US 20090264718 A1
A quantitative measurement system includes an external unit and an internal unit are provided for obtaining quantitative analyte measurements, such as within the body. In one example of an application of the system, the internal unit would be implanted either subcutaneously or otherwise within the body of a subject. The internal unit contains optoelectronics circuitry, a component of which may be comprised of a fluorescence sensing device. The optoelectronics circuitry obtains quantitative measurement information and modifies a load as a function of the obtained information. The load in turn varies the amount of current through coil, which is coupled to a coil of the external unit. A demodulator detects the current variations induced in the external coil by the internal coil coupled thereto, and applies the detected signal to processing circuitry, such as a pulse counter and computer interface, for processing the signal into computer-readable format for inputting to a computer.
1. In a system comprising (a) an internal sensor unit having a circuit and (b) an external sensor unit, a method for determining the concentration of an analyte, comprising:
using the external sensor unit to provide power to the internal sensor;
while the external sensor unit is providing power to the internal sensor unit,
communicating to the external sensor unit information from which the concentration of the analyte can be determined, wherein the communicating step comprises changing an impedance of the circuit as a function of the concentration of the analyte, wherein a change in the impedance of the circuit causes a voltage in the external sensor unit to change; and
obtaining measurements of the voltage; and
generating information from the voltage measurements, wherein the information includes information from which the concentration of the analyte can be determined.
2. The method of
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8. Apparatus for retrieving information from a sensor device, comprising:
an internal sensor unit for taking quantitative analyte measurements, including a first coil forming part of a power supply for said sensor unit, a load coupled to said first coil, and a sensor circuit for modifying said load in accordance with sensor measurement information obtained by said sensor circuit, said sensor circuit including a signal channel detector responsive to analyte measurement information, and a reference channel detector responsive to reference measurement information, outputs of said signal channel detector and said reference channel detector being combined in said sensor information for modifying said load, wherein said signal channel detector is configured to produce an output determinative of a positive transition time of said load modification, and said reference channel detector is configured to produce an output determinative of a negative transition time of said load modification;
an external unit including a second coil which is mutually inductively coupled to said first coil upon said second coil being placed within a predetermined proximal distance from said first coil, an oscillator for driving said second coil to induce a charging current in said first coil, and a detector for detecting variations in a load on said second coil induced by changes to said load in said internal sensor unit and for providing information signals corresponding to said load changes; and
a processor for receiving and processing said information signals;
wherein said reference channel detector is configured to produce an output determinative of a positive transition time of said load modification, and said signal channel detector is configured to produce an output determinative of a negative transition time of said load modification.
9. A sensor system, comprising:
an internal unit, including:
a tank circuit comprising a first coil and a capacitor, and
a optoelectronics circuitry coupled to the tank circuit, said optoelectronics circuitry being configured to (1) obtain quantitative measurement information and (2) change the impedance of a circuit connected to the tank circuit as a function of the obtained quantitative measurement information; and
an external unit, including:
a second coil,
an oscillator coupled to the second coil, and
a detector coupled to the second coil, said detector being configured to detect a change in said impedance when the second coil is inductively coupled to the first coil.
10. The sensor system of
11. The sensor system of
12. The sensor system of
13. The sensor of
This application is a divisional of U.S. patent application Ser. No. 10/332,619, filed Oct. 21, 2003, which is a national stage application filed under 35 U.S.C. §371 of PCT/US01/20390, filed Jun. 27, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09/605,706, now U.S. Pat. No. 6,400,974, issued Jun. 4, 2002.
1. Field of the Invention
This invention relates to a circuit and method for processing the output of an implanted sensing device for detecting the presence or concentration of an analyte in a liquid or gaseous medium, such as, for example, the human body. More particularly, the invention relates to a circuit and method for processing the output of an implanted fluorescence sensor which indicates analyte concentration as a function of the fluorescent intensity of a fluorescent indicator. The implanted fluorescence sensor is a passive device, and contains no power source. The processing circuit powers the sensor through inductively coupled RF energy emitted by the processing circuit. The processing circuit receives information from the implanted sensor as variations in the load on the processing circuit.
