WO2009008932A2

WO2009008932A2 - Implantable wireless cmos biosensor

Info

Publication number: WO2009008932A2
Application number: PCT/US2008/004731
Authority: WO
Inventors: M. Mekhail Anwar; Paul Matsudaira
Original assignee: Whitehead Institute
Priority date: 2007-04-12
Filing date: 2008-04-11
Publication date: 2009-01-15
Also published as: WO2009008932A3

Abstract

System and methods for detection and measurement of analytes, e.g., within a human body are described. The system includes at least one sensor module which can be placed in the body of a subject and is capable of measuring at least one analyte present in the blood or interstitial fluid. In some embodiments, at least two sensor modules are placed in close proximity with a blood vessel, and the concentration of an analyte, e.g., glucose, is measured. In some embodiments the device is a wireless device and the implantable CMOS-based unit transmits signals to an external unit housing a display, light source, and power source.

Description

IMPLANTABLE WIRELESS CMOS BIOSENSOR

FIELD AND BACKGROUND OF THE INVENTION

[001] The study of biology is progressing towards systems-based biology, where the entire space of gene activation and/or protein function is analyzed. To achieve this, the use of DNA and protein arrays, such as microarrays, has become widespread. In addition, the in-vivo sensing of cellular behavior and reactions provides important information in the study and treatment of various conditions.

[002] Nearly all forms of biosensors utilize a biological entity (i.e. antibody, protein, DNA, drug, etc) to interface with the target (i.e. ligand: virus, receptor, protein, bacteria, etc). An instrument is then used to read that reaction, and relay its results to the outside world. This is traditionally accomplished with an external device. These devices read signals such as light (from fluorescently labeled entities), radioactivity, mass, electric charge etc. These devices tend to be large and expensive. Additional approaches to reading microarrays and performing measurements of biological substances in mixtures are needed.

SUMMARY OF THE INVENTION

[003] The present invention relates to a wireless complementary metal oxide semiconductor (CMOS) imager that is useful for microarray imaging (such as protein and DNA mircroarrays) as well as for implantable sensors.

[004] According to one aspect of the present invention, there is provided a system for identifying a biological sample. The system includes a sensor having at least one photodiode for converting photons obtained from interaction with the sample into electrons and for providing analog electrical output; an analog to digital converter in electrical communication with the photodiode for converting the analog output into a digital signal, wherein at least the photodiode and the analog to digital converter form a CMOS circuit, and a processor for processing the digital signal.

[005] According to another aspect of the present invention, there is provided a sensor for identifying an interaction in a microarray. The sensor includes a pixel array of photodiodes wherein a size of each pixel of the pixel array is less than 150 micrometers. In some embodiments, a size of each pixel ranges from less than the size of a spot on the microarray to a maximum of the pitch between spots on the microarray. In some embodiments, the size of each pixel is less than twice the size of a spot on the microarray. In some embodiments, an outer layer substantially surrounds the pixel array, wherein the outer layer provides a fluid barrier between electrical components of said sensor and said biological sample. [006] According to another aspect of the invention there is provided a sensor comprising at least first and second sensor modules, each sensor module comprising an array of photodetectors, wherein the first and second sensor modules are positionable in a functional relationship with respect to each other and with respect to a sample. According to another aspect of the invention there is provided a system comprising the afore-mentioned sensor modules, a light source, and a processor. In some embodiments the first and sensor modules are physically attached to one another. In some embodiments the first and sensor modules are components of an implantable device. In some embodiments the first and second sensor modules are positionable around a blood vessel and the sensor modules are configured to obtain measurements of light incident on the blood vessel and light transmitted through the blood vessel and its contents, thereby affording a measurement of light absorbed by the blood vessel and its contents. [007] According to another aspect of the invention, there is provided a method for measuring a sample. The method includes providing a wireless CMOS biosensor having a pixel array of photodetectors, which are optionally photodiodes, providing a microarray of the biological sample, wherein the microarray has a one-to-one correspondence with the pixel array, tagging the biological sample with a fluorescent label, placing the biosensor proximal to the microarray, illuminating the biosensor and the biological sample, wherein the illuminating causes the tagged biological sample to emit photons, converting the photons into an electrical signal using the CMOS biosensor, and wirelessly receiving the electrical signal, wherein the electrical signal is representative of an amount of tagged biological sample.

