Abstract:
A system and method for continuous non-invasive glucose monitoring is disclosed. According to one embodiment of the present invention, the method includes the steps of (1) contacting a remote device to an area of biological membrane having a permeability level, the remote device comprising a sensor and a transmitter; (2) extracting the at least one analyte through and out of the area of biological membrane and into the sensor; (3) generating an electrical signal representative of a level of the at least one analyte; (4) transmitting the electrical signal to a base device; (5) processing the electrical signal to determine the level of the at least one analyte; and (6) displaying the level of the at least one analyte in real time. The system includes a remote device that includes a sensor that generates an electrical signal representative of the concentration of the at least one analyte; and a transmitter that transmits the electrical signal. The system further includes a base device that includes a receiver that receives the electrical signal; a processor that processes the electrical signal; and a display that displays the processed signal in real time.

Description:
BACKGROUND OF THE INVENTION 
       [0001]    1. Field of the Invention 
         [0002]    The present invention generally relates to transdermal transport using ultrasound or other skin permeation methods, and, more particularly, to a system and method for continuous non-invasive glucose monitoring. 
         [0003]    2. Description of Related Art 
         [0004]    The benefits of an intensive glucose management protocol on the mortality of critically ill adult patients is starting to be understood. Dr. James Stephen Krinsley has reported that, in a study recently conducted at the Intensive Care Unit at Stamford Hospital, a protocol that attempts to keep blood glucose levels lower than 140 mg/dL was associated with a significant decrease in mortality among critically ill patients. See Krinsley, James Stephen “Effect of Intensive Glucose Management Protocol on the Mortality of Critically Ill Adult Patients,”  Mayo Clin Proc . August 2004; 79(8): 992-1000 (the contents of which are incorporated by reference in their entirety). 
         [0005]    Before Dr. Krinsley&#39;s protocol was introduced, the standard of care at the ICU, which was typical for most ICUs, was to tolerate moderate levels of hyperglycemia. Thus, insulin was typically not administered unless the blood glucose levels exceeded 200 mg/dL on two successive finger sticks. If the blood glucose level was not above 200 mg/dL, no treatment was provided. 
         [0006]    With Krinsley&#39;s protocol in place, the glucose levels of patients in the ICU was initially to be measured at least every three hours. To accomplish this, nurses were required to perform a finger stick initially every three hours to obtain a glucose value. If the glucose value exceeded 200 mg/dL on two successive finger sticks, intravenous insulin was administered to the patient. For lower glucose levels, subcutaneous regular insulin was administered. If the glucose value was below 140 mg/dL, no treatment was administered. 
         [0007]    Dr. Krinsley&#39;s protocol imposed a significant amount of extra work on the nursing staff at the hospital. It required a willingness and commitment on behalf of the nursing staff to take repeated glucose measurements, and by a finger stick. 
       SUMMARY OF THE INVENTION 
       [0008]    According to one embodiment of the present invention, a method for real time remote monitoring and display of a level of at least one analyte in a body fluid of a subject is disclosed. The method includes the steps of (1) contacting a remote device to an area of biological membrane having a permeability level, the remote device comprising a sensor and a transmitter; (2) extracting the at least one analyte through and out of the area of biological membrane and into the sensor; (3) generating an electrical signal representative of a level of the at least one analyte; (4) transmitting the electrical signal to a base device; (5) processing the electrical signal to determine the level of the at least one analyte; and (6) displaying the level of the at least one analyte in real time. 
         [0009]    According to another embodiment of the present invention, a system for real time remote monitoring of a level of at least one analyte in a body fluid is disclosed. The system includes a remote device that includes a sensor that generates an electrical signal representative of the concentration of the at least one analyte; and a transmitter that transmits the electrical signal. The system further includes a base device that includes a receiver that receives the electrical signal; a processor that processes the electrical signal; and a display that displays the processed signal in real time. 
         [0010]    According to another embodiment of the present invention, a transdermal sensor is disclosed. The transdermal sensor includes a substrate having a first and a second surface. A first electrode trace is formed on the first surface of the substrate. A second electrode trace is formed on the second surface of the substrate. A third electrode trace is formed on the second surface of the substrate. A fourth electrode trace is formed on the second surface of the substrate. A fifth electrode trace is formed on the second surface of the substrate. A dielectric is formed on the second surface of the substrate. A plurality of electrical contacts are provided. 
