U.S. patent application number 15/836085 was filed with the patent office on 2018-04-12 for implanted sensor processing system and method for processing implanted sensor output.
This patent application is currently assigned to Senseonics, Incorporated. The applicant listed for this patent is Senseonics, Incorporated. Invention is credited to Jeffery C. LESHO.
Application Number | 20180098699 15/836085 |
Document ID | / |
Family ID | 31993722 |
Filed Date | 2018-04-12 |
United States Patent
Application |
20180098699 |
Kind Code |
A1 |
LESHO; Jeffery C. |
April 12, 2018 |
IMPLANTED SENSOR PROCESSING SYSTEM AND METHOD FOR PROCESSING
IMPLANTED SENSOR OUTPUT
Abstract
A quantitative measurement system includes an external unit and
an internal unit and is provided for obtaining quantitative analyte
measurements, such as within the body. In one example application,
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.
Inventors: |
LESHO; Jeffery C.;
(Brookeville, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Senseonics, Incorporated |
Germantown |
MD |
US |
|
|
Assignee: |
Senseonics, Incorporated
Germantown
MD
|
Family ID: |
31993722 |
Appl. No.: |
15/836085 |
Filed: |
December 8, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15456980 |
Mar 13, 2017 |
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15836085 |
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12493478 |
Jun 29, 2009 |
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15456980 |
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10332619 |
Oct 21, 2003 |
7553280 |
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PCT/US01/20390 |
Jun 27, 2001 |
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12493478 |
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09605706 |
Jun 29, 2000 |
6400974 |
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10332619 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 2562/08 20130101;
A61B 5/076 20130101; A61B 5/14546 20130101; A61B 2560/0252
20130101; A61B 5/14532 20130101; A61B 5/1459 20130101; A61B 5/0031
20130101 |
International
Class: |
A61B 5/00 20060101
A61B005/00; A61B 5/1459 20060101 A61B005/1459 |
Claims
1. A system comprising: a sensor unit for taking quantitative
analyte measurements, the sensor unit including a first inductor
forming part of a power supply for said sensor unit, a load coupled
to said first inductor, and a sensor circuit for modifying said
load in accordance with sensor measurement information obtained by
said sensor circuit; a reader including a second inductor that is
mutually inductively coupled to said first inductor upon said
second inductor being placed within a predetermined proximal
distance from said first inductor, a driver for driving said second
inductor to induce a charging current in said first inductor, a
detector for detecting variations in a load on said second inductor
induced by changes to said load in said sensor unit and for
providing information signals corresponding to said load changes,
and a processor for receiving and processing said information
signals.
2. The system of claim 1, wherein said sensor circuit comprises an
indicator that emits radiation in proportion to levels of said
analyte.
3. The system of claim 2, wherein said load comprises a
photosensitive resistor that receives radiation from said
indicator.
4. The system of claim 2, wherein said sensor circuit further
comprises a radiation source configured to emit electromagnetic
radiation that stimulates emission of the radiation.
5. The system of claim 2, wherein said indicator emits fluorescent
radiation in proportion to levels of said analyte.
6. The system of claim 5, wherein said load comprises a
photosensitive resistor that receives fluorescent radiation from
said indicator.
7. The system of claim 4, wherein said radiation source for
emitting electromagnetic radiation stimulates emission of
fluorescent radiation.
8. The system of claim 1, wherein said sensor unit is implantable
in the body of a mammal.
9. The system of claim 1, wherein said power supply further
includes a charging capacitor that is charged by said charging
current.
10. The system of claim 1, wherein said detector of said reader
includes an amplitude modulation (AM) demodulator for detecting
changes in amplitude of a voltage waveform caused by changes in
said load, said voltage waveform being inductively reflected into
said second inductor through said first inductor.
11. The system of claim 10, wherein said processor includes a pulse
counter for converting said detected changes in waveform amplitude
into pulses suitable for being converted into computer-readable
form.
12. The system of claim 1, wherein said reader includes a computer
configured to receive the processed information signals.
13. The system of claim 1, wherein said sensor circuit comprises an
indicator that absorbs radiation in proportion to levels of said
analyte.
14. The system of claim 1, wherein the sensor unit is an internal
sensor unit.
15. The system of claim 14, wherein the internal sensor unit is a
partially or fully internal sensor unit.
