Patent Publication Number: US-9414775-B2

Title: Purification of glucose concentration signal in an implantable fluorescence based glucose sensor

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     The present application is a continuation-in-part of U.S. patent application Ser. No. 13/853,095, filed on Mar. 29, 2013, which is incorporated by reference in its entirety and claims the benefit of priority to U.S. Provisional Application Ser. No. 61/617,414, filed on Mar. 29, 2012, which is also incorporated herein by reference in its entirety. 
    
    
     BACKGROUND 
     1. Field of Invention 
     The present invention relates generally to determining a concentration of glucose in interstitial fluid of a living animal using an optical sensor implanted in the living animal. Specifically, the present invention relates to purification of a raw signal including a glucose-modulated component to remove noise (e.g., offset and/or distortion) and converting the processed signal to a glucose concentration. 
     2. Discussion of the Background 
     A sensor may be implanted within a living animal (e.g., a human) used to measure the concentration of glucose in a medium (e.g., interstitial fluid (ISF) or blood) within the living animal. The sensor may include a light source (e.g., a light-emitting diode (LED) or other light emitting element), indicator molecules, and a photodetector (e.g., a photodiode, phototransistor, photoresistor or other photosensitive element). Examples of implantable sensors employing indicator molecules to measure the concentration of an analyte are described in U.S. Pat. Nos. 5,517,313 and 5,512,246, which are incorporated herein by reference in their entirety. 
     Broadly speaking, in the context of the field of the present invention, indicator molecules are molecules having one or more optical characteristics that is or are affected by the local presence of an analyte such as glucose. The indicator molecules may be fluorescent indicator molecules, and the fluorescence of the indicator molecules may be modulated, i.e., attenuated or enhanced, by the local presence of glucose. 
     The implantable sensor may be configured such that fluorescent light emitted by the indicator molecules impacts the photodetector, which generates a raw electrical signal based on the amount of light received thereby. The generated raw electrical signal may be indicative of the concentration of glucose in the medium surrounding the indicator molecules, but the raw signal may also include noise (e.g., offset and/or distortion) that affects the accuracy of the glucose concentration measurement produced from the raw signal. 
     There is presently a need in the art for a more accurate sensor capable of measuring glucose concentration in a medium of a living animal. 
     SUMMARY 
     One aspect of the invention may provide a method of determining a concentration of glucose in a medium of a living animal using an optical sensor implanted in the living animal and a sensor reader external to the living animal. The method may include emitting, using a light source of the optical sensor, excitation light to indicator molecules of the optical sensor. The indicator molecules may have an optical characteristic responsive to the concentration of glucose. The method may include generating, using a photodetector of the optical sensor, a raw signal indicative of the amount of light received by the photodetector. The light received by the photodetector may include glucose-modulated light emitted by the indicator molecules and at least one of excitation light emitted by the light source and non-glucose modulated light emitted by the indicator molecules. The method may include conveying, using an inductive element of the optical sensor, the raw signal. The method may include receiving, using an inductive element of the sensor reader, the conveyed raw signal. The method may include tracking, using circuitry of the sensor reader, the cumulative emission time that the light source has emitted the excitation light. The method may include tracking, using circuitry of the sensor reader, the implant time that has elapsed since the optical sensor was implanted in the living animal. The method may include adjusting, using circuitry of the sensor reader, the received raw signal to compensate for offset and distortion based on the tracked cumulative emission time and the tracked implant time. The method may include converting, using circuitry of the sensor reader, the adjusted signal into a measurement of glucose concentration in the medium of the living animal. 
     Another aspect of the invention may provide a system for determining a concentration of glucose in a medium of a living animal. The system may include and optical sensor implanted in the living animal and a sensor external to the living animal. The optical sensor may include: indicator molecules, a light source, a photodetector, and an inductive element. The indicator molecules may have an optical characteristic responsive to the concentration of glucose. The light source may be configured to emit excitation light to the indicator molecules. The photodetector may be configured to generate a raw signal indicative of the amount of light received by the photodetector. The light received by the photodetector may include glucose-modulated light emitted by the indicator molecules and at least one of excitation light emitted by the light source and non-glucose modulated light emitted by the indicator molecules. The inductive element may be configured to convey the raw signal. The sensor reader may include an inductive element and circuitry. The inductive element may be configured to receive the conveyed raw signal. The circuitry may be configured to: track the cumulative emission time that the light source has emitted the excitation light; track the implant time that has elapsed since the optical sensor was implanted in the living animal; adjust the received raw signal to compensate for offset and distortion based on the tracked cumulative emission time and the tracked implant time; and convert the adjusted signal into a measurement of glucose concentration in the medium of the living animal. 
     Another aspect of the invention may provide a method of determining a concentration of glucose in a medium of a living animal using an optical sensor implanted in the living animal and a sensor reader external to the living animal. The method may include emitting, using a light source of the optical sensor, excitation light to indicator molecules of the optical sensor. The indicator molecules may have an optical characteristic responsive to the concentration of glucose. The method may include generating, using a photodetector of the optical sensor, a raw signal indicative of the amount of light received by the photodetector. The light received by the photodetector may include glucose-modulated light emitted by the indicator molecules and at least one of excitation light emitted by the light source and non-glucose modulated light emitted by the indicator molecules. The method may include measuring, using a temperature sensor of the optical sensor, a temperature of the optical sensor. The method may include conveying, using an inductive element of the optical sensor, the raw signal and measured temperature. The method may include receiving, using an inductive element of the sensor reader, the conveyed raw signal and the conveyed temperature. The method may include tracking the cumulative emission time that the light source has emitted the excitation light. The method may include tracking the implant time that has elapsed since the optical sensor was implanted in the living animal. The method may include temperature correcting, using circuitry of the sensor reader, the received raw signal to compensate for temperature sensitivity of the light source based on the received measured temperature. The method may include offset adjusting, using the circuitry of the sensor reader, the temperature corrected raw signal to compensate for offset based on the tracked cumulative emission time. The method may include distortion adjusting, using the circuitry of the sensor reader, the offset adjusted raw signal to compensate for distortion based on the tracked cumulative emission time and the tracked implant time. The method may include normalizing, using the circuitry of the sensor reader, the distortion adjusted raw signal to a normalized raw signal that would be equal to one at zero glucose concentration based on the measured temperature, the tracked cumulative emission time, and the tracked implant time. The method may include converting, using the circuitry of the sensor reader, the normalized raw signal into a measurement of glucose concentration in the medium of the living animal. 
     Still another aspect of the invention may provide a method of determining a concentration of glucose in a medium of a living animal using an optical sensor implanted in the living animal and a sensor reader external to the living animal. The method may include emitting, using a light source of the optical sensor, excitation light to indicator molecules of the optical sensor. The indicator molecules may have an optical characteristic responsive to the concentration of glucose. The method may include generating, using a photodetector of the optical sensor, a raw signal indicative of the amount of light received by the photodetector. The light received by the photodetector may include glucose-modulated light emitted by the indicator molecules and at least one of excitation light emitted by the light source and non-glucose modulated light emitted by the indicator molecules. The method may include tracking the cumulative emission time that the light source has emitted the excitation light. The method may include tracking the implant time that has elapsed since the optical sensor was implanted in the living animal. The method may include adjusting the raw signal to compensate for offset and distortion based on the tracked cumulative emission time and the tracked implant time. The method may include converting the adjusted signal into a measurement of glucose concentration in the medium of the living animal. 
     Another aspect of the invention may provide a method of determining a concentration of glucose in a medium of a living animal using an optical sensor implanted in the living animal and a sensor reader external to the living animal. The method may include emitting, using a light source of the optical sensor, excitation light to indicator molecules of the optical sensor. The indicator molecules may have an optical characteristic responsive to the concentration of glucose. The method may include generating, using a photodetector of the optical sensor, a raw signal indicative of the amount of light received by the photodetector. The light received by the photodetector may include glucose-modulated light emitted by the indicator molecules and at least one of excitation light emitted by the light source and non-glucose modulated light emitted by the indicator molecules. The method may include measuring, using a temperature sensor of the optical sensor, a temperature of the optical sensor. The method may include tracking the cumulative emission time that the light source has emitted the excitation light. The method may include tracking the implant time that has elapsed since the optical sensor was implanted in the living animal. The method may include temperature correcting the raw signal to compensate for temperature sensitivity of the light source based on the measured temperature. The method may include offset adjusting the temperature corrected raw signal to compensate for offset based on the tracked cumulative emission time. The method may include distortion adjusting the offset adjusted raw signal to compensate for distortion based on the tracked cumulative emission time and the tracked implant time. The method may include normalizing the distortion adjusted raw signal to a normalized raw signal that would be equal to one at zero glucose concentration based on the measured temperature, the tracked cumulative emission time, and the tracked implant time. The method may include converting the normalized raw signal into a measurement of glucose concentration in the medium of the living animal. 
     Further variations encompassed within the systems and methods are described in the detailed description of the invention below. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The accompanying drawings, which are incorporated herein and form part of the specification, illustrate various, non-limiting embodiments of the present invention. In the drawings, like reference numbers indicate identical or functionally similar elements. 
         FIG. 1  is a schematic view illustrating a sensor system embodying aspects of the present invention. 
         FIG. 2  illustrates a raw signal purification and conversion process that may be performed by the circuitry of an optical sensor in accordance with an embodiment of the present invention. 
         FIG. 3  illustrates the components of the excitation light received by the photodetector that contribute to the offset in the raw signal in accordance with an embodiment of the present invention. 
         FIG. 4  illustrates the reactions and kinetics of the related species of the indicator molecules in accordance with an embodiment of the present invention. 
         FIG. 5  illustrates the relationship between normalized glucose-modulated fluorescence (I/I 0 ) and glucose concentration in accordance with an embodiment of the present invention. 
         FIG. 6  illustrates a circuit diagram that may be used in accordance with one embodiment of the present invention. 
         FIG. 7  illustrates a Clarke error grid showing the experimental results of 18 sensors embodying aspects of the present invention and implanted in Type I diabetic subjects. 
         FIG. 8  illustrates experimental results of a sensor embodying aspects of the present invention during six read sessions. 
         FIG. 9  is a schematic view illustrating a sensor reader embodying aspects of the present invention. 
         FIG. 10  illustrates a raw signal purification and conversion process that may be performed by the circuitry of a sensor reader in accordance with an embodiment of the present invention. 
     
