Hemocompatibility is on of the test requested to assess the safety of a medical devices that come in contact with blood. It is obvious that among the whole set of medical devices manufactured worldwide, those devices that are in conctact with human blood require further evidence in terms of safety, as they might have a potential impact on the safety of the patients.
We have been already discussing on design validation and specifically of the ISO 10993 family of standards; these ISO standards are in fact the reference points for all the biocompatibility testing that need to be performed over medical devices. In details, we have been talking about ISO 10993-1, the parent of the ISO 10993 series, that contains the requirements related to the so-called biological risk assessment and the details of the type of testing to be performed depending on the type of medical devices. Moreover, we have been discussing on the requirements related to ISO 10993-5, related to cytotoxicity testing for medical devices.
In this article, as already mentioned before, we will go through the requirements for hemocompatibility of medical devices, including the testing technique and the associated ISO 10993-4:2017 : Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood.
Hemocompatibility: An Introduction
When a medical device comes in contact with blood, many risk factors shall be taken in considerations, such as for example hemolysis and thrombosis. This is the reason why specific tests need to be carried out on these types of devices.
Some commonly used medical devices, such as catheters, xxtracorporeal membrane oxygenator 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 type of tests to be performed are reported in table 1 of ISO 10993-4; these tests are basically dependent from the devices. Different tests are envisioned in the context of ISO 10993-4:
- Thrombosis
- Coagulation
- Platelets
- Hematology
- Complement System
We will go more in details for some of these tests in the section below.
Type of Tests for hemocompatibility evaluation of medical devices
There are basically three types of test it is possible to perform:
- in vitro tests
- ex-vivo tests
- in vivo tests
As specified by the standard, for in-vitro tests many variables shall be taken in considerations, such as for example haematocrit, anticoagulants, sample collection, sample age, sample storage, aeration and pH, temperature, etc.
Ex vivo tests shall be performed when the intended use of the device is ex vivo, for example an external communicating device.
There are many ex-vivo tests available to evaluate the hemocompatibility of medical devices; ex vivo test systems are available for monitoring platelet adhesion, emboli generation, fibrinogen deposition, thrombus mass, white-cell adhesion, platelet consumption, and platelet activation, for example. .
The advantages of ex vivo tests over in vitro tests are that flowing native blood is used (providing physiological flow conditions), several materials can be evaluated since the chambers can be changed, and it is possible to monitor some events in real time.
In vivo testing involves implanting the material or device in animals. Vascular patches, vascular grafts,, heart valves and circulatory assist devices are examples of configurations used in in vivo testing.
Change Management for Medical Devices and impact on Hemocompatibility
We have been already discussing change management within QualityMedDev website, including the concept of substantial changes. Moreover, now that we hare in the transition period for the EU Medical Device Regulation, article 120 defines the possibility to implement changes not considered substantial while keeping the EU Certificate under the previous Medical Device Directive.
Regarding the hemocompatibility evaluation, changes shall be considered case by case and at this moment there is no specific guideline. The ISO 10993-4 defines 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“. Obviously, while evaluating the change, risk assessment considerations based on ISO 14971 and ISO/TR 24971 shall always apply.
Methods for hemocompatibility evaluations
The ISO 10993-4 defines different types of tests for the evaluation of hemocompatibility of medical devices.
For example, the evaluation of thrombosis effects of the medical device under evaluation can be performed by different tests, such as:
- Percent occlusion
- Flow reduction
- Gravimetric analysis (thrombus mass)
- Light microscopy (adhered platelets, leukocytes, aggregates, erythrocytes, fibrin, etc. )
- Pressure drop across device
- Labelled antibodies to thrombotic components
- Scanning EM (platelet adhesion and aggregation; platelet and leukocyte morphology, fibrin)
Similar methods are described for the evaluation of other factors related to hemocompatibility, such as for example, coagulation and platelet activation.
Biological Risk Assessment Template
QualityMedDev presents a Biological Risk Assessment Template, a document that will definitely support and facilitate the documentation related to theological safety of medical devices. This document defines the strategy for biological risk assessment, which is, in other words, the application of ISO 14971 requirements into the evaluation of the biological safety of medical devices.
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