2. Background Art
U.S. Pat. No. 5,517,313, the disclosure of which is incorporated herein by reference, describes a fluorescence sensing device comprising a layered array of a fluorescent indicator molecule-containing matrix (hereafter “fluorescent matrix”), a high-pass filter and a photodetector. In this device, a light source, preferably a light-emitting diode (“LED”), is located at least partially within the indicator material, such that incident light from the light source causes the indicator molecules to fluoresce. The high-pass filter allows emitted light to reach the photodetector, while filtering out scattered incident light from the light source. An analyte is allowed to permeate the fluorescent matrix, changing the fluorescent properties of the indicator material in proportion to the amount of analyte present. The fluorescent emission is then detected and measured by the photodetector, thus providing a measure of the amount or concentration of analyte present within the environment of interest.
One advantageous application of a sensor device of the type disclosed in the '313 patent is to implant the device in the body, either subcutaneously or intravenously or otherwise, to allow instantaneous measurements of analytes to be taken at any desired time. For example, it is desirable to measure the concentration of oxygen in the blood of patients under anesthesia, or of glucose in the blood of diabetic patients.
In order for the measurement information obtained to be used, it has to be retrieved from the sensing device. Because of the size and accessibility constraints on a sensor device implanted in the body, there are shortcomings associated with providing the sensing device with data transmission circuitry and/or a power supply. Therefore, there is a need in the art for an improved sensor device implanted in the body and system for retrieving data from the implanted sensor device.
In accordance with the present invention, an apparatus is provided for retrieving information from a sensor device, comprising an internal sensor unit for taking quantitative analyte measurements, including a first coil forming part of a power supply for said sensor unit, a load coupled to said first coil, and a sensor circuit for modifying said load in accordance with sensor measurement information obtained by said sensor circuit; an external unit including a second coil which is mutually inductively coupled to said first coil upon said second coil coming into a predetermined proximity distance from said first coil, an oscillator for driving said second coil to induce a charging current in said first coil, and a detector for detecting variations in a load on said second coil induced by changes to said load in said internal sensor unit and for providing information signals corresponding to said load changes; and a processor for receiving and processing said information signals.
The invention will be more fully understood with reference to the following detailed description of a preferred embodiment in conjunction with the accompanying drawings, which are given by way of illustration only and thus are not limitative of the present invention, and wherein:
The system includes an external unit 101 and an internal unit 102. In one example of an application of the system, the internal unit 102 would be implanted either subcutaneously or otherwise within the body of a subject. The internal unit contains optoelectronics circuitry 102 b, a component of which may be comprised of a fluorescence sensing device as described more fully hereinafter with reference to
A variable RF oscillator 101 a provides an RF signal to coil 101 f, which in turn provides electromagnetic energy to coil 102 d, when the coils 101 f and 102 d are within close enough proximity to each other to allow sufficient inductive coupling between the coils. The energy from the RF signal provides operating power for the internal unit 102 to obtain quantitative measurements, which are used to vary the load 102 c and in turn provide a load variation to the coil 101 f that is detected by the external unit and decoded into information. The load variations are coupled from the internal unit to the external unit through the mutual coupling between the coils 101 f and 102 d. The loading can be improved by tuning both the internal coil and the external coil to approximately the same frequency, and increasing the Q factor of the resonant circuits by appropriate construction techniques. Because of their mutual coupling, a current change in one coil induces a current in the other coil. The induced current is detected and decoded into corresponding information.