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
       FIG. 1  is a schematic view of a sensor system embodying aspects of the present invention. In one non-limiting embodiment, the system includes a sensor  100  and an external sensor reader  101 . In the embodiment shown in  FIG. 1 , the sensor  100  may be implanted in a living animal (e.g., a living human). The sensor  100  may be implanted, for example, in a living animal&#39;s arm, wrist, leg, abdomen, or other region of the living animal suitable for sensor implantation. For example, in one non-limiting embodiment, the sensor  100  may be implanted between the skin and subcutaneous tissues. In some embodiments, the sensor  100  may be an optical sensor (e.g., a fluorometer). In some embodiments, the sensor  100  may be a chemical or biochemical sensor. 
     A sensor reader  101  may be an electronic device that communicates with the sensor  100  to power the sensor  100  and/or obtain analyte (e.g., glucose) readings from the sensor  100 . In non-limiting embodiments, the reader  101  may be a handheld reader, a wristwatch, an armband, or other device placed in close proximity to the sensor  100 . In one embodiment, positioning (i.e., hovering or swiping/waiving/passing) the reader  101  within range over the sensor implant site (i.e., within proximity of the sensor  100 ) will cause the reader  101  to automatically convey a measurement command to the sensor  100  and receive a reading from the sensor  100 . 
     In some embodiments, the sensor reader  101  may include an inductive element  103 , such as, for example, a coil. The sensor reader  101  may generate an electromagnetic wave or electrodynamic field (e.g., by using a coil) to induce a current in an inductive element  114  of the sensor  100 , which powers the sensor  100 . The sensor reader  101  may also convey data (e.g., commands) to the sensor  100 . For example, in a non-limiting embodiment, the sensor reader  101  may convey data by modulating the electromagnetic wave used to power the sensor  100  (e.g., by modulating the current flowing through a coil  103  of the sensor reader  101 ). The modulation in the electromagnetic wave generated by the reader  101  may be detected/extracted by the sensor  100 . Moreover, the sensor reader  101  may receive data (e.g., measurement information) from the sensor  100 . For example, in a non-limiting embodiment, the sensor reader  101  may receive data by detecting modulations in the electromagnetic wave generated by the sensor  100 , e.g., by detecting modulations in the current flowing through the coil  103  of the sensor reader  101 . 
     The inductive element  103  of the sensor reader  101  and the inductive element  114  of the sensor  100  may be in any configuration that permits adequate field strength to be achieved when the two inductive elements are brought within adequate physical proximity. 
       FIG. 9  is a schematic view of a sensor reader  101  according to a non-limiting embodiment. In some embodiments, the sensor reader  101  may have a connector  902 , such as, for example, a Micro-Universal Serial Bus (USB) connector. The connector  902  may enable a wired connection to an external device, such as a personal computer or smart phone. The sensor reader  101  may exchange data to and from the external device through the connector  902  and/or may receive power through the connector  902 . The sensor reader  101  may include a connector integrated circuit (IC)  904 , such as, for example, a USB-IC, which may control transmission and receipt of data through the connector  902 . The sensor reader  101  may also include a charger IC  906 , which may receive power via the connector  902  and charge a battery  908 . 
     In some embodiments, the sensor reader  101  may have a wireless communication IC  910 , which enables wireless communication with an external device, such as, for example, a personal computer or smart phone. In one non-limiting embodiment, the communication IC  910  may employ a standard, such as, for example, a Buetooth Low Energy (BLE) standard (e.g., BLE 4.0), to wirelessly transmit and receive data to and from an external device. 
     In some embodiments, the sensor reader  101  may include voltage regulators  912  and/or a voltage booster  914 . The battery  908  may supply power (via voltage booster  914 ) to radio-frequency identification (RFID) reader IC  916 , which uses the inductive element  103  to convey information (e.g., commands) to the sensor  101  and receive information (e.g., measurement information) from the sensor  100 . In the illustrated embodiment, the inductive element is a flat antenna. However, as noted above, the inductive element  103  of the sensor reader  101  may be in any configuration that permits adequate field strength to be achieved when brought within adequate physical proximity to the inductive element  114  of the sensor  100 . In some embodiments, the sensor reader  101  may include a power amplifier  918  to amplify the signal to be conveyed by the inductive element  103  to the sensor  100 . 
     The sensor reader  101  may include a peripheral interface controller (PIC) microcontroller  920  and memory  922  (e.g., Flash memory), which may be non-volatile and/or capable of being electronically erased and/or rewritten. The PIC microcontroller  920  may control the overall operation of the sensor reader  101 . For example, the PIC microcontroller  920  may control the connector IC  904  or wireless communication IC  910  to transmit data and/or control the RFID reader IC  916  to convey data via the inductive element  103 . The PIC microcontroller  920  may also control processing of data received via the inductive element  103 , connector  902 , or wireless communication IC  910 . 
     In some embodiments, the sensor reader  101  may include a display  924  (e.g., liquid crystal display), which PIC microcontroller  920  may control to display data (e.g., glucose concentration values). In some embodiments, the sensor reader  101  may include a speaker  926  (e.g., a beeper) and/or vibration motor  928 , which may be activated, for example, in the event that an alarm condition (e.g., detection of a hypoglycemic or hyperglycemic condition) is met. The sensor reader  101  may also include one or more additional sensors  930 , which may include an accelerometer and/or temperature sensor, that may be used in the processing performed by the PIC microcontroller  920 . 
     In one non-limiting embodiment, as illustrated in  FIG. 1 , sensor  100  includes a sensor housing  102  (i.e., body, shell, capsule, or encasement), which may be rigid and biocompatible. In exemplary embodiments, sensor housing  102  may be formed from a suitable, optically transmissive polymer material, such as, for example, acrylic polymers (e.g., polymethylmethacrylate (PMMA)). 
     In some embodiments, the sensor  100  includes indicator molecules  104 . Indicator molecules  104  may be fluorescent indicator molecules (e.g., Trimethyltrifluromethylsilane (TFM) fluorescent indicator molecules) or absorption indicator molecules. In some embodiments, the indicator molecules  104  may reversibly bind glucose. When an indicator molecule  104  has bound glucose, the indicator molecule may become fluorescent, in which case the indicator molecule  104  is capable of absorbing (or being excited by) excitation light  329  and emitting light  331 . In one non-limiting embodiment, the excitation light  329  may have a wavelength of approximately 378 nm, and the emission light  331  may have a wavelength in the range of 400 to 500 nm. When no glucose is bound, the indicator molecule  104  may be only weakly fluorescent. 
     In some non-limiting embodiments, sensor  100  may include a polymer graft  106  coated, diffused, adhered, or embedded on at least a portion of the exterior surface of the sensor housing  102 , with the indicator molecules  104  distributed throughout the polymer graft  106 . In some embodiments, the polymer graft  106  may be a fluorescent glucose indicating polymer. In one non-limiting embodiment, the polymer is biocompatible and stable, grafted onto the surface of sensor housing  102 , designed to allow for the direct measurement of interstitial fluid (ISF) glucose after subcutaneous implantation of the sensor  100 . 
     In some non-limiting embodiments, the polymer graft  106  may include three monomers: the TFM fluorescent indicator, hydroxyethylmethacrylate (HEMA), and polyethylene glycol methacrylate (PEG-methacrylate). In one embodiment, the polymer graft  106  may include the three monomers in specific molar ratios, with the fluorescent indicator comprising 0.1 molar percent, HEMA comprising 94.3 molar percent, and PEG-methacrylate comprising 5.6 molar percent. The PEG-methacrylate may act as a cross-linker and be what creates a sponge-like matrix. Conventional free radical polymerization may be used to synthesize the polymer that is grafted onto the sensor  100 . 
     In some embodiments, the sensor  100  may include a light source  108 , which may be, for example, a light emitting diode (LED) or other light source, that emits radiation, including radiation over a range of wavelengths that interact with the indicator molecules  104 . In other words, the light source  108  may emit the excitation light  329  that is absorbed by the indicator molecules in the matrix layer/polymer  104 . As noted above, in one non-limiting embodiment, the light source  108  may emit excitation light  329  at a wavelength of approximately 378 nm. 
     In some embodiments, the sensor  100  may also include one or more photodetectors (e.g., photodiodes, phototransistors, photoresistors or other photosensitive elements). For example, in the embodiment illustrated in  FIG. 1 , sensor  100  has a first photodetector  224  and a second photodetector  226 . However, this is not required, and, in some alternative embodiments, the sensor  100  may only include the first photodetector  224 . 
     Some part of the excitation light  329  emitted by the light source  108  may be reflected from the polymer graft  106  back into the sensor  100  as reflection light  331 , and some part of the absorbed excitation light may be emitted as emitted (fluoresced) light  331 . In one non-limiting embodiment, the emitted light  331  may have a higher wavelength than the wavelength of the excitation light  329 . The reflected light  333  and emitted (fluoresced) light  331  may be absorbed by the one or more photodetectors (e.g., first and second photodetectors  224  and  226 ) within the body of the sensor  100 . 
     Each of the one or more photodetectors may be covered by a filter  112  (see  FIG. 3 ) that allows only a certain subset of wavelengths of light to pass through. In some embodiments, the one or more filters  112  may be thin glass filters. In some embodiments, the one or more filters  112  may be thin film (dichroic) filters deposited on the glass and may pass only a narrow band of wavelengths and otherwise reflect most of the light. In one non-limiting embodiment, the second (reference) photodetector  226  may be covered by a reference photodiode filter that passes light at the same wavelength as is emitted from the light source  108  (e.g., 378 nm). The first (signal) photodetector  224  may detect the amount of fluoresced light  331  that is emitted from the molecules  104  in the graft  106 . In one non-limiting embodiment, the peak emission of the indicator molecules  104  may occur around 435 nm, and the first photodetector  224  may be covered by a signal filter that passes light in the range of about 400 nm to 500 nm. In some embodiments, higher glucose levels/concentrations correspond to a greater amount of fluorescence of the molecules  104  in the graft  106 , and, therefore, a greater number of photons striking the first photodetector  224 . 
