Chapter 16
New Biocompatible Polymer Application for Implantable Glucose Sensor 1
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Kazuhiko Ishihara , Nobuo Nakabayashi , Kenro Nishida , Michiharu Sakakida , and Motoaki Shichiri Downloaded by UNIV OF MICHIGAN ANN ARBOR on April 9, 2014 | http://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/bk-1994-0556.ch016
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Institute for Medical and Dental Engineering, Tokyo Medical and Dental University, Kanda-surugadai, Chiyoda-ku, Tokyo 101, Japan Department of Metabolic Medicine, Kumamoto University School of Medicine, Honjo, Kumamoto 860, Japan 2
To develop a new biocompatible polymer with attention to the formation of biomembrane-like structure on the surface, 2-methacryloyloxyethyl phosphorylcholine(MPC) copolymers with n-butyl methacrylate(BMA) were synthesized. The poly(MPC-co-BMA) showed excellent blood compatibility, that is, inhibition of cell adhesion and activation and re duction of protein adsorption from human blood. On the other hand, phospholipid adsorption from human plasma on the poly(MPC-co -BMA)surface was enhanced with an increase in MPC composition in the copolymer. Thisfindingsuggested that the phospholipid adsorption on the poly(MPC-co-BMA) plays an important role in the reduction of thrombogenicity of the copolymer. Moreover, the poly(MPC-co-BMA) membrane has good permeability for solute. Therefore, it can be ap plied to a medical membrane required both biocompatibility and per meability. The surface of a needle-type glucose sensor with electron mediator was covered with the poly(MPC-co-BMA) membrane and its activity in vivo was investigated. The output signal from the sensor was stabilized by the covering and the glucose concentration in subcutane ous tissue could be detected for 14 days when the sensor was applied to human patient. When artificial materials contact living organisms, serious responses such as thrombus formation, unfavorable immunoresponse, capsulation, etc., are observed. This is a very important response for living but induces many problems in the treatment of patients using the artificial medical devices. Therefore, biocompatibility, particularly blood compatibility, is the most important property required for biomedical materials. The molecular design of biocompatible polymers is classified into four categories
0097-6156/94/0556-0194$08.00/0 © 1994 American Chemical Society
In Diagnostic Biosensor Polymers; Usmani, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
Downloaded by UNIV OF MICHIGAN ANN ARBOR on April 9, 2014 | http://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/bk-1994-0556.ch016
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New Biocompatible Polymer
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as shown in Table 1 based on the approach to regulation of blood materials interactions (7). Since the normal endothelial surface does not induce thrombus for mation, we considered that the tailor-made polymers which can regulate phospholipid adsorption from plasma and produce a biomembrane-like surface have excellent blood compatibility (2). This concept is newer and is based on the properties of natural phospholipids themselves. It is assumed that polymers having a strong affin ity for phospholipids could be used to construct a biomembrane-like structure by adsorbing phospholipids from blood and organizing them on the polymer surface. Phospholipid molecules have a self-organizing property with each other and form a bilayer membrane structure (3). Therefore, polymers having a phospholipid polar group are expected to have a strong affinity for phospholipid molecules. A methacrylate with a phospholipid polar group in the side chain, 2-methacryloyloxyethyl phosphorylcholine (MPC, Fig. 1), and its copolymers with various methacrylates and styrene were prepared (4-6), M P C can be dissolved in alcohol and easily polymerized with other vinyl mono mers by conventional radical copolymerization using a radical initiator. Moreover, the M P C copolymers obtained are soluble in alcohol but insoluble in water, depending on the M P C composition. This is one of the good characteristics required for biomedical polymers for surface modification of medical devices. Among these copolymers, poly(MPC-c0-n-butyl methacrylate (BMA))s exhibit excellent blood compatibility as shown by reduction of platelet adhesion and aggregation and suppression of protein adsorption (7-10). In this review, the blood compatibility of poly(MPC-co-BMA) against human whole blood, the mechanism of nonthrombogenicity observed on the polymer sur face, and application of the poly(MPC-co-BMA) for an implantable glucose sensor are described. BLOOD COMPATIBILITY OF M P C COPOLYMERS In Table 2, the whole blood coagulation time on the polymer measured by the LeeWhite method is summarized Ql). The results clearly indicated reduced thrombogenicity on the M P C copolymers. The coagulation time on glass was 8.4 ± 0.46 min and that on poly(BMA)(no MPC) was 9.6 ±1.3 min. However, there was no significant difference (P>0.05). With a coating of poly[2-hydroxyethyl methacrylate)(HEMA)] and M P C copolymers, the coagulation time was significantly increased compared with glass and a poly(BMA) coating case(P (min) 8.4 9.6 21 21 28
± 0.46 ± 13 ± 1.2
t-Test °) *P>0.05 U—|**P0.05), whereas ** means significant difference(P