         [0011]    It is a technical advantage of the present invention that a system for continuous non-invasive glucose monitoring is disclosed. It is another technical advantage of the present invention that a method for continuous non-invasive glucose monitoring is disclosed. It is another technical advantage of the present invention that a transdermal sensor is disclosed. It is still another technical advantage of the present invention that a remote device and a base device are disclosed. It is another technical advantage of the present invention that the remote device and the base device may communicate by a wireless protocol, such as a wireless application protocol link, a general packet radio service link, a Bluetooth radio link, an IEEE 802.11-based radio frequency link, a RS-232 serial connection, an IEEE-1394 (Firewire) connection, a fibre channel connection, an infrared (IrDA) port, a small Computer Systems Interface (SCSI) connection, and a Universal Serial Bus (USB) connection. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]    For a more complete understanding of the present invention, the objects and advantages thereof, reference is now made to the following descriptions taken in connection with the accompanying drawings in which: 
           [0013]      FIG. 1  illustrates a block diagram of a system for continuous, noninvasive monitoring of a subject&#39;s glucose levels according to one embodiment of the invention; 
           [0014]      FIG. 2  illustrates exemplary modules that may be associated with system of  FIG. 1 ; 
           [0015]      FIG. 3   a  is a top perspective view of and  FIG. 3   b  is a bottom perspective view of a remote device according to one embodiment of the present invention; 
           [0016]      FIG. 4  is an illustration of a sensor according to one embodiment of the present invention; 
           [0017]      FIG. 5  is an illustration of a transdermal sensor according to one embodiment of the present invention; 
           [0018]      FIG. 6  is a detailed schematic for a remote device according to one embodiment of the present invention; 
           [0019]      FIG. 7  is an illustration of a state machine executed by controller according to one embodiment of the present invention; 
           [0020]      FIG. 8  is a data format in accordance with one embodiment of the present invention is provided; 
           [0021]      FIG. 9  is a schematic for a base device according to one embodiment of the invention; 
           [0022]      FIG. 10  is an example of a display according to one embodiment of the present invention; 
           [0023]      FIG. 11  is an illustration of a method for continuous, noninvasive monitoring of a subject&#39;s glucose level according to one embodiment of the present invention; and 
           [0024]      FIG. 12  illustrates a method for identifying errors in the transmission of data according to one embodiment of the present invention. 
       
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
       [0025]    Preferred embodiments of the present invention and their advantages may be understood by referring to  FIGS. 1-12 , wherein like reference numerals refer to like elements, and are described in the context of a portable skin permeation system for pretreating an area of skin with ultrasound and then transdermally extracting a continuous flux of glucose to be measured by a sensor. 
         [0026]    It is known that ultrasound can be used to increase the permeability of the skin, thereby allowing the extraction of analytes, such as glucose, through the skin. For example, U.S. Pat. No. 6,234,990 to Rowe et al., the disclosure of which is hereby incorporated by reference, discloses methods and devices using a chamber and ultrasound probe to non-invasively extract analyte and deliver drugs (i.e., broadly transdermally transport substances). This provides many advantages, including the ability to create a small puncture or localized erosion of the skin tissue, without a large degree of concomitant pain. The number of pain receptors within the ultrasound application site decreases as the application area decreases. Thus, the application of ultrasound to a very small area will produce less sensation and allow ultrasound and/or its local effects to be administered at higher intensities with little pain or discomfort. 
         [0027]    By applying a brief duration of ultrasound, the outer most layer of skin (i.e., stratum corneum) becomes permeable. In an exemplary embodiment of the invention, the area of the pretreated skin site is approximately 0.8 cm 2 . In-vivo studies demonstrate that skin conductivity is significantly enhanced by ultrasound pretreatment and that the enhancement lasts for approximately twenty-four (24) hours. In order to control the ultrasound pretreatment, particularly the duration thereof, the change in skin conductance (or impedance) is measured during the application of ultrasound. When a desired level of skin conductivity is achieved, and hence a desired level of skin permeability, application of ultrasound is terminated. After permeation, passive diffusion or iontophoresis enhances the transport of a drug, such as an anesthetic agent, across the treated skin site. In the case of iontophoresis, a low-level current to a drug delivery electrode and a grounding electrode are employed. The potential difference between the two electrodes allows the drug ions to migrate efficiently from the drug delivery electrode into the skin. The delivery dose is proportional to the level of applied current and the treatment time. Similarly, analytes can be passively or iontophoretically transported across the skin for measurement. 
         [0028]    Moreover, U.S. Pat. No. 6,190,315 to Kost et al., the disclosure of which is incorporate by reference, discloses that application of ultrasound is only required once for multiple deliveries or extractions over an extended period of time rather than prior to each extraction or delivery. That is, it has been shown that if ultrasound having a particular frequency and a particular intensity of is applied, multiple analyte extractions or drug deliveries may be performed over an extended period of time. For example, if ultrasound having a frequency of 20 kHz. and an intensity of 10 W/cm 2  is applied, the skin retains an increased permeability for a period of up to four hours. 
         [0029]    Nevertheless, the amount (e.g., duration, intensity, duty cycle) of ultrasound necessary to achieve this permeability enhancement varies widely. Several factors on the nature of skin must be considered. For example, the type of skin which the substance is to pass through varies from species to species, varies according to age, with the skin of an infant having a greater permeability than that of an older adult, varies according to local composition, thickness and density, varies as a function of injury or exposure to agents such as organic solvents or surfactants, and varies as a function of some diseases such as psoriasis or abrasion. 
         [0030]    Once the permeability of the skin is increased, by ultrasound or by another means, the system of the present invention may be implemented.  FIG. 1  illustrates a block diagram of a system for continuous, noninvasive monitoring of a subject&#39;s glucose levels according to one embodiment of the invention. System  100  generally includes remote device  110  and base device  150 . Remote device  110 , which preferably includes sensor  120 , is provided to a subject and produces a signal (e.g., an amperometric current signal) related to an analyte concentration, such as glucose, in the subject. Remote device  110  may consist of a reusable assembly that produces a signal that represents the magnitude of the current produced by transdermal sensor. Remote device may also produce signals that represent the subject&#39;s skin temperature and the charge level of batteries. Remote device  110  also preferably includes transmission unit  130  that transmits the signal to base device  150 . Remote device may also include a unique identifier, such as an identification number. 