     In some embodiments, sensor  100  may include a substrate  116 . In some non-limiting embodiments, the substrate  116  may be a semiconductor substrate and circuitry may be fabricated in the semiconductor substrate  116 . The circuitry may include analog and/or digital circuitry. Also, although in some preferred embodiments the circuitry is fabricated in the semiconductor substrate  116 , in alternative embodiments, a portion or all of the circuitry may be mounted or otherwise attached to the semiconductor substrate  116 . In other words, in alternative embodiments, a portion or all of the circuitry, which may include discrete circuit elements, an integrated circuit (e.g., an application specific integrated circuit (ASIC)) and/or other electronic components, may be fabricated in the semiconductor substrate  116  with the remainder of the circuitry is secured to the semiconductor substrate  116 , which may provide communication paths between the various secured components. In some embodiments, circuitry of the sensor  100  may have the structure described in U.S. patent application Ser. No. 13/650,016, which is incorporated herein by reference in its entirety, with reference to  FIG. 11D . 
       FIG. 6  is block diagram illustrating the functional blocks of the circuitry of sensor  100  according to a non-limiting embodiment in which the circuitry is fabricated in the semiconductor substrate  116 . As shown in the embodiment of  FIG. 6 , in some embodiments, an input/output (I/O) frontend block  536  may be connected to the external inductive element  114 , which may be in the form of a coil  220 , through coil contacts  428   a  and  428   b . The I/O frontend block  536  may include a rectifier  640 , a data extractor  642 , a clock extractor  644 , clamp/modulator  646  and/or frequency divider  648 . Data extractor  642 , clock extractor  644  and clamp/modulator  646  may each be connected to external coil  220  through coil contacts  428   a  and  428   b . The rectifier  640  may convert an alternating current produced by coil  220  to a direct current that may be used to power the sensor  100 . For instance, the direct current may be used to produce one or more voltages, such as, for example, voltage VDD_A, which may be used to power the one or more photodetectors (e.g., photodetectors  224  and  226 ). In one non-limiting embodiment, the rectifier  640  may be a Schottky diode; however, other types of rectifiers may be used in other embodiments. The data extractor  642  may extract data from the alternating current produced by coil  220 . The clock extractor  644  may extract a signal having a frequency (e.g., 13.56 MHz) from the alternating current produced by coil  220 . The frequency divider  648  may divide the frequency of the signal output by the clock extractor  644 . For example, in a non-limiting embodiment, the frequency divider  648  may be a 4:1 frequency divider that receives a signal having a frequency (e.g., 13.56 MHz) as an input and outputs a signal having a frequency (e.g., 3.39 MHz) equal to one fourth the frequency of the input signal. The outputs of rectifier  640  may be connected to one or more external capacitors  118  (e.g., one or more regulation capacitors) through contacts  428   h  and  428   i.    
     In some embodiments, an I/O controller  538  may include a decoder/serializer  650 , command decoder/data encoder  652 , data and control bus  654 , data serializer  656  and/or encoder  658 . The decoder/serializer  650  may decode and serialize the data extracted by the data extractor  642  from the alternating current produced by coil  220 . The command decoder/data encoder  652  may receive the data decoded and serialized by the decoder/serializer  650  and may decode commands therefrom. The data and control bus  654  may receive commands decoded by the command decoder/data encoder  652  and transfer the decoded commands to the measurement controller  532 . The data and control bus  654  may also receive data, such as measurement information, from the measurement controller  532  and may transfer the received data to the command decoder/data encoder  652 . The command decoder/data encoder  652  may encode the data received from the data and control bus  654 . The data serializer  656  may receive encoded data from the command decoder/data encoder  652  and may serialize the received encoded data. The encoder  658  may receive serialized data from the data serializer  656  and may encode the serialized data. In a non-limiting embodiment, the encoder  658  may be a Manchester encoder that applies Manchester encoding (i.e., phase encoding) to the serialized data. However, in other embodiments, other types of encoders may alternatively be used for the encoder  658 , such as, for example, an encoder that applies 8B/10B encoding to the serialized data. 
     The clamp/modulator  646  of the I/O frontend block  536  may receive the data encoded by the encoder  658  and may modulate the current flowing through the inductive element  114  (e.g., coil  220 ) as a function of the encoded data. In this way, the encoded data may be conveyed wirelessly by the inductive element  114  as a modulated electromagnetic wave. The conveyed data may be detected by an external reading device by, for example, measuring the current induced by the modulated electromagnetic wave in a coil of the external reading device. Furthermore, by modulating the current flowing through the coil  220  as a function of the encoded data, the encoded data may be conveyed wirelessly by the coil  220  as a modulated electromagnetic wave even while the coil  220  is being used to produce operating power for the sensor  100 . See, for example, U.S. Pat. Nos. 6,330,464 and 8,073,548, which are incorporated herein by reference in their entireties and which describe a coil used to provide operative power to an optical sensor and to wirelessly convey data from the optical sensor. In some embodiments, the encoded data is conveyed by the sensor  100  using the clamp/modulator  646  at times when data (e.g., commands) are not being received by the sensor  100  and extracted by the data extractor  642 . For example, in one non-limiting embodiment, all commands may be initiated by an external sensor reader (e.g., reader  101  of  FIG. 1 ) and then responded to by the sensor  100  (e.g., after or as part of executing the command). In some embodiments, the communications received by the inductive element  114  and/or the communications conveyed by the inductive element  114  may be radio frequency (RF) communications. Although, in the illustrated embodiments, the sensor  100  includes a single coil  220 , alternative embodiments of the sensor  100  may include two or more coils (e.g., one coil for data transmission and one coil for power and data reception). 
     In an embodiment, the I/O controller  538  may also include a nonvolatile storage medium  660 . In a non-limiting embodiment, the nonvolatile storage medium  660  may be an electrically erasable programmable read only memory (EEPROM). However, in other embodiments, other types of nonvolatile storage media, such as flash memory, may be used. The nonvolatile storage medium  660  may receive write data (i.e., data to be written to the nonvolatile storage medium  660 ) from the data and control bus  654  and may supply read data (i.e., data read from the nonvolatile storage medium  660 ) to the data and control bus  654 . In some embodiments, the nonvolatile storage medium  660  may have an integrated charge pump and/or may be connected to an external charge pump. In some embodiments, the nonvolatile storage medium  660  may store identification information (i.e., traceability or tracking information), measurement information and/or setup parameters (i.e., calibration information). In one embodiment, the identification information may uniquely identify the sensor  100 . The unique identification information may, for example, enable full traceability of the sensor  100  through its production and subsequent use. In one embodiment, the nonvolatile storage medium  660  may store calibration information for each of the various sensor measurements. 
     In some embodiments, the analog interface  534  may include a light source driver  662 , analog to digital converter (ADC)  664 , a signal multiplexer (MUX)  666  and/or comparator  668 . In a non-limiting embodiment, the comparator  668  may be a transimpedance amplifier, in other embodiments, different comparators may be used. The analog interface  534  may also include light source  108 , one or more photodetectors (e.g., first and second photodetectors  224  and  226 ), and/or a temperature sensor  670  (e.g., temperature transducer). 
     In some embodiments, the one or more photodetectors (e.g., photodetectors  224  and  226 ) may be mounted on the semiconductor substrate  116 , but, in some preferred embodiments, the one or more photodetectors  110  may be fabricated in the semiconductor substrate  116 . In some embodiments, the light source  108  may be mounted on the semiconductor substrate  116 . For example, in a non-limiting embodiment, the light source  108  may be flip-chip mounted on the semiconductor substrate  116 . However, in some embodiments, the light source  108  may be fabricated in the semiconductor substrate  116 . 
     In a non-limiting, exemplary embodiment, the temperature transducer  670  may be a band-gap based temperature transducer. However, in alternative embodiments, different types of temperature transducers may be used, such as, for example, thermistors or resistance temperature detectors. Furthermore, like the light source  108  and one or more photodetectors, in one or more alternative embodiments, the temperature transducer  670  may be mounted on semiconductor substrate  116  instead of being fabricated in semiconductor substrate  116 . 
     The light source driver  662  may receive a signal from the measurement controller  532  indicating the light source current at which the light source  108  is to be driven, and the light source driver  662  may drive the light source  108  accordingly. The light source  108  may emit radiation from an emission point in accordance with a drive signal from the light source driver  662 . The radiation may excite indicator molecules  104  distributed throughout the graft  106 . The one or more photodetectors (e.g., first and second photodetectors  224  and  226 ) may each output an analog light measurement signal indicative of the amount of light received by the photodetector. For instance, in the embodiment illustrated in  FIG. 6 , the first photodetector  224  may output a first analog light measurement signal indicative of the amount of light received by the first photodetector  224 , and the second photodetector  226  may output a first analog light measurement signal indicative of the amount of light received by the second photodetector  226 . The comparator  668  may receive the first and second analog light measurement signals from the first and second photodetectors  224  and  226 , respectively, and output an analog light difference measurement signal indicative of the difference between the first and second analog light measurement signals. The temperature transducer  670  may output an analog temperature measurement signal indicative of the temperature of the sensor  100 . The signal MUX  666  may select one of the analog temperature measurement signal, the first analog light measurement signal, the second analog light measurement signal and the analog light difference measurement signal and may output the selected signal to the ADC  664 . The ADC  664  may convert the selected analog signal received from the signal MUX  666  to a digital signal and supply the digital signal to the measurement controller  532 . In this way, the ADC  664  may convert the analog temperature measurement signal, the first analog light measurement signal, the second analog light measurement signal, and the analog light difference measurement signal to a digital temperature measurement signal, a first digital light measurement signal, a second digital light measurement signal, and a digital light difference measurement signal, respectively, and may supply the digital signals, one at a time, to the measurement controller  532 . 