16. The system of claim 1, wherein the driver comprises an
oscillator.
17. A sensor device for detecting the presence or concentration of
an analyte in a medium, comprising: a sensor body; an indicator
having a characteristic that is affected by the presence or
concentration of an analyte; a detector configured to detect a
signal from said indicator, said signal being indicative of the
characteristic of the indicator; and a first inductor coupled to
said detector, said first inductor being adapted to receive from a
second inductor a magnetically induced electric current, and being
further adapted to induce in said second inductor an electric
current that changes as a function of the signal detected by said
detector.
18. The sensor device of claim 17, further comprising a radiation
source in said sensor body, wherein the radiation source is
configured to emit radiation within said sensor body.
19. The sensor device of claim 18, wherein the indicator is
positioned on said sensor body to receive radiation emitted by said
radiation source.
20. The sensor device of claim 18, wherein said characteristic is
an optical characteristic, and the detector comprises a
photosensitive element configured to receive light emitted by said
indicator.
21. The sensor device of claim 17, wherein magnetically induced
electric current supplies power to the sensor device.
22. The sensor device of claim 17, wherein the sensor body is an
enclosed sensor body and has an outer surface surrounding said
sensor body.
23. The sensor device of claim 17, wherein the detector is located
in the sensor body.
24. The sensor device of claim 17, wherein the first inductor is
located in the sensor body.
25. The sensor device of claim 17, wherein the indicator comprises
a matrix layer on the exterior surface of the sensor body, and
indicator molecules are distributed throughout the matrix layer.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/456,980, which was filed on Mar. 13, 2017,
which is a continuation of U.S. patent application Ser. No.
12/493,478, which was filed on Jun. 29, 2009, abandoned, and is a
divisional of U.S. patent application Ser. No. 10/332,619, which
was filed on Oct. 21, 2003, now U.S. Pat. No. 7,553,280, and is a
national stage application filed under 35 U.S.C. .sctn. 371 of
PCT/US01/20390, which was filed on Jun. 27, 2001, and is a
continuation-in-part of U.S. patent application Ser. No.
09/605,706, which was filed on Jun. 29, 2000, now U.S. Pat. No.
6,400,974, all of which are incorporated by reference herein in
their entireties.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] 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.
Background Art
[0003] 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.
[0004] 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.
[0005] 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.
SUMMARY OF THE INVENTION
[0006] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] 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:
[0008] FIG. 1 is a block diagram of one preferred embodiment
according to the present invention;
[0009] FIG. 2 is a schematic diagram of an internal sensor device
unit according to one preferred embodiment of the invention;
[0010] FIGS. 3 and 4 are waveform diagrams illustrating signal
waveforms at various points in the sensor device circuit;
[0011] FIGS. 5A-5E are diagrams of signals produced by the external
data receiving unit;
[0012] FIG. 6 is a schematic, section view of an implantable
fluorescence-based sensor according to the invention;
[0013] FIG. 7 is a schematic diagram of the fluorescence-based
sensor shown in FIG. 6 illustrating the wave guide properties of
the sensor;
[0014] FIG. 8 is a detailed view of the circled portion of FIG. 6
demonstrating internal reflection within the body of the sensor and
a preferred construction of the sensor/tissue interface layer;
[0015] FIG. 9 is a schematic diagram of an internal sensor device
unit according to a second preferred embodiment of the invention;
and
[0016] FIG. 10 is a timing diagram illustrating voltage levels of
various terminals of the comparator of FIG. 9 as the detector
circuit cycles through its operation.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0017] FIG. 1 shows a block diagram of one preferred embodiment of
an implanted fluorescence sensor processing system according to the
present invention.
[0018] 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 102b, a component of which may be
comprised of a fluorescence sensing device as described more fully
hereinafter with reference to FIGS. 6-8. The optoelectronics
circuitry 102b obtains quantitative measurement information and
modifies a load 102c as a function of the obtained information. The
load 102c in turn varies the amount of current through coil 102d,
which is coupled to coil 101f of the external unit. An amplitude
modulation (AM) demodulator 101b detects the current variations
induced in coil 101f by coil 102d coupled thereto, and applies the
detected signal to processing circuitry, such as a pulse counter
101c and computer interface 101d, for processing the signal into
computer-readable format for inputting to a computer 101e.
