Apparatus and method for non-invasive blood analyte measurement

<u style="single">Technical field to which the invention belongs</u>The present invention generally relates to a method for monitoring a human blood analyzer, particularly a non-invasive blood analyzer measuring device and a measuring method for monitoring a blood analyzer such as glucose in a diabetic patient. Conventional Techniques The use of real-time physiological data to evaluate options and make decisions regarding the treatment of various medical conditions is an attractive subject for both patients and healthcare professionals. Techniques for obtaining such data in a non-invasive manner are particularly attractive in that they can minimize patient distress and eliminate infectious germ contamination. Such non-invasive techniques are especially important in situations that require frequent monitoring, such as diabetes mellitus. Diabetes mellitus is a common disease that afflicts 14 million people in the United States and several times more in developed countries. There are several different types of diabetes, all of which are common in that they are associated with metabolic dysfunction. In diabetic individuals, blood glucose levels are not regulated according to normal physiological effects. In particular, diabetic patients tend to have high blood glucose levels. This condition is called hyperglycemia and is due to insulin deficiency, decreased insulin levels, or resistance to the action of insulin. Diabetes mellitus is associated with a high degree of morbidity, including heart disease, renal disease, retinopathy, and neuropathy. The pain and loss of these complications on the patient and society is enormous. There is no cure for diabetes mellitus, but there are effective treatments. All such treatment techniques have the common goal of keeping blood glucose levels within normal physiological limits. This is most universally achieved by a combination of diet and medications such as insulin and / or internal hypoglycemic agents. The recently completed "Study on Diabetes Suppression and Complications DCCT)" has finally demonstrated that normalization of blood glucose levels, to any extent, alleviates the long-term pathology associated with diabetes. Frequent measurement of blood glucose is one of the essential factors for normalization. There is. In intensive therapy, blood glucose measurement results are used to rapidly change insulin dosages. In addition, for longer-term therapy, the measurement results should be recorded and used as a useful source of information to assist doctors in adjusting or fine-tuning the treatment plan of each patient. Traditional methods for diabetics to monitor their glucose levels themselves are divided into two methods: analyzing body fluids taken from the body and not requiring body fluids. These can be further subdivided into open and non-invasive techniques. Invasive techniques involve breaking the skin wall and usually require a sample of blood taken from the patient; while non-invasive techniques do not require breaking the skin wall. The method of measuring glucose levels in body fluids is largely based on the oxidation of glucose by oxygen in the presence of glucose oxidase. Glucose concentration is determined by correlation with the amount of a particular by-product of this reaction. The most common measurement target is the electrical energy generated by the above oxidation reaction, which is measured using electrodes. Such methods include US Pat. No. 4,392,933 to Nakamura et al., US Pat. No. 4,436,094 to Cerami, and US Pat. No. 4,431, to Bessman et al. It is the subject of No. 004. Electrical energy is measured by some kind of electronic device and displayed in terms of glucose concentration. Blood is used as a standard body fluid for glucose oxidase-based measurements of glucose levels in diabetics. The drawback of this approach is that it is invasive because it requires a patient's blood sample. Samples are usually taken from well-developed body tissue of blood vessels, such as fingertips, using a small lancet (puncture needle). This procedure is quite painful and many diabetics do not like it. In addition to physical distress, this method can also leave scars on the tips of the fingers, which is not desirable from the standpoint of preventing infections and is often a cumbersome and inconvenient alternative. Recently, several techniques for collecting body fluids non-invasively have been proposed. For example, US Pat. No. 5,139,023 describes a method for measuring glucose levels in body fluids obtained via the skin or mucous membranes. The main drawback of this method and similar ones is that the correlation of the body fluid thus obtained with the blood glucose concentration is delayed and indefinite. In addition to the above, all methods of measuring glucose levels using body fluids as samples have the common disadvantage that each sample requires a separate disposable test piece. This is necessary to prevent the transmission of infectious substances. However, these disposable devices are a major part of the current expense of blood glucose monitoring technology. As a result of such expenses, diabetics may reduce the frequency of monitoring their blood glucose levels. Motivated by the above-mentioned obstacles in the glucose level measurement method that relies on body fluids, research has been conducted on devices that measure blood glucose levels non-invasively without breaking the skin wall. Such ideas No. 023 describes a method for measuring glucose levels in body fluids obtained via the skin or mucous membranes. The main drawback of this method and similar ones is that the correlation of the body fluid thus obtained with the blood glucose concentration is delayed and indefinite. In addition to the above, all methods of measuring glucose levels using body fluids as samples have the common disadvantage that each sample requires a separate disposable test piece. This is necessary to prevent the transmission of infectious substances. However, these disposable devices are a major part of the current expense of blood glucose monitoring technology. As a result of such expenses, diabetics may reduce the frequency of monitoring their blood glucose levels. Motivated by the above-mentioned obstacles in the glucose level measurement method that relies on body fluids, research has been conducted on devices that measure blood glucose levels non-invasively without breaking the skin wall. Such ideas No. 023 describes a method for measuring glucose levels in body fluids obtained via the skin or mucous membranes. The main drawback of this method and similar ones is that the correlation of the body fluid thus obtained with the blood glucose concentration is delayed and indefinite. In addition to the above, all methods of measuring glucose levels using body fluids as samples have the common disadvantage that each sample requires a separate disposable test piece. This is necessary to prevent the transmission of infectious substances. However, these disposable devices are a major part of the current expense of blood glucose monitoring technology. As a result of such expenses, diabetics may reduce the frequency of monitoring their blood glucose levels. Motivated by the above-mentioned obstacles in the glucose level measurement method that relies on body fluids, research has been conducted on devices that measure blood glucose levels non-invasively without breaking the skin wall. Such ideas<u style="single">Example</u>Is described in U.S. Pat. No. 4,882,492 to Schlager and U.S. Pat. No. 0 282 234 A1 to Dowling. It is a method to make it. The microprocessor calculates the glucose level from the result of a series of absorption measurements. If the target body tissue has well-developed blood vessels such as fingertips and ear canals, the glucose level measurement result described above approximates the blood glucose level. The major drawback of this approach, however, is that other blood components have an absorption spectrum similar to glucose. As a result, it becomes difficult to accurately measure the blood glucose level in the actual medical environment. Further, a potential disadvantage of this method is that the optical technology used can be expensive. Another device for measuring abnormal blood glucose is Testerman, "Method of Measuring Blood Glucose Level by Sensing Evoked Action Potentials in Peripheral Nerve", Research Disclosure 227: 92 (March 1983). The device disclosed by Testerman can detect the difference in the nerve response to electrical stimulation when the blood glucose level is normal and abnormally high. Such devices, however, have the same drawbacks as in fluid-based blood glucose measurement methods: they are invasive (using a hypodermic needle to examine neural responses). Moreover, such devices are unable to correlate nerve measurements to specific blood glucose levels and can only detect differences in nerve response between normal and abnormally high blood glucose levels. ..