and carcinogenic potential would be low due to its structure, so it could also be regarded as safe at the level found.

Over an extraction period of 30 days, the concentrations of all five compounds were well within the PQRI threshold. Another ten compounds were detected over the extended time but they were all at very low levels.

It cannot be concluded that the same compounds would leach out into the knee after implantation because the conditions are different. Using phosphate-buffered saline, which is widely used in physiological studies, the extraction efficiency of most components was poor. So, aqueous acetone was chosen as a good compromise, even though it is a poor representation of in vivo conditions. It is likely that these extraction conditions represent a worst-case scenario for the knee inserts.

The key benefits of this procedure are that it can be applied to intact medical devices in a procedure that is open to some automation. The use of SBSE prevents analyte losses by eliminating the preconcentration step and the thermal desorption GC/MS method can measure antioxidant breakdown products at low levels.