[0019] A variable RF oscillator 101a provides an RF signal to coil
101f, which in turn provides electromagnetic energy to coil 102d,
when the coils 101f and 102d 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 102c and in turn provide a load variation
to the coil 101f 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 101f and 102d. 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.
[0020] RF oscillator 101a drives coil 101f, which induces a current
in coil 102d. The induced current is rectified by a rectifier
circuit 102a and used to power the optoelectronics 102b. 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 102c
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 102d, thereby
causing a change in the magnetic field surrounding external coil
101f. This change in magnetic field causes a proportional change in
the voltage across coil 101f, which is observable as an amplitude
modulation. The following equation describes the voltage seen on
the external coil:
V=I[Z+((.omega.M).sup.2)/Zs] (1)
where [0021] V=voltage across the external coil [0022] I=current in
the external coil [0023] Z=impedance of the primary coil [0024]
.omega.=frequency (rad/sec) [0025] M=mutual inductance between the
coils [0026] Zs=impedance of the sensor equivalent circuit
[0027] 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.
[0028] FIG. 2 shows a schematic diagram of one embodiment of an
internal sensor device unit according to the invention. The coil
102d (L1) in conjunction with capacitor C1, diode D1 (rectifier
102a) zener diode D2 and capacitor C2 constitute a power supply for
the internal unit 102. Current induced in coil L1 by the RF voltage
applied to external coil 101f by oscillator 101a (see FIG. 1) is
resonated in the L-C tank formed by L1 and capacitor C1, rectified
by diode D1, and filtered by capacitor C2. Zener diode D2 is
provided to prevent the voltage being applied to the circuit from
exceeding a maximum value, such as 5 volts. As is known by those
skilled in the art, if the voltage across capacitor C2 starts to
exceed the reverse breakdown voltage of the zener diode D2, diode
D2 will start to conduct in its reverse breakdown region,
preventing the capacitor C2 from becoming overcharged with respect
to the maximum allowable voltage for the circuit.
[0029] Voltage regulator 205 receives the voltage from capacitor C2
and produces a fixed output voltage V.sub.ref 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 V.sub.ref/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
V.sub.comp. 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
f=1/(1.38*Rphoto*C3) (2)
Rphoto=R.sub.2fc[10.sup.-.gamma. log(a/2fc)] (3)
[0030] Where [0031] R.sub.2fc (=24 k.OMEGA.) is the resistance of
photoresistor 203 at 2 footcandles [0032] .gamma.(=0.8) is the
sensitivity of the photoresistor [0033] a=the incident light level
in footcandles
[0034] 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.
[0035] 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).
[0036] 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 102a to begin charging capacitor C2, changing the
instantaneous load on the tank circuit including internal coil
102d. This load is reflected into the impedance of the external
coil 101f as given by equation (1).
[0037] The sensor operation for a single pulse is illustrated in
FIG. 3. Channel 4 is the DC voltage on C2, channel 3 shows the same
pulse on the external coil 101f, and the output of the AM
demodulator is shown at channel 2. Channel 1 shows the output of a
comparator which converts the AM demodulator output to a square
wave capable of being processed by a digital counter. FIG. 4 shows
two complete operation cycles, with the same channel designations
indicating the same points in the circuit.
[0038] The external unit 101 uses a microprocessor to implement the
pulse counter 101c. When sufficient data has been received to
obtain a valid reading, the processor shuts down the RF oscillator.
FIGS. 5A-5E illustrate timing diagrams for a measurement reading.
FIG. 5A shows the envelope of the RF voltage signal applied to the
external coil; FIG. 5B shows the waveform of the internal power
supply voltage; FIG. 5C shows a waveform of the intensity of LED
202; FIG. 5D shows the output of the AM demodulator 101b; and FIG.
5E shows the timing of the state of circuit operations in
accordance with the power supplied to the sensor unit. The internal
unit power supply ramps up as the field strength increases. When
the power supply output crosses the threshold voltage of the LED
plus the feedback voltage, the LED turns on. The AM demodulator
output contains the measurement data and digital data in the form
of ID codes and other parameters specific to the subject in which
the internal unit is implanted. This data is encoded on the RF
voltage signal through time division multiplexing of the
optoelectronic output with digital identification and parameter
storage circuits (not shown). The digital circuits use the RF
voltage to generate appropriate clock signals.
[0039] 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.