     In some embodiments, the measurement controller  532  may receive one or more digital measurements and generate measurement information, which may be indicative of the presence and/or concentration of an analyte (e.g., glucose) in a medium in which the sensor  100  is implanted. In some embodiments, the generation of the measurement information may include conversion of a digitized raw signal (e.g., the first digital light measurement signal) into a glucose concentration. For accurate conversion, the measurement controller  532  may take into consideration the optics, electronics, and chemistry of the sensor  100 . Further, in some embodiments, the measurement controller  532  may be used to obtain a purified signal of glucose concentration by eliminating noise (e.g., offset and distortions) that is present in the raw signals (e.g., the first digital light measurement signals). 
     In some embodiments, the circuitry of sensor  100  fabricated in the semiconductor substrate  116  may additionally include a clock generator  671 . The clock generator  671  may receive, as an input, the output of the frequency divider  648  and generate a clock signal CLK. The clock signal CLK may be used by one or more components of one or more of the I/O frontend block  536 , I/O controller  538 , measurement controller  532 , and analog interface  534 . 
     In a non-limiting embodiment, data (e.g., decoded commands from the command decoder/data encoder  652  and/or read data from the nonvolatile storage medium  660 ) may be transferred from the data and control bus  654  of the I/O controller  538  to the measurement controller  532  via transfer registers and/or data (e.g., write data and/or measurement information) may be transferred from the measurement controller  532  to the data and control bus  654  of the I/O controller  538  via the transfer registers. 
     In some embodiments, the circuitry of sensor  100  may include a field strength measurement circuit. In embodiments, the field strength measurement circuit may be part of the I/O front end block  536 , I/O controller  538 , or the measurement controller  532  or may be a separate functional component. The field strength measurement circuit may measure the received (i.e., coupled) power (e.g., in mWatts). The field strength measurement circuit of the sensor  100  may produce a coupling value proportional to the strength of coupling between the inductive element  114  (e.g., coil  220 ) of the sensor  100  and the inductive element of the external reader  101 . For example, in non-limiting embodiments, the coupling value may be a current or frequency proportional to the strength of coupling. In some embodiments, the field strength measurement circuit may additionally determine whether the strength of coupling/received power is sufficient to perform an analyte concentration measurement and convey the results thereof to the external sensor reader  101 . For example, in some non-limiting embodiments, the field strength measurement circuit may detect whether the received power is sufficient to produce a certain voltage and/or current. In one non-limiting embodiment, the field strength measurement circuit may detect whether the received power produces a voltage of at least approximately 3V and a current of at least approximately 0.5 mA. However, other embodiments may detect that the received power produces at least a different voltage and/or at least a different current. In one non-limiting embodiment, the field strength measurement circuit may compare the coupling value field strength sufficiency threshold. 
     In the illustrated embodiment, the clamp/modulator  646  of the I/O circuit  536  acts as the field strength measurement circuit by providing a value (e.g., I couple ) proportional to the field strength. The field strength value I couple  may be provided as an input to the signal MUX  666 . When selected, the MUX  666  may output the field strength value I couple  to the ADC  664 . The ADC  664  may convert the field strength value I couple  received from the signal MUX  666  to a digital field strength value signal and supply the digital field strength signal to the measurement controller  532 . In this way, the field strength measurement may be made available to the measurement controller  532  and may be used in initiating an analyte measurement command trigger based on dynamic field alignment. However, in an alternative embodiment, the field strength measurement circuit may instead be an analog oscillator in the sensor  100  that sends a frequency corresponding to the voltage level on a rectifier  640  back to the reader  101 . 
     In some embodiments, the sensor  100  may be used to obtain accurate ISF glucose readings in patients, and the circuitry of the sensor  100  (which may, for example, include measurement controller  532 ) may convert the raw signal generated by the photodetector  224  into a glucose concentration. For accurate conversion, the circuitry of the sensor  100  may take into consideration the optics, electronics, and chemistry of the sensor  100 . Further, in some embodiments, the circuitry may be used to obtain a purified signal of glucose concentration by eliminating noise (e.g., offset and distortions) that are present in raw signals from the sensor  100 . 
     In some embodiments, the circuitry may use parameters measured during manufacturing of the sensor  100  and parameters characterized as a result of in vitro and in vivo tests to convert the raw signals generated by the sensor  100  into glucose concentrations. In some embodiments, the intermediate steps performed by the circuitry of the sensor  100  in determining a glucose concentration from a raw signal may be: (i) purifying the raw signal, (ii) normalizing the purified signal to produce a normalized signal Sn that is directly proportional to glucose concentration, and (iii) converting the normalized signal Sn into a glucose concentration. 
     The purification may involve compensating for/removing impurities, such as an offset produced by the excitation light  329  and distortion produced by non-glucose modulated light emitted by the indicator molecules  104 . In some embodiments, the purification may also involve correcting the raw signal for temperature sensitivity. Accordingly, the purified signal may be proportional to the glucose modulated indicator fluorescence emitted by the indicator molecules  104 . 
     The raw signals from the sensor  100 , as captured by the photodetector  224 , may contain noise (e.g., offset and distortions), which are not related to actual glucose modulation of the indicator molecules  104 . The fluorescent amplitude of the light  331  emitted by the indicator molecules  104 , as well as some elements of the electronic circuitry within the sensor  100 , may be temperature sensitive. The circuitry may, therefore, purify the raw signal by removing the non-glucose-modulated offset/distortion of the raw signal and correcting for temperature sensitivity before normalizing the signal and converting the normalized signal to a glucose concentration. 
       FIG. 2  illustrates an exemplary raw signal purification and conversion process  200  that may be performed by the circuitry of optical sensor  100 , which may be, for example, implanted within a living animal (e.g., a living human), in accordance with an embodiment of the present invention. The process  200  may include a step S 202  of tracking the amount of time t i  that has elapsed since the optical sensor was implanted in the living animal. Because oxidation and thermal degradation begins when the sensor  100  is implanted, the implant time t i  may be equivalent to the oxidation time t ox  and the thermal degradation time t th . 
     In some embodiments, the circuitry of sensor  100  may include an implant timer circuit that is started when the sensor is implanted. For example, in one non-limiting embodiment, the implant timer circuit may be a counter that increments with each passing of a unit of time (e.g., one or more milliseconds, one more seconds, one or more minutes, one or more hours, or one or more days, etc.). However, this is not required, and, in some alternative embodiments, the circuitry of the sensor  100  may track the implant time t i  by storing the time at which the sensor was implanted (e.g., in nonvolatile storage medium  660 ) and comparing the stored time with the current time, which may, for example, be received from the external reader  101  (e.g., with an measurement command from the external reader  101 ). In other alternative embodiments, the sensor  100  may store the time at which the sensor was implanted, i.e., the implant time t i  (e.g., in nonvolatile storage medium  660 ), which may then be read by an external unit (e.g., sensor reader  101 ) for calculation of the implant time t i . As explained in detail below, the tracked implant time t i  may be used in compensating for distortion in the raw signal, normalizing the raw signal, and/or converting the normalized signal Sn to a glucose concentration. 
     The process  200  may include a step S 204  of tracking the cumulative amount of time t e  that the light source  108  has emitted the excitation light  329 . Because the indicator molecules  104  are irradiated with the excitation light  329 , the cumulative emission time t e  may be equivalent to the photobleaching time t pb . 
     In some embodiments, the circuitry of sensor  100  includes an emission timer circuit that is advanced while the light source  108  emits excitation light  329 . For example, in one non-limiting embodiment, the emission timer circuit may be a counter that increments with each passing of a unit of time (e.g., one or more milliseconds, one more seconds, one or more minutes, one or more hours, or one or more days, etc.) while the light source  108  emits excitation light  329 . However, this is not required. For example, in some alternative embodiments, the light source  108  may emit excitation light  329  for a set amount of time for each measurement, and the counter may increment once for each measurement taken by the sensor  100 . As explained in detail below, the tracked cumulative emission time t e  may be used in compensating for offset in the raw signal, compensating for distortion in the raw signal, normalizing the raw signal, and/or converting the normalized signal Sn to a glucose concentration. 
     The process  200  may include a step S 206  of emitting excitation light  329 . The excitation light  329  may be emitted by light source  108 . In some embodiments, step S 206  may be carried out in response to a measurement command from the external sensor reader  101  (e.g., under the control of a measurement controller). Execution of step S 206  may cause incrementing of the tracked cumulative emission time t e , which may be equivalent to the photobleaching time t pb . 
     The process  200  may include a step S 208  of generating a raw signal indicative of the amount of light received by a photodetector (e.g., first photodetector  224 ). In some embodiments, the raw signal may be generated by the first (signal) photodetector  224 . In some non-limiting embodiments, the raw signal may be digitized by the ADC  664 . 
     As shown in equation 3, the raw signal may contain an offset Z and distortion I distortion .
 