<u style="single">Abstract of the invention</u>The present invention provides a measuring device and a measuring method for non-invasively measuring a component (that is, a blood analyzer) that can be analyzed in an individual's blood. The concentration of the target blood analysis product is measured by stimulating the body tissue with a stimulator, detecting the response to the stimulus with the detector, and correlating the detected response of the body tissue with the concentration of the analysis product with a correlator. To do. It also optionally comprises an obstruction mechanism to block the flow of blood to the stimulating and / or responsive body tissues. The analysis target to be measured may be a physiological analysis such as blood glucose level or a non-physiological analysis such as cocaine that affects internal tissues. The body tissue to be stimulated may be the same as the tissue to be detected, or may be another tissue. In one of the embodiments, the stimulator includes at least two stimulus electrodes for applying electrical stimuli to the body tissue, and the detector detects the electrical response to the electrical stimulus from the body tissue and gives an electrical response signal. Includes detection electrodes. The device also includes a control device for controlling the intensity and length of the electrical stimulus and correlating the response signal with the concentration of the user's analyte. The device may also be equipped with one or more input / output devices that assist in the interaction between the user and the monitor. For example, in one of the embodiments, the alphanumeric display gives the user the concentration of the blood analyte as a visual instruction, and the speaker gives the user the concentration of the blood analyzer as an audible instruction. It also has a keyboard that allows the user to control certain operations on the monitor. Various combinations are possible for storing the stimulator and the detector. In one example, where both the body tissue to be stimulated and detected is the median nerve, the stimulation electrode and the occlusion mechanism are a cuff suitable for sticking to the user's finger near the first site of the nerve. It is stored. The detector, on the other hand, is housed in a wristband suitable for fastening to the user's wrist near a second site of the nerve. With the present invention, an individual's blood, such as glucose levels in a diabetic patient, can be used. It enables a measuring device and a measuring method for measuring the concentration of a liquid analyte quickly and reliably. Moreover, these favorable properties are achieved in a non-invasive manner (ie, without breaking the skin wall), thereby causing physical and psychological distress to the user, the potential for transmission of infectious substances, and The inconvenience is minimized. The measuring device and measuring method described in the present application utilize the change of the analysis substance dependence within the physiological or biochemical function of the body tissue to measure the concentration of the analysis substance in humans non-invasively. For example, in one of the preferred embodiments, the measurement of a user's blood glucose level utilizes blood glucose-dependent changes in the electrophysiological function of peripheral nerves such as the median nerve. In essence, the measuring device and measuring method described in the present application use one of the peripheral nerves as a detector for glucose in the body. Therefore, this device has an advantage that it is not necessary to install an artificial detector inside the body of an individual or to collect the body fluid of the person. A further advantage of the present invention is that it does not require a disposable instrument in the process of its measurement. Therefore, the expense of each test piece can be excluded, and the resulting cost reduction has the added effect of increasing the frequency of analysis by each individual. Moreover, the advantage of the present invention is that it avoids expensive components and uses easily available analog and digital electronic devices. Further, an advantage of the present invention is that it is easy to use. This is due to the adoption of software-based controls that minimize the need for user expertise. To. For example, in one of the preferred embodiments, the measurement of a user's blood glucose level utilizes blood glucose-dependent changes in the electrophysiological function of peripheral nerves such as the median nerve. In essence, the measuring device and measuring method described in the present application use one of the peripheral nerves as a detector for glucose in the body. Therefore, this device has an advantage that it is not necessary to install an artificial detector inside the body of an individual or to collect the body fluid of the person. A further advantage of the present invention is that it does not require a disposable instrument in the process of its measurement. Therefore, the expense of each test piece can be excluded, and the resulting cost reduction has the added effect of increasing the frequency of analysis by each individual. Moreover, the advantage of the present invention is that it avoids expensive components and uses easily available analog and digital electronic devices. Further, an advantage of the present invention is that it is easy to use. This is due to the adoption of software-based controls that minimize the need for user expertise. To. For example, in one of the preferred embodiments, the measurement of a user's blood glucose level utilizes blood glucose-dependent changes in the electrophysiological function of peripheral nerves such as the median nerve. In essence, the measuring device and measuring method described in the present application use one of the peripheral nerves as a detector for glucose in the body. Therefore, this device has an advantage that it is not necessary to install an artificial detector inside the body of an individual or to collect the body fluid of the person. A further advantage of the present invention is that it does not require a disposable instrument in the process of its measurement. Therefore, the expense of each test piece can be excluded, and the resulting cost reduction has the added effect of increasing the frequency of analysis by each individual. Moreover, the advantage of the present invention is that it avoids expensive components and uses easily available analog and digital electronic devices. Further, an advantage of the present invention is that it is easy to use. This is due to the adoption of software-based controls that minimize the need for user expertise.<u style="single">[Simple explanation of drawings]</u>It is considered that a more complete understanding of the present invention itself and the above-mentioned features of the present invention can be obtained from the following detailed description of the present invention. FIG. 1 is a block diagram of a non-invasive blood analyzer measurement system according to the present invention; FIG. 2 is a diagram of one embodiment of the analyzer measurement system described in FIG. 1; FIG. 3 is a diagram of FIG. FIG. 4 is a schematic representation of an analytical object measurement system; FIG. 4 is an illustration of a cuff as an explanation for storing the stimulator and occlusion mechanism of the present invention; FIG. 5 is a plan view of a wristband as an explanation for storing the detector of the present invention. FIG. 5A is a partial cross-sectional view of the side surface of the containment described in FIG. 5; FIG. 6 is a schematic view of the detector of the present invention; FIG. 7 is a flow diagram of the blood analyzer measurement process; FIG. 8A. Is the first half of the flow chart of the blood glucose measurement process; Figure 8B is the second half of the flow chart described in Figure 8A; Figure 9 shows the waveforms of the complex activity potentials corresponding to the various stimulation levels; and Figure 10 shows the conditions. The attached complex activity potential waveform is shown.<u style="single">Description of preferred embodiments</u>First, in FIG. 1, this figure shows a blood analyzer measurement system 10 that measures the concentration of a blood analyzer by communicating with the user's body tissue 30. The analyzer measurement system 10 is provided with a stimulator 23 for applying the stimulus 28 to the body tissue 30 under the control of the controller 20. Also equipped is the detector 25, which detects the response signal 27 of the body tissue to the stimulus 28. The response signal 27 by the detected body tissue 30 is provided with an indicator that the correlation meter correlates with the analysis substance concentration of the user as described later and indicates the analysis substance concentration according to the correlation value. The blood analyzer to be measured is all blood components that can be analyzed, and may be a physiological analyzer such as blood glucose level or a non-physiological analyzer that affects body tissues such as cocaine. .. The controller 20 has the ability to execute stored instructions, generate and process analog and digital signals, perform calculations, and store data for later retrieval, eg, as shown in the present application. It can take various forms such as a microcontroller or a personal computer. The stimulus 28 may be added to the same body tissue that detects the response signal 27. However, as another method, the stimulus 28 may be added to the first body tissue, and the response signal 27 may be detected in the second body tissue that responds to the stimulus. In general, body tissue 30 is some kind of nerve, muscle or other tissue that is some sensitive tissue that produces a detectable response 27 to the applied stimulus 28 as a function of the analyte concentration. In the examples described herein, the body tissue 30 is a nerve and the blood analyzer to be monitored is glucose. A typical nerve used in this procedure is the median nerve or the ulnar nerve. It has been observed that nerve glucose concentration is in a steady-state relationship with blood glucose levels in blood vessels 31 that communicate with nerve 30. Nerve 30 has a glucose concentration in it (ie [Glu]] when it is hypoxic._nerve) Is commensurate with the electrical activity. In particular, the response of nerve 30 to an electrical stimulus 28 applied to its hypoxic site has the characteristics of nerve glucose concentration prior to the nerve becoming hypoxic. By repeatedly applying this type of stimulus and measuring the associated neural response, blood glucose levels can be estimated with a high degree of accuracy. More specifically, the usefulness of peripheral nerve 30 as an in-vivo sensor for in-vivo blood glucose and a non-invasive blood glucose measuring instrument as described in the present application is the biological properties of peripheral nerves, including: Relying on some: 1. Glucose levels in peripheral nerves are called neurogenic or nerve glucose levels and are directly related to blood glucose levels. 