[0040] A sensor 10 according to one aspect of the invention, which
operates based on the fluorescence of fluorescent indicator
molecules, is shown in FIG. 6. The sensor 10 is composed of a
sensor body 12; a matrix layer 14 coated over the exterior surface
of the sensor body 12, with fluorescent indicator molecules 16
distributed throughout the layer; a radiation source 18, e.g. an
LED, that emits radiation, including radiation over a wavelength or
range of wavelengths which interact with the indicator molecules,
i.e., in the case of a fluorescence-based sensor, a wavelength or
range of wavelengths which cause the indicator molecules 16 to
fluoresce; and a photosensitive element 20, e.g. a photodetector,
which, in the case of a fluorescence-based sensor, is sensitive to
fluorescent light emitted by the indicator molecules 16 such that a
signal is generated in response thereto that is indicative of the
level of fluorescence of the indicator molecules. The sensor 10
further includes a module or housing 66 containing electronic
circuitry, and a temperature sensor 64 for providing a temperature
reading. In the simplest embodiments, indicator molecules 16 could
simply be coated on the surface of the sensor body. In preferred
embodiments, however, the indicator molecules are contained within
the matrix layer 14, which comprises a biocompatible polymer matrix
that is prepared according to methods known in the art and coated
on the surface of the sensor body. Suitable biocompatible matrix
materials, which must be permeable to the analyte, include
methacrylates and hydrogels which advantageously can be made
selectively permeable to the analyte.
[0041] 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.RTM.. 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 FIG. 2.
[0042] As shown in FIG. 7, radiation (e.g., light) is emitted by
the radiation source 18 and at least some of this radiation is
reflected internally at the surface of the sensor body 12, e.g., as
at location 22, thereby "bouncing" back-and-forth throughout the
interior of the sensor body 12.
[0043] 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.
[0044] As demonstrated by FIG. 8, at least some of the light
emitted by the fluorescent indicator molecules 16 enters the sensor
body 12, either directly or after being reflected by the outermost
surface (with respect to the sensor body 12) of the matrix layer
14, as illustrated in region 30. Such fluorescent light 28 is then
reflected internally throughout the sensor body 12, much like the
radiation emitted by the radiation source 18 is, and, like the
radiation emitted by the radiation source, some will strike the
interface between the sensor body and the surrounding medium at
angles too small to be reflected and will pass back out of the
sensor body.
[0045] As further illustrated in FIG. 6, the sensor 10 may also
include reflective coatings 32 formed on the ends of the sensor
body 12, between the exterior surface of the sensor body and the
matrix layer 14, to maximize or enhance the internal reflection of
the radiation and/or light emitted by fluorescent indicator
molecules. The reflective coatings may be formed, for example, from
paint or from a metallized material.
[0046] 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 FIG. 2. Filter 34, as is
known from the prior art, prevents or substantially reduces the
amount of radiation generated by the source 18 from impinging on
the photosensitive surface of the photosensitive element 20. At the
same time, the filter allows fluorescent light emitted by
fluorescent indicator molecules to pass through it to strike the
photosensitive region of the detector. This significantly reduces
"noise" in the photodetector signal that is attributable to
incident radiation from the source 18.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.TM. 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.
[0051] 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 FIG. 8, for example,
the sensor/tissue interface layer 36 may include three sublayers
36a, 36b, and 36c. The sublayer 36a, a layer which promotes tissue
ingrowth, preferably is made from a biocompatible material that
permits the penetration of capillaries 37 into it, even as fibrotic
cells 39 (scar tissue) accumulate on it. Gore-Tex.RTM. Vascular
Graft material (ePTFE), Dacron.RTM. (PET) Vascular Graft materials
which have been in use for many years, and MEDPOR Biomaterial
produced from high-density polyethylene (available from POREX
Surgical Inc.) are examples of materials whose basic composition,
pore size, and pore architecture promote tissue and vascular
ingrowth into the tissue ingrowth layer.
[0052] The sublayer 36b, 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 36a so as to prevent tissue ingrowth. A presently
preferred material from which the sublayer 36b 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).
[0053] The third sublayer 36c 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 36c.
[0054] As will be recognized, the sensor as shown in FIG. 6 is
wholly self-contained such that no electrical leads extend into or
out of the sensor body, either to supply power to the sensor (e.g.,
for driving the source 18) or to transmit signals from the sensor.