RF oscillator 101 a drives coil 101 f, which induces a current in coil 102 d. The induced current is rectified by a rectifier circuit 102 a and used to power the optoelectronics 102 b. Data is generated by the optoelectronics in the form of a pulse train having a frequency varying as a function of the intensity of light emitted by a fluorescence sensor, such as described in the aforementioned '313 patent. The pulse train modulates the load 102 c in a manner so as to temporarily short the rectifier output terminal to ground. This change in load causes a corresponding change in the current through the internal coil 102 d, thereby causing a change in the magnetic field surrounding external coil 101 f. This change in magnetic field causes a proportional change in the voltage across coil 101 f, which is observable as an amplitude modulation. The following equation describes the voltage seen on the external coil:
As shown by equation (1), there is a direct relationship between the voltage across the external coil and the impedance presented by the internal sensor circuit. While the impedance Zs is a complex number having both a real and imaginary part, which corresponds respectively to changes in amplitude and frequency of the oscillation signal, the system according to the present embodiment deals only with the real part of the interaction. It will be recognized by those skilled in the art that both types of interaction may be detected by appropriately modifying the external circuit, to improve the signal-to-noise ratio.
Voltage regulator 205 receives the voltage from capacitor C2 and produces a fixed output voltage Vref to the noninverting input of operational amplifier 201. The output terminal of the operational amplifier 201 is connected to a light-emitting diode (LED) 202 connected in series with a feedback resistor R1. The inverting input terminal of operational amplifier 201 is supplied with the voltage across R1, to thereby regulate the current through LED 202 to Vref/R1 (ignoring small bias current). Light emitted from LED 202 is incident on the sensor device (not shown) and causes the sensor device to emit light as a function of the amount of the particular analyte being monitored. The light from the sensor device impinges on the photosensitive resistor 203, whose resistance changes as a function of the amount of light incident thereon. Photoresistor 203 is connected in series with a capacitor C3, and the junction of the photoresistor and the capacitor C3 is connected to the inverting input terminal of comparator 204. The other end of photoresistor 203 is connected to the output terminal of the comparator 204 through a conductor Vcomp. The output of the comparator 204 is also connected to a load capacitor C4 and a resistor network R2, R3 and R4. The comparator forms a variable resistance oscillator, with switching points determined by the values of R2, R3 and R4. C3 is a charge-up capacitor, which determines the base frequency of the oscillator for a given light level. This frequency is given by
Equation (3) can be inverted to determine the intensity of light for a given photoresistance; in conjunction with equation (2), the light intensity can be determined from frequency. Of course, the values given above are provided as examples only for purposes of explanation. Such values are determined on the basis of the particular photoresistor geometry and materials used.
The comparator 204 switches to a high output when Vtime=V/3, Vcomp=V, and Vtrip=2V/3. Capacitor C3 begins to charge with time constant Rphoto*Ctime. When Vtime reaches 2V/3 the comparator switches states to a low output, changing Vcomp to Vcomp=0, and Vtrip to Vtrip=V/3. At this point C3 will discharge through Rphoto. Therefore a 50% duty cycle is established, with the frequency being determined by equation (2). Rphoto varies as a function of incident light, given by equation (3).
C4 is a load capacitor, which causes a voltage across C2 to decrease when the comparator switches states. C4 must be charged from 0V to Vdc when comparator 204 switches to a high output level state. The current through C4 is supplied by C2, causing the voltage across C2 to decrease. This in turn causes current to flow through rectifier 102 a to begin charging capacitor C2, changing the instantaneous load on the tank circuit including internal coil 102 d. This load is reflected into the impedance of the external coil 101 f as given by equation (1).
The sensor operation for a single pulse is illustrated in
The external unit 101 uses a microprocessor to implement the pulse counter 101 c. When sufficient data has been received to obtain a valid reading, the processor shuts down the MF oscillator.
The internal storage circuits can store ID codes and parametric values such as calibration constants. This information is returned along with each reading or quantitative measurement. The signals are clocked out by switching from analog pulse train loading to digitally controlled loading at a predefined point in the measurement sequence. This point is detected in the external unit by detecting a predefined bit synchronization pattern in the output data stream. The ID number is used to identify a particular subject and to prevent data corruption when two or more subjects are in the vicinity of the external unit. The calibration factors are applied to the measurement information to obtain analyte levels in clinical units.
