Hemocompatibility testing (ISO 10993-4)

In an effort to harmonize biocompatibility testing worldwide, the International Standards Organization (ISO) developed a standard for “Biological evaluation of medical devices” (ISO 10993), it is currently a 20-part standard which is used to evaluate the effects of medical device materials on the body.

 

Blood-contacting medical devices and (bio)materials have to be tested according to part 4 of the ISO 10993 standard. The standard is applicable to external communicating devices, either with an indirect blood path (e.g. blood collection devices, storage systems) or in direct contact with circulating blood (e.g. catheters, extracorporeal circulation systems), and implant devices (stents, heart valves, grafts). Testing should be performed for five categories, based on primary processes: thrombosis, coagulation, platelets, haematology and complement. In this system all relevant aspects of blood activation are taken into consideration, but, and this is most important, testing should simulate clinical conditions as much as possible. Thus, most devices should be tested with heparinised blood under circulating conditions.

 

HaemoScan offers hemocompatibility testing with it’s own developed in vitro model [1], the Hemobile. Our model has shown to perform better than the Chandler model and the roller pump model [2], with the biggest advantages being less blood trauma induced by the model itself, pulsatile flow, and higher flow rates. Results can be used for certification purposes or to gain more insight into a products hemocompatibility.

Hemobile

Figure 1. Schematic representation of the Hemobile. The device provides a pulsatile flow at a frequency similar to the arterial circulation. A) Cilinder with test material, B) One-way ball valve to ensure a unidirectional flow, C) tubing filled with fresh human blood.

 

In vitro model

Flow models for hemocompatibility testing may consist of animal models or in-vitro test systems. Animal models have the disadvantage of being expensive, time consuming and insensitive due to overwhelming short term effects of tissue damage. Small models, such as ours, have the advantage of being suitable for testing different biomaterials with blood from one donor, which eliminates donor variability.

 

Human blood

It has been shown that the composition of blood differs considerably between various species, which leads to over- or under-estimation of human blood reactions to biomaterials. The use of human blood is therefore more relevant to the interpretation of results and offers a more detailed array of test methods, since most available methods are based on human blood components. HaemoScan uses fresh venous blood from healthy volunteers for all their testing.

 

(Pulsatile) flow

The major differences observed between cell interaction under static and flow conditions has made clear that whole-blood flow models are required for testing haemocompatibility inasmuch as the test device will be used clinically in the blood circulation. A key determinant of blood activation and adhesion of cells is wall shear stress; the force exerted by the flow per surface area. When blood is in contact with biomaterial surfaces, fluid mechanics, and especially the shear stress, have a strong influence on the damage of red cells and platelets. Red cell damage may occur at high shear stress.

Platelets are even more easily damaged by shear stress. Platelet damage is not only influenced by the maximum shear, but also by the duration of the shear force. Only for very short exposure times are platelets able to withstand higher shear stress than red cells.From a fluid mechanical point of view, differences in flow situations may therefore lead to different problems with blood.

The reasoning for pulsatile flow is that mimicking the physiological situation as much as possible will give a better test outcome. Furthermore, platelet and erythrocyte aggregation and deformability are sensitive to pulsatility.

The adjustable flow and shear of the Hemobile renders it a model that allows standardised testing of medical devices at the cost of low intrinsic blood damage.

 

References

 [1] T. Yoshizaki, N. Tabuchi, W. van Oeveren, A. Shibamiya, T. Koyama, and M. Sunamori, “PMEA polymer-coated PVC tubing maintains anti-thrombogenic properties during in vitro whole blood circulation.,” The International journal of artificial organs, vol. 28, no. 8, pp. 834–40, Aug. 2005.

 [2] W. van Oeveren, I. F. Tielliu, and J. de Hart, “Comparison of modified chandler, roller pump, and ball valve circulation models for in vitro testing in high blood flow conditions: application in thrombogenicity testing of different materials for vascular applications.,” International journal of biomaterials, vol. 2012, p. 673163, Jan. 2012.