2. In hypoxia (ie, the supply of oxygen to body tissues is very low or absent), the electrophysiological function of nerves is proportional to nerve glucose concentration. 3. The electrophysiological function of peripheral nerves can be measured non-invasively. Using the above three characteristics, a set of non-invasive electrophysiological measurements of hypoxic peripheral nerves is converted into the individual's blood glucose level by the method described below. As mentioned above, the glucose concentration in the peripheral nerve is in a steady state with the blood glucose level. In other words, nerve glucose concentration is directly proportional to blood glucose level. Unlike most other tissues, the above relationships are insulin-independent in peripheral nerves. Furthermore, changes in blood glucose levels appear as similar changes in nerve glucose concentration. Steady state re-establishes within 10 minutes of changes in blood glucose levels. Therefore, the measured value of nerve glucose concentration is highly reliable and serves as a guideline for a relatively rapid blood glucose level. Peripheral nerves consist of tens of thousands of individual transmission fibers called axons. The peripheral nervous system (PNS) in humans and the majority of vertebrates requires large amounts of biochemical energy to maintain its normal functioning as a long-range signaling system. This energy is mainly elicited by the hydrolysis of the phosphate group of the adenosine triphosphate (ATP) molecule, which is ubiquitous in the tissue. Axons replenish their ATP through two biochemical processes: That is, oxidative phosphorylation and glycolysis. Each of these two processes becomes dominant under different conditions, producing different amounts of ATP and certain metabolic by-products. In aerobic conditions, that is, in the presence of sufficient oxygen, ATP is efficiently produced by the oxidative phosphorylation reaction through the decomposition of glucose and the decomposition of fatty acids. Under anaerobic conditions, that is, lack of sufficient oxygen, ATP is not sufficiently produced by simple decomposition of glucose. In addition, lactic acid is produced as a by-product of this process, leading to intracellular acidification of axons, resulting in a decrease in axon pH. Anaerobic conditions can be imposed externally on peripheral nerves by obstructing blood vessels to which oxygen, glucose and other nutrients are delivered. Occlusion is achieved by wrapping an obstruction mechanism 24, such as a compression band 24, around the nerves on the surface of both the upper and lower limbs, such as the user's arm or finger. The use of compression zone 24 does not harm nerve 30 or other tissues as long as the compression zone is relaxed within a reasonable amount of time (eg, 45 minutes). The occlusion mechanism 24 presses on the tissue surrounding the blood vessel 31 that supplies oxygen and nutrients to the nerve 30, and can take various forms such as a pneumatic cuff shown in FIGS. 2 and 4 and described below. .. The occlusion mechanism 24 is controlled by a controller 20 that determines the timing and length of blocking blood flow according to a predetermined process. Glycolysis is strictly dependent on neural glucose concentration. Therefore, the ability of axons to maintain ATP levels and prevent intracellular acidification under hypoxic conditions depends on neural glucose levels. During such hypoxia, axons do not obtain (or very little) additional glucose, so the efficiency of glycolysis during this period is comparable to the nerve glucose concentration prior to hypoxia. Dependent. Moreover, the electrophysiological properties of each axon change with decreasing ATP and pH, resulting in the electrophysiological properties of the nerve as a whole being affected in a parallel manner. Axons are impulse-conducting tissues, in which impulses represent the major signal units. According to the present invention, the impul An electrochemical event called action potential involving all-or-none conduction is artificially initiated by electrical stimulation with stimulation 28. Therefore, in the embodiment, the stimulus 28 is an electric pulse stimulus applied by the electrodes 77 and 78 (Fig. 4). Peripheral nerves 30, or more generally, other forms of stimuli 28 for stimulating any sensitive body tissue include magnetic stimuli, optical stimuli, and other forms of electromagnetic energy stimuli ( For example high frequency), sensory stimuli (eg vibration, temperature, or pressure), use of inorganic or organic chemicals (eg sodium, neurotransmitters, anesthetics), or use of biological substances (eg protein, nucleic acid DNA / RNA). In an embodiment, the stimulator 23 comprises at least two stimulating electrodes 77, 78 (FIG. 4) that are in physical contact with the skin surface 32 that directly covers the nerve 30 and a current generator. Current flows between at least two relatively close electrodes. The electrical pulse stimulus 28 may be a current pulse as in the embodiment or a voltage pulse, and is controlled by a controller 20 that determines the length and magnitude of the stimulus 28 according to a predetermined process as described below. Most of the current of the stimulus 28 passes directly between the stimulus electrodes 77 and 78 without entering the subcutaneous nerve 30, but a part of the current enters the nerve and stimulates the axon fibers that compose it. The number of fibers stimulated depends on the magnitude of the current as well as certain geometric and biophysical properties of the fibers. In general, the relationship between the stimulating current and the activated axon is an S-shaped function. Each of the stimulated axons generates an action potential almost simultaneously and propagates it in both directions from the stimulation point. The detector 25 receives a converging response signal 27 called a composite action potential (CAP) from all stimulated axons and can take various forms. For this purpose, the detector 25 includes one or more detection electrodes that are in physical contact with the skin surface 32 that directly covers the nerve 30, such as the two detection electrodes 85 in FIG. The detector 25 is located at the site where the stimulus is applied, or Instead, it may be placed at a site slightly away from the stimulation point. For example, if both the stimulated body tissue and the detected body tissue 30 are taken from the median nerve, the stimulator 23 is adjacent to the first part of the tissue and detected on the user's finger, as shown in FIG. The vessel 25 may be placed on the user's wrist adjacent to a second site of tissue. The amplitude of the complex action potential is a measure of the number of stimulated axons. As mentioned above, the electrophysical properties of axons change with decreasing ATP concentration and pH. The most important effect is the increase in current required to stimulate one of the axons. Therefore, changes in ATP and pH will be reflected in the amplitude and other parameters of the combined action potential. Since such changes are dependent on nerve glucose under hypoxic conditions, the combined action potential acts as a transmitter of nerve glucose concentration. The detector 25 further includes an electronic circuit that amplifies and processes the response signal 27 (FIG. 6), and is connected to the controller 20 that determines the response signal 27 by correlating it with the concentration of the analyte. For example, in the case of the blood glucose monitor system 10, the controller 20 correlates certain features of the detected response signal 27 with the blood glucose level as described below on the basis of a predetermined function. After the response signal is converted by the controller 20 into a display of the concentration of the analyte, this information is given, for example, in an alphanumeric display that gives the user the concentration of the blood analyte as a visual indication, or as an audible indication of the same concentration. Provided to the user by a user output device 22 such as a speaker. At the same time, one or more user input devices 21 connected to the controller 20 are provided to provide