WO2011084713A1

WO2011084713A1 - Glucose sensor and controller with user selectable output

Info

Publication number: WO2011084713A1
Application number: PCT/US2010/061163
Authority: WO
Inventors: Anthony P. Furnary; Soya Gamsey
Original assignee: Glumetrics, Inc.
Priority date: 2009-12-17
Filing date: 2010-12-17
Publication date: 2011-07-14

Abstract

Preferred embodiments of the present invention relate to detection of glucose in blood or interstitial fluid. More particularly, the disclosed device allows a user to select from among different glucose sensor output options, including conventional blood or plasma glucose concentrations (mg/dl) and the level of glucose activity (mmoles glucose/kg water).

Description

GLUM.069WO PATENT GLUCOSE SENSOR AND CONTROLLER WITH USER SELECTABLE OUTPUT

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 61/287,640, filed December 17, 2009, the disclosure of which is hereby expressly incorporated by reference and hereby expressly made a portion of this application.

BACKGROUND OF THE INVENTION

Field of the Invention

[0002] Preferred embodiments of the present invention relate to detection of glucose in blood or interstitial fluid. More particularly, the disclosed device allows a user to select from among different glucose sensor output options, including conventional blood glucose concentration (mg/dl) and the level of glucose activity (mmoles glucose/kg water). Description of the Related Art

[0003] Health care providers have long recognized the need to monitor patients' glucose levels closely. This is particularly important in the critical care setting. The accurate measurement of glucose levels is also important in the medical management of individuals with diabetes. Elevated glucose levels are associated with a variety of microvascular and macrovascular complications including nephropathy, neuropathy, and retinopathy, problems with wound healing, as well as an elevated risk of cerebrovascular and cardiovascular disease. Abnormally low glucose levels can also cause significant problems and can lead to anxiety, weakness, and in extreme cases coma and death.

[0004] Glucose concentrations are typically measured either using milligrams of glucose per deciliter of fluid or in SI Units which measure millimoles of glucose per liter of fluid. The fluid used as the reference is generally either whole blood or plasma. For example, the American Diabetic Association bases its criteria for the diagnosis and treatment of diabetes on the glucose concentration in plasma. By contrast, the World Health Organization uses glucose concentration in whole blood in all of its diagnostic and treatment criteria. An example of a treatment protocol based on blood glucose might call for the administration of a set quantity of carbohydrate for a blood glucose level below 60, the administration of 3 units of regular insulin for blood glucose measured between 151 and 200, the administration of 5 units for a reading of 201 to 250, and so on.

[0005] Clinicians typically rely on point-of-care testing that seems to measure glucose concentration in plasma, e.g., using glucometers to read test strips that filter separate plasma from cells in a drop of whole blood. While the results can be available quickly, they vary depending on the patient's hematocrit, plasma protein and lipid profiles, etc., and can often be falsely elevated (See e.g., Chakravarthy et al., 2005 "Glucose determination from different vascular compartments by point-of-care testing in critically ill patients" Chest 128(4) October, 2005 Supplement: 220S-221S). More accurate determinations can be obtained by first separating the cellular components of whole blood. However, this requires separation of the plasma from the cellular components of blood, e.g., by centrifugation. Subsequently, isolated plasma must be stored and/or transported and/or diluted prior to analysis. Storage and processing conditions, e.g., temperature, dilution, etc., will almost certainly perturb the in vivo equilibrium between the bound and free (bioavailable) glucose. Consequently, regardless of the technology subsequently employed for measuring plasma glucose concentration (e.g., glucose oxidase, mass spectrometry, etc.), the measured glucose concentration is likely no longer reflective of the amount of physiologically relevant glucose activity, i.e., the amount of bioavailable glucose in vivo.