[008] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

[009] The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. In the drawings: FIG. 1 is a block diagram illustration of a system for identifying a sample, in accordance with embodiments of the present invention;

FIG. 2 is a planar view diagrammatic illustration of biosensor chip from the system of FIG. 1, in accordance with embodiments of the present invention; FIG. 3 is a diagrammatic illustration of a pixel from the chip of FIG. 2, in accordance with embodiments of the present invention;

FIG. 4 is a block diagram illustration showing the various components of a sensor and processor from the system of FIG. 1 ;

FIGS. 5A and 5B are circuit diagrams for a sensor photodiode and reference photodiode from the pixel of FIG. 3;

FIG. 6 is a circuit diagram illustration of an amplifier for use with the chip of FIG. 2, in accordance with embodiments of the present invention;

FIG. 7 is a circuit diagram illustration of an analog to digital converter for use with the chip of FIG. 2, in accordance with embodiments of the present invention; FTG. 8 is a graphical illustration of a clock signal that is generated from the sine wave of a wireless interface from the system of FIG. 1 ;

FIGS. 9A and 9B are diagrammatic illustrations of a light source in accordance with embodiments of the present invention;

FIG. 10 is an illustration of direct UV illumination of a commercial CMOS camera using Qdots; FIG. 1 1 is a calibration curve showing the number of photons incident on a sensor of the present invention versus applied voltage;

FTG. 12 is a graphical illustration of pixel output from ramping LED voltage;

FTG. 13A and 13B are graphical illustrations of amplifier output versus incident light;

FIG. 14 is a graphical illustration of digital values from amplifier output; FIG. 15 is a graphical illustration of differential output with noise; and

FIG. 16 is a graphical illustration comparing varying concentrations of GFP using the CMOS sensor of the present invention versus a CCD camera.

FIG. 17 is an illustration of an implantable sensor comprising two sensor modules each comprising an array of photodetectors. FIG. 18 is an illustration of another embodiment of an implantable sensor in which two sensor modules each comprising an array of photodetectors are attached and electrically coupled to a substrate.

FIG. 19 is a schematic illustration showing powering of the sensor by inductive coupling.

FTG. 20 is a schematic illustration of light illuminating and passing through a both sensor modules and a vessel positioned between the sensor modules. FIG. 21 is an illustration of a sensor module comprising multiple photodetectors, each capable of detecting light of a different wavelength. FIG. 22 is a plot showing the characteristic IR absorption of glucose and water between 2 μm and 2.5 μm and illustrating the inventive method for eliminating the absorption of water from the glucose measurement.

FIG. 23 depicts side and front views of a differential optical sensor assembly, including two optical sensor modules (detectors) wire bonded onto metallized quartz substrates.

FIG. 24 shows a schematic diagram of a glucose sensing system of the present invention, including a differential sensor assembly that includes two sensor modules, an infrared light source

(LED), lens, filter wheel, and interface circuitry. The sensor assembly is implantable and includes data processing circuitry and transmits data to an external unit. The light source, filters, lens, and interface circuitry, would be integrated into an external unit that displays and/or stores the information.

FIG. 25 shows implementation details of the optical emission and detection in an exemplary embodiment of the glucose sensor. The LED is modulated at a low frequency, typically between 1 and 100 kHz. The photodiode is incorporated into an integrator circuit with a reset mechanism. The signal at the output of the integrator is captured and processed.

DETAILED DESCRIPTION

[0010] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. It will be understood by those of ordinary skill in the art that the present invention may be practiced without these specific details. In other instances, well- known methods, procedures, components and structures may not have been described in detail so as not to obscure the present invention.

[0011] Reference is now made to FIG. 1, which is a block diagram illustration of a system 10 for identifying a sample, in accordance with embodiments of the present invention. System 10 includes a biosensor chip 12 having a sensor 14 and a processor 16, a sample 18 to be analyzed, a light source 20 and a wireless interface 22. Sample 18 is positionable in contact with or in close proximity to biosensor chip 12, both of which may be illuminated by light source 20. The proximity of sample 18 to chip 12 is dependent on the spot size of sample 18 and may be, for example, within a distance which is several times the spot size. Sensor 14 senses and converts photons emitted by sample 18 into electrical current, and processor 16 processes signals associated with the current to provide data output. Most or all of the individual components of processor 16 are positioned on the chip itself and comprise a CMOS circuit. Wireless interface 22 provides power and a clock to chip 12, and receives data output from processor 16.