Signal= I+Z+I   distortion   (3)
 
where Signal is the raw signal generated by the photodetector, I is the glucose-modulated fluorescence from the indicator molecules  104 , Z is an offset, and I distortion  is distortion produced by the indicator molecules  104  (e.g., distortion produced by photo, thermal, and/or oxidative decay species of). In order to accurately calculate the glucose-modulated fluorescence I emitted by the indicator molecules  104 , the raw signal may be purified by removing the offset Z and the distortion I distortion  from the raw signal. In addition, for accurate calculation of the fluorescence from the glucose indicator I, the raw signal may be corrected for temperature sensitivity. Accordingly, the process  200  may include steps S 210 , S 212 , S 214 , and/or S 216  of measuring temperature, correcting for temperature sensitivity, compensating for offset Z, and compensating for distortion I distortion , respectively.
 
     In step S 210 , the temperature T of the optical sensor  100  may be measured. In some embodiments, the temperature may be measured by the temperature sensor  670 . As explained below, in some embodiments, the measured temperature T may be used for correcting the raw signal for temperature sensitivity. 
     In step S 212 , the circuitry of sensor  100  may temperature correct the raw signal based on the temperature T of the sensor  100 , which may be measured in step S 210 . In particular, in some non-limiting embodiments, the measurement controller  532  may perform the temperature correction. As noted above, the fluorescent amplitude of the light  331  emitted by the indicator molecules  104 , as well as some elements of the circuitry within the sensor  100  (e.g., light source  108 ), may be temperature sensitive. In one non-limiting embodiment, the circuitry (e.g., measurement controller  532 ) may correct for the temperature sensitivity as shown in equation 4:
 
[Signal] T =Signal(1+( T− 37) c   z )  (4)
 
wherein the Signal is the raw signal generated by the photodetector (e.g., photodetector  224 ), [Signal] T  is the temperature corrected raw signal, and c z  is the temperature sensitivity of the optical sensor. In one non-limiting embodiment, the temperature sensitivity may simply be the temperature sensitivity of the light source  108 .
 
     In step S 214 , the circuitry of sensor  100  may compensate for the offset Z present in the raw signal. In some embodiments, the offset Z may be hardware based. For example, in some embodiments, the offset Z may be related at least in part to the peak wavelength of the excitation light  329  emitted by the particular light source  108  used in sensor  100  and/or the tolerance of the particular optical band-pass filter  112  used in sensor  100 . 
     The offset Z present in the raw signal may result from excitation light  329  emitted from light source  108  that reaches the photodetector (e.g., first (signal) photodetector  224 ). The excitation light  329  that reaches the photodetector is convoluted in the total light that reaches photodetector, and, thus, produces an offset in the raw signal generated by the photodetector. 
     As illustrated in  FIG. 3 , the excitation light  329  emitted from light source  108  that reaches the photodetector may include (i) a reflection light component  335  that is reflected from the graft  106  (e.g., gel) before reaching the photodetector and (ii) a bleed light component  337  that reaches the photodetector without encountering the graft  106 . The reflection light component  335  may produce a reflection component Z gel  of the offset Z, and the bleed light component  337  may produce a bleed component Z bleed  of the offset Z. 
     In some embodiments, the offset Z may be measured during the manufacturing of the sensor  100 . However, the offset Z may increase due to photobleaching of the indicator molecules  104 . In particular, as indicator molecules  104  become photo-bleached, the overall absorbance of the graft/gel  106  decreases, which increases the reflectance of the graft/gel  106 , the amount of excitation light  329  reflected from the graft/gel  106 , and the intensity of the reflection light component  335 . Accordingly, in some embodiments, in order to compensate for the offset in the raw signal, the circuitry of the sensor  100  may dynamically track the offset (e.g., by using the tracked cumulative emission time t e ). 
     In some embodiments, the circuitry of sensor  100  (e.g., measurement controller  532 ) may compensate for the offset Z present in the raw signal by calculating the offset Z and removing (e.g., subtracting) the offset Z from the raw signal. For example, in embodiments where the raw signal is temperature corrected, the calculated offset Z may be removed from the raw signal by subtracting the calculated offset Z from the temperature corrected raw signal [Signal] T . 
     In one non-limiting embodiment, the circuitry of the sensor  100  (e.g., measurement controller  532 ) may calculate the offset Z as shown in equation 5:
 
[ Z]=Z   gel (1+φ Z (1 −e   −k     pb     t     pb   ))+ Z   bleed   (5)
 
where Z gel  is the component of the offset Z produced by the reflection light component  335  (i.e., the excitation light  329  spillover component that is reflected from the graft  106  (e.g., gel) and received by the photodetector), φ z  is the percent increase of Z gel  when the indicator is fully photo-bleached, k pb  is the rate of photobleaching, t pb  is the photobleaching time, and Z bleed  is the component of the offset Z produced by the bleed light component  337  (i.e., the portion of the excitation light  329  received by the photodetector that reaches the photodetector without encountering the graft  106 ). In some embodiments, the circuitry (e.g., measurement controller  532 ) may use the tracked cumulative emission time t e  for the photobleaching time t pb .
 