a means for the user to interact with the monitor 10. The illustrated input device is a keyboard 37 (Fig. 2). Next, referring to FIG. 2, the figure shows one of the embodiments of the Analytical Instrument Measuring Device or Monitor 10 utilizing the optional occlusion mechanism 24, which includes the body unit 35, cuff 40, and wristband. It shows that 41 is attached. Cuff 40 is the stimulator's electrodes 77, 78 (Fig. 4) and pressure The sensor band 24 is stored, and the wristband 41 stores the detector 25. It will be appreciated by those skilled in the art that there may be a variety of different physical combinations of the stimulator 23, the occlusion mechanism 24 and the detector 25. An essential restriction in any embodiment is that the stimulator electrodes 77, 78 (FIG. 4), compression band 24 and detector electrode 85 (FIG. 5) interact with the body tissue of interest. Contacting the user at an anatomical site (including multiple) suitable for action. For example, as an alternative, the stimulator electrodes 77, 78, compression band 24 and detector electrode 85 may be stored in rigid gloves that are contoured to the user's hand. In this method, the above components are arranged in the same anatomical relationship as shown in FIG. Another arrangement used for the monitoring system 10 is to store the stimulator electrodes 77 and 78, the compression band 24 and the detector electrode 85 all in a cuff like the cuff 40 in FIG. In this case, the detection will be performed in the immediate vicinity of the stimulation site. Note that, for example, in an alternative embodiment of a mechanism in which the first body tissue is stimulated and the response to the stimulus is detected in the second body tissue, the stimulator electrodes 77, 78 and the compression band are related to the user. Many other arrangements are possible in arranging 24 and the detector electrode 85, all within the spirit of the present invention. The main unit 35 includes a user input device 21 (Fig. 1), a user output device 22 (Fig. 1), and additional functions that operate as input and / or output devices, all of which are collectively referred to as a user interface device. To do. One such input device is the keyboard 37, which includes a plurality of operating mechanisms that the user can operate, which allows the user to send commands and messages to the main unit 35. The user can operate the alphanumeric key 48, for example, the MEASURE command key that executes calibration and measurement procedures, and the pre-stored measurement value is transmitted to a remote location via a modem. SEND instruction key, as well as analysis It comes with an instruction key 49 for entering certain system instructions, such as the HALT instruction key that ends the object measurement process, which are further detailed in relation to Figures 7, 8A and 8B below. explain. The keyboard 37 may be embossed with Braille to assist the visually impaired. One method of the user output device 22 (FIG. 1) is an alphanumeric liquid crystal display device 36 that displays the concentration of the analyte and other messages for the user. Another output device 22 is the speaker 47, which provides useful auditory feedback to individuals using the monitor 10, especially the visually impaired. Other additional user interface devices extend the functionality of the Analytical Concentration Monitor 10. Specifically, the serial interface port 44 enables communication with a personal computer. The memory interface 45 for the non-volatile memory cartridge improves the data storage and software processing capabilities of the device. Data can be transmitted over a telephone line using the telephone jack 46, which automatically records the measured values of the analyzed material using a computer in a remote location and conveys the measured values of the analyzed material to a doctor at a remote location. Becomes possible. The main unit 35 is housed in a box-shaped cover 42. Two flexible connectors 38 and 39 connect the body unit 35 to the cuff 40 and wristband 41, respectively. The cable 38 connecting the cuff 40 to the main body unit 35 is composed of a flexible and airtight rubber tube through which the compression band 24 expands and contracts due to indoor air. Connector cable 38 also comes with four insulated wires attached to the tube. These wires pass the stimulating current to the stimulator electrodes 77 and 78 (Fig. 4) located in the cuff 40, and transmit the temperature signal from the temperature sensor 79 (Fig. 4) also located in the cuff 40. It is a thing. The cable 39 that connects the detector 25 to the main unit 35 consists of a group of insulated wires. These wires are the response signal 27 measured by the detector 25. Is also a means of supplying power to the electronic circuit of the detector 25 in the wristband 41 (Fig. 6). Next, referring to FIG. 3, a schematic diagram of the main unit 35 is shown here. In the embodiments described herein, the controller 20 is a single-chip microprocessor, such as Motorola's M68HC16. Other single-chip or multi-chip microcontrollers may be used instead. It is desirable that the microcontroller 20 be provided with a random access memory, a read-only memory, a plurality of analog-to-digital converters, and a plurality of input / output wirings. The microcontroller 20 operates according to a software program stored in a read-only memory. The program runs the process of analyzer concentration measurement, controls the user interface device, and performs diagnostic tests. The functions that the microcontroller 20 is in charge of may be expanded by using a retrofit non-volatile memory cartridge that is used by inserting it into the interface cartridge slot 45 of the main unit 35. The microcontroller 20 connects to a user interface device that includes an alphanumeric display device 36, a keyboard 37, and a speaker 47. More specifically, the alphanumeric display device 36 is coupled to and controlled by a group of digital output signals 50 on the microcontroller 20. The display content of the display device 36 is determined by the controller 20 that adjusts the state of the digital output signal 50 in the microcontroller 20. Examples of displayed messages include blood glucose levels and measurement status. The keyboard 37 provides a group of digital input signals 57 to the microcontroller 20. The logic levels of these signals 57 correspond to the specific keys pressed on the keyboard 37. The controller 20 determines which key is pressed by monitoring the proper digital input signal 57. One of the output signals of the microcontroller 20 is the input of the amplifier 61, which This drives the speaker 47. The controller 20 vibrates the logic level of the output pin between predetermined high and low frequencies to generate sound of an arbitrary frequency. The main body unit 35 serves as a means for controlling the air pressure in the compression band 24. In a preferred embodiment of the body unit 35, the air pump 65 pumps room air entering through the air inlet 66 to increase the pressure in the tube 67 communicating with the compression zone 24. Power to the air pump 65 is controlled by a solid state relay 58 where a single digital output line on the microcontroller 20 gives the start signal. At the same time, the pressure transducer 68 detects the pressure in the inflated tube 67. This pressure is equal to the pressure in the compression zone 24, that is, the pressure on the user's finger. The converter 68 generates an analog signal proportional to this pressure. The signal is amplified by the DC amplifier 60 and converted into a digital signal by the analog-to-digital converter on the microcontroller 20. The controller 20 analyzes this digital signal. The air switch 69 is controlled by a solid state relay 59 that receives a start signal from a single digital output line on the microcontroller 20. When the air switch 69 is opened, the pressure in the connecting tube 67, that is, in the compression zone 24, passes through the switch 69 and is rapidly released from the air outlet 70 to the outside. The controller 20 adjusts the pressure in the compression zone 24 by moving the air pump 65 until the pressure in the compression zone 24 detected by the transducer 68 exceeds a predetermined set value. When the measurement time ends or the operator presses the [HALT] command key (Fig. 2), the controller 20 activates an output signal that selectively connects or cuts off the power to the air switch 69. Release the pressure of the compression band 24. The main unit 35 processes the DC analog signal emitted by the temperature sensor 79 (Fig. 4) in the cuff 40. This temperature signal is amplified by the DC amplifier 54 and then digitized by the analog-to-digital converter on the microcontroller 20. this The controller 20 analyzes the digital signal. The stimulus generator 56 is a precise, load-independent, low-current signal 28 that flows through the stimulator electrodes 77, 78 (FIG. 4) located within the cuff 40 to electrically stimulate the body tissue 30. (Fig. 1) is generated. This stimulus generator 56 delivers 0 to 10 mA current pulses. It has the ability to generate in a cycle of 1 to 1000 milliseconds. The amplitude of the same current pulse is, for example, Maxim. A digital-to-analog converter 55 such as the MX7520 controls with an analog signal generated in response to a digital signal from the microcontroller 20. The controller 20 adjusts the pulse