         [0031]    Base device  150  preferably includes processor  160  that processes the signal to determine the analyte concentration in the subject. Base device  150  preferably also includes display  170  that displays the results for a user. 
         [0032]      FIG. 2  illustrates exemplary modules that may be associated with system  100  for carrying out the various functions and features of the embodiments described herein. In some embodiments, the modules may be included that perform the following functions: (1) quantify the current produced by remote device  110 ; (2) measure the subject&#39;s skin temperature; (3) measure the voltage level of a battery that may be used to power system  100 ; (4) transmit data among system  100  modules; (5) receive data representing measured values and store them in memory units; (6) receive at least a calibration standard for the subject&#39;s glucose level via an input device; (7) predict the subject&#39;s glucose level, the glucose level&#39;s rate of change, and the percent change in the user&#39;s skin temperature; (8) transmit data to base device  130 ; (9) operate the device&#39;s alarm functions; and (10) operate the device&#39;s error functions. A brief description of each module is provided below. Although the modules are discussed individually by function, it should be understood that a single module may perform more than one function, or, alternatively, that more than one module may be required to perform one function. 
         [0033]    Sensor module  205  may monitor the amperometric current produced at remote device  110  and produce a time-stamped measurement of its magnitude. In some embodiments of the system  100 , sensor module  205  may use a potentiostat to measure this current. This value is related to the subject&#39;s glucose level. 
         [0034]    Temperature module  210  may produce a time-stamped measurement of the subject&#39;s skin temperature. In some embodiments of the system  100 , temperature module  210  may use a thermally sensitive resistors (i.e., a thermistor) to measure the temperature. Other mechanisms for measuring the subject&#39;s skin temperature may also be used. 
         [0035]    Battery module  215  may measure the voltage level of battery or other power source that may be used to power at least some of the modules in system  100 . In some embodiments of system  100 , battery module  215  may use a voltmeter to measure this value. 
         [0036]    Relay module  220  may transmit data among at least some of the modules of system  100  using any wired or wireless, digital or analog interface or connection. In some embodiments of system  100 , relay module  220  may use a radio frequency transmitter to transmit data among modules. 
         [0037]    Memory module  225  may receive data sent from relay module  220  and store it in memory units. Any suitable type of memory may be used. In one embodiment, a non-volatile memory that can store seven days of data may be used. Other types and sizes of memory may be used as appropriate. 
         [0038]    Input module  230  may allow a user to enter data for the system, such as glucose level calibration data. This may be based on a measurement taken from a blood sample. In some embodiments of system  100 , input module  230  may use a keypad to allow a user to input calibration data. 
         [0039]    Prediction module  235  may combine calibration data with the signals representing the current in remote device  110  to predict the subject&#39;s current glucose level, the glucose level&#39;s rate of change, and the percent change of the subject&#39;s skin temperature. In some embodiments of system  100 , prediction module  235  may include a microcontroller to predict a subject&#39;s glucose levels. 
         [0040]    Transmit module  240  may transmit a signal to base device  150  using any wired or wireless, digital or analog interface or connection. In some embodiments of the system, this signal may contain data representing, for example, the current in remote device  110 , the subject&#39;s predicted glucose value, the predicted rate of change of the subject&#39;s glucose value, the measured current voltage of batteries, the percent change of the subject&#39;s skin temperature, etc. 
         [0041]    Transmit module  240  may also transmit a signal to a hospital&#39;s central patient database. 
         [0042]    Alarm module  245  may allow the user to set parameters for the devices&#39; alarm function. These alarms may be set to become active when certain conditions are met, such as when the subject&#39;s glucose level reach certain values, when a predicted rate of change reaches a certain value, or when battery voltages reach a certain level. The alarms will be discussed in greater detail, below. 
         [0043]    Error module  250  may verify that any data transmitted between system  150  modules is transmitted accurately and securely. 
         [0044]    In some embodiments of the invention, modules associated with system  100  may be located independently, with remote device  110 , with base device  150 , or located with both. For example, in system  100 , sensor module  205 , temperature module  210 , battery module  215 , relay module  220 , and transmit module  240  may be colocated with remote device  110 . In this embodiment, the remaining modules of system  100  may be located with base device  150 . 
         [0045]    Referring to  FIGS. 3   a  and  3   b , an exemplary embodiment remote device  110  is provided.  FIG. 3   a  is a top perspective view of remote device  110  and  FIG. 3   b  is a bottom perspective view of remote device  110 . Upper portion  310  of remote device  110  includes operational indicator  315 , such as a LED, temperature module  320 , such as a thermistor, battery  325 , and contacts  330  for making contact with contacts  355  on sensor  350 . Upper portion  310  may also include relay module (not shown) and transmit module (not shown). 
         [0046]    Lower portion  360  of remote device  110  includes target ring  365  and adhesive  370 . 
         [0047]    The upper portion  310  and lower portion  360  of remote device  110  preferably interface so they are easily detachable after use, but are not easily detachable during use. In one embodiment, lower portion  360  is disposable, while upper portion  310  is reuseable. 
