systems aquire special significance in medicine for in vivo measurements with .... used as implants in medicine show that among the many factors defining the ...
AcsllAIo~ B CHEMICAL Sensors
and Actuators B 24-25 (1995) 159-161
Using the site-binding model for an explanation of the blood compatibility of some materials used in biomedical sensors A.S. Poghossian State EngineeringUniversityof Armenia, Terian 105, Yemvan 375009. Armenia
Abstract Blood clotting time is the most obvious indication of the biological incompatibility of materials that are in contact with blood. The results of the investigation of blood clotting time are presented for 12 different materials that are widely used in biomedical chemical-sensor technology. The most important factors that define the antithrombogenic properties of materials are the surface-state charges and electrochemical phenomena taking place at the solid-state-blood interface. Using the sitebinding model, a mechanism that can explain the high antithrombogenic properties of some materials is proposed and discussed. Keywordrr Biomedical sensors; Blood compatibility; Site-binding model
1. Introduction Due to their miniature size, higher reliability, low fabrication costs, the feasibility of integrating chemical sensors and electronic signal-processing circuit on a single chip and mass production capability, microelectronic sensors and so-called miniaturized total analysis systems aquire special significance in medicine for in vivo measurements with intravascular or intracavity application of sensors. There are a number of specific requirements for the materials of biomedical sensors for in vivo applications, one of which is their biocompatibility. One of the most important criteria for the biocompatibility of materials in contact with blood is the blood clotting time. At the present time the blood compatibility of some metals and polymer materials, used as implants in surgery, has been mainly investigated [1,2]. Several theories (surface tension, free surface energy, specific adsorption, etc.) have been used to explain the blood compatibility of these materials. In the present work we present the results of an experimental investigation of the time of blood coagulation on some materials that are widely used in integrated sensor technology, particularly during the development of biomedical microelectronic sensors. Amongst these materials are silicon wafers, implanted with corresponding impurity SiO, films, which can be used as Na+-, K’- and F--selective membranes, S&N,, Ta,O, and Al,O, films used as the membrane in pHsensitive ISFETs, PVC films, which are used to fabricate ion- and enzyme-sensitive membranes, acrylic cement 0925.4OW95/$09.50 0 1995 Elsevier Science S.A. All rights reserved SSDI 0925-4005(94)-01490-9
used as a packaging material and Teflon, thin films of which may be used as membranes in microelectronic reference electrodes, etc. Using the site-binding model, we also suggest a mechanism to explain the high antithrombogenic properties of some materials.
2. Experimental
The blood coagulating test was a simplified form of the Fonio method [3]. The main point of the method consists in the following: on the sample, which represents a silicon wafer or an Si-SiO, structure covered by a film of the investigated material, we apply 0.1 ml of human venous blood (the blood pH was from 7.2 to 7.4). The starting point of the blood coagulation was determined by measuring the time period from the moment of placing the blood on the sample to the point of the first formation of fine strings of fibrous matter when the tip of a glass stick was put into and removed from the blood, and the subsequent absence of flow of the blood even upon inclination of the sample. The end of coagulation is considered to be the time of appearance of a blood clot. All the measurements were carried out at room temperature. The deposition methods of the investigated materials are presented in Table 1.
A.S. Poghossian 1 Sensors and Actuators B 24-2s (1995) 159-161
160
Table 1 The average relative time for the beginning of blood coagulation on the tested samples Material
Deposition method
Teflon
ready-made film
100
S&N,
chemical vapour deposition
IQ-72
TazO,
thermal oxidation of tantalum thin film
7LL72
ALO,
chemical vapour deposition
7&72
AI PVC Acrylic cement
vacuum deposition spin coating spin coating
66 s&62
Photorcsist (Kodak metal etch resist)
spin coating
5862
Package BK-9 on the basis of epoxy resin (Polymer-Glue Company, Armenia)
dip coating
5&62
SiOz
thermally grown
52
Si
n-type Si wafer, resistivity 4.5 R cm
44
Glass
Fyex glass plate
38
Blood clotting time (%)
58-62
3. Results and discussion The average relative blood clotting time of ten tests for various samples is presented in Table 1 in terms of a percentage. Teflon, which is considered to be one of the most inert and biocompatible medical polymers, and glass wafers were tested for comparison. The time of blood coagulation on Teflon was from 11 to 13 min, which was taken as 100%. The standard deviation was about 5%. It appears from Table 1 that among the tested materials, the best blood compatibility was found for Si,N,, Ta,O, and Al,O, films (except Teflon), which allows them to be used as membranes in biomedical pH ISFETs for durable in vivo measurements. A comparatively bad blood compatibility was found with silicon and glass surfaces. At the present time none of the suggested mechanisms of interactions of blood with a foreign body completely explains the antithrombogenic properties of the material. However, investigations on the thromb-formation properties of some metals and polymer materials [1,2] used as implants in medicine show that among the many factors defining the antithrombogenic properties of materials, the most important is the charged condition of the surface of the foreign body and electrochemical phenomena taking place at the foreign body-blood interface. The adsorption of some blood component
on the surface of materials occurs when they are in contact with blood. Very often there is an adsorption of negatively charged proteins of the blood plasma, which cause future thromb formation. Note that the main reason for the absence of thromb formation in blood vessels is the presence of a negative potential at the inner walls of the vascular channel in contact with the flowing blood. Heparin, which is used as an anticoagulant component, also possesses a negative surface potential. It is supposed that the negative surface charge appearing as a result of electrochemical phenomena at the foreign body-blood interface prevents the adsorption of the negatively charged proteins of the blood plasma that stimulate thromb formation. Using this supposition and the site-binding model, we suggest a mechanism to explain the higher antithrombogenic properties of Si,N,, Ta,O, and A&O, films in comparison with SiOZ films. The site-binding theory is widely used for analysis of pH ISFETs with inorganic oxide or nitride films. It is known that the surface of these films contains hydroxyl groups, the dissociation degree of which depends on pH and contributes to a pH-dependent surface potential [4,5]. At pH>pH p.z.c. (p.z.c. =point of zero charge) the surface is negative charged, which takes place when the above-mentioned films are in contact with the blood (values of pH p.z.c. reported in the literature are 2.5 for SiO,, 3 for Ta,OS, 4.2 for A&O, and 5-6 for S&N, [6-S]). The density of the surface binding sites is of the order of (0.2-.5)~10’~ cm-’ for SiO, and (0.8-l) x 10” cm-’ for Al,O,, Ta,O, and Si,N, [9,10]. The higher the concentrations of surface hydroxyl groups, the greater the negative surface charge of the S&N,, Ta,O, and A&O, films, perhaps resulting in their higher antithrombogenic properties as compared with SiO, films.
4. Conclusions In this work an attempt has been made (by a simplified site-binding model) to explain the high antithrombogenic properties of some inorganic materials. For a better understanding of the antithrombogenic properties of different materials, it is necessary to develop a more detailed physicochemical model of the interaction of multicomponent blood with a solid-state surface, which takes into consideration the surface morphology and the following surface reactions: (i) hydrogen and hydroxyl ion adsorption at surface binding sites; (ii) physical adsorption of anions, cations and organic molecules; (iii) chemisorption (specific adsorption) of anions, cations and organic molecules. Knowledge of the processes taking place in the initial stage is extremely important. With this purpose in view, in further investigations we hope to carry out simultaneous measurements of in-
AS. Poghossion I Sensors and Achmtors B 24-25 (1995) 159-161
terface potential, blood conductivity and blood clotting time.
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