A sensor 10 according to one aspect of the invention, which operates based on the fluorescence of fluorescent indicator molecules, is shown in
The sensor body 12 advantageously is formed from a suitable, optically transmissive polymer material which has a refractive index sufficiently different from that of the medium in which the sensor will be used such that the polymer will act as an optical wave guide. Preferred materials are acrylic polymers such as polymethylmethacrylate, polyhydroxypropylmethacrylate and the like, and polycarbonates such as those sold under the trademark Lexan®. The material allows radiation generated by the radiation source 18 (e.g., light at an appropriate wavelength in embodiments in which the radiation source is an LED) and, in the case of a fluorescence-based embodiment, fluorescent light emitted by the indicator molecules, to travel through it. Radiation source or LED 18 corresponds to LED 202 shown in
As shown in
It has been found that light reflected from the interface of the sensor body and the surrounding medium is capable of interacting with indicator molecules coated on the surface (whether coated directly thereon or contained within a matrix), e.g., exciting fluorescence in fluorescent indicator molecules coated on the surface. In addition, light which strikes the interface at angles (measured relative to a direction normal to the interface) too small to be reflected passes through the interface and also excites fluorescence in fluorescent indicator molecules. Other modes of interaction between the light (or other radiation) and the interface and the indicator molecules have also been found to be useful depending on the construction of and application for the sensor. Such other modes include evanescent excitation and surface plasma resonance type excitation.
As demonstrated by
As further illustrated in
An optical filter 34 preferably is provided on the light-sensitive surface of the photodetector 20, which is manufactured of a photosensitive material. Photodetector 20 corresponds to photodetector 203 shown in
The application for which the sensor 10 according to one aspect of the invention was developed in particular—although by no means the only application for which it is suitable—is measuring various biological analytes in the human body, e.g., glucose, oxygen, toxins, pharmaceuticals or other drugs, hormones, and other metabolic analytes. The specific composition of the matrix layer 14 and the indicator molecules 16 may vary depending on the particular analyte the sensor is to be used to detect and/or where the sensor is to be used to detect the analyte (i.e., in the blood or in subcutaneous tissues). Two constant requirements, however, are that the matrix layer 14 facilitate exposure of the indicator molecules to the analyte and that the optical characteristics of the indicator molecules (e.g., the level of fluorescence of fluorescent indicator molecules) are a function of the concentration of the specific analyte to which the indicator molecules are exposed.
To facilitate use in-situ in the human body, the sensor 10 is formed, preferably, in a smooth, oblong or rounded shape. Advantageously, it has the approximate size and shape of a bean or a pharmaceutical gelatin capsule, i.e., it is on the order of approximately 300-500 microns to approximately 0.5 inch in length L and on the order of approximately 300 microns to approximately 0.3 inch in depth D, with generally smooth, rounded surfaces throughout. The device of course could be larger or smaller depending on the materials used and upon the intended uses of the device. This configuration permits the sensor 10 to be implanted into the human body, i.e., dermally or into underlying tissues (including into organs or blood vessels) without the sensor interfering with essential bodily functions or causing excessive pain or discomfort.
Moreover, it will be appreciated that any implant placed within the human (or any other animal's) body—even an implant that is comprised of “biocompatible” materials—will cause, to some extent, a “foreign body response” within the organism into which the implant is inserted, simply by virtue of the fact that the implant presents a stimulus. In the case of a sensor 10 that is implanted within the human body, the “foreign body response” is most often fibrotic encapsulation, i.e., the formation of scar tissue. Glucose—a primary analyte which sensors according to the invention are expected to be used to detect—may have its rate of diffusion or transport hindered by such fibrotic encapsulation. Even molecular oxygen (O2), which is very small, may have its rate of diffusion or transport hindered by such fibrotic encapsulation as well. This is simply because the cells forming the fibrotic encapsulation (scar tissue) can be quite dense in nature or have metabolic characteristics different from that of normal tissue.