         [0048]    Although remote device  110  and certain portions thereof are illustrated as being circular, other geometries may be used as necessary. 
         [0049]    Referring to  FIG. 4 , an illustration of sensor  350  according to one embodiment of the present invention is provided. Sensor  350  includes adhesives  405  and  410 . Adhesives  405  and  410  may be commercially-available medical adhesives. In one embodiment, adhesive  405  may be an adhesive ring MED 3044 with a 9/16 inch inner diameter, and a 1⅜ inch outer diameter, and adhesive  410  may be an adhesive disc MED 3044 with a 1⅜ inch diameter. Both are available from Avery Dennison, 150 North Orange Grove Boulevard, Pasadena, Calif. 91103-3596, USA. 
         [0050]    Sensor  350  also includes working electrode  415 , counter electrode  420 , and reference electrode  425 . In one embodiment, working electrode  415  is formed by sputter coating pure platinum (Pt) material, and both counter electrode  420  and reference electrode  425  are formed by screen printing carbon and Ag/AgCl materials. 
         [0051]    Referring to  FIG. 5 , an illustration of sensor  350  according to one embodiment of the present invention is provided. Electrode  500  may of sensor  350  has an outer diameter of 9/16″. Electrode  500  is mounted on substrate  550 , which is preferably heat annihilated PET. Electrode  500  includes, on a front surface of substrate  550 , silver  505  on a front of substrate  550 , silver/silver chloride  510 , platinum  515 , carbon  520 , and clear dielectric  525 . On a back surface of substrate  550 , silver (not shown) is provided. Connection points to electronics are located on the back of the sensor using a mill-and-fill and printing process by CTI. 
         [0052]    Sensor  350  may be provided with a hyrdogel (not shown). In one embodiment, hydrogel may be polyethylene glycol diacrylate (PEG-DA) hydrogel with entrapped glucose oxidase (GOx). Such a hydrogel is disclosed in U.S. patent application Ser. No. ______, entitled “Biocompatible Chemically Crosslinked Hydrogels For Glucose Sensing,” Attorney Docket No. 62803.000066, filed Dec. 2, 2005, the disclosure of which is incorporated reference in its entirety. The hydrogel may be sized to be inserted in the inner diameter of adhesive  405 . 
         [0053]    Once sensor  355  is connected and adhered to the subject&#39;s skin, it may begin to produce a signal representing an amperometric current proportionate to the subject&#39;s glucose level. 
         [0054]    Referring to  FIG. 6 , a detailed schematic for remote device  110  according to one embodiment of the present invention is provided. Remote device  110  includes switch  610 . Switch  610  may be a contact switch that is triggered when remote device  110  is secured to a subject. For example, transmitter  615  may be electrically disconnected until remote device  110  is secured to a subject. 
         [0055]    Remote device  110  also includes battery  620 . In one embodiment, battery  620  is a single 3V Lithium “coin-cell.” It is anticipated that this type of battery will power remote device  110  for a minimum of 1 week. In one embodiment, the voltage of battery  620  is transmitted to and monitored by base device  150 . This voltage may be transmitted at a predetermined time interval, discussed below. 
         [0056]    Potentiostat  625  is provided to quantify the amperometric current produced by sensor  350 . In one embodiment, potentiostat  625  sets remote device  110  at a predetermined voltage, such as 500 mV. Once set, sensor  350  will initially start with a high current, such as 50 μA and then ramps down to 200 nA. While at a high current, it is important that potentiostat  625  does not saturate (i.e. the working electrode moves above ground). For this reason, currents above 1 μA will be detected with a low value resistor (kOhms) and currents below 1 μA will be accurately measured with a high value resistor (MOhms). 
         [0057]    In one embodiment, potentiostat  625  is bi-polar, splitting the supply voltage in half. For example, potentiostat  625  may split supply voltage 3 V DC into +/−1.5 V DC. Because, in one embodiment, the data from potentiostat  625  is downloaded to base device  150  periodically, adequate filtering and roll-off may be provided to average the data over the predetermined time interval. 
         [0058]    In addition, signal filtering (not shown) may be provided to reduce spurious noise events, such as current spikes on the order of 5 nA to 10 nA, or greater per minute. 
         [0059]    Thermistor  630  is provided to monitor the temperature near the surface of the subject&#39;s skin. In one embodiment, this data may be transmitted to base device  150  at a predetermined interval, discussed below. 
         [0060]    Analog to digital (A/D) converters  635  are provided to digitize the outputs of potentiostat  625 , thermistor  630 , and the voltage of battery  620 . In one embodiment, this data is collected and stored in memory for transmission to base device  150 . Although three A/D converters  635  are illustrated in  FIG. 5 , additional A/D converters may be used, or a single A/D converter with a multiplexed input may also be used. 
         [0061]    Controller  640 , which may be a miniature low power controller or state machine is provided to coordinate all hardware interaction. Controller  640  will be discussed in greater detail, below. 
         [0062]    Memory  645  is provided to store a unique identifier that is common between the transmitter  615  and base device  150 . In one embodiment, base device  150  may be programmed such that it will only recognize data from a transmitter with a certain unique identifier. Memory  645  may be programmed via programming port  650 . 