duration and pulse amplitude of the stimulus 28 by setting the logic state of these output signals. The stimulus generator 56 uses an insulating amplifier (not shown) to separate its output stage from the power supply of the main unit 35. It will be appreciated here that the stimulus generator 56 may have many different embodiments to achieve the above functions. For example, a 3-terminal adjustable regulator such as the Texas Instruments TL783C can be used as an adjustable current source to stimulate it. The main unit 35 receives the response signal from the detector 25 via the connector 39. An insulation amplifier 53, such as Burr-Brown's ISO100 optical coupling linear insulation amplifier, provides a high pressure buffer between the body unit 35 and the detector 25 in direct contact with the user's skin. The bandpass filter 52, whose passband is approximately 20 to 20 kHz, excludes the frequency components of the response signal 27, which is outside the frequency range where signals from peripheral nerves are most easily detected. A programmable gain amplifier 51 whose gain can be programmed between approximately 10 and 500 is the final stage of software-controlled amplification prior to digitization by the analog-to-digital converter in the microcontroller 20. The gain of the amplifier 51 is determined by the logic level of the output signal of the microcontroller 20. The gain is adjusted by the controller 20 so that the amplitude of the response signal 27 to be measured is maintained in the optimum digitization range (for example, ± 5 volts) in the analog-to-digital converter of the microcontroller. Next, referring to FIG. 4, here, an example of implementation of the cuff 40 (FIG. 2) for accommodating the compression band 24 and the stimulator electrodes 77 and 78 is shown in relation to the user's finger 80. The compression band 24 is a thin and hard tubular plus Containing in a tic cover 75, it contains a stretched donut-shaped sac 76 made of airtight rubber that is extensible and can maintain pressures up to 400 millimercury. The outer surface of the sac 76 is glued to the inner surface of the cover 75. The stimulator electrodes 77 and 78 and the temperature sensor 79 are on the inner surface of the sac 76. In the embodiments described, the stimulator electrodes 77 and 78 are thin disks made of a corrosion resistant conductive material such as platinum, iridium, or other metal or alloy. The size and shape of the stimulator electrodes 77 and 78 can vary depending on the dimensions of the user's finger 80 (eg, differences between adults and children). Usually the stimulator electrodes 77 and 78 have a diameter of approximately 1 cm. A single insulated wire runs through the capsule 76 and connects to the stimulator electrodes 77 and 78. This wire reaches the main unit 35 via the connector 38, where it hits the stimulus generator 56. The temperature sensor 79 may be any device that generates a temperature-dependent analog signal, such as the AD590 solid-state temperature sensor from Analog Devices. Two wires are connected to the temperature sensor 79 to the connector 38, and the latter to the main unit 35. The bladder 76 rapidly expands with the room air sent through the connector 38 from the air inlet 66 located in the body unit 35 (FIG. 3). Since the cuff 40 is housed in a rigid material 75, the sac 76 expands inward, resulting in pressure on the user's finger 80. Such inward swelling of the sac causes two consequences. First, the pressure inside the finger 80 increases with the degree of compression. When the pressure in the sac is high enough, the pressure of the tissue in the finger 80 exceeds the systolic pressure, resulting in temporary arterial blood flow to the compressed part of the finger 80 and its distal (ie, towards the fingertips). Block the target. The stimulator electrodes 77 and 78 and the temperature sensor 79 are then located inside the sac 76, ensuring that the sac swelling ensures that these elements are firmly attached to the user's finger 80. However, the sac 76 is suitable for electrodes 77 and 78 and the skin. It is not necessary to inflate to its maximum pressure to force a good contact. It is important that the stimulator electrodes 77 and 78 are in close contact with the finger 80 because it reduces the impedance involved in the electrode's contact with the skin, resulting in stimulation of the underlying nerve 43 (Figure 2). This is because it lowers the voltage that must be established in the meantime. In addition, this arrangement is caused by the movement of the finger 80 during the measurement of the interdermal impedance of the electrodes and serves to minimize variations that could result in poor quality of analytical material measurements without countermeasures. The stimulator electrode 78 is a cathode 78 and serves as an active electrode, while the stimulator electrode 77 is an anode 77 and serves as a reference electrode. The reason for placing the cathode 78 proximally as shown in FIG. 4 is that optimal nerve stimulation and recording is obtained when the active electrode is closest to the recording electrode. In this device, the recording electrode 85 is located inside the detector 25 placed on the wrist. When the current generated by the stimulus generator 56 passes between the cathode 78 and the anode 77, a portion of it passes through the nerve 43, stimulating the nerve 43 beneath the electrodes 77 and 78. Next, referring to FIGS. 5 and 5A, here is a sketch showing a different perspective of the wristband 41. Specifically, FIG. 5 is a plan view of the wristband 41, FIG. 5A is a side view, and the detector 25 housed therein is thin, giving the wristband the appearance of a wristwatch. Is illustrated. The wristband 41 consists of a plastic cover 86 and a band 88. The cover 86 serves as a support structure for the detector electrode 85 and the detection circuit 92. The detector electrode 85 is a strip of metal with a high degree of conductivity and corrosion resistance, such as platinum, iridium, or other metals or alloys. The exact dimensions of the detector electrode 85 depend on the physical dimensions of the user (eg, adult vs. child, or male vs. female). Each of the detector electrodes 85 is connected to the detection circuit 92 mounted on the circuit board in the wristband 41 with one electric wire 91. This wire 91 is short, with a length of a few millimeters or less. Therefore, before buffering the response signal 27 described below, insulation is provided to minimize noise collection. The band 88 is for ensuring that the detector electrode 85 is in close contact with the skin of the user's wrist. Both ends of obi 88 are short velcro^TMOne piece 87 is attached, making it easy to put on and take off the same parts. A strip of conductive material 89 (eg platinum or iridium) is placed at one end of the component, which serves as a reference electrode. Wrap obi 88 around your wrist and velcro^TMWhen the piece 87 is tightened, the reference electrode 89 contacts the skin on the back of the wrist, which is far enough away from nerve 43 (Fig. 2) to function as a reference. The response signal output of the detector 25 is a buffered and amplified analog signal, which represents an actual neural signal and is sent to the main unit 35 via the connector 39. The connector cable 39 also transmits a power signal that powers the detection circuit 92. Next, referring to FIG. 6, a schematic diagram of the detector 25 is shown here including the detection circuit 92 and the detector electrode 85. The detection circuit 92 serves as a means for buffering high-impedance electrode-skin contact and pre-amplifying the response signal 27. The impedance of the skin / electrode contacts is generally quite high. In many situations (eg, electromyography, etc.), a conductive gel is placed between the skin and the detection electrodes to reduce this impedance. However, the instruments described in the present invention do not require such gels. In this embodiment, the fear of impedance problem is overcome by buffering the response signal 27 detected by the detector electrode 85 at a distance from the actual detection site. Since the signal detected from the sensory nerve is usually in the unit of microvolts and is generally quite weak, the response signal 27 is pre-amplified before being transferred to the main unit 35 in order to prevent a decrease in the signal-to-noise ratio. It is advantageous to keep it. More specifically, the detection circuit 92 is attached with an instrument amplifier 95 that generates an output signal proportional to the difference in potential between the two detector electrodes 85. The detector electrode 85 is connected to the measuring instrument amplifier 95 by a short insulated wire 91. Since the response signal 27 is in microvolt units and the impedance of the electrode / skin contact is very high, it is advantageous to use an amplifier for measuring instruments with FET input, such as INA111 by Burr-Brown's monolithic IC. Very high input impedance (10) for the same type¹²It has a low bias current (less than 20 picoamps), and a common mode blocking ratio of approximately 115 decibels. For example, an amplifier with a gain of approximately 1000 amplifies the microvolt-level response signal 27 detected by the electrode 85 to a millivolt stand, thereby reducing sensitivity to various forms of noise. The output of the measuring instrument amplifier 95 is filtered by a high-pass filter 96 to remove the DC component. The common mode reference 97 to the detector 25 is obtained by buffering the signal at the reference electrode 89 via the virtual ground circuit 98. The output of the detector 25 is the processed response signal 99, which is transferred to the main unit 35, where it is isolated by the insulation amplifier 53 (FIG. 3). The power to the detector 25 is supplied from the insulated power supply located in the main unit 35. For the above reasons, the detector 25 is electrically separated from the external power supply to the main unit 35.