     In step S 216 , the circuitry of sensor  100  may compensate for the distortion I distortion  present in the raw signal. In particular, in some embodiments, the measurement controller  532  may perform the distortion compensation. The distortion I distortion  may be chemistry (photochemistry) and kinetics based. The distortion I distortion  may be any non-glucose-modulated light in the emission light  331  arriving at the photodetector from the indicator molecules  104 . For example, photo, thermal, and oxidative decay species of the indicator molecules  104  may emit fluorescent light that is not modulated by glucose. In fact, most of the distortion I distortion  may be due to various matrix species kinetically related to the parent indicator BA (i.e., the active indicator species) as shown in  FIG. 4 . 
     In some embodiments, the glucose indicator molecule BA, within an in-vivo environment, may undergo a steady loss of signal amplitude over time. The glucose indicator molecule BA may be temperature sensitive. In some embodiments, oxidation, thermal degradation, and photobleaching may be the dominant mechanisms of the signal degradation. In some embodiments, the oxidation, thermal degradation, and photobleaching may all be chronic and predictable under a first order decay function on the loss of signal amplitude. This decay may establish the end of useful life for the overall sensor product. In some embodiments, the glucose indicator BA may be degraded by the three decay mechanisms (i.e., oxidation, thermal degradation, and photobleaching). 
     In regard to oxidative decay species Ox, in some non-limiting embodiments, under in-vivo conditions, oxidation pressure from ambient and normal reactive oxidation species (ROS), the glucose indicator BA may progressively undergo a highly specific oxidative de-boronation. This reaction may remove the boronate recognition moiety of the indicator molecule BA. The resulting deboronated indicator (i.e., oxidized indicator Ox) may be fluorescent (e.g., at a lower quantum efficiency than the glucose indicator BA) and may not modulate. Moreover, the oxidized species Ox may be temperature sensitive and may decay due to photo activation, photobleaching, and/or thermal degradation. 
     In regard to photo-activated decay species PA, when the oxidized indicator Ox is photo activated, it may produce a major product (i.e., photo-activated oxidated species PA). Photo-activated oxidated species PA may be fluorescent (e.g., at a higher quantum efficiency than oxidized species Ox) and may not modulate. Similar to the oxidized species Ox, the photo-activated oxidated species PA may be temperature sensitive and may decay due to photobleaching and/or thermal degradation. 
     In regard to thermal degradation product species Th, the glucose indicator BA, the oxidized indicator Ox, and the photo-activated decay species PA, may all thermally degrade. Similar to the oxidized species Ox and the photo-activated oxidated species PA, the resulting thermally degraded indicator Th may be fluorescent (e.g., at a lower quantum efficiency than the glucose indicator BA) and does not modulate. The thermal degradation product species Th may be temperature sensitive and may decay due to photobleaching. 
     The oxidated species Ox, photo-activated oxidated species PA, and thermal degradation product species Th illustrated in  FIG. 4  are fluorescent derivatives of the base glucose-indicator BA. However, only the base glucose-indicator BA of the indicator molecules  104  is a glucose modulated species. Therefore, to obtain the most accurate measurement of glucose concentration based on the emission light  331  received by the photodetector, the fluorescence I produced by the base glucose-indicator BA, which carries glucose concentration information, may be de-convoluted from the emission light  331 , which also include fluorescence from the oxidated species Ox, photo-activated oxidated species PA, and thermal degradation product species Th. In other words, the oxidated species Ox, photo-activated oxidated species PA, and thermal degradation product species Th are distortion-producing species, and the non-glucose-modulated light I distortion  from these species may be removed from the raw signal. Accordingly, the circuitry of the sensor  100  may track each of the distortion-producing species and remove them from the final signal that is converted to a glucose concentration measurement. 
     As shown in  FIG. 4 , the matrix species also include completely oxidated (i.e., lights out) species LO. This species LO, which is a derivative of the base glucose-indicator BA, has been photobleached and may not emit fluorescence. 
     The fluorescence [I distortion ] from all the distortion-producing species is:
 
[ I   distortion ]=[Ox]+[Th]+[PA]  (8)
 
where [Ox], [PA], and [Th] are fluorescence from the oxidated species Ox, photo-activated oxidated species PA, and thermal degradation product species Th, respectively.
 
     When the sensor is new (e.g., at manufacturing), the distortion producing subspecies (e.g., Ox, Th, and PA) of the indicator molecules  104  have not yet formed and may contribute nothing significant to the initial raw signal at turn-on. However, the distortion I distortion  may increase from the time the sensor  100  is inserted in vivo. In particular, once the sensor  100  is inserted in vivo, the distortion producing subspecies (e.g., Ox, Th, and PA) may form progressively. Accordingly, in some embodiments, the circuitry of the sensor  100  may kinetically track the distortion-producing species (e.g., by using the tracked implant time t i ). 
     In some embodiments, the circuitry of sensor  100  (e.g., measurement controller  532 ) may compensate for the distortion I distortion  present in the raw signal by calculating the fluorescence emitted from one or more of the distortion producing species (e.g., Ox, Th, and PA) and removing (e.g., subtracting) the non-glucose modulated fluorescence I distortion  from the raw signal. For example, in embodiments where the raw signal is temperature corrected, the calculated non-glucose modulated fluorescence I distortion  may be removed from the raw signal by subtracting the calculated distortion I distortion  may be from the temperature corrected raw signal [Signal] T . 
     In one non-limiting embodiment, the circuitry of the sensor  100  (e.g., measurement controller  532 ) may calculate the fluorescence emitted from one or more of the distortion producing species (e.g., oxidated species Ox, photo-activated oxidated species PA, and thermal degradation product species Th) as shown in equations 9-11:
 
[OX]= I   0,QC %  F   Ox [(1 −e   −k     ox     t     ox   ) e   −k     th     t     th     e   −k     pb     t     pb     e   −k     pa     t     pb   ][1−( T− 37) c   OX ]  (9)
 
[Th]= I   0,QC %  F   Th └(1 −e   −k     th     t     th   ) e   −k     pb     t     pb   ┘[1−( T− 37) c   Th ]  (10)
 
[PA]= I   0,QC %  F   PA [(1 −e   −k     ox     t     ox   ) e   −k     th     t     th     e   −k     pb     t     pb   (1 −e   −k     pa     t     pb     ) )][1−( T− 37) c   PA ]  (11)
 
where I 0,QC  is the fluorescence intensity of the base glucose indicator at zero glucose concentration I 0  obtained from manufacturing quality control (QC); % F Ox , % F Th , and % F PA  are the relative quantum efficiencies of Ox, Th, and PA, respectively, to the base glucose indicator BA; k ox , k th , and k pb  are rates for oxidation, thermal degradation, and photobleaching, respectively; t ox , t th , and t pb  are oxidation time, thermal degradation time, and photobleaching time, respectively; and c Ox , c Th , and c PA  are the temperature correction coefficients of Ox, Th and PA, respectively. In some embodiments, the circuitry of the sensor  100  (e.g., measurement controller  532 ) may use the tracked cumulative emission time t e  for the photobleaching time t pb . In some embodiments, the circuitry of the sensor  100  may use the tracked implant time t i  for the oxidation time t ox  and thermal degradation time t th .
 
     The process  200  may include a step S 218  of normalizing the raw signal, which in some embodiments may have be temperature corrected, offset compensated, and/or distortion compensated, into a normalized signal Sn. In some embodiments, the normalized signal Sn may be directly proportional to glucose concentration. 
     In its simplest form, the normalized signal Sn may be represented by the following equation: 
                   Sn   =     I     I   0               (   12   )               
where I is the glucose-modulated fluorescence from the indicator molecules  104  and I 0  is baseline glucose-modulated fluorescence at zero glucose concentration.
 
     As explained above, only the glucose-modulated fluorescence I carries glucose concentration information, but the raw signal generated by the photodetector affected by temperature sensitivity and additionally contains an offset Z and a non-glucose modulated signal I distortion . The raw signal may be corrected for temperature sensitivity and the offset Z and a non-glucose modulated signal I distortion  may be removed, and, accordingly, the normalized signal Sn is may be represented by the following equation: 
                   Sn   =           [   Signal   ]     T     -   Z   -     I   distortion         I   0               (   13   )               
where [Signal] T  is the temperature corrected raw signal.
 
     The circuitry of the sensor  100  (e.g., measurement controller  532 ) may remove noise from the raw signal and normalize it so that the normalized signal Sn may have a constant value at infinite glucose concentration. In other words, the normalized signal at infinite glucose concentration (Sn max ) may not change even the indicator molecules  104  are photobleached, oxidate, and thermally degrade. If the noise were not removed, the noise may compress the modulation shown in  FIG. 5  (i.e., the Y-axis displacement from zero to infinite glucose), and the extent to which the modulation were compressed may change based on the extent to which the indicator molecules  104  were photobleached, oxidated, and/or thermally degraded. 
     In some embodiments, the circuitry of sensor  100  (e.g., measurement controller  532 ) may normalize the glucose-modulated fluorescence I by calculating the baseline glucose-modulated fluorescence at zero glucose concentration (i.e., I 0 ) and dividing the glucose-modulated fluorescence I by the calculated I 0 . 
     In one non-limiting embodiment, the circuitry of the sensor  100  may calculate the baseline glucose-modulated fluorescence at zero glucose concentration I 0  according to the following equation:
 
 I   0   =I   0,QC   e   −k     ox     t     ox     e   −k     th     t     th     e   −k     pb     t     pb[   1−( T− 37) c   f ]  (14)
 
where I 0,QC  is the I 0  obtained from manufacturing quality control (QC); e −k     ox     t     ox   e −k     th     t     th   e −k     pb     t     pb    is the glucose indicator decay due to the superimposition of oxidation, thermal degradation, and photobleaching; k ox , k th , and k pb  are rates for oxidation, thermal degradation and photobleaching, respectively; t ox , t th , and t pb  are oxidation time, thermal degradation time, and photobleaching time, respectively; c f  is the temperature correction coefficient of the glucose indicator; and T is the temperature of the optical sensor  100 , which may be measured by the temperature sensor  670  in step S 210 . In some embodiments, the circuitry of the sensor  100  may use the tracked cumulative emission time t e  for the photobleaching time t pb . In some embodiments, the circuitry of the sensor  100  (e.g., measurement controller  532 ) may use the tracked implant time t i  for the oxidation time t 0  and thermal degradation time t th . The circuitry of the sensor  100  may be configured to kinetically track the first order decay loss of signal that occurs over time (e.g., by using the tracked cumulative emission time t e  and tracked implant time t i ).
 
