In vitro hemocompatibility testing of biomaterials according to the ISO 10993-4

Abstract

The development of synthetic materials, textured polymers and metals and their increasing use in medicine make research of biomaterials’ hemocompatibility very relevant. Problems arise from the polymorphism and diversity of the different materials, the static and dynamic test models and the patients’ individual biologic factors. First, methods, models, tests as well as preanalytical factors have to be standardized according to the current knowledge in medicine laid down in the ISO 10993 part 4. The routine controls used in clinical chemistry and hematology have to be performed. Information about normal ranges (mean value, standard deviation, 95% confidence interval) should be provided. Tests have to be performed within a minimal delay of usually 2 h since some properties of blood change rapidly following collection. Various conditions (depending on the wall shear rate) were simulated within the centrifugation system and a Chandler system. Qualities and aspects of hemocompatibility such as platelet activation, oxidative burst, hemolysis, fibrinolysis, fibrin formation, generation of thrombin, contact activation, and complement activation were analysed and the results were entered non-dimensionally into a non-dimensional score system, where 0 points stand for the best and 65 points for the worst evaluation. We found a good correlation between the total score and contact activation, thrombin generation and leukocyte activation in a low shear stress system and a good correlation between the total score and thrombin generation, hemolysis and platelet activation in the high shear stress system. Further on the effect of additives and sterilization procedures can be measured. The concepts presented underline the relevance/importance of an efficient diagnostic approach to hemocompatibility that takes account of clinical and socio-economic concerns.

Introduction

The progress in the development of biomaterials has been hindered by the lack of basic information on the nature of the tissues, organs and systems that are replaced, repaired or supported.

A great body of data [1] describing the material and biological aspects has been accumulated. Unfortunately, these data are not only scattered throughout different types of publication but are obtained from experimental and clinical studies that vary greatly in accuracy and precision [2], [3], [4].

For efficient in vitro hemocompatibility testing we have to discuss the principles, scientific basis and the interpretation of major topics such as:

• physicochemical characteristics and stability of the biomaterials

• models and test conditions

• standardization of inserted blood and phlebotomy under non-activating conditions

• reference materials, controls

• laboratory tests

• plausibility aspects and interpretation.

The aspects of surface chemistry, surface degradation and the physical structure are critical indicating the reaction of blood with artificial surfaces. Under normal conditions, platelets do not adhere to endothelial cells in the circulating blood. Exposure of the blood to foreign surfaces leads to deposition of a layer of proteins and cells, often accompanied by activation of the immune system and the coagulation system.