[0012] Reference is now made to FIG. 2, which is a planar view diagrammatic illustration of biosensor chip 12, in accordance with embodiments of the present invention. In one embodiment, chip 12 is a rectangular chip which is positionable in close proximity to sample 18. In one embodiment, chip 12 is approximately 3 x 3 mm in size. It should be readily apparent, however, the chip 12 may be any size suitable for imaging and sensing microarrays or biological in-vivo interactions. Chip 12 is comprised of an array of pixels 24, and processor components including a voltage rectifier and regulator 28, and an analog to digital converter 30. Chip 12 further includes an antenna which is configured to communicate with an external reader. In one embodiment, the antenna is comprised of inductor coils 26. Inductor coils 26 comprise a wireless interface 22, and operate to generate the power and clock signal from the RF wave and to send received digital data to the external reader. Additional processor components are further included on each pixel, as will be described in greater detail hereinbelow. In embodiments of the present invention, pixels 24 are designed and sized to directly correspond to a microarray having samples therein for analysis. For example, the size of each pixel is designed to correspond to the size of each sample in a microarray. Each pixel is within a multiple of the size of the sample, where the upper limit is the pitch of the array spots, and the lower limit is the size of the spot itself. Thus, for example, if each spot is 100 micrometers, and is separated from the next spot by 200 micrometers, the pixel could range from 100-300 micrometers. In one embodiment, the pixels are less than 150 micrometers. In some embodiments, the pixels are approximately 12O x 120 micrometers in size. In some embodiments, the size of each pixel is less than twice the size of a spot on the microarray. In the embodiment shown herein, the pixel array is a 64-pixel array. It should be readily apparent that other configurations are possible and are included within the scope of the invention. Chip 14 may further include an outer layer providing a fluid barrier between electrical components of chip 14 and sample 18. This is possible due to the wireless interface 22, which will be described in greater detail further hereinbelow, and further allows for chip 14 to be implantable in a human body. In one embodiment, the outer layer is a biocompatible material, such as a biocompatible polymer. PDMS (Sylgard 184, Dow Corning) is one example among many known in the art. In some embodiments the outer layer is optically transparent to light of wavelengths of interest to be measured. For example, for an implantable sensor, it may be of interest to detect substances that absorb in the infrared region of the spectrum, or a portion thereof.

[0013] Reference is now made to FIG. 3, which is a diagrammatic illustration of a pixel 24 in accordance with embodiments of the present invention. Pixel 24 includes a sensor photodiode 44 and a reference photodiode 46, in electrical communication with source followers 40 and hold capacitors 42. Hold capacitors 42 may be any size suitable for pixel 24, and are generally chosen to be the largest capacitors that will fit into the designated space on pixel 24. In one embodiment, hold capacitors 42 are 50 pF poly-poly capacitors. Sensor photodiode 44 is a photodiode typically used in a CMOS circuit, and may be, for example, an N-plus P-sub diode, an N-well P-sub diode, a P-plus N-well P-sub diode, an N- plus P-well diode or any other suitable photodiode. In some embodiments, different pixels within the pixel array have different diodes. In one embodiment, three rows of pixels are comprised of N-plus P- sub diodes, three rows of pixels are comprised of N-well P-sub diodes, and the remaining two rows of pixels are comprised of P-plus N-well P-sub diodes. It should be readily apparent that such configurations are exemplary and that many other combinations of diode types are possible and are included within the scope of the invention. Reference photodiode 46 is a photodiode which is covered with a metal to measure the dark current. Sensor photodiode 44 and reference photodiode 46 are placed as far away from each other as possible to avoid carriers from one "leaking" to the other. Outputs from sensor photodiode 44 and reference photodiode 46 are subtracted to eliminate noise from the pixel and in one embodiment are laid out in a common centroid arrangement. This configuration provides for a fully differential pixel architecture which can compensate for the high noise level which may occur due to the wireless interface. It will also be evident that embodiments of the invention may employ photodetectors other than photodiodes. Thus the term "photodiode" as used herein should be understood to be replaceable by "photodetector, wherein the photodetector is optionally a photodiode".

