Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving oxidoreductase
Reexamination Certificate
2000-05-10
2001-03-13
Leary, Louis N. (Department: 1623)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving oxidoreductase
C435S004000
Reexamination Certificate
active
06200772
ABSTRACT:
This application is the national phase of international application PCT/GB98/02457 filed Aug. 17, 1998 which designated the U.S.
This invention relates to sensor devices, and more particularly to improved sensor devices useful in analytical methods involving the detection or measurement of analytes, especially in enzyme-based sensor systems.
It is well known to make a variety of sensor devices in which an electrode is employed to provide output signals by which the presence or absence of an analyte in a sample can be determined. For this, an analyte (or a species derived from it) which is electro-active generates a detectable signal at an electrode, and this signal can be used as the basis for detection or measurement of the presence and/or amount of the analyte in a sample.
Bio-sensors have been found to be very successful in use for such purposes, especially when the bio-component is an enzyme. An enzyme has the advantage that it can be more specific to the analyte sought and also, when the analyte itself is not sufficiently electro-active, can be used to interact with the analyte to generate another species which is electro-active and to which the electrode can respond to produce the desired output signals. The classic example of such a sensor is the glucose oxidase enzyme-electrode, in which an immobilised glucose oxidase enzyme catalyses the oxidation of glucose to form hydrogen peroxide, which is then detected and determined by amperometric measurement of the effect it produces (increase in electrical current) at a polarised electrode.
Many such sensors have been proposed, and most of these rely upon some form of membrane to control the extent to which the analyte (e.g. glucose) present in a sample under investigation can gain access to the sensing electrode, at which it can the be detected and determined. The main function of the membrane is to separate as far as possible those components which are desirable from interferents, i.e. components which interfere with the desired determination reactions or take part in reactions of their own which compete with those of the analyte compound sought and distort or overwhelm the signals to be measured.
Many different materials have been proposed for use in such membranes—some as the material forming the membrane itself, and some as coatings to be carried on the surface of another material. In general, these may function either by their porosity (whereby the selectivity of the membrane will depend on which individual components can pass through the pores or holes) or by their permeability (whereby the selectivity of the membrane will depend on which individual components can pass through the membrane material itself).
It is difficult to find membranes which are sufficiently satisfactory or reliable in use, and especially in vivo.
We have now found that, although polyurethanes are among the various materials hitherto proposed for membranes, an unexpectedly satisfactory form of sensor is obtained when the membrane is made of a polyurethane modified with a non-ionic surfactant.
Thus according to our invention we provide an improved sensor device which comprises a detector means and a membrane positioned to protect the detector from direct contact with a sample to be examined, characterised in that the said membrane comprises a modified polyurethane which is substantially non-porous and incorporates a non-ionic surfactant as modifier.
Especially, we provide an improved sensor device which comprises an active (working) electrode and a membrane positioned to protect the electrode from direct contact with a sample to be examined, characterised in that the said membrane comprises a modified polyurethane which is substantially non-porous and incorporates a non-ionic surfactant as modifier.
According to our invention we also provide the modified polyurethanes, wherein the modifier incorporated therein is anon-ionic surfactant, as novel compositions in their own right. These may be in a variety of forms and a preferred form, which is especially useful for the purposes of the analytical sensor devices and methods described herein, is that of a thin membrane. Their formation, the components from which they can be made, and the proportions of components are more fully described herein.
The sensor device may be applied to allow detection and measurement of electrolytically active species directly, i.e. when such species can pass through the membrane and then reach the active electrode (or any alternative detector which may be used in its place) and may be measured directly. However, we find that the invention is especially applicable to producing improved enzyme electrodes, in which an enzyme converts an analyte species into another species which is electrolytically active and can be detected at the active electrode, thereby providing an indirect measure of the analyte on which the enzyme acted.
Thus according to our invention we also provide, as a preferred embodiment, an improved sensor device which comprises
(1) an active (working) electrode;
(2) an enzyme enclosed between two membranes - - -
(3) an inner membrane adjacent to the active electrode (1) and
(4) an outer membrane positioned to contact a sample to be examined,
characterised in that at least one of these two membranes comprises a modified polyurethane which is substantially non-porous and incorporates a non-ionic surfactant as modifier.
The mechanism by which our surfactant-modified polyurethanes function and are permeable is not yet clearly understood, but it is very surprising that these particular ones can be permeable towards a variety of low molecular weight species (e.g. sugars such as glucose) in solution—usually in aqueous solution—and do not necessarily have to be as small (in molecular terms) as gaseous materials.
The invention is not confined to use of an electrode as the means for detecting and measuring the analyte or another compound derived from it, i.e. electrochemical means, and any alternative detector may, if desired, replace the active electrode (1) specified in the sensor devices defined above. Likewise, although we find it most convenient to use amperometric measurement of electrochemical activity, and the invention is illustrated with particular reference to this mode, other modes of electrochemical measurement may be used if desired.
Preferably the surfactant-modified polyurethane is used to form the outer membrane (4), as this allows the benefits and advantages of the surfactant-modified polyurethane to be obtained. However, if desired, it may be used in a position which is not the outermost of the four parts specified above; for example, it may be desirable to add some further layer or screen over the modified polyurethane layer (4) to protect it from damage, or even, in some particular situation, to position the polyurethane layer between the active electrode and the enzyme layer, but the sequence set out above is the preferred one.
By the term “substantially non-porous” we mean that the surfactant-modified polyurethane it is not constructed or formed in a way that provides any discrete pores or holes in it, but nevertheless it is permeable.
The non-ionic surfactant may be any known surfactant compound. Especially it may be a compound having a molecular structure combining both (A) a hydrophilic moiety and (B) a hydrophobic moiety, in which the moieties (A) and (B) have sufficient activity for the combination to function as a surfactant.
Preferably, the non-ionic surfactant contains a poly-oxy-alkylene chain, for example one derived from multiple units of poly-oxyethylene groups (—CH
2
—CH—O—)
n
. Such compounds are well known in the art and many are commercially available, usually being condensates of various proportions of ethylene oxide with a compound containing a hydrophobic moiety—especially with hydroxy-compounds, for example a phenol, a fatty alcohol, or the like, or mixtures thereof. A common one is a condensate of 7 to 10 molar proportions of ethylene oxide with an alkylated phenol, e.g. nonylphenol. Examples include condensates of ethylene ox
Ahmed Sayed
Rigby Geraldine Patricia
Vadgama Pankaj Maganlal
Leary Louis N.
Pillsbury Madison & Sutro LLP
Sensalyse Holdings Limited
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