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Many commonly used medical devices, such as catheters, cardiopulmonary bypass systems, and endovascular grafts, are intended to come in contact with circulating blood. Therefore, these devices require an assessment for hemocompatibility risks such as hemolysis and thrombosis prior to submitting to a regulatory agency for market approval. The testing required for the evaluation of these specific endpoints depends on the exposure type and duration of the specific medical device under focus, and the guidance is captured in Table 1 of ISO 10993-4 Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood.
The tests highlighted in the standard are used to evaluate the different aspects of hemocompatibility. For example, hemolysis determines the degree of red blood cell lysis and the release of hemoglobin caused by medical devices, materials, and their extracts in vitro. Other specific hemocompatibility tests can also be designed to simulate the geometry, contact conditions, and flow dynamics of the medical device or material during clinical applications and determine blood, material, and device interactions.
For devices having direct contact with circulating blood (regardless of contact duration), the U.S. FDA recommends that hemolysis, complement activation, and thrombogenicity testing be considered, if not otherwise addressed during the risk assessment process. On the other hand, for devices having only indirect contact with circulating blood, like tubing used for intravenous (IV) solutions, only indirect hemolysis testing may be appropriate, as complement activation and in vivo thrombogenicity testing are generally not needed for indirect blood-contacting devices. Furthermore, ISO 10993-4 indicates that “Devices or device components which come into very brief/transient contact with circulating blood (e.g., lancets, hypodermic needles, capillary tubes that are used for less than 1 min) generally do not require blood/device interaction testing.” Thus, the necessity for hemocompatibility testing should be considered based upon an appropriate risk analysis.
While the ISO-certified tests are a good place to start when putting together the biocompatibility testing plan, assessing hemocompatibility for devices that contact the circulatory system may sometimes pose difficulties due to the specific setup of the typical tests recommended by ISO 10993-4 and FDA. For instance, oxygenators and hemodialyzers have a large internal surface area that makes the typical visual assessment of thrombus formation difficult if not impossible to execute. Additionally, various external devices, such as extracorporeal circuits and other devices where blood is directed through the device and back into the patient, cannot be directly inserted into a test animal, making the FDA-preferred in vivo dog thrombosis study futile for these particular devices. Thus, a different set of thrombosis assays should be considered for these devices to evaluate the hemocompatibility-related risks that may arise from their intended use. Examples include static tests such as platelet and leucocyte count/activation and partial thromboplastin time (indicated in Table 1 of ISO 10993-4 with superscript c).
But what about a medical device that undergoes a change after all the biocompatibility testing has been performed? Manufacturers and regulatory bodies face this question every day. For instance, changes in manufacturing and processing parameters can have an impact on biocompatibility. Another common change that might impact biocompatibility is a change in resin supplier. However, not all changes require full evaluation of the biocompatibility, including hemocompatibility, of a medical device. The guidance in all applicable standards including ISO 10993, the FDA guidance document, and ISO 14971 highlights the importance of using a risk-based approach when defining the path forward to deciding which additional testing is truly needed after changes have been implemented. For instance, the FDA guidance specifically states that, “When assessing device modifications, the sponsor should specifically state if the modification does not result in a change to any direct or indirect tissue-contacting components and no further biocompatibility information would typically be needed. However, if the change could affect other parts of the device with direct or indirect contact that were not changed, a biocompatibility evaluation should be conducted to assess the potential impact of the change.” ISO 10993-4 also highlights that, “modifications in a clinically accepted device shall be considered for their effect on blood/device interactions and clinical functions. Examples of such modifications include changes in design, geometry, changes in surface or bulk chemical composition of materials and changes in texture, porosity or other properties.” Overall, all changes should be considered on a case-by-case basis and addressed using a written risk assessment that accompanies the biocompatibility files associated with the given medical device.
Based on the recommendations of the U.S. FDA, the risk assessment should generally begin with assessment of the device, including the material components, the manufacturing processes, the clinical use of the device (including the intended anatomical location), and the frequency and duration of exposure. Based on the available information, the potential risks from a biocompatibility perspective should be identified. These include risks associated with alterations to the physical or chemical characteristics of the device, aspects of manufacturing and processing that could alter the physicochemical characteristics of the device, and so forth. The same rationale must be applied to the hemocompatibility aspect of the modified device.
As indicated previously, the intent of assessing hemocompatibility of a device involves two aspects: (i) whether the components produce an effect through the ability of chemicals to migrate out of the materials, or (ii) whether the device is inclined to cause thrombosis or hemolysis due to its surface characteristics. In other terms, identify whether the new material releases chemical compounds (leachates) that affect compatibility with blood or whether the design changes affect the geometry or surface properties of the said device that could result in possible thrombus formation.
The FDA guidance defines that “for assessment of changes only to the material, but not to the geometry or surface characteristics of the device, testing in a 'static' environment (e.g., with gentle agitation of the blood in the absence of simulated clinical flow conditions) may be sufficient.” Therefore, the first step in assessing the modified device for hemocompatibility should focus on defining whether the surface characteristics have remained the same. Surface characteristics are defined by the surface smoothness like cracks or crevices found on the blood-contacting parts of the device. This is an essential component of the assessment because the impact of surface alterations due to processing, even at the micron level, could result in geometrical or chemical changes at the surface which, in turn, could result in an adverse biological response (even if the base material has a long history of safe use in similar applications). The surface analysis can, for instance, be performed with high-magnitude microscopy techniques, such as scanning electron microscopy (SEM), to define whether the new surface is similar to the previous version of the device.
If surface characteristics are demonstrated to be similar, then an additional in vivothrombosis test using the NAVI model or equivalent alternative animal model may not be necessary. According to ISO 10993-2, animal tests are deemed to be justified only when they have been shown to be relevant and reliable for the purposes for which they are undertaken, and the resulting data are essential to properly characterize and evaluate the test material in the context in which it is to be used in medical devices. Therefore, if surface characteristics remain the same, the overall risk for any surface-friction-related hemo-incompatibility can be considered low and the device is expected to behave similarly to the previously tested configuration. With that in mind, it should still be evaluated whether the leachates from the new material could result in any issues when the device is placed in contact with blood. The FDA guidance indicates that “in particular, a battery of in vitro tests to include assessment of platelets (e.g., adhesion, activation), and the coagulation system (e.g., Thrombin-Antithrombin Complex (TAT), Partial Thromboplastin Time (PTT)) may be used as a substitute for in vivo thrombogenicity testing.” Blood cell adhesion, for example using the platelet count assay, is a measure of the blood compatibility of a material when considered in conjunction with distal embolization or evidence of activation of one or more hematological factors. The PTT test, on the other hand, measures the ability or potential of the medical device extract to form blood clots. These are two examples of static in vitrotests that could be used to evaluate the extractable profile of the medical device after it has undergone some changes in the components that have contact to the circulatory system.
Therefore, if surface characteristics are demonstrated to be similar to the already cleared and marketed version of the device and the screening tests for hemocompatibility and thrombogenicity show no elevated potential for adverse reactions, it can be concluded that the device in its new configuration is hemocompatible and further testing for other hemocompatibility-related (ISO 10993-4) endpoints can be deemed unnecessary.