[0014] Reference is now made to FIG. 4, which is a block diagram illustration showing the various components of sensor 14 and processor 16, and how they are interrelated. An inductor coil 26, located on chip 12, provides an RF signal to a clock generator 36, which generates a pulse and sends it to a clock and decoder 34, positioned on chip 12. Clock/decoder 34 divides the signal by any chosen number (equaling the number of bits of resolution needed). Clock/decoder activates each pixel 24 serially for readout, and the readout signal is amplified by amplifier 32, and sent to analog/digital converter 30. Analog to digital converter 30 uses clock 34 to derive the digital conversion for the analog signal. Any implementation of an analog to digital converter can be used. In this embodiment, the integrating current is set by a switch capacitor circuit whose clock is governed by the clock from the RF signal, thus making the analog to digital converter, which samples the output from amplifier 32 and integrates until a threshold voltage is reached. The time it takes for the threshold to be reached is recorded by latching the value of the clock. This becomes the digital signal. The integrating current is derived from the power supply, and is based off of a switch capacitor circuit, so that the analog to digital converter is frequency independent (ie the higher the frequency, the larger the current, and the shorter the time). The final signal is then sent back to inductor 26.

[0015] The standard CMOS photosensor design is a traditional three transistor design whereby an NMOS reset transistor charges the photodiode (and associated parasitic capacitance) to V , t- V where

Vdd is a power supply voltage, and Vt is the threshold voltage of the reset transistor. The reset transistor is turned off, and the photodiode converts photons to a current which discharges the parasitic capacitance. Because the depletion region capacitance is a function of the reverse bias, the parasitic capacitor functions as a non-linear gain element. During readout, the row/column switch is activated, and the source follower reads out the voltage on the photodiode. This voltage is amplified, and converted to a digital signal. After readout, the reset transistor is activated, the photodiode voltage is reset, and the process repeats. Pixels can be selectively read out by using a select transistor. Frequently, the readout circuitry utilizes correlated double sampling (CDS) to reduce fixed pattern noise, such as amplifier offsets. In addition, depending on the power, speed, and noise requirements, the amplifier and A/D can be located at the chip level, row/column level, or even at the pixel level. In the present application, a slightly modified design is used. Each photodiode is connected to a PMOS reset transistor instead of the traditional NMOS, because the area is not limiting, and the photodiode can be reset to V . .

. In addition, image lag can be reduced by using a PMOS reset transistor.

[0016] Reference is now made to FIGS. 5A and 5B, which are circuit diagrams for the sensor photodiode and reference photodiode, respectively. Briefly, sensor photodiode 44 (or reference photodiode 46, as shown in FIG. 5B) is connected to a voltage source via a PMOS device. This allows sensor photodiode 44 to have a rapid and complete reset, eliminating image lag. The photodiode current draws current off of the parasitic capacitance, causing a decrease in voltage in response to light. The output from sensor photodiode 44 is buffered by first source follower 40, which has a switch to eliminate power consumption when not in use. The output is stored on hold capacitor 42 and can be read out at a later time by second source follower 41. The small signal output of the pixel is, v₀ = , where P is the incident photons per second, C_Ph, is the photodiode parasitic capacitance,

φ is the quantum efficiency, and A₅/, is the source follower gain (~.8). Second source follower 41 then reads the stored voltage and transmits it to the analog to digital converter 30. This is a serial operation. The pixel can also operated in a mode where both source followers are activated simultaneously, and there is no sample and hold operation. [0017] Due to the presence of a wireless interface, power must be conserved, while achieving the necessary sensitivity and speed. As an example, a fixed power budget of 150 μAmps x 1.5V⁶ may be used for all other design considerations. In one embodiment, a single amplifier is used for the entire chip and as such, the pixels must be serially converted to a digital value and output. A method of illumination referred to as "light modulation" is now described. In order to use light modulation, each pixel must integrate during the same time period (i.e. when the light is on, or the light is off). Therefore, each pixel must have memory so that the value of each pixel can be stored at the end of the cycle, and then serially read out and converted to a digital value. The operation of each pixel 24 is as follows.

1. The illuminating light is turned on for time t .

2. All pixels 24 integrate the current generated by sensor photodiode 44 plus the dark current measured by reference photodiode 46.