         [0063]    Programming port  650  is provided to allow firmware and/or a unique identifier to be programmed. Any suitable interface may be used. 
         [0064]    Transmitter  615  may be provided to transmit data to base device  150 . Transmitter  615  may communicate via any wired or wireless, digital or analog interface or connection including a Wireless Application Protocol (WAP) link, a General Packet Radio Service (GPRS) link, a Bluetooth radio link, an IEEE 802.11-based radio frequency link, a RS-232 serial connection, an IEEE-1394 (Firewire) connection, a Fibre Channel connection, an infrared (IrDA) port, a Small Computer Systems Interface (SCSI) connection, or a Universal Serial Bus (USB) communication. Other non-protocol based communication methods may also be employed. Transmitter  615  may transmit data to base device  150  at a predetermined interval, such as once every minute. Other intervals may be used as required. 
         [0065]    In one embodiment, the same data may be transmitted multiple times during the predetermined interval. For example, if the predetermined time interval is one minute, the same data may be transmitted three times during the predetermined interval. These transmissions may occur at random intervals during the predetermined interval. This provides redundancy to the transmission. 
         [0066]    The operation frequency and power are set so that transmitter  615  can communicate with base device  150 . Preferably, the operation frequency and power are in compliance with FCC and FDA requirements. 
         [0067]    In one embodiment, prior to transmitting, transmitter  615  checks to ensure that no other transmitter within range are transmitting. This reduces the likelihood of data corruption. 
         [0068]    Resistor Rshunt  655  and switch  660  are provided to set the range of the sensor. When switch  660  is closed, the resistance seen is 1 K ohm. This sets the range of the sensor at greater than 1 μA. If switch  660  is opened, the resistance seen is 1 M ohm. This sets the range of the sensor at less than 1 μA. 
         [0069]      FIG. 7  is an illustration of a state machine executed by controller  640 . At state  705 , if the power is on, the state machine proceeds to state  710 . 
         [0070]    In state  710 , the timer is reset (i.e., the timer is set to zero) and then started. In state  720 , shunt resistor Rshunt is closed. Resistor Rshunt switches in or out a 1 k ohm resistor that is in parallel with the 1 M ohm sense resistor. When resistor Rshunt is open, the measurement resistance is 1 M ohm. Thus, a current of 1 μA is measured as a drop of 1 volt across the resistor. Essentially this provides a very sensitive gain of 1V/1 μA. 
         [0071]    When resistor Rshunt is closed, the measurement resistance is 1K ohm in parallel with 1 M ohms, or 999 Ohms (approximately 1K ohm). The 1 μA now represents a 1 mV drop across the resistor. This reduces the sensitivity to 1 mV/μA. 
         [0072]    During sensor conditioning the sensor operates at higher currents therefore the 1 mV/μA gain is used. Once the sensor stabilizes at a lower current, the resistor Rshunt is opened and a gain of 1V/μA is used. 
         [0073]    In state  725 , the system waits for a predetermined passage of time, such as a minute. Once that predetermined time is met, in states  730 ,  740 , and  745  measurements are made or captured. For example, in step  730 , the current at potentiostat  725  is measured. If the current is less than 1 μAmp, in step  735 , shunt resistor Rshunt is opened. 
         [0074]    In state  740 , the voltage at battery  620  is measured, and at state  745  the subject&#39;s temperature is measured. 
         [0075]    In state  750 , the collected data is formatted for transmission. Any suitable data format may be used. Referring to  FIG. 8 , a data format in accordance with one embodiment of the present invention is provided. Data format  800  includes current field  810 , battery voltage field  820 , subject temperature field  830 , device identification number field  840 , minute field  850 , and checksum  860 . Rshunt field (not shown) may be provided to indicate whether Rgain is shunted or not shunted. Additional or fewer fields may be included as necessary and/or desired. 
         [0076]    In one embodiment, current field  810  may have a width of 16 bits, battery voltage field  820  may have a width of 7 bits, subject temperature field  830  may have a width of 8 bits, device identification number field  840  may have a width of 16 bits, minute field  850  may have a width of 16 bits, and checksum  860  may have a width of 16 bits. 
         [0077]    Referring again to  FIG. 7 , in state  755 , the state machine waits to transmit the formatted data. In one embodiment, the state machine waits to ensure that no other devices are transmitting at the same time. 
         [0078]    In state  760 , the formatted data is transmitted to base device  150 . Following transmission, the state machine loops back to state  725 . 
         [0079]    Referring again to  FIG. 1 , base device  150  receives the signal transmitted from remote device  110 . Base device  150  processes the received signal, resulting in a signal that is indicative of the predicted analyte concentration in the subject. 
         [0080]    Referring to  FIG. 9 , schematics for base device  150  according to one embodiment of the invention are provided. Base device  150  includes receiver  910  that receives the signal transmitted by remote device  110 . In one embodiment, as base device  150  receives data from remote device  110 , the data is error checked and written to non-volatile memory  935 . This will be described in greater detail, below. 
