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Method to Maintain Oxidative Capacity of Test Solutions for Oxidative Degradation Screening

Catalog of Regulatory Science Tools to Help Assess New Medical Devices 

This Regulatory Science Tool (RST) is a Laboratory Method outlining the use of a hydrogen peroxide solution to screen for oxidative degradation. This method allows for maintenance, monitoring and reporting of solution concentration and oxidative capacity and is demonstrated with UHMWPE as a non-resorbable polymer susceptible to oxidative degradation. 

Technical Description

This Regulatory Science Tool is a Laboratory Method that uses a hydrogen peroxide (H2O2) solution to screen for oxidative degradation. This method also (i) identifies a H2O2 concentration range of ~10-400 mM, (ii) allows for maintenance, monitoring, and reporting of H2O2 solution concentration, and (iii) uses UHMWPE as an example of a non-resorbable polymer susceptible to oxidative degradation. This method is intended to evaluate the long-term oxidative stability and degradation of UHMWPE [1]. This method offers an approach to maintain consistent H₂O₂ concentrations in aqueous solutions. Following the described procedure, H₂O₂ levels are adjusted in real-time when concentrations fall below predefined thresholds.

This RST method encompasses two key procedures for using the test method described in Section S1 of the Supporting Documentation:

  • Calibration of test system: This procedure involves correlating the current generated by this test system with known H₂O₂ concentrations to produce a calibration curve.
  • Maintenance of H₂O₂ Concentration: This procedure utilizes a fluid feedback loop, automatically activated by a microcomputer, to replenish the H₂O₂ concentration in the test solution when it falls below a set threshold.

The User Manual provides detailed instructions for assembling the test system using low-cost, open-source components.

Intended Purpose 

The intended purpose of this RST is to provide a laboratory method for maintaining the oxidative capacity of test solutions for in vitro oxidative degradation screening. This method can be used to assess susceptibility to oxidative degradation and rank resistance to oxidation in medical devices and components.

This method tightly maintains H₂O₂ concentrations and obviates manual replacement of H₂O₂ [2,3,4,5,6,7]. The controlled concentration and temperature ranges minimize both variability H₂O₂ decomposition kinetics and non-representative degradation pathways, such as diffusion-limited oxidation (DLO), which skews degradation towards the sample surface and limits it in the bulk [8]. This tool allows for comparative studies to assess the oxidative degradation and durability of samples. 

The primary output of this tool is the real-time, quantitative measurement and continuous monitoring of H₂O₂ concentration throughout the testing process. Samples treated using this method can be further characterized using techniques like Fourier Transform Infrared Spectroscopy (FTIR), in accordance with relevant standards. 

The modular design of the test system allows for easy replication while using open-source and low-cost components. Additionally, the method provides control over three key parameters: H₂O₂ concentration, solution temperature, and experiment duration, enabling users to simulate a range of oxidative degradation conditions [1,9,10].

This method is demonstrated using UHMWPE, which is widely used in medical devices and is susceptible to oxidative degradation. Determination of applicability to other polymers is the responsibility of the user and is discussed in the Limitations section further below.

Testing

The details of the testing are reported in Reference 1 below. Briefly, they comprise: 

  • Repeatability: Four identical test setups were independently calibrated to correlate current generated by the electrodes and H₂O₂ concentrations and demonstrated strong inter-setup repeatability of system calibration.
  • Linearity of Calibration: Testing showed a linear relationship between the current generated by the electrodes and H₂O₂ concentrations in the range of approximately 10–400 mM. At higher concentrations, a deviation from linearity was observed. Independent validation of H₂O₂ concentrations using UV-Vis spectroscopy confirmed that the H₂O₂ concentration was maintained for as long as 4 weeks.
  • FTIR Characterization: FTIR Analysis was performed to assess type and extent of oxidation. Oxidation peaks at or near 1715 cm-1 confirmed oxidative degradation consistent with physiological oxidative pathways.

Limitations

This RST provides a method for maintaining the oxidative capacity of test solutions for in vitro oxidative degradation screening. However, it is important to note the following limitations:

  • Method sensitivity and optimization: The electrochemical components of this test method are highly sensitive to test conditions (e.g. test solution buffer, test temperature). Users are advised to confirm the range of H₂O₂ concentrations within which reliable monitoring is feasible, as well as identify and account for any deviations or adjustments made during prolonged use. Regular calibration is recommended to account for potential changes in electrode performance over time.
  • Clinical relevance: This method does not provide direct clinical predictions. Rather, it primarily assesses hydrolytic and oxidative degradation chemical pathways and does not claim to fully replicate the complex and dynamic in vivo environments of polymeric medical devices post-implantation. Physiological factors such as biomechanical stresses, wear, biological interactions (lipid absorption, enzymes, proteins, immune cells) and radiation are not accounted for in this test.
  • Applicability to other non-resorbable polymers: This RST method is intended to maintain oxidative capacity of test solutions and has been demonstrated using UHMWPE. If a user wishes to apply this RST method to a different non-resorbable polymer, no modifications to the test setup components are recommended. However, the following factors should be considered:
    • Hydrogen peroxide compatibility
      • Confirm that the polymer should not interfere with the electrochemical reactions used to monitor H₂O₂ concentration. Specifically, the polymer or its degradation byproducts should not react with the electrodes or alter the electrochemical signals.
      • Confirm that the polymer does not produce reactive intermediates or degradation products that could falsely influence the H₂O₂ detection.
    • Selection of test conditions
      • H₂O₂ Concentration: The concentration of H₂O₂ should be optimized to simulate the oxidative stress relevant to the intended application of the polymer. Excessively high concentrations may alter the dominant degradation pathways, while very low concentrations may not produce detectable changes within the experimental timeframe.
      • Temperature: Select a temperature that accelerates oxidative degradation without introducing non-physiological degradation mechanisms. Elevated temperatures should be justified based on the polymer's thermal stability and the desired acceleration factor.
      • Duration: Estimate the duration of the test based on the expected degradation kinetics of the polymer. Prolonged tests may be necessary for polymers with high oxidative resistance.
    • Characterization of degradation
      • Ensure that appropriate analytical techniques are used to evaluate the degradation of the polymer being tested. For example:
        • FTIR spectroscopy could be used to identify oxidative products such as carbonyl groups.
        • Gel Permeation Chromatography (GPC) may be used to assess change in polymer molecular weight.
        • Mechanical testing or other techniques may be necessary for materials where structural integrity is a critical parameter.
      • Justify the selected characterization techniques based on the polymer’s chemical composition and the intended application.
    • Test setup
      • Confirm that the electrochemical setup (e.g., electrode materials, potentiostat configuration) works effectively with the polymer being tested. This includes demonstrating that the calibration curve for H₂O₂ remains linear and reproducible under the selected conditions.
        • Document any modifications made to the test setup for compatibility with the new polymer.
      • Polymer-specific considerations
        • Polymers with unique properties (e.g., high antioxidant content, fillers, or complex formulations) may require additional considerations, such as:
          • Adjustments to test solution composition to avoid interactions with additives.
          • Prolonged equilibration periods to ensure uniform exposure to oxidative agents.
        • For device testing, account for any interactions between the polymer and other device components that may influence degradation.

Supporting Documentation

The User Manual includes the general guidelines for test method setup; the control scripts for calibration and H₂O₂ concentration maintenance procedures; and the Python codes used for the respective experiments.  

References:

  1. Jain, T., Danesi, H., Lucas, A., Dair, B. and Vorvolakos, K. (2024), Accelerated In Vitro Oxidative Degradation Testing of Ultra-High Molecular Weight Polyethylene (UHMWPE). J Biomed Mater Res, 112: e35495. https://doi.org/10.1002/jbm.b.35495
  2. M. F. Rocha, A. A. P. Mansur, and H. S. Mansur, “FTIR Investigation of UHMWPE Oxidation Submitted to Accelerated Aging Procedure,” Macromolecular Symposia 296, no. 1 (2010): 487–492, https://doi.org/10.1002/MASY.20105 1065.
  3. R. Lerf, D. Zurbrügg, and D. Delfosse, “Use of Vitamin E to Protect Cross-Linked UHMWPE From Oxidation,” Biomaterials 31, no. 13 (2010): 3643–3648, https://doi.org/10.1016/J.BIOMATERIALS.2010.01.076.
  4. D. K. Dempsey, C. Carranza, C. P. Chawla, et al., “Comparative Analysis of In Vitro Oxidative Degradation of Poly(Carbonate Urethanes) for Biostability Screening,” Journal of Biomedical Materials Research. Part A 102, no. 10 (2014): 3649–3665, https://doi.org/10.1002/JBM.A.35037.
  5. Sies, H. Hydrogen Peroxide as a Central Redox Signaling Molecule in Physiological Oxidative Stress: Oxidative Eustress. Redox Biol 2017, 11, 613. https://doi.org/10.1016/J.REDOX.2016.12.035.
  6. Lerf, R.; Zurbrügg, D.; Delfosse, D. Use of Vitamin E to Protect Cross-Linked UHMWPE from Oxidation. Biomaterials 2010, 31 (13), 3643–3648. https://doi.org/10.1016/J.BIOMATERIALS.2010.01.076.
  7. DK, D.; C, C.; CP, C.; P, G.; JH, E.; S, C.; EM, C.-H. Comparative Analysis of in Vitro Oxidative Degradation of Poly(Carbonate Urethanes) for Biostability Screening. J Biomed Mater Res A 2014, 102 (10), 3649–3665. https://doi.org/10.1002/JBM.A.35037.
  8. Celina, Mathew C. 2013. “Review of Polymer Oxidation and Its Relationship with Materials Performance and Lifetime Prediction.” Polymer Degradation and Stability 98 (12): 2419–29. https://doi.org/10.1016/j.polymdegradstab.2013.06.024.
  9. Jain T, Tantisuwanno C, Paul A, et al. Accelerated in vitro oxidative degradation testing of polypropylene surgical mesh. J Biomed Mater Res. 2023; 111(12): 2064-2076. https://doi.org/10.1002/jbm.b.35308
  10. Street MG, Welle CG, Takmakov PA. Automated reactive accelerated aging for rapid in vitro evaluation of neural implant performance. Rev Sci Instrum. 2018; 89(9):094301. https://doi.org/10.1063/1.5024686 

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