[0006] Despite the shortcomings noted for the aforementioned methods of measuring glucose concentration in blood and plasma, such indices are almost universally used by clinicians in making treatment decisions. Essentially all established treatment protocols, diagnoses, and prognostic criteria are based on blood or plasma glucose concentrations. It follows therefore that any new system of glucose quantification, even one with numerous advantages over previous measurement systems (e.g., glucose activity), would take some time to gain acceptance by clinicians. Moreover, diagnostic criteria would have to be rewritten and new treatment protocols formulated to take advantage of any new standard for quantifying the levels of circulating glucose.

SUMMARY OF THE INVENTION [0007] A blood glucose monitoring system is disclosed with user selectable output. The monitoring system comprises: (a) a glucose sensor configured to reside in a blood vessel and provide a signal related to the level of glucose activity; (b) a data processing unit programmed to convert the level of glucose activity to a blood glucose concentration and/or a plasma glucose concentration; (c) a toggle system operable by the user and coupled to the data processing unit for selecting a desired output from among the level of glucose activity, the blood glucose concentration, and the plasma glucose concentration; and (d) an output device configured to allow the user to receive the output.

[0008] In some embodiments, the toggle system comprises a knob, button, switch, touchpad, computer interface, or other means of relaying commands to the data processing device. In some embodiments, the user can elect to receive blood or plasma glucose concentrations in the form of conventional mg/dL units. In some embodiments, the user can elect to receive blood or plasma glucose concentrations in the form of SI Units (mmol/L). In some embodiments, the output device is selected from the group consisting of a graphic display, printer, network data connection, or other means of transmitting information to the user. In some embodiments, the hematocrit level is input into the processor.

[0009] A blood glucose monitor with user selectable output is disclosed in accordance with another aspect of the invention. The monitor comprises: (a) a data processing unit programmed to convert a measured level of glucose activity to a blood glucose concentration and/or a plasma glucose concentration; (b) a toggle system operable by the user and coupled to the data processing unit for selecting a desired output from among the level of glucose activity, the blood glucose concentration, and the plasma glucose concentration; and (c) an output device configured to allow the user to receive the output.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 is a block diagram showing the components of a controller in accordance with one preferred embodiment of the glycemic control system.

[0011] FIG. 2 shows aspects of the optical signal path in accordance with one embodiment of the present system. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0012] Glucose activity as used herein reflects a measurement of the amount of free, bioavailable glucose. It represents the amount of glucose present per kilogram of water in the blood. It is measured in millimoles per kilogram of water. This provides a means of quantifying glucose that is not affected by the presence of red blood cells, protein concentration, lipid concentration, or oxygenation. Because protein-bound glucose is not part of the measured glucose activity level, the result represents an accurate quantification of the freely circulating glucose that is actually available for use by the body. Therefore, glucose activity measurements can provide a more physiologically relevant index a patient's glycemic status than either plasma or blood glucose concentrations.

[0013] Glucose activity also offers a number of advantages for use in glycemic control systems wherein a sensor capable of measuring glucose activity is operably coupled to a device capable of administering a glucose activity modulator such as insulin. Because the beta cells of the pancreas bind and respond to glucose activity (and not total blood glucose concentration, etc.) in regulating insulin secretion, a measurement of glucose activity represents the closest approximation to the body's own mechanism for glycemic control. Indeed, glucose activity can be measured as disclosed herein through implanted sensors configured to reversibly bind free glucose and elicit a detectable signal related to the amount of glucose binding. This allows for near-instantaneous monitoring and feedback in a manner approximating physiologic glucose control.

[0014] However, because established treatment protocols and diagnostic criteria have been based on blood and plasma glucose concentration (typically expressed as mg/dl) for decades, there would likely be a significant transitional period before glucose activity (measured in mmol/kg water) could fully replace the conventional blood glucose paradigms. Therefore, there is a significant and unmet need to be able to convert glucose activity data from glucose activity sensors (as disclosed herein) to more familiar plasma or blood glucose concentrations until diagnostic and treatment protocols for this new glycemic index are formulated and in widespread use.