         [0081]    In one embodiment, base device  150  monitors the operation of remote device  110 . In one embodiment, when base device  150  detects that remote device  110  has been transmitting for a predetermined time, indicating that remote device is attached to a subject, base device  150  prompts the operator to enter calibration data from the blood draw. The calibration data may be a time-stamped measurement of the subject&#39;s glucose level taken from a venous blood sample or finger stick meter reading. Preferably, this may take place after one hour of operation. Therefore the blood draw time and date occur between Sensor On +1 hour and the Current Sensor Time. 
         [0082]    Programming port  915  is provided in the same manner as programming port  550 . 
         [0083]    Interface  920  is provided to allow access to the data stored and/or received by base device  150 . In one embodiment this may be a RS-232 serial connection. Other communications protocols, such as a Wireless Application Protocol (WAP) link, a General Packet Radio Service (GPRS) link, a Bluetooth radio link, an IEEE 802.11-based radio frequency link, an IEEE-1394 (Firewire) connection, a Fibre Channel connection, an infrared (IrDA) port, a Small Computer Systems Interface (SCSI) connection, or a Universal Serial Bus (USB) connection may also be used. 
         [0084]    Interface  920  may also transmit data to the hospital&#39;s patient database and to a patent terminal, central nurse&#39;s station, etc. 
         [0085]    In one embodiment, seven days worth of data will be stored in a buffer and downloaded via interface  920 . 
         [0086]    Clock  925  is provided. In one embodiment, clock  925  is used to time-stamp data that is received from remote device  110 . 
         [0087]    Base device  150  is provided with processor  930 . Processor  930  may be either a 16 or 18-series microcontroller. For example, the MicroChip PIC-18 family of processors may be used. In one embodiment, processor  930  preferably includes an internal analog to digital converter (not shown) and program memory (not shown). Processor  930  also preferably includes memory  935 , such as a nonvolatile memory. Memory  935  can be located internal to processor  930 , or it can be located external to processor  930 . In one embodiment, memory  935  should be of adequate size to hold a minimum of 24 hours worth of data. 
         [0088]    Processor  930  executes software, firmware, and/or microcode. This will be discussed in greater detail, below. 
         [0089]    Memory  935  may store a unique identification code in the same manner as memory  645 . 
         [0090]    Base device  150  includes a power supply, such as battery pack  940 . In one embodiment, battery pack  940  supplies base device  150  with power for 1 week without replacement. In one embodiment, battery pack  940  may be a rechargeable battery pack. 
         [0091]    During operation, battery voltage may be monitored. This may require an analog to digital converter (not shown). If the voltage of battery pack  940  falls below a predetermined voltage, the operator is alerted. This may include a visual indication, or an audible indication. Preferably, powering-down base device  150 , or replacing battery pack  940  does not result in any data being lost. 
         [0092]    Alarm  950  and mute switch  955  are provided. In one embodiment, alarm  950  is a piezoelectric alarm that is used to alert the operator of certain events, alarm states and error conditions. These, as well as other types of alarms and notifications will be discussed in greater detail below. 
         [0093]    In one embodiment, mute switch  955  is provided to mute or silence alarm  950 . 
         [0094]    Base device  150  may include an input device, such as keypad  960 . Keypad  960  may include several input switches, such as nine poly dome-type switches, that are used to input data and control remote device  110  and/or base device  150 . In another embodiment a touch-screen may be used. 
         [0095]    Base device  150  also includes display  965 . In one embodiment, display  965  is a liquid crystal display. The operating characteristics of display  965  may be configured (e.g., contrast, viewing angle, backlight, etc.) as necessary. 
         [0096]    Display  965  may graphically present information to a user in real time. For example, in one embodiment of the invention. a subject&#39;s glucose level may be graphically displayed for a certain period of time. Notable events, such as actual blood measurements, injections of insulin, etc. may be graphically displayed on the timeline so that the impact of such on the subject&#39;s glucose level may be viewed. 
         [0097]    Other parameters, such as the subject&#39;s glucose rate of change, temperature, and temperature rate of change, may also be graphically displayed. In addition to display  965 , base device  150  may also include LEDs (not shown) as necessary to provide status information (e.g., power on/off, battery status, etc.) to the user. 
         [0098]    Referring to  FIG. 10 , an example of a display according to one embodiment of the present invention is provided. Display  1000  includes graphical representation  1010  of blood glucose versus time. In one embodiment, graphical plot  1010  for the past four hours is displayed; other time periods may be displayed as desired. In another embodiment, the scales may be selected by a user. 
         [0099]    Marker  1020  may be provided to indicate when insulin was administered to the subject. In one embodiment, marker  1020  may comprise a vertical line, such as that shown in  FIG. 10 . Label  1030  may also be provided to indicate what marker  1020  is marking. In another embodiment, marker  1020  may be selected by a user such that it most effectively indicates the time at which the insulin was administered 
         [0100]    Marker  1020  may also provide additional information, such as the doseage of the insulin, the person who administered the insulin, and the time of that the administration occurred. This may be continuously provided in display  1000 , or it may be provided in a drop-down box (not shown) that is selected by a user. 
         [0101]      FIG. 11  illustrates a method  1100  for continuous, noninvasive monitoring of a subject&#39;s glucose level, preferably in an intensive care unit, according to one embodiment of the invention. In some embodiments, method  1100  may be performed by system  100  of  FIG. 1 . 
