Surgery – Diagnostic testing – Measuring or detecting nonradioactive constituent of body...
Reexamination Certificate
1998-06-23
2001-08-14
O'Connor, Cary (Department: 3736)
Surgery
Diagnostic testing
Measuring or detecting nonradioactive constituent of body...
C600S347000, C600S309000
Reexamination Certificate
active
06275717
ABSTRACT:
TECHNICAL FIELD
This invention relates to devices and methods for measuring an analyte in vivo, and in particular to sensors for use in such devices and methods.
BACKGROUND OF THE INVENTION
Our WO 96/14026, incorporated herein by reference, describes an analyte-controlled liquid delivery device and analyte monitor in which an analyte such as glucose is detected by a platinum-iridium sensor needle having an enzymatic coating such as glucose oxidase. The sensor needle is typically located on a housing having a lower surface for application to the skin of a subject. Glucose in the presence of the enzymatic coating undergoes a reaction with oxygen, and one of the by-products of the reaction is hydrogen peroxide. This in turn is broken down by the platinum in the sensor needle which forms an electrode of an electrical circuit. The level of concentration of glucose is proportional to the magnitude of the current. Thus, the magnitude of the current through the electrical circuit can be used to determine the concentration of glucose.
It has been found that when enzymatic sensors are mass-produced (like many other products), there are slight variations between batches, although individual sensors in each batch are identical. Accordingly to avoid errors in measurements made using such sensors, each production batch can be calibrated.
One method of calibrating such sensors is to use them to measure a standard solution of the analyte for which they are intended, and thereby determining the signal strength achieved from a known concentration of analyte. By making one or more measurements in this way for a statistically valid sample of sensors in a batch it is possible to determine a calibration function which can in theory be used to derive the analyte concentration in vivo from the measured signal.
However, due to the sensitive nature of enzymes, the performance of a sensor may vary over the shelf life of the sensor. Additionally, when the sensor is actually used, it is in a different environment from that in which the batch was calibrated. The sensor will form part of a system in use which is partly biological and which will vary between individual subjects. For example, the laboratory batch calibration function may not take account of the presence of unwanted substances in vivo which give a false background signal.
For these reasons, it has been found that sensors characterised by a laboratory batch calibration are unsatisfactory because such calibration does not permit the performance of the sensor in vivo to be accurately predicted in all cases.
It is thus an object of the present invention to provide a quick and accurate method of in vivo calibration of an analyte sensor.
A further problem associated with enzymatic sensors is that they are subject to a deterioration in performance. This can happen as a result of the enzymatic material being physically or chemically degraded, or as a result of a build up of biological material on the sensor, for example. In WO 96/14026, incorporated herein by reference, a method of detecting a decrease in the performance level of a sensor is disclosed. In this method, a pulsatile sampling technique is used in which pulses of current are detected at or about a peak value and at or about a base line value. The ratio of the two measured currents was found to be independent of the concentration of the analyte being measured, such that if this ratio was found to change over time, one could deduce that the performance of the sensor had changed in some way (usually due to degradation). The present invention seeks to provide an alternative and more reliable method of monitoring sensor performance and degradation.
The present invention seeks to provide an alternative method of testing a sensor to detect changes in the sensor performance.
In measuring an analyte by means of a chemical or electrochemical reaction which requires oxygen, difficulties can arise when the measurement must be carried out in vivo. The quantity of dissolved oxygen in the blood or tissue at the location of the sensor may not be sufficient. If there is an insufficient supply of oxygen, then the rate of reaction of the analyte (and hence the detected level of analyte) may be limited by the available oxygen. This can give rise to false readings which are potentially extremely dangerous, such as in cases where the measured analyte level is used as the basis for the possible administration of a therapeutic agent.
In the case of glucose, this could lead to a diabetic patient being measured as having normal glucose levels when in fact glucose levels had increased to a point where insulin is required to reduce those levels. An error in detection of the glucose level can therefore give rise to problems and indeed dangers to diabetic patients. The same is also true in respect of other substances for which there is a medical need for in vivo analysis and measurement. For these reasons, it is clearly advantageous and important to improve the performance and accuracy of such devices and sensors.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides for a method of calibrating an analyte sensor in vivo, comprising the steps of:
(a) providing a first predetermined stimulus to the sensor when the sensor is applied to a subject to produce a first sensor signal;
(b) measuring the first sensor signal; and
(c) determining a calibration function based on the first measured sensor signal resulting from the predetermined stimulus,
whereby the calibration function when applied to further signals received from the sensor can be used to provide a calibrated output.
The provision of a predetermined stimulus in vivo enables the sensor response to be calibrated, since the theoretical response of the sensor to such a stimulus can be determined beforehand. Accordingly, the method according to the invention provides a way of using the response attained from a predetermined stimulus to evaluate the response to subsequent stimuli, i.e. actual measurements recorded by the sensor in vivo, taking into account the condition of the sensor and the conditions encountered in use.
Preferably, the first predetermined stimulus is generated by providing a supply of material to which the sensor is sensitive, such that the material stimulates the sensor when the sensor is applied to a subject.
By supplying a material to which the sensor is sensitive, one can reliably generate a stimulus for the sensor which can be accurately predetermined beforehand.
Suitably, the material is provided in the vicinity of the sensor in a form in which it is soluble in biological fluids present in the area of the subject to which the sensor is applied.
A soluble material will be released to the sensor upon application to the body, and since the speed of dissolution and the transport of dissolved material in the body can be accurately predicted, so can the time at which the material reaches the sensor and the concentration of material thereby encountered by the sensor.
In preferred embodiments, the material comprises an analyte or a precursor or derivative thereof.
The important factor is that the sensor generates a reliable response to whichever material is chosen, but by choosing the analyte or a closely related substance as the relevant material, a relatively simple sensor which is only required to be sensitive to one substance or a small range of substances can be used. As a further example, instead of using the analyte to be detected, one could choose a salt of the analyte which exhibits a high solubility in vivo.
Suitably, the predetermined stimulus is adapted to saturate the sensor such that the first signal is a maximum signal.
When a sensor is such that it can be saturated by a sufficiently large stimulus, it can be preferable to use this phenomenon in calibrating the sensor as it enables a reproducible first predetermined stimulus, i.e. a saturation stimulus to be provided in all cases, thereby removing uncertainty as to whether the means for providing a predetermined stimulus will in fact achieve exactly the right level of uncer
Gross Joseph
Katz Moshe George
Reingewirtz Meir
Elan Corporation, plc
Maher Kathleen L.
Natnithithadha Navin
O'Connor Cary
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