[0015] In preferred embodiments, the invention disclosed herein comprises a toggle system on a controller that enables a user to select whether to receive information on a patient's glucose levels in the form of glucose activity (e.g., mmol/kg water), blood glucose concentration (e.g., mg/dL blood), or plasma glucose (e.g., mg/dL plasma). The toggle system can comprise a button, switch, knob, touchpad, computer interface, or any other control device that can be operably coupled with a controller comprising a data processing unit capable of performing mathematical calculations. In some embodiments, the controller can be integral with the data processing unit. In some such embodiments, the interface between the controller and the data processing unit can be by means of a direct electrical and/or mechanical connection. In other embodiments, the controller can interface with the data processing unit remotely via wired, wireless, network or other type of connection.

[0016] Preferred embodiments would be capable of converting glucose activity to blood and/or plasma glucose concentrations. In some embodiments wherein the user wishes to convert glucose activity to blood or plasma glucose concentration, the user may elect to receive this data in mg/dL system or in SI units (mmol/L), such that the displayed or output blood or plasma glucose concentration is in the selected units. If the user wishes to receive said data in the form of SI units, it will be necessary for the data processing device to perform a simple additional calculation, wherein the mg/dL output is multiplied by 0.0555. Once the necessary calculations are complete, many embodiments of the processing device can then relay the data to a user using an operably coupled data output device.

Glucose Activity Sensors

[0017] The glucose sensors of the present invention can be utilized under a variety of conditions. The particular configuration of a sensor may depend on the use for which it is intended and the conditions under which it will operate. One embodiment includes a sensor configured for implantation into a patient or user. For example, implantation of the sensor may be made in the arterial or venous systems for direct testing of glucose activity in blood. Alternatively, a glucose activity sensor may be implanted in the interstitial tissue for determining the glucose activity in interstitial fluid. The site and depth of implantation may affect the particular shape, components, and configuration of the sensor.

[0018] In preferred embodiments, glucose activity can be directly measured using an optical detector system designed to detect and quantify glucose activity. In one such embodiment, glucose activity is measured using a sensor comprising a light sensitive chemical indicator system disposed within the light path of an optical fiber, which is sized and configured to be deployed within a blood vessel or within the interstitial space. The chemical indicator system is configured to interact with free, unbound glucose dissolved within the aqueous compartment of the plasma.

[0019] Examples of such chemical indicator systems and sensor configurations for intravascular or interstitial glucose monitoring include the optical sensors disclosed in U.S. Patent Nos. 5,137,033, 5,512,246, 5,503,770, 6,627,177, 7,417,164 and 7,470,420, and U.S. Patent Publ. Nos. 2008/0188722, 2008/0188725, 2008/0187655, 2008/0305009, 2009/0018426, 2009/0018418, and co-pending U.S. Patent Appl. Nos. 11/296,898, 12/187,248, 12/172,059, 12/274,617 and 12/424,902; each of which is incorporated herein in its entirety by reference thereto.

[0020] In certain preferred embodiments, the chemical indicator system comprises a fluorophore (or fluorescent dye) capable of absorbing light at an excitation wavelength and generating a detectable fluorescent signal at an emission wavelength. In certain preferred embodiments, the chemical indicator system also comprises a glucose binding moiety capable of reversibly binding glucose and interacting with the fluorophore in a manner related to the amount of glucose binding. In certain preferred embodiments, the fluorophore is operably coupled to the glucose binding moiety, such that the detectable fluorescent signal generated by the fluorophore is modulated by the interaction between the fluorophore and the glucose binding moiety. Preferably, the intensity of the emission wavelength is modulated. The operable coupling between the fluorophore and glucose binding moiety may be a direct covalent coupling, an indirect covalent coupling (e.g., via a linker), or a non-covalent association (e.g., an electrostatic attraction). Various embodiments may include more than one fluorophore and more than one glucose binding moiety. Further, some fluorophores that may be useful in such a chemical indicator system may be capable of absorbing light at more than one excitation wavelength and generating detectable signals at more than one emission wavelength.