         [0102]    In step  1105 , the permeability of an area of a subject&#39;s skin is increased. This may be accomplished by any suitable mechanism, including the application of ultrasound, mechanical disruption, laser skin ablation, electroporation, RF ablation, microneedles, chemical peel, etc. In one embodiment, the SonoPrep® Skin Permeation Device, available from Sontra Medical Corp., Franklin, Mass., may be used to increase the permeability of the area of skin. Other devices, such as the QuickPrep™ automated patient prep system available from Quinton, Inc., 303 Monte Villa Parkway, Bothell, Wash. 98021-8906, may also be used. 
         [0103]    In step  1110 , the remote device is positioned and affixed to the area of skin. Preferably, remote device is affixed to the area of skin by a medical grade adhesive. Remote device should be securely affixed so that it is not unintentionally removed from the area of skin, but not preferably does not cause significant skin damage when removed. 
         [0104]    A medium may be provided between the surface of the skin and the sensor in order to keep the two in aqueous contact. In one embodiment, a hydrogel disc may be positioned between the skin and the sensor. Referring to  FIG. 4 , the hydrogel disc is preferably inserted in the interior portion of adhesive ring  405 . 
         [0105]    Referring again to  FIG. 11 , in step  1115 , once the remote device is affixed, the sensor begins to produce a signal, such as an amperometric current, that is representative of a subject&#39;s glucose level. In step  1120 , the magnitude of the signal is measured, and may associated with the current time (i.e., time-stamped). Additionally, other modules, such as the temperature module and the battery module, may measure the subject&#39;s skin temperature and the voltage level of the a battery, respectively. These measurements may also be time-stamped. 
         [0106]    In step  1125 , the time-stamped measurements may be transmitted from the remote device to the base device. As discussed above, this transmission may be made by any suitable wired or wireless protocol. Prior to transmission, a unique identification number and checksum value may be added to this data in order to produce a secure and accurate transmission. 
         [0107]    In step  1130 , the base device receives the transmitted data and stores it in memory. In one embodiment, the base device may verify the integrity of this transmitted data. This may be accomplished through the use of a checksum value. In addition, the identification number may be compared to one that is stored in the base device&#39;s memory. 
         [0108]    At step  1135 , the user may input at least a glucose calibration standard for the subject. This calibration standard may be a time-stamped measurement of the subject&#39;s glucose level taken from a venous blood sample or finger stick meter reading. The user may input this calibration standard through the use of a keypad or other input device attached to the base device. 
         [0109]    At step  1140 , the base device may combine the time-stamped data representing the current produced by the remote device and the inputted calibration standard to predict the value of the subject&#39;s glucose level. The base device may calculate the predicted glucose value, current, and percent change in skin temperature by using the following equations: 
         [0000]      Predicted Glucose t   =I   t ×(Measured Glucose t=cal   /I   t=cal );
 
         [0000]        I   t =sensor current−baseline; and
 
         [0000]      Displayed Temp t =(Temp t /Temp t=cal )×100
 
         [0110]    where baseline is a preprogrammed value in nA. 
         [0000]      Predicted Glucose Rate of change=Predicted Glucose T −Predicted Glucose T=1  
 
         [0111]    Predicted glucose displayed may also be adjusted to compensate for temperature changes and temporal changes. This is discussed in greater detail in U.S. patent application Ser. No. 10/974,963, entitled “System and Method for Analyte Sampling and Analysis,” the disclosure of which is incorporated by reference in its entirety. 
         [0112]    In some embodiments of the method, these calculations may be performed by the prediction module using a microcontroller. 
         [0113]    At step  1145 , the base device displays this data, including data representing the current in the remote device; the subject&#39;s predicted glucose value; the predicted rate of change of the subject&#39;s glucose value and a future estimated glucose value (T+10 minutes, for example) based on the rate of change; the voltage of the batteries in either remote device, base device, or both; the percent change of the subject&#39;s skin temperature; and the status of the piezo alarm. The number of minutes that have elapsed since the remote device was first attached to the subject may also be displayed. 
         [0114]    In one embodiment, the results may be displayed graphically, as discussed above with reference to  FIG. 10 . 
         [0115]    As discussed above, the method and device of the present invention included an alarm function that provides an audible and/or visual notification when predetermined conditions are met. In one embodiment, the following alarms may be provided: (1) hypoglycemic; (2) hypoglycemic anticipated; (3) hyperglycemic; (4) hyperglycemic anticipated; (5) low remote device battery; (6) low base device battery; (7) communication link lost; (8) communication link disturbed; (9) bad sensor data; (10) 1 hour left; and (11) 24 hours exceeded. Other alarms may be provided as necessary and desired. 
         [0116]    These messages may also be transmitted to and displayed on a patient terminal via a central database, and/or displayed at a central nurse&#39;s station. 
         [0117]    In general, a single measurement that meets a predetermined condition is insufficient to trigger an alarm. Rather, two (or more) consecutive alarm conditions are required to trigger the alarm. The number of consecutive alarm conditions may be increased or decreased as necessary and/or desired. 
         [0118]    Each of these alarms will be discussed in greater detail below. Although a variety of conditions precedent for each alarm may be used, a set of preferred conditions will be discussed. 