     The process  200  may include a step S 220  of converting the normalized signal Sn to a glucose concentration. The conversion of the normalized signal Sn into a glucose concentration may be based on the relationship between percent modulation and glucose as shown in  FIG. 5 . As described above, the percent modulation I/I 0  versus glucose concentration may be constant throughout the life of the glucose sensor  100 . The end of life of the glucose sensor  100  may arise when the signal to noise ratio declines over time to a point where the error specification can no longer be maintained. 
     In some embodiments, the circuitry may use an interpretive algorithm to convert the normalized signal Sn into glucose concentration. The interpretive algorithm may be derived through a standard curve based on the following reaction:
 
 A+B←→BA   (15)
 
where A is glucose indicator, B is glucose, and BA is glucose-indicator complex. The fluorescence of the indicator increases upon binding glucose.
 
     The equilibrium expression for the dissociation defining Sn max  (i.e., the normalized signal Ns at infinite glucose concentration) is 
     
       
         
           
             
               
                 
                   
                     K 
                     d 
                   
                   = 
                   
                     
                       
                         [ 
                         A 
                         ] 
                       
                       ⁡ 
                       
                         [ 
                         B 
                         ] 
                       
                     
                     
                       [ 
                       AB 
                       ] 
                     
                   
                 
               
               
                 
                   ( 
                   16 
                   ) 
                 
               
             
           
         
       
     
     The glucose concentration [A] is 
                     [   A   ]     =       K   d     ⁢       [   AB   ]       [   B   ]                 (   17   )               
where K d  is constant, and [AB] and [B] terms must be determined from measurement. The following derivation illustrates how the glucose concentration [A] may be calculated at any one measurement (e.g., for any normalized signal Sn) based on the relationship shown in equations 16 and 17.
 
     The total fluorescence F emitted by the indicator molecules  104  is:
 
 F=F   B   +F   AB   (18)
 
where F R  is the fluorescence from the unbound indicator, and F AB  is the fluorescence from the glucose indicator complex.
 
     According to Beer&#39;s law:
 
 F=I   e   ebcφ   (19)
 
where F is fluorescence of the species, I e  is excitation light, e is molar extinction coefficient, b is path length, c is concentration of the fluorescer, and Φ is quantum efficiency.
 
     By substituting specifically for the concentration terms for each of the glucose indicator A and the glucose-indicator complex AB, the fluorescence F is:
 
 F=I   0   eb[B]φ   B   +I   0   eb[AB]φ   AB   (20)
 
     By defining: 
                     q   B     =       ϕ   B     ⁡     (       [   B   ]     +     [   AB   ]       )               (   21   )                 q   AB     =       ϕ   AB     ⁡     (       [   B   ]     +     [   AB   ]       )               (   22   )                 f   B     =       [   B   ]         [   B   ]     +     [   AB   ]                 (   23   )                 f   AB     =       [   AB   ]         [   B   ]     +     [   AB   ]                 (   24   )               
equation (20) becomes:
 
 F=I   e   eb ( f   B   q   B   +f   AB   q   AB )  (25)
 
     The fluorescent signal value at zero glucose concentration F min , which is the lowest fluorescent signal value from the sensor, is:
 
 F   min   =I   e   ebq   B   (26)
 
     The opposite boundary condition occurs when glucose concentration is very high, almost all (e.g., 99.99%) of fluorescence signal is from the glucose indicator complex AB, and almost none (e.g., approaching zero) of the fluorescence signal is from unbound indicator B. The fluorescent signal value at glucose saturation F max , which is the highest possible value of fluorescence, is:
 
 F   max   =I   e   ebq   AB   (27)
 
     By incorporating the equations for F min  and F max  (i.e., equations 26 and 27) into equation 25, equation 25 becomes
 
 F=F   min   f   B   +F   max   f   AB   =F   min   f   B   +F   max (1 −f   B )  (28)
 
     Therefore, 
     
       
         
           
             
               
                 
                   
                     
                       f 
                       B 
                     
                     = 
                     
                       
                         
                           F 
                           max 
                         
                         - 
                         F 
                       
                       
                         
                           F 
                           max 
                         
                         - 
                         
                           F 
                           min 
                         
                       
                     
                   
                   ⁢ 
                   
                     
 
                   
                   ⁢ 
                   and 
                 
               
               
                 
                   ( 
                   29 
                   ) 
                 
               
             
             
               
                 
                   
                     f 
                     AB 
                   
                   = 
                   
                     
                       1 
                       - 
                       
                         f 
                         B 
                       
                     
                     = 
                     
                       
                         F 
                         - 
                         
                           F 
                           min 
                         
                       
                       
                         
                           F 
                           max 
                         
                         - 
                         
                           F 
                           min 
                         
                       
                     
                   
                 
               
               
                 
                   ( 
                   30 
                   ) 
                 
               
             
           
         
       
     
     The glucose concentration [A] is: 
     
       
         
           
             
               
                 
                   
                     [ 
                     A 
                     ] 
                   
                   = 
                   
                     
                       
                         K 
                         d 
                       
                       ⁢ 
                       
                         
                           [ 
                           AB 
                           ] 
                         
                         
                           [ 
                           B 
                           ] 
                         
                       
                     
                     = 
                     
                       
                         
                           K 
                           d 
                         
                         ⁢ 
                         
                           
                             f 
                             AB 
                           
                           
                             f 
                             B 
                           
                         
                       
                       = 
                       
                         
                           K 
                           d 
                         
                         ⁢ 
                         
                           
                             F 
                             - 
                             
                               F 
                               min 
                             
                           
                           
                             
                               F 
                               max 
                             
                             - 
                             F 
                           
                         
                       
                     
                   
                 
               
               
                 
                   ( 
                   31 
                   ) 
                 
               
             
           
         
       
     
     By substituting the normalized fluorescence Sn determined by the circuitry of the sensor  100  for the fluorescence F, the glucose concentration [A] becomes: 
                     [   A   ]     =       K   d     ⁢       Sn   -     Sn   min           Sn   max     -   Sn                 (   32   )               
where the dissociation constant K d  and normalized signal at glucose saturation Sn max  may be determined during manufacturing, the normalized signal Sn is generated by the circuitry of the sensor  100  by processing the raw signal generated by the photodetector of the sensor  100 , and Sn min  (i.e., I 0 /I 0 ) is equal to one.
 