All of the electronics illustrated in FIG. 2 may be housed in a
module 66 as shown in FIG. 6.
[0055] A second preferred embodiment of the invention is shown in
FIG. 9, in which two detectors are employed, a signal channel
detector 901 and a reference channel detector 902. In the first
embodiment as shown in FIG. 2, a single detector 203 is used to
detect radiation from the fluorescent indicator sensor device.
While this system works well, it is possible that various
disturbances to the system will occur that may affect the accuracy
of the sensor output as originally calibrated.
[0056] 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.
[0057] 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.
[0058] 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
CO.sub.2, 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.
[0059] 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.
[0060] As shown in FIG. 9, the signal and reference channel
detectors are back-to-back photodiodes 901 and 902. While
photodiodes are shown, many other types of photodetectors also
could be used, such as photoresistors, phototransistors, and the
like. LED 903 corresponds to light source 202 in FIG. 2. In
operation, comparator 904 is set to trigger at 1/3 and 2/3 of the
supply voltage Vss, as biased by resistors 905, 906, and 907. The
trigger voltages for comparator 904 could be modified, if desired,
by changing the values of the resistors. Capacitor C2 is a timing
element, the value of which is adjusted for the magnitude of the
signal and reference channels. The current through each photodiode
is a function of the intensity or power of incident light entering
it, as represented by the equation I=RP, where
[0061] I=current
[0062] R=responsivity (Amp/Watt) and
[0063] P=light power in watts.
[0064] In the fluorescence embodiment, the incident light power
impinging upon the photodiode detectors changes with analyte
concentration.
[0065] FIG. 10 is a timing diagram showing the voltage levels of
the terminals 904a, 904b, and 904c of the comparator 904. At the
cycle start, the voltage level of output terminal 904c is at ground
(low output state), the voltage level of capacitor C2 (which
corresponds to the voltage level at input terminal 904b) is at 2/3
Vss, and the voltage level of input terminal 904a is at 1/3 Vss. In
this instance, photodiode 901 is forward-biased and photodiode 902
is reverse-biased. The voltage drop across the forward-biased
photodiode 901 is simply its threshold voltage, while the
reverse-biased photodiode 902 exhibits a current flow proportional
to the incident light impinging upon it. This current discharges
the capacitor C2 at a rate of dV/dt=I902/C2, until it reaches a
voltage level of 1/3 Vss as shown in FIG. 10. Inserting the above
equation for photodiode current results in the equation
dV/dt=RP/C2. Solving for P, P=(dV*C2)/(dt*R), where
[0066] dV=difference between comparator trigger points (in the
example 1/3 Vss)
[0067] C2=value of capacitor C2 in farads
[0068] dt=time to charge or discharge (as measured by the external
unit) and
[0069] R=responsivity (in amps/watts) of the photodetector
[0070] At this time, the comparator 904 switches to a high output
state Vss on output terminal 904c. The trigger point (input
terminal 904a) is now at 2/3 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.
[0071] Photodiode 901 now controls the charging of capacitor C2 at
a rate of dV/dt=I901/C2 until the voltage of capacitor C2 reaches
2/3 Vss. When the voltage across capacitor C2 reaches 2/3 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 FIG. 10.
[0072] 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 FIG. 10,
wherein the capacitor charge current is higher than the capacitor
discharge current. Because the same capacitor is charged and
discharged, the different charge and discharge times are a function
only of the difference between the incident light levels on the two
photodiode detectors. Consequently, the duty cycle of the
squarewave produced by the comparator 904 is indicative of changes
between incident light on the signal channel photodiode and
incident light on the reference channel photodiode. Suitable
algorithms for taking into account changes in duty cycle of the
squarewave from the comparator in determining analyte concentration
are generally known in the art (see prior art references discussed
supra) and will not be further discussed herein.
[0073] 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 904c 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.
[0074] As also will be recognized, the fluorescence-based sensor
embodiments described in FIGS. 6-8 are just examples to which the
disclosed invention may be applied. The present invention may also
be applied in a number of other applications such as, for example,
an absorbance-based sensor or a refractive-index-based sensor as
described in U.S. patent application Ser. No. 09/383,148, filed
Aug. 28, 1999, incorporated herein by reference.
[0075] 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.
* * * * *