         [0119]    The hypoglycemic alarm may be triggered when two consecutive glucose predictions are below a preset limit. In one embodiment, the preset limit may be 60 mg/dl. In addition, the preset limit may vary from subject to subject. 
         [0120]    The hypoglycemic anticipated alarm may be triggered when five minute averaged rate of change predicts that two consecutive glucose readings will be below the hypoglycemic preset limit within ten minutes. 
         [0121]    The hyperglycemic alarm may be triggered when two consecutive glucose predictions are above a preset limit. In one embodiment, the preset limit may be 200 mg/dl. In one embodiment, the preset limit may be 160 mg/dl. In addition, as with the preset limit for the hypoglycemic alarm, the preset limit may vary from subject to subject. 
         [0122]    The hyperglycemic anticipated alarm may be triggered when five minute averaged rate of change predicts that two consecutive glucose readings will be above the hyperglycemic preset limit within ten minutes. 
         [0123]    The low remote device battery and low base device battery alarms may be triggered when the measured voltage on either battery falls below a predetermined voltage. In one embodiment, the predetermined voltage may be set in order to provide at least a certain amount of time before the battery fails. For example, when the battery voltage for the remote device falls below 2.8 VDC for two consecutive transmissions, or when the battery voltage for the remote device falls below 6.0 VDC, the respective alarms are triggered. 
         [0124]    Power-saving techniques, such as a reduction in power to the display, may be employed to conserve power once the alarm condition is met. 
         [0125]    The communication link lost alarm may be triggered when two consecutive measurements are missed. 
         [0126]    The communication link disturbed alarm may be triggered when two consecutive data streams with valid identification code have invalid check sum values. 
         [0127]    The bad remote device data alarm may be triggered when two consecutive data streams have sensor currents below a predetermined value, such as 10 nA (any time) or above a predetermined value, such as 1 uA, after a certain period of operation, such as 35 minutes. 
         [0128]    The 1 hour left alarm may be triggered when two consecutive data streams report times greater than 1380 minutes (i.e., 23 hours). 
         [0129]    The 24 hours exceeded alarm may be triggered when two consecutive data streams report times greater than 1440 minutes (i.e., 24 hours) 
         [0130]    The alarms may be displayed until the mute switch is pressed. In the case of multiple alarms, the base device may queue the alarms in a first in first out sequence. Each time the mute switch is pressed, the current alarm will be cleared and the next alarm in the queue will be displayed. In one embodiment, certain alarms, such as hypoglycemic and hyperglycemic will have priority over all other alarms and be displayed regardless of their position in the queue. 
         [0131]      FIG. 12  illustrates a method for identifying errors in the transmission of data. In step  1205 , data may be transmitted wirelessly between the remote device and the base device of the system. As discussed above, in some embodiments, this data may contain a measurement of the current produced at remote device, a measurement of the subject&#39;s skin temperature, and a measurement of the transmitter unit&#39;s battery. This data may also have been formatted to include a timestamp value, checksum value, and a ID number. 
         [0132]    In step  1210 , the security and accuracy of this transmitted data may be verified. In one embodiment of the method, an error module may use a microprocessor to compare the timestamp of the most recent data transmission to that of previous transmissions, to compare the data identification f the most recent data transmission to that which is stored in the base device&#39;s memory, to verify the transmitted data&#39;s checksum value, and to analyze the value of the current produced in the remote device. 
         [0133]    In step  1215 , the system may notify the user if the data is found to be insecure or inaccurate. In one embodiment of the method, the error module may sound an alarm if (1) a comparison of the data timestamps shows that two consecutive transmissions have been missed (2) two consecutive data transmissions have incorrect checksum values (3) a predetermined number of measurements for the current in remote device are below or above certain preset values. In one embodiment, it two measurements are below or above the preset values, the alarm is activated. 
         [0134]    In one embodiment, system  100  may interface with a mechanism for providing insulin. Thus, with this addition, not only is the hypoglycemic or hypoglycemic conditions detected and/or predicted, but the conditions are appropriately treated automatically. In one embodiment, the initiation of treatment requires human authorization, i.e., the insulin cannot be administered without a human authorizing the administration. In other embodiments, human authorization is only required for the administration of insulin in extreme conditions. 
         [0135]    The present invention contemplates a system that continuously monitors the amount of insulin treatment and the effect of that insulin treatment on the subject&#39;s glucose level. Because the effect of insulin on a glucose level will vary from subject to subject, and even within the same subject, the system may attempt to determine an optimum insulin treatment based on past performance. However, until several insulin treatments are observed, it may be difficult for the contemplated system to accurately determine the amount of an insulin treatment required. Therefore, until a sufficient number of observations have been completed, the system may require all insulin to be administered by a human. 
         [0136]    The various embodiments of the systems and methods described and claimed herein provide numerous advantages. For example, the systems and methods permit continuous, noninvasive detection of a subject&#39;s glucose levels. Thus, a user can monitor the a subject&#39;s post operative glucose levels more frequently, effectively, and comfortably. Such improved systems and methods for monitoring post operative glucose levels may help to reduce a subject&#39;s risk of infection and reduce hospitalization. 
         [0137]    Other embodiments, uses, and advantages of the present invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. The specification and examples should be considered exemplary only.