     The process  200  may include the step S 222  of conveying the glucose concentration to the external sensor reader  101 . In some embodiments, the glucose concentration may be conveyed using the inductive element  114  of the sensor  100 . 
     According to some embodiments of the invention, during sensor manufacturing, one or more sensors  100  may be cycled through a computer automated quality control measurement system. This system may measure parameters (e.g., c z , K d , Sn max , Z gel , Z bleed ). The cycle may include operating newly manufactured sensor  100  at two different temperatures (e.g., 32° C. and 37° C.) at three different glucose concentrations (e.g., 0 mM, 4.0 mM, and 18.0 mM glucose). The automated system may track the performance of each sensor  100  under these changing conditions and make specific measurements for each sequential temperature and concentration test. In some embodiments, other parameters (e.g., K pb , K pa , K th , φ z , c f , c Th , c ox , c PA , % F Ox ,% F PA  and % F Th ) may be developed from designed and controlled in vitro experiments, and still other parameters (e.g., K Ox ) may be developed from in vivo tests. One or more parameter values may be determined for each manufactured sensor  100  and used by the circuitry of the sensor  100  in processing a raw signal and converting the normalized signal Sn to a glucose concentration (e.g., according to the corresponding serial number of the sensor  100 ). 
     In a non-limiting example of sensors that may be used to determine a concentration of glucose in a medium, experimental results were obtained using eighteen sensors incorporating one or more aspects of the present invention and implanted into type-I diabetic subjects. Data was collected during 6 in-clinic sessions to determine the sensor performance and the accuracy of the algorithm in vivo. The sensors were removed 28 days after insertion. The Mean Absolute Relative Difference (MARD) for all the 18 sensors from day 3 data collection through day 28 is 13.7%. Day 0 data collection was excluded as, in some embodiments, the sensor may not be fully responsive to glucose during a heal-up period. A total of 3,466 paired data points were obtained to evaluate sensor performance, and blood glucose measured by YSI machine was used as a reference.  FIG. 7  is a Clarke error grid showing the 3,466 paired data points with 3328 data points (96.02%) in either the A range (i.e., values within 20% of the reference sensor) or the B range (i.e., values outside of 20% range but that may not lead to inappropriate treatment).  FIG. 8  illustrates experimental results of a sensor embodying aspects of the present invention during six read sessions.  FIG. 8  shows the performance of one of the implanted sensors during the six read sessions and shows that the sensor tracks the blood glucose well. The MARD for this sensor is 13%. Other embodiments of the sensor may be used to produce different results. 
     In some embodiments, as described above, the circuitry of the sensor  100  (which may, for example, include measurement controller  532 ) may eliminate noise (e.g., offset and distortions) present in the raw signal generated by the photodetector  224  and convert the purified raw signal into a glucose concentration, and the sensor  100  may convey the glucose concentration to the sensor reader  101 . However, this is not required, and, in alternative embodiments, the sensor  100  may convey the raw signal generated by the photodetector  224  to the sensor reader  101 , and circuitry of the sensor reader  101  (which may, for example, include PIC microcontroller  920 ) may eliminate noise present in the raw signal generated by the photodetector  224  and convert the purified raw signal into a glucose concentration. For example, in some embodiments, the circuitry of the sensor reader  101  may (i) purify the raw signal, (ii) normalize the purified signal to produce a normalized signal Sn that is directly proportional to glucose concentration, and (iii) convert the normalized signal Sn into a glucose concentration. 
       FIG. 10  illustrates an exemplary raw signal purification and conversion process  1000  that may be performed by a system including the sensor  100 , which may be, for example, implanted within a living animal (e.g., a living human), and a sensor reader  101 , which may be external to the living animal but in the proximity of the sensor  100  (e.g., on an armband or wristband attached to the living animal), in accordance with an embodiment of the present invention. The process  1000  may include a step S 1002  of tracking the amount of time t i  that has elapsed since the optical sensor  100  was implanted in the living animal. As noted above, because oxidation and thermal degradation begins when the sensor  100  is implanted, the implant time t i  may be equivalent to the oxidation time t 0  and the thermal degradation time t th . 
     In some embodiments, the circuitry of sensor reader  101  may include an implant timer circuit that is started when the sensor  100  is implanted. For example, in one non-limiting embodiment, the implant timer circuit may be a counter that increments with each passing of a unit of time (e.g., one or more milliseconds, one more seconds, one or more minutes, one or more hours, or one or more days, etc.). However, this is not required, and, in some alternative embodiments, the circuitry of the sensor reader  101  may track the implant time t i  by storing the time at which the sensor  100  was implanted (e.g., in memory  922 ) and comparing the stored time with the current time. In other alternative embodiments, the sensor  100  may receive the time at which the sensor was implanted, i.e., the implant time from the sensor reader  101  (e.g., when the sensor  100  and sensor reader  101  are first linked together) and store the received implant time t i  (e.g., in nonvolatile storage medium  660 ). The sensor reader  101  may receive the time at which sensor  100  was implanted from the sensor  100  for calculation of the implant time t i . The tracked implant time t i  may be used in compensating for distortion in the raw signal, normalizing the raw signal, and/or converting the normalized signal Sn to a glucose concentration. 
     The process  1000  may include a step S 1004  of tracking the cumulative amount of time t e  that the light source  108  has emitted the excitation light  329 . Because the indicator molecules  104  are irradiated with the excitation light  329 , the cumulative emission time t e  may be equivalent to the photobleaching time t pb . 
     In some embodiments, the circuitry of sensor  100  may include an emission timer circuit that is advanced while the light source  108  emits excitation light  329 . For example, in one non-limiting embodiment, the emission timer circuit may be a counter that increments with each passing of a unit of time (e.g., one or more milliseconds, one more seconds, one or more minutes, one or more hours, or one or more days, etc.) while the light source  108  emits excitation light  329 . The count may be conveyed by the sensor  100  to the sensor reader  101 . However, this is not required. For example, in some alternative embodiments, the light source  108  may emit excitation light  329  for a set amount of time for each measurement, and the counter may increment once for each measurement taken by the sensor  100 . Here again, the count may be conveyed by the sensor  100  to the sensor reader  101 . In another alternative embodiment, the light source  108  may emit excitation light  329  for a set amount of time for each measurement, and the circuitry of the sensor reader  101  may include an emission timer circuit that is incremented once for each measurement command issued by the sensor reader  101  to the sensor  100  or for each measurement received by the sensor reader  101  from the sensor  100 . The tracked cumulative emission time t e  may be used in compensating for offset in the raw signal, compensating for distortion in the raw signal, normalizing the raw signal, and/or converting the normalized signal Sn to a glucose concentration. 
     The process  1000  may include a step S 1006  of emitting excitation light  329 , a step S 208  of generating a raw signal indicative of the amount of light received by a photodetector, and/or a step S 1010  of measuring the temperature T of the optical sensor  100 , which may correspond to steps S 206 , S 208 , and S 210 , respectively, of the process  200  described above with reference to  FIG. 2 . 
     The process  1000  may include a step S 1012  of conveying the raw signal indicative of the amount of light received by a photodetector, which may be a digitized raw signal, and/or the measured temperature. In some embodiments, the raw signal and/or measured temperature may be conveyed using the inductive element  114  of the sensor  100 . The sensor reader  101  may receive the conveyed raw signal and/or measured temperature (e.g., using the inductive element  103  of the sensor reader  101 ). 
     The process  1000  may include a step S 1014  of temperature correcting the raw signal based on the measured temperature of the sensor  100 , a step S 1016  of compensating for the offset Z present in the raw signal, a step S 1018  of compensating for the distortion I distortion  present in the raw signal, a step S 1020  of normalizing the raw signal, and a step S 1022  of converting the normalized signal Sn to a glucose concentration. These steps may correspond to steps S 212 , S 214 , S 216 , S 218 , and S 220 , respectively, of the process  200  described above with reference to  FIG. 2 , except that steps S 1014 , S 1016 , S 1018 , S 1020 , and S 1022  may be performed the circuitry of the sensor reader  101  (e.g., by the PIC microcontroller  920 ) instead of by the circuitry of the sensor  100  (e.g., by measurement controller  532 ). 
     In some embodiments, the sensor reader  101  may store (e.g., in memory  922 ) parameters specific to the sensor  100  and use the parameters during performance of steps S 1014 , S 1016 , S 1018 , S 1020 , and/or S 1022 . In some non-limiting embodiments, the sensor reader  101  may download some or all of the parameters specific to the sensor  100  from a web server. In some non-limiting embodiments, the sensor reader  101  may receive some or all of the parameters specific to the sensor  100  from the sensor  100 , which may store the parameters (e.g., in nonvolatile storage medium  660 ) and convey the parameters to the sensor reader  101  (e.g., using inductive element  114 ). In some embodiments, the parameters specific to the sensor  100  may include static parameters and/or dynamic parameters. For instance, in some non-limiting embodiments, the parameters specific to the sensor  100  may include static sensor parameters (e.g., K pb , K pa , K th , φ z , c f , c Th , c ox , c PA , % F Ox ,% F PA  and/or % F Th ) developed from controlled in vitro experiments and/or static sensor parameters (e.g., K Ox ) developed from in vivo tests. In some non-limiting embodiments, the sensor reader  101  may store parameters for only one sensor  100  at a time and be paired to a particular sensor  100  after receiving the sensor&#39;s parameters (e.g., by downloading them from a web server or receiving them from the sensor  100 ). However, in alternative embodiments, the sensor reader  101  may store parameters for more than one sensor  100 . For example, in one non-limiting embodiment, the sensor reader  101  may store parameters for all of the sensors  100  with which the sensor reader  101  may be used. 
     In another alternative embodiment, the circuitry of the sensor  100  (which may, for example, include measurement controller  532 ) may eliminate noise (e.g., temperature sensitivity, offset, and distortions) present in the raw signal generated by the photodetector  224 , the sensor  100  may convey the purified raw signal to the sensor reader  101 , and the sensor reader  101  may convert the purified raw signal into a glucose concentration. 
     Embodiments of the present invention have been fully described above with reference to the drawing figures. Although the invention has been described based upon these preferred embodiments, it would be apparent to those of skill in the art that certain modifications, variations, and alternative constructions could be made to the described embodiments within the spirit and scope of the invention. For example, the circuitry of the sensor  100  and/or the sensor reader  101  may be implemented in hardware, software, or a combination of hardware and software. The software may be implemented as computer executable instructions that, when executed by a processor, cause the processor to perform one or more functions.