To overcome this potential hindrance to or delay in exposing the indicator molecules to biological analytes, two primary approaches are contemplated. According to one approach, which is perhaps the simplest approach, a sensor/tissue interface layer—overlying the surface of the sensor body 12 and/or the indicator molecules themselves when the indicator molecules are immobilized directly on the surface of the sensor body, or overlying the surface of the matrix layer 14 when the indicator molecules are contained therein—is prepared from a material which causes little or acceptable levels of fibrotic encapsulation to form. Two examples of such materials described in the literature as having this characteristic are Preclude™ Periocardial Membrane, available from W.L. Gore, and polyisobutylene covalently combined with hydrophiles as described in Kennedy, “Tailoring Polymers for Biological Uses,” Chemtech, February 1994, pp. 24-31.
Alternatively, a sensor/tissue interface layer that is composed of several layers of specialized biocompatible materials can be provided over the sensor. As shown in
The sublayer 36 b, on the other hand, preferably is a biocompatible layer with a pore size (less than 5 micrometers) that is significantly smaller than the pore size of the tissue ingrowth sublayer 36 a so as to prevent tissue ingrowth. A presently preferred material from which the sublayer 36 b is to be made is the Preclude Periocardial Membrane (formerly called GORE-TEX Surgical Membrane), available from W.L. Gore, Inc., which consists of expanded polytetra-fluoroethylene (ePTFE).
The third sublayer 36 c acts as a molecular sieve, i.e., it provides a molecular weight cut-off function, excluding molecules such as immunoglobulins, proteins, and glycoproteins while allowing the analyte or analytes of interest to pass through it to the indicator molecules (either coated directly on the sensor body 12 or immobilized within a matrix layer 14). Many well known cellulose-type membranes, e.g., of the sort used in kidney dialysis filtration cartridges, may be used for the molecular weight cut-off layer 36 c.
As will be recognized, the sensor as shown in
A second preferred embodiment of the invention is shown in
Examples of such disturbances include: changes or drift in the component operation intrinsic to the sensor make-up; environmental conditions external to the sensor; or combinations thereof. Internal variables may be introduced by, among other things: aging of the sensor's radiation source; changes affecting the performance or sensitivity of the photosensitive element; deterioration of the indicator molecules; changes in the radiation transmissivity of the sensor body, of the indicator matrix layer, etc.; and changes in other sensor components; etc. In other examples, the optical reference channel could also be used to compensate or correct for environmental factors (e.g., factors external to the sensor) which could affect the optical characteristics or apparent optical characteristics of the indicator molecule irrespective of the presence or concentration of the analyte. In this regard, exemplary external factors could include, among other things: the temperature level; the pH level; the ambient light present; the reflectivity or the turbidity of the medium that the sensor is applied in; etc. The optical reference channel can be used to compensate for such variations in the operating conditions of the sensor. The reference channel is identical to the signal channel in all respects except that the reference channel is not responsive to the analyte being measured.
Use of reference channels in optical measurement is generally known in the art. For example, U.S. Pat. No. 3,612,866, the entire disclosure of which is incorporated herein by reference, describes a fluorescent oxygen sensor having a reference channel containing the same indicator chemistry as the measuring channel, except that the reference channel is coated with varnish to render it impermeable to oxygen.