<u style="single">Action of invention</u>Here, the multi-step operation of the monitor 10 will be described with reference to FIG. 7. The operation of the monitor 10 is initiated in step 100 by placing the instrument at the appropriate anatomical site (s) of the user. In the embodiment described in FIG. 2, where the median nerve 43 acts as a glucose sensor in the body, the middle finger (third finger) or index finger (second finger) in the cuff 40, as shown in FIGS. 2 and 4. Put in. The signal-to-noise ratio is maximized by adhering to the following two positioning principles. First, position the cuff 40 as close to the base of the finger as possible, not the tip of the finger. Second, the ventral surface of the finger should be in contact with the stimulator electrodes 77 and 78 as shown in FIG. Two velcro wristbands 41^TMAttach the piece 87 to either end of the band 88 and secure it to your wrist. In one of the preferred embodiments, the wristband 41 is placed in the midline of the wrist, thereby maximizing the response signal 27 detected. As an alternative, the cuff 40 can be attached to the 4th or 5th finger, and the wristband 41 can be placed in the inner position (ulnar nerve) to measure the blood glucose level using the ulnar nerve. Other peripheral nerves, such as the peripheral nerves of the lower limbs, may also be used when the use of the upper limbs is inappropriate or impossible. Now turn on the monitor 10. The user starts the operation of the monitor 10 by the procedure 100 of activating an appropriate key such as the [MEASURE] command key on the keyboard 37 on the main unit 35 (FIG. 2), for example. Monitor 10 must be calibrated prior to each use. This operation is performed when the user activates the [MEASURE] command key and starts measuring the analyte. The above calibration operation is performed in step 104, but the purpose of the calibration is to determine the optimal stimulation level. For example, in an example of a blood glucose monitor, calibration procedure 104 stimulates a nerve several times with stimuli of various different amplitudes and, depending on the detected nerve signal, is described below in the context of FIGS. 8A, 8B and 9. It involves determining the amplitude of the stimulus that can evoke such a maximum neural signal response. If the calibration process in step 104 is unsuccessful, for example if the signal-to-noise ratio associated with the response signal 27 is too low to determine the optimal stimulus amplitude, the user is notified of the situation in step 108. Such errors can occur when attempting to detect a response signal from a seriously ill nerve. The calibration operating procedure 104 is then repeated by a command activated by the user (ie, activation of the [MEASURE] instruction key by the user), or instead the monitoring operation is terminated (ie, the [HALT] instruction by the user). Key activation). Upon successful calibration, the body tissue that blocks and stimulates blood flow to that tissue and / or the body that detects it Optional step 112 to hypoxia the tissue may be performed. In the blood glucose monitoring embodiment described, this procedure involves inflating the compression zone 24 within the cuff 40. The expansion of the compression band 24 is executed by the controller 20 (FIG. 3) operating the relay 58 as described above. Repeatedly, in response to the operation of the relay 58, the air in the room is sent to the tube 67 which is in contact with the compression zone 24, which inflates the compression zone and blocks the blood flow to the nerve 43, and at the same time, the stimulator electrode 77 and Make sure 78 (Figure 4) is in close contact with the user's fingers. Step 116 initializes the timer associated with controller 20 (Figure 1). This timer determines the timing of the various stages of the analytical object measurement task in subsequent step 120. For example, this timer determines how long the body tissue to be stimulated is kept in a hypoxic state, the time during which the body tissue is stimulated, the timing to detect the response of the body tissue to the given stimulus, and the like. .. After that, the analysis product is measured in the processing procedure 120. More specifically, step 120 applies a stimulus with the characteristics determined by the calibration operation to the body tissue for a predetermined duration, detects the response to the stimulus, or another body tissue, and further stimulates the body tissue. It includes a multi-step substep in which the detection steps are repeated at a predetermined repetition rate for a predetermined duration. Further, the detected response signals or parameters representing those signals are stored for later use by the monitor. In step 124, the obstruction mechanism is opened, thereby resuming blood flow to the stimulated and / or responding body tissues. After opening the blockage mechanism, monitor 10 converts the response signal detected in step 128 into the analyte concentration. This procedure involves various substeps, such as normalizing the vector, including the extraction parameters of the detected response signal, and multiplying the normalized vector by the vector correlation coefficient, which will be discussed later in the figure. In the process of converting the neural response signal to glucose concentration, as described in 8A and Figure 8B. Further details will be described in relation to this. Finally, the analysis product concentration obtained as described above is displayed to the user in step 132. This display can be achieved using, for example, an alphanumeric display such as the display device 36 shown in FIG. 2, or a speaker 47 for auditory instruction of the measurement analyzer. Further, the display provided in step 132 may be a remote display, for example, a display for a remote doctor via a modem and a telephone jack 46 (FIG. 2). Alternatively, the display according to step 132 can be provided to either the user or the physician at some point after the measurement process of the monitor 10 is completed, for example, the storage device attached to the main unit 35, or the storage device after the measurement. It may be a delay display of the kind that can be realized by storing it in the storage device of a personal computer in a communication state with the main unit 35 via the serial port shown in FIG. The operation of the analyzer monitor 10 is terminated in step 136 as shown. With respect to FIGS. 8A and 8B, explanatory flow charts regarding the operation of the blood glucose level monitor 10 described above are shown here. The sequence of processes begins with the cuff 40 and wristband 41 (attaching Figure 2) to the user's appropriate anatomical site in step 150 as described above, then in step 151, keyboard 37 (Figure 2). Goes under the supervision of controller 20. Step 161 determines whether a [HALT] command has been received. At any time while operating monitor 10, the monitor can be activated by activating the [HALT] command key on keyboard 37 (Fig. 2). The work is interrupted and the operation is completed by proceeding to step 200 (Fig. 8B). In step 157, it is determined whether or not the [SEND] command has been received. The [SEND] command key is activated at any time during the operation of the monitor 10. Then, the measured values stored up to that point are transmitted to a remote location via the telephone jack 46 and the modem. In step 152, in response to the operation of the [MEASURE] command key on the keyboard 37 shown in FIG. , Determines if the [MEASURE] command has been received. If the [MEASURE] command has been received After confirming that, the monitor 10 measures the temperature of the finger in step 153. If the temperature is not within acceptable limits (eg, the difference from room temperature is within a few degrees), the user is notified in step 154 and the keyboard 37 is monitored in preparation for the user's operation in step 151. If the temperature is confirmed to be within the permissible limit in step 153, the monitor 10 performs the calibration work in steps 155 to 166. In particular, in step 155, a nerve such as the median nerve 43 in FIG. 2 is stimulated with the stimulus 28 (FIG. 1), the response signal 27 of the median nerve 43 to the applied stimulus is detected, and the response signal 27 is digitized. And save. More specifically, as described above, the stimulus generator 56 (FIG. 3) generates the stimulus signal 28 in response to the digital signal from the controller 20. The stimulus 28 is transmitted to the stimulator electrodes 77 and 78 (Fig. 4) via the connector 38. An example of a stimulus signal is a pulsed current waveform with a duration of approximately 200 microseconds. The amplitude of the stimulus signal is set to a predetermined value, for example, 3 mA. The response signal 27 generated by the median nerve 43 in response to the added stimulus signal 