3. At the end of t. , the light is turned off. Simultaneously, on all pixels, first source follower 40 samples the photodiode voltage and stores it onto hold capacitor 42. 4. The light is kept off for t. , and the photodiodes continue to integrate dark current. During this time, the values on hold capacitors 42 are serially decoded. Second source follower 41 is turned on, and the voltages on hold capacitor 42 (from both the reference and sensor photodiodes) is transferred to a differential amplifier 32. The amplifier output is then sent to the analog to digital converter 30. The digital output is then stored in a shift-register. If the digital output or amplifier output indicates that the analog to digital converter is reaching its dynamic range limits, a reset signal is sent via reset transistor to pixel 24. Therefore each pixel can operate independently, and only resets when necessary.

5. After the pixel has been decoded, the process repeats for the next pixel. During the next pixel's conversion process, the previous pixel's digital data is modulated at some amount less than the fclk clock frequency, ^~~ _j ^~, and sent out via the inductor coil.

[0018] A calibration routine compensates for the non-linear gain of amplifiers and of the parasitic capacitance of the photodiode. In one embodiment, chip 12 is illuminated with a constant light source, wherein the change in voltage as a function of time should be constant. By recording the digital output during this process, data is calibrated off-line to remove non-linearities. In another embodiment, one pixel comprises only the reference pixel, and in place of the light sensing pixel a capacitor is used. This pixel will only (differentially) measure the dark current, which is assumed to be constant, as its only dependence is on temperature. In another embodiment, a current source can be used instead of the dark current. The output from this constant current input is recorded, and used to calibrate the amplifier and analog to digital converter.

AMPLIFIER

[0019] Amplifier 32 is positioned on chip 12, and receives output from each of pixels 24. In another embodiment, separate amplifiers are used for each pixel. Reference is now made to FIG. 6, which is a circuit diagram illustration of amplifier 32, in accordance with embodiments of the present invention. The particular design shown in FIG. 6 was chosen based on its simplicity, linearity and insensitivity to temperature variation. However, it should be readily apparent that many other designs are possible, and that any suitable amplifier may be used. The amplifier is open loop to allow for simplicity of design, and high gain and speed with minimal power consumption. The amplifier uses a resistor at the source of the input transistors to eliminate temperature effects on the gain characteristics, and to linearize the gain. This limits output swing, and reduces the gain.

[0020] In another embodiment, the source resistor is eliminated, and a calibration scheme is employed to adjust the nonlinear gain. The calibration pixel has the photodiode that is exposed to light replaced with a capacitor. The remaining covered photodiode only draws dark current. The dark current is constant (as long as the temperature is stable), and this provides a constant current (equivalent to constant light) input to the amplifier and analog to digital converter. The digital circuitry, which typically advances to the next pixel after the current one is finished with the analog to digital conversion, stays on the calibration pixel for a set number of cycles. This allows the input voltage to be ramped (due to the constant current of the dark current) and sweep the amplifier and analog to digital converter. This cycle repeats several times to get a good calibration, and allows for correlation of the output digital value with the amount of charge at the input. The digital circuitry activates the calibration at pre-set intervals to allow recalibration during data acquisition.

ANALOG TO DIGITAL CONVERTER [0021] Reference is now made to FIG. 7, which is a circuit diagram illustration of an analog to digital converter, in accordance with embodiments of the present invention. However, it should be readily apparent that many other designs are possible, and that any suitable analog to digital converter may be used. The output of the amplifier is sampled onto the input capacitor. After sampling for t , , a current source then charges the capacitor until the NMOS FET is turned on. This switches the output from 1 to 0, and the inverters buffer the output and clean up the signal. This threshold voltage is set at an integer number of threshold voltages (depending on the number of diode connected transistors). The current source is designed so that it can charge the capacitor to the necessary voltage in the time allotted.

When the voltage on the capacitor reaches the threshold voltage of the converter, the output of the converter switches, and the value of the counter is latched into an array of flip flops. The resolution of the analog to digital converter depends on how many clock bits are saved. In one embodiment, there are

12 clock bits during t , , and the resolution is given by equation 19.

^VR

AV= - (19)

2ⁿbits

In another embodiment, all circuits are threshold voltage referenced so as to avoid offset between the amplifier common mode output voltage and the range of the analog to digital converter. The bias current source for the amplifier is set by I = Vt/Rstartup, where Rstartup is the startup resistor. The common mode output voltage is then I x Rload, which is Vt x (Rload/Rstartup). Therefore, variations in sheet resistance will cancel out. Furthermore, to allow for varying frequencies (the integration time goes as

1/f), the current sources is a mirror of a switch capacitor current source, which allows the current to vary linearly with