U.S. Pat. Nos. 4,861,727 and 5,190,729, the entire disclosures of which are incorporated herein by reference, describe oxygen sensors employing two different lanthanide-based indicator chemistries that emit at two different wavelengths, a terbium-based indicator being quenched by oxygen and a europium-based indicator being largely unaffected by oxygen. U.S. Pat. No. 5,094,959, the entire disclosure of which is also incorporated herein by reference, describes an oxygen sensor in which a single indicator molecule is irradiated at a certain wavelength and the fluorescence emitted by the molecule is measured over two different emission spectra having two different sensitivities to oxygen. Specifically, the emission spectra which is less sensitive to oxygen is used as a reference to ratio the two emission intensities. U.S. Pat. Nos. 5,462,880 and 5,728,422, the entire disclosures of which are also incorporated herein by reference, describe a ratiometric fluorescence oxygen sensing method employing a reference molecule that is substantially unaffected by oxygen and has a photodecomposition rate similar to the indicator molecule. Additionally, Muller, B., et al, ANALYST, Vol. 121, pp. 339-343 (March 1996), the entire disclosure of which is incorporated herein by reference, describes a fluorescence sensor for dissolved CO2, in which a blue LED light source is directed through a fiber optic coupler to an indicator channel and to a separate reference photodetector which detects changes in the LED light intensity.
In addition, U.S. Pat. No. 4,580,059, the entire disclosure of which is incorporated herein by reference, describes a fluorescent-based sensor containing a reference light measuring cell for measuring changes in the intensity of the excitation light source—see, e.g., column 10, lines 1, et seq.
As shown in
In the fluorescence embodiment, the incident light power impinging upon the photodiode detectors changes with analyte concentration.
At this time, the comparator 904 switches to a high output state Vss on output terminal 904 c. The trigger point (input terminal 904 a) is now at ⅔ Vss, and the polarity of the photodiodes 901 and 902 is now reversed. That is, photodiode 901 is now reverse-biased and photodiode 902 is now forward-biased.
Photodiode 901 now controls the charging of capacitor C2 at a rate of dV/dt=I901/C2 until the voltage of capacitor C2 reaches ⅔ Vss. When the voltage across capacitor C2 reaches ⅔ Vss, the output of the comparator 904 again switches to the low output state. So long as the system is powered and incident light is present on the photodiodes, the cycle will continue to repeat as shown in
If the incident light intensity on each photodiode detector 901 and 902 is equal, then the comparator output will be a 50% duty cycle. If the incident light on each photodiode detector is not equal, then the capacitor charge current will be different than the capacitor discharge current. This is the case shown in
Once the squarewave is established, it must be transferred to the external unit. This is done by loading the internal coil 908, and then detecting the change in load on the external coil inductively coupled to the internal coil. The loading is provided by resistor 910, which is connected to the output terminal 904 c of the comparator 904. When the comparator is in a high output state, an additional current Vss/R910 is drawn from the voltage regulator 909. When the comparator is in a low output state, this additional current is not present. Consequently, resistor 910 acts as a load that is switched into and out of the circuit at a rate determined by the concentration of analyte and the output of the reference channel. Because the current through resistor 910 is provided by the internal tuned tank circuit including coil 908, the switching of the resistor load also switches the load on the tank including internal coil 908. The change in impedance of the tank caused by the changing load is detected by a corresponding change in load on the inductively coupled external coil, as described above. The voltage regulator 909 removes any effects caused by coil placement in the field. The LED 903 emits the excitation light for the indicator molecule sensor. Power for the LED 903 is provided by the voltage regulator. It is important to keep the intensity of the LED constant during an analyte measurement reading. Once the output of the voltage regulator is in regulation, the LED intensity will be constant. The step recovery time of the regulator is very fast, with the transition between loading states being rapid enough to permit differentiation and AC coupling in the external unit.
As also will be recognized, the fluorescence-based sensor embodiments described in
The invention having been thus described, it will be apparent to those skilled in the art that the same may be varied in many ways without departing from the spirit and scope of the invention. For example, while the invention has been described with reference to an analog circuit, the principles of the invention may be carried out equivalently through the use of an appropriately programmed digital signal processor. Any and all such modifications are intended to be encompassed by the following claims.