28 is detected by the detector electrodes 85 (FIGS. 5 and 5A), and this is called a combined action potential (CAP). Figure 9 shows 3. It is explanatory drawing of CAP 210 detected by the stimulus signal 212 of 3mA. The detected CAP 210 is digitized by microcontroller 20 (Figure 3) and stored in a dedicated area of random access memory. In processing step 156, the detected CAP Determine if 210 has a signal-to-noise ratio above a predetermined level. As mentioned above, under certain circumstances (eg, diseased nerves) the evoked CAP has a poor signal-to-noise ratio. If the signal-to-noise ratio of the CAP is below a predetermined reference, the nerve is repeatedly stimulated in step 158. More specifically, in procedure 158, the nerve is applied with the same stimulus at a rate of approximately 2-4 times per second over a predetermined time. The CAP responses detected by this repetitive stimulus are averaged into one average CAP, digitized as described in the context of step 162 below, from which parameters are extracted and stored. If the detected CAP signal-to-noise ratio does not exceed a predetermined reference even after processing step 158, an error occurs in step 163 due to some available output device, such as an alphanumeric display device 36. The message is presented to the operator. The keyboard 37 is then monitored in preparation for the operation in step 151 of the user. For example, the user may press the [MEASURE] command key again to retry the calibration operation. If the signal-to-noise ratio of the CAP detected in step 156 is determined to be acceptable (ie, whether it was acceptable from the beginning or improved in step 158), then processing step 162 is performed, at this stage the micro. The controller 20 extracts a predetermined signal parameter from the digitized CAP waveform and stores it. Typical waveform parameters to be extracted and saved are the peak peak value of the CAP (that is, the difference between the maximum and minimum points of the amplitude), the total area under the CAP, the width of the CAP, and the incubation period of the CAP (that is, the nerve). The interval from the application of the stimulus signal to the appearance of the CAP). The extracted parameters are stored in the storage device attached to the microcontroller 20. Next, processing procedure 164 is executed, in which it is determined whether or not the nerve to be stimulated has been subjected to a predetermined number of stimuli of different amplitudes. It turns out that the nerve is not receiving the prescribed stimulus If so, the processing procedure 155 is repeated with different amplitudes. Figure 9 shows the CAP 218 thus aroused. In the illustrated blood glucose measurement process, the predetermined number of stimuli applied to the nerve during the calibration operation is 3, and the amplitudes are 3.3, 3.8, and 5 mA, respectively. That is, in this example, step 164 revealed that the nerve had not yet received the above three stimuli, and as a result step 155 was repeated with a stimulus 216 with an amplitude of 3.8 mA, digitizing the resulting CAP 218. Save that parameter. After performing step 164 a second time, the third process step 155 is repeated, at which point a stimulus 222 with an amplitude of 5mA is applied to the nerve, and the detected CAP 224 is digitized and stored by the microcontroller 20. To do. Nerve stimulation by the stimulation signals 212, 216, and 222 with these three increasing amplitudes (ie, repeating step 155) should be performed approximately every 5 to 10 seconds. Once the nerve has applied a predetermined number of stimuli of different amplitudes, finished processing the CAPs evoked by it, and saved the parameters, then process step 166 is performed, where the optimum stimulus amplitude is determined. More specifically, determine the magnitude of the electrical stimulus signal that causes a CAP of approximately 50% of the maximum CAP that can be evoked. I use this stimulus signal Repeated with a stimulus 216 with an amplitude of 8mA, the resulting CAP 218 is digitized and its parameters stored. After performing step 164 a second time, the third process step 155 is repeated, at which point a stimulus 222 with an amplitude of 5mA is applied to the nerve, and the detected CAP 224 is digitized and stored by the microcontroller 20. To do. Nerve stimulation by the stimulation signals 212, 216, and 222 with these three increasing amplitudes (ie, repeating step 155) should be performed approximately every 5 to 10 seconds. Once the nerve has applied a predetermined number of stimuli of different amplitudes, finished processing the CAPs evoked by it, and saved the parameters, then process step 166 is performed, where the optimum stimulus amplitude is determined. More specifically, determine the magnitude of the electrical stimulus signal that causes a CAP of approximately 50% of the maximum CAP that can be evoked. I use this stimulus signal Repeated with a stimulus 216 with an amplitude of 8mA, the resulting CAP 218 is digitized and its parameters stored. After performing step 164 a second time, the third process step 155 is repeated, at which point a stimulus 222 with an amplitude of 5mA is applied to the nerve, and the detected CAP 224 is digitized and stored by the microcontroller 20. To do. Nerve stimulation by the stimulation signals 212, 216, and 222 with these three increasing amplitudes (ie, repeating step 155) should be performed approximately every 5 to 10 seconds. Once the nerve has applied a predetermined number of stimuli of different amplitudes, finished processing the CAPs evoked by it, and saved the parameters, then process step 166 is performed, where the optimum stimulus amplitude is determined. More specifically, determine the magnitude of the electrical stimulus signal that causes a CAP of approximately 50% of the maximum CAP that can be evoked. I use this stimulus signal_50%It is called a stimulus signal and is used as a standard stimulus when measuring the concentration of the analyte. It is possible to use the other part of the maximum evoked CAP as the optimal stimulation amplitude, but relatively small changes in the electrophysiological properties of the peripheral nerves are I_50%Since it appears as a big change in the CAP evoked by the stimulus signal, 50% was adopted. The above maximum evoked CAP is required as a point where the peak peak value does not increase even if the magnitude of the stimulus is increased. This value is less than the maximum stimulus, eg, stimulus signals 212, 216, and 222 with amplitudes of 3.3, 3.8, and 5 mA, respectively, without the actual maximal stimulus (which can be unpleasant for the user). It can be estimated by extrapolating the peak value of CAP from. Once the maximum CAP peak peak value is found, its 50% amplitude and associated stimulus (ie I)_50%Stimulation) is easily determined by interpolating the measured values. Then processing step 170 is performed, where I_50%The stimulus signal is repeatedly applied to the nerve using the stimulator electrodes 77 and 78 (Fig. 4) for a predetermined time at a rate of about 2 to 4 times per second, and the CAP response signal is detected by the detector electrode 85 (Fig. 5 and 5A). By doing I_50%Measure the peak value of CAP evoked by the stimulus. In step 170, the CAP response signal thus obtained is also digitized and averaged. Finally, as described above in relation to the processing procedure 162, the parameters of the average waveform are extracted and saved for later use in the normalized measurement. More specifically, the magnitude of the response signal after that is expressed as a partial ratio of the response detected in step 170. Once I_50%Once the stimulus signal and response have been confirmed and stored in steps 166 and 170, respectively, the calibration process is complete and monitor 10 proceeds to the user's blood glucose measurement phase. Therefore, step 172 is then performed, in which nerve 43 (FIG. 2) is hypoxicized by the rapid expansion of compression zone 24. The pressure in the compression zone required to block blood flow is predetermined according to a published method that associates this pressure with the width of the compression zone 24, the diameter of the user's fingers, and the systolic pressure of the user. The above published method is described in the article listed below and is incorporated herein by reference: a) "The digital tourniquet:" How safe is it? "By JDLuban, J.Koeneman, and K.Kosar, Journal of Hand Surgery, 5: 664-669 (1984) b)" New finger cuffs for use with digital tourniquets "by JAMcEwen, PTGropper, and RWMcGraw, Journal of Hand Surgery, 6: 888-892 (1988) When the compression zone 24 reaches a predetermined pressure setting point, the timer of the microcontroller is initialized in step 174. Subsequent measurements of electrical stimulation and nerve signals Temporarily plan according to this timer. During the minutes when the compression zone 24 is inflated and the nerves are hypoxic, a series of electrophysiological measurements of neural function are obtained by steps 176-184. Prior to the measurement of, a waiting time of 60 seconds is set in step 175 to activate the hypoxic state. In step 176, I_50%During hypoxia, the stimulus signal is applied to the nerve using stimulator electrodes 77, 78 (Fig. 4) and the CAP response signal is detected by detector electrode 85 (Fig. 5 and 5A)._50%Measure the peak value of the CAP evoked by the signal. Step 176 also digitizes the CAP response signal thus obtained. If the signal-to-noise ratio of the CAP thus obtained is low, the nerve is applied with the same stimulus at a rate of approximately 2 to 4 times per second over a predetermined time. The CAP reactions detected by this repetitive stimulus are averaged into one average CAP and digitized. Finally, the parameters are extracted and stored from the above single or average CAP as described above in relation to the processing procedure 162. In the subsequent step 178, a waiting period of 60 seconds is first set, and then the conditional CAP (that is, the ratio of the unconditional CAP to the conditional CAP amplitude) is obtained in step 180. If explained according to FIG. 10, this ratio is I, as shown in the figure._50%Stimulation 202 is applied to the nerve, followed by about 500 ms after I_50%Add a conditioning stimulus 204, which is approximately 1.5 to 5 times larger than the stimulus, and yet another I_50%Obtained by adding stimulus 206 approximately 5 ms after conditioned stimulus 204. First I_50%Let 208 be the label for CAP originating from stimulus 202 and 209 be the label for CAP originating from stimuli 204 and 206. If the signal-to-noise ratio of either the conditional or unconditional CAP is low, the sequence of the three stimuli is repeated for a predetermined time at a rate of approximately once per second. These repetitive stimuli are aroused and the detected conditional and unconditional CAP responses are averaged and referred to as the average unconditional CAP and the average conditional CAP. A single or average unconditional CAP208's peak peak value marker a₁And, the peak value of the conditional CAP209 alone or on average is labeled as a.₂And. Therefore, the ratio of the unconditional CAP to the conditional CAP, which is the subject of the decision in step 180, is a₁/ a₂Given in. This ratio is saved in step 180. In the preferred process for determining blood glucose levels, measurements from steps 176 to 180 are taken alternately every 60 seconds for 4 minutes. Therefore, after finding the ratio of the unconditional CAP to the conditional CAP in step 180, a waiting time of 60 seconds is set in step 182. Then, in step 184, it is determined whether or not 4 minutes have passed since the timer was activated in step 174. If 4 minutes have passed, the CAP measurement is complete and then the results are processed by steps 186-190 to correlate with the user's blood glucose level. Instead, if 4 minutes have not yet passed, repeat steps 176-182. Here, the measurement process described in the present application includes, for example, changing the measurement interval (that is, for example, every 45 seconds or 90 seconds for the illustrated 60-second interval), and changing the measurement time (that is, exemplifying). For example, 2 minutes or 5 minutes, or change the type of measurement (ie, I)_50%It will be appreciated by those skilled in the art that changes can be easily made by means of stimulus signals and / or procedures other than the conditional CAP process). Therefore, changes to the illustrated procedure are expected and within the scope of the present invention. If it is determined that 4 minutes have passed in step 184, which indicates that the measurement has been completed, the compression band 24 is rapidly contracted in step 185. This is performed by the microcontroller 20 by activating the open relay 59, and the air in the compression zone 24 is released from the outlet 70. Then, in steps 186-190, the entire electrophysiological nerve measurement is converted to blood glucose by the microcontroller 20 using a correlation function to determine the user's blood glucose. That is, in step 186, I detected in steps 176 and 180, respectively._50%A vector array "m" of measurements containing one or more extraction parameters generated from the CAP waveform and the conditional CAP waveform is generated. The measured vector "m" represents a tentative specimen of neural function in hypoxic conditions. The measured value vector established as a result of the above measurement process therefore consists of four specific measured values as shown in Eq. (1): m = [a₆₀, a₁₈₀, b₁₂₀, b₂₄₀] (1) The timing of each measured value according to the number of seconds is specified by a subscript. For example a₁₈₀Is 3 minutes after the onset of hypoxia_50%Representing the amplitude of the CAP response, b₁₂₀Is 2 minutes after the onset of hypoxia_50%Represents the unconditional to conditional ratio in the CAP response. Although the measured value vector is described in the present application as including the amplitude of the detected CAP response, other CAP parameters such as the incubation period and / or the width may be used as the measured value vector. The element of the measurement vector is an absolute measure of neural function (eg I)_50%Represents CAP) to stimuli, but minimizes natural variables in peripheral nerve function between individuals and long-term changes (eg, due to aging) for a particular individual. Therefore, the normalized value vector shown in Eq. (2) is obtained as a result:<img file="JP3876331B2_D0001.tif" />Here, N represents a comprehensive normalization function. The specific normalization procedure depends on the particular type of measurement. For example, I in hypoxia_50%Peak peak value of CAP in response to the stimulus signal (ie [a]₆₀, A₁₈₀]), I before hypoxia_50%Relative value divided by the peak value of the response (obtained in processing step 170)<img file="JP3876331B2_D0002.tif" />To get. On the other hand, the unconditional to conditional CAP ratio (ie [b]₁₂₀, B₂₄₀]), Since it is already a relative value, normalization is not necessary. Vector of normalized measurements,<img file="JP3876331B2_D0003.tif" />Is converted to blood glucose according to a function, F, as shown in equation (3) below:<img file="JP3876331B2_D0004.tif" />The above function, F, may be a linear or non-linear analytical function, or may be calculated by an artificial neural network. For most individuals, blood glucose levels are linearly associated with the sum of electrophysiological measurements. In other words, [glucose]_bloodIs as shown in equation (4) below<img file="JP3876331B2_D0005.tif" />Is a linear function of:<img file="JP3876331B2_D0006.tif" />Where T represents the transposed matrix of the vector. Equation (4) is used to quickly and reliably convert the electrophysiological measurements achieved with the devices of steps 176-180 into concurrent blood glucose levels. This is a vector array of correlation coefficients c = [c₁, c₂, c₃, c₄] Is multiplied by the transposed matrix of the measured vector, and this is performed in step 190. When the blood glucose level is determined by the above method, the value is presented to the user by a user output device 22 (FIG. 1) such as an alphanumeric display device 36 (FIG. 2). Where the vector array of correlation coefficients, c = [c₁, c₂, c₃, c₄], Is determined in advance and stored in the non-volatile storage inside the microcontroller 20. This vector is a vector of normalized measurements,<img file="JP3876331B2_D0007.tif" />Glucose from the electrophysiological function of certain hypoxic nerves, characterized by [glucose]_bloodIt represents the correspondence to ,. More specifically, the correlation coefficient vector, c, in Eq. (4) is the blood glucose level in normal and diabetic populations ([glucose]]._blood) And neural function<img file="JP3876331B2_D0008.tif" />It is obtained from a statistical analysis of a database consisting of a large number of sets of measurements by simultaneous measurement of. Blood glucose levels are determined by a generally accepted and reliable standard method. Currently, the most accurate measurements are made with venous blood by skilled personnel in specialized clinical trials. Measurements of electrophysiological neural function were performed using the device of the present invention. Optimal correlation coefficient (ie [c in Equation 4]₁, c₂, c₃, c₄]) Was determined by applying multiple regression analysis or other multidimensional optimization techniques (eg, Monte Carlo simulations and artificial neural networks) to the database by simultaneous measurement of blood glucose and CAP parameters. If a database could be obtained from multiple individuals, the correlation coefficient could be further improved for that individual only, based on simultaneous measurements of additional blood glucose and electrophysiological function in a particular individual. Alternatively, the database can be categorized by a set of corresponding coefficients for selection according to the characteristics of the diabetic population, such as age, gender, type of diabetes, and the characteristics of the user. This kind of "tuning" of the correlation coefficient is only needed for a very small group of individuals. As described above, the correlation coefficient is stored in the non-volatile memory inside the microcontroller 20 in order to calculate the blood glucose level in real time according to the equation (4). The coefficients can be updated at any time by replacing the values in memory. Although the preferred embodiments of the present invention have been described above, it will be understood by those skilled in the art that there may be other embodiments in which the ideas are integrated. Therefore, the invention should only be constrained by the spirit and scope of the accompanying claims.