[0021] In some embodiments, the above described chemical indicator system also comprises a polymer matrix that is permeable to glucose, wherein the fluorophore and the glucose binding moiety are immobilized therein and capable of sufficient molecular interaction to facilitate glucose-dependent modulation of the detectable fluorescent signal. In various embodiments, the fluorophore and glucose binding moiety may be covalently or non- covalently associated with the polymer matrix.

[0022] In one preferred embodiment of the glucose activity sensor of the present invention, the chemical indicator system comprises HPTS-triCys-MA (fluorophore) and 3,3'- oBBV (glucose binding moiety) immobilized within a glucose permeable polymer matrix and disposed within a cavity in the distal end region of an optical fiber. The opening to the cavity is preferably covered by a semipermeable membrane which is permeable to free dissolved glucose, but not macromolecular or cell associated glucose. The preferred HTPS-tri-Cys-MA fluorophore and the benzylboronic acid substituted viologen (3,3'-oBBV) are described in US Patent No. 7,417,164, entitled FLUORESCENT DYES FOR USE IN GLUCOSE SENSING, the entire disclosure of which is incorporated herein by reference thereto. In such glucose activity sensors, the 3,3'-oBBV glucose-binding moiety associates with the HPTS-triCys-MA fluorophore through electrostatic attraction in the absence of free glucose, wherein the viologen acts as a quencher, suppressing the emission signal of the dye in response to interrogation by an excitation light signal. As free glucose diffuses through the semipermeable membrane and the polymer matrix and binds to the aromatic boronic acid groups on the 3,3'-oBBV, the charge is altered, and the glucose binding moiety (sometimes referred to hereinafter as the "quencher") dissociates from the fluorophore, thereby allowing fluorescent emission in response to the excitation light. The intensity of the fluorescent emission signal in this preferred embodiment of the glucose activity sensor is therefore proportional to the concentration of free, bioavailable glucose.

[0023] Other indicator chemistries, such as those disclosed in U.S. Patent Nos. 5,176,882 to Gray et al. and 5,137,833 to Russell, can also be used in accordance with embodiments of the present invention; both of which are incorporated herein in their entireties by reference thereto. In some embodiments, an indicator system may comprise an analyte binding protein operably coupled to a fluorophore, such as the indicator systems and glucose binding proteins disclosed in U.S. Patent Nos. 6,197,534, 6,227,627, 6,521,447, 6,855,556, 7,064,103, 7,316,909, 7,326,538, 7,345,160, and 7,496,392, U.S. Patent Application Publication Nos. 2003/0232383, 2005/0059097, 2005/0282225, 2009/0104714, 2008/0311675, 2008/0261255, 2007/0136825, 2007/0207498, and 2009/0048430, and PCT International Publication Nos. WO 2009/021052, WO 2009/036070, WO 2009/021026, WO 2009/021039, WO 2003/060464, and WO 2008/072338 which are hereby incorporated by reference herein in their entireties.

[0024] In further preferred embodiments, the glucose activity sensor is adapted to facilitate ratiometric correction of glucose activity measurements for optical artifacts of the system as disclosed in co-pending US Publication No 2008-0188725 Al and US Application No. 12/612,602, and for pH as disclosed in co-pending US Publication No. 2008-0188722 Al, which are hereby incorporated by reference herein in their entireties.

[0025] Preferred sensor configurations are described in co-pending US Application No. 12/612,602, entitled IMPROVED OPTICAL SENSOR CONFIGURATION FOR RATIOMETRIC CORRECTION OF BLOOD GLUCOSE MEASUREMENT; incorporated herein in its entirety by reference.

Glucose Activity Sensors Operably Coupled to a Controller

[0026] In some embodiments, the glucose activity sensor described above is further incorporated into a system whereby optical information (fluorescent emission signal) about a patient's glucose activity can be converted to an electrical (analog or digital) signal and communicated to a user programmable (or pre-programmed) controller. The controller may comprise an integral visual and/or audio output device, such as a conventional computer monitor/display, alarm, speaker, and/or an integral or operably coupled printer. Preferably, the controller comprises a visual display that indicates the present glucose activity level (mmoles glucose/kg water), the trend (steady, rising or falling), and the relative rate of change. In preferred embodiments, the controller comprises one or more data processing units or devices, as well as storage device(s), computer and/or network connectivity interfaces (e.g., USB ports, etc.).

[0027] Controller electronics are well known. In one embodiment, the controller may comprise electronics and receiver/display unit configurations such as those described in US Patent Appl. No. 2009/0188054 Al, the entire disclosure of which is incorporated herein by reference.

[0028] The controller may also be in communication with other devices, including e.g., data processing device(s), storage devices, and/or networks. In some embodiments, the patient's glucose activity level can be transmitted to a data network for viewing via a computer or other network interface device. Embodiments that transmit information in this manner are disclosed in U.S. Patent Numbers 6,024,699, 6,168,563, 6,645,142, 6,976,958 and 7,156,809, the disclosures of which are incorporated herein in their entirety by reference thereto. In yet other embodiments, information about the patient's glucose activity level can be transmitted through voice synthesizer or earcon. An example of a system that transmits information to the user via auditory output is disclosed in U.S. Patent Number 7,440,786 the disclosure of which are incorporated herein in their entirety by reference thereto.

[0029] In many embodiments, the controller can be configured to alert the user if the measured glucose activity level rises above or falls below a certain threshold. Examples of such devices that are capable of alerting the user of abnormal glucose levels are described in U.S. Patent Numbers 5,497,772 and 5,791,344, and US Patent Publication No. 2009/0177054A1; the disclosures of which are incorporated herein in their entirety by reference thereto. Such an alarm function may also desirably be initiated based on rates of glucose activity change, e.g., if the glucose activity is dropping rapidly, then an alarm may alert medical personnel that rapid intervention (infusion of glucose) may avert a critical condition before a programmed threshold is reached and thereby facilitate glycemic control. Of course, in some preferred embodiments discussed in greater detail below, the glucose activity level and/or rate of change thereof is communicated from the controller to a blood glucose modulating unit (e.g., an insulin and glucose infusion pump).

[0030] Besides receiving information from the sensor, the controller preferably also controls the light interrogation of the sensor chemistry, e.g., by actuating LED's to provide the excitation light and/or reference light. Of course other light sources, e.g., laser light, may be employed in some embodiments depending on the sensor optics and the indicator chemistry. In some preferred embodiments, the frequency of light interrogation can be controlled based on the blood glucose activity. For example, where the glucose activity level is steady, interrogation rate may be relatively slow/infrequent, thereby conserving energy (battery life in portable controllers) and minimizing any photo-bleaching effect on the indicator chemistry. However, where the glucose activity level is increasing or decreasing the interrogation rate may be increased. This is especially desirable, where glucose activity is dropping and establishing real-time or near real-time glucose monitoring may have greater clinical relevance.

Example of Controller

[0031] In one preferred embodiment, the controller enables a number of functions to be described herein; primarily, however, its fundamental purpose is to "interrogate" (illuminate) the sensor chemistry and to respond to the resultant fluorescent signals which are proportional to the glucose concentration present, and to convert the signal into a glucose value for display and trending. Preferably, it also measures the temperature of the sensor tip and uses the temperature to correct for the glucose concentration as a function of sensed temperature. Preferably, the glucose concentration is also corrected by an indirect measurement of pH which is derived from the same signals fluorescent signals as used for the glucose concentration measurement (algorithmically as described for example in 2008- 0188722 Al).

[0032] In preferred embodiments, the controller connects to the optical sensor and makes the measurements of signal intensity and temperature to produce a glucose value based on the modulation of the fluorescent chemistry. Preferably, it includes a User Interface which is comprised of a LCD and simple keypad, which enables the user to input various parameters e.g., alarm limits, values for the in-vivo adjustment, set the display mode, confirmation of pre-patient insertion calibration of the sensor, etc. Likewise, in preferred embodiments, it will also produce error codes and advise the user via the LCD and built-in alarm buzzer when errant conditions or situations are detected.

[0033] The controller may communicate to an external PC via an IrDA port, for the purpose of programming specific parameters prior to any use, and also for downloading data after use to the PC for further display, printing and report generation. [0034] The major functional blocks of the controller are itemized in Table 1, although it is to be understood that these are illustrative of one preferred embodiment of a controller useful in the systems described herein. Any of the specific functional blocks may be substituted with art-recognized equivalents or alternatives. Likewise, in some embodiments of the controller, not all of these functional blocks be included.

TABLE 1

[0035] With reference to FIG. 1, the microcontroller 1 is at the core of the controller. It and all other circuitry is powered by the Power Supply circuit 14, which obtains its input power from 4 x AA NiMH batteries 13. Microcontroller 1 monitors the Power Supply voltage via Battery Monitor Circuit 12. [0036] Microcontroller 1 controls all of the elements of the system including the User Interface devices (Keypad 9, LCD 5 and the Audible alarm 6) and provides all control for the Optical Subassembly 7. The Optical Subassembly 7 includes LEDs 7a for illuminating the Sensor 17 and detectors 7b for receiving the fluorescent and reference signals. The Optical Subassembly communicates with the Sensor 17 and the Microcontroller 1. In a preferred embodiment, the Optical Subassembly 7 is comprised of two LEDs 7a of two different wavelengths, and two photodiode detectors 7b. The LEDs may be controlled by signals from Microcontroller 1 and an interface circuit (not shown), and via embedded software, can be set to pulse periodically and sequentially e.g., 1/min, 5/min, etc. and at any pulse width between 1 ms to 100 ms. The amplitude of the LED drive current is also adjustable by the Microcontroller 1 up to about 50 ma from virtually 0 ma.

[0037] Synchronous with the LED pulse, the two photodiode detectors 7b receive the "green" and or "blue" signals; green being the result of the fluorescent response of the chemistry and blue being the "reflected" or reference signal. It should be noted that other sensor embodiments could utilize other referencing signals, and that "blue" is just an illustration for the current design embodiment.

[0038] The photodiode detectors 7b are configured in a fairly typical, but highly optimized "transimpedance amplifier" configuration which converts the sensed photodiode current to a voltage. Signal currents are typically in the low picoampere range, from perhaps a few picoamps to a few hundred picoamps. The detected pulses - from each detector - are then amplified and the signals digitized via dual A/D convertors within the Dual Detector Circuit. The A/D convertors enable the digital voltages to be read and stored by the Microcontroller 1.

[0039] It should be noted that the variable parameters at which the LEDs are excited (pulse rate, amplitude, and pulse width) can be adjusted in response to conditions of the patient. For example, the rate could be adjusted to be more frequent at lower glucose levels, and/or when the glucose values are changing rapidly to provide a higher density of information which could be relevant for clinical decision making. Likewise, at higher glucose levels, the excitation values (pulse rate, pulse width) might be reduced in order to reduce the power consumption and extend the overall use time if needed. [0040] The Thermocouple Measurement circuitry 8 measures the sensor temperature via thermocouple embedded within the sensor itself. Likewise, the heater temperature of the separate Calibration Chamber heater is controlled by Heater Controller 4.

[0041] The User Interface 5 is preferably a graphical LCD (e.g., configured as 240 x 160 pixels) which provides all of the controller's information including the calculated (and pH/temperature corrected) glucose value, trend information, rate of change, alarms and alerts, and in conjunction with Keypad 9 enables the User to input and adjust parameters.

[0042] With reference to FIG. 2, an aspect of the optical signal path is the actual transmission of the optical signals from the monitor Optical Subassembly 7 to the sensor (the efferent path) and from the Sensor 17 to the Optical Subassembly 7 (the afferent path). The optical signal transmission is accomplished with the use of a bundled fiber optic cable, which contains a mix of fibers for the efferent and afferent signals. The orientation of the fibers is such that specific fibers are mapped for the efferent blue signals and likewise a number of fibers mapped for the afferent green and blue signals. This particular fiber mapping is an example of one mapping format; other mappings may be used to match new sensor designs which require more or less light or different wavelengths of light for enhanced functionality.

Converting Glucose Activity To Blood Or Plasma Glucose Concentration

[0043] In preferred embodiments, as described above, the controller is operably coupled to the glucose activity sensor. In some embodiments, the controller device can be physically attached to, or an integral part of, a glucose activity sensor. In other embodiments, the controller can be operably coupled to the glucose activity sensor via a network or wireless connection. In preferred embodiments, data concerning the patient's glucose activity level can automatically be input into the controller, e.g., via the operably coupled sensor, or manually input into the controller, e.g., data regarding hematocrit and other blood chemistry measurements. In accordance with preferred embodiments of the invention, the controller comprises a toggle system that allows a user to select the desired output (e.g., glucose activity, blood and/or plasma glucose concentration). The toggle system can comprise a button, switch, knob, touchpad, computer interface, or any other selection actuator that can be operably coupled to the controller. [0044] In some embodiments, when a user actuates the toggle system to instruct the controller to provide data output in the form of blood or plasma glucose concentration, the control system can direct the data processing unit to perform calculations capable of converting glucose activity data to the desired measurement format. The calculations can be performed using established formulae depending on whether the conversion is to plasma or blood glucose concentration.

Glucose Activity to Blood Glucose Concentration

[0045] When a user elects to convert a measured glucose activity to blood glucose concentration [BG], the toggle system can direct the data processing unit to perform a mathematical calculation to convert the glucose activity to [BG]. This calculation requires that the device determine the percentage of blood composed of water. Because blood consists almost entirely of red blood cells and plasma, the water components of these two elements must be determined separately in order to calculate the total volume of water. The percentage of blood composed of red blood cells (hematocrit or HCT) is measured. Since red blood cells are 71% water, the HCT is multiplied by 0.71 to determine the percentage of the HCT composed of water. This sum is then adjusted to take into account the fact that the mass of water at body temperature is 0.99kg/liter. As a result the HCT portion of the blood is 70.29% water. In some embodiments, the patient's HCT can be directly input by the user into the controller. In other embodiments, the HCT can be input automatically by direct data input from any operably coupled means of accessing, storing, or measuring HCT; in one embodiment, the sensor may further comprise a means for estimating HCT (e.g., optical density).

[0046] In order to calculate [BG] from glucose activity, it is also necessary to determine the amount of water present in the remaining plasma component of the blood [(1- HCT) x 0.939394]. The water present in the HCT and the plasma components of the blood can then be added together to determine the total amount of water present. The conversion of glucose activity to [BG] is summarized as equation (1):

[BG] = Glucose Activity x (HCT x 0.7029) + [(1-HCT) x 0.939394] [0047] Thus, in some embodiments, the controller may comprise the necessary algorithms and program instructions to convert direct measurements of glucose activity, along with HCT input, into conventional [BG] values, and further comprise a user selectable toggle system to allow toggling between the measured glucose activity and the calculated [BG] values.

Glucose Activity to Plasma Glucose Concentration

[0048] In some embodiments, the data processing unit can calculate plasma glucose concentration [PG] from glucose activity by determining the percentage of water present in the plasma. The mass of water at body temperature is 0.99kg/liter. Plasma is made up of approximately 93% water. Therefore the conversion factor for plasma is 0.93 divided by 0.99 which yields 0.939394. Therefore, [PG] can be calculated by equation (2):

[PG] = Glucose Activity x 0.939394 (2)

[0049] When so instructed, the data processing unit can convert glucose activity to [PG] using equation (2). These results can then be made available to the user using a data output device (e.g., display, printer, etc.).

[0050] While a number of preferred embodiments of the invention and variations thereof have been described in detail, other modifications and methods of using and medical applications for the same will be apparent to those of skill in the art. Accordingly, it should be understood that various applications, modifications, and substitutions may be made of equivalents without departing from the spirit of the invention or the scope of the claims.

Claims

WHAT IS CLAIMED IS:

1. A blood glucose monitor with user selectable output, comprising:

a glucose sensor configured to reside in a blood vessel and provide a signal related to the level of glucose activity;

a data processing unit programmed to convert the level of glucose activity to a blood glucose concentration and/or a plasma glucose concentration;

a toggle module operable by a user and coupled to the data processing unit for selecting a desired output from among the level of glucose activity, the blood glucose concentration, and the plasma glucose concentration; and an output module configured to allow the user to receive the desired output.

2. The blood glucose monitor of Claim 1, wherein said toggle module comprises a knob, button, switch, touchpad, computer interface, or other means of relaying commands to the data processing unit.

3. The blood glucose monitor of Claim 1, wherein the user can select to receive blood or plasma glucose concentrations in the form of mg/dL units.

4. The blood glucose monitor of Claim 1, wherein the user can select to receive blood or plasma glucose concentrations in the form of mmol/L units.

5. The blood glucose monitor of Claim 1, wherein the output device is selected from the group consisting of a graphic display, printer, network data connection, or other means of transmitting information to the user.

6. The blood glucose monitor of Claim 1, wherein a hematocrit level is received by the data processing unit.

7. The blood glucose monitor of Claim 1 , wherein the glucose sensor comprises an elongate member;

a glucose-responsive indicator disposed along a distal portion of the elongate member, comprising a fluorophore operably coupled to an analyte binding moiety, wherein analyte binding causes a change in the emission intensity of the fluorophore, and wherein the glucose-responsive indictor is disposed within a light path of an optical fiber

a porous membrane covering at least the indicator along the distal portion of the elongate member.

8. The blood glucose monitor of Claim 1, wherein the data processing unit further comprises a calculation module comprising a first algorithm characterized by: [Blood Glucose Concentration] = Glucose Activity x (Hematocrit x 0.7029) + [(1 - Hematocrit) x 0.939394].

9. The blood glucose monitor of Claim 8 wherein the calculation module further comprises a second algorithm characterized by: [Plasma Glucose Concentration] = Glucose Activity x 0.939394.

10. The blood glucose monitor of Claim 1 further comprising a hematocrit information receiving module.

1 1. The blood glucose monitor of Claim 1, further comprising a hematocrit measurement device.

12. A method for monitoring glucose in a subject, the method comprising:

deploying a glucose sensor configured to measure glucose activity in the subject, the glucose sensor comprising:

an optical fiber capable of propagating light along a light path, an equilibrium, non-consuming chemical indicator system disposed within the light path of the optical fiber, wherein the chemical indicator system comprises:

a fluorophore capable of generating a fluorescent emission signal in response to an excitation light signal, and

a glucose binding moiety operably associated with the fluorophore and adapted to modify an intensity of the fluorescent emission signal in relation to the amount of glucose bound;

interrogating the chemical indicator system with an excitation light signal; detecting the intensity of the fluorescent emission signal;

calculating the glucose activity based on the fluorescent emission signal; selecting one or more glucose measurement output mode selected from the group consisting of glucose activity, blood glucose concentration, and plasma glucose concentration; and

outputting a glucose measurement data according to the selected output mode.

13. The method for monitoring glucose of Claim 13, further comprising converting the glucose activity to blood glucose concentration by a first algorithm characterized by: [Blood Glucose Concentration] = Glucose Activity x (Hematocrit x 0.7029) + [(1 - Hematocrit) x 0.939394].

14. The method for monitoring glucose of Claim 13, further comprising converting the glucose activity to plasma glucose concentration by a first algorithm characterized by: [Plasma Glucose Concentration] = Glucose Activity x 0.939394.

15. The method for monitoring glucose of Claim 13, wherein the glucose measurement data comprises glucose activity, blood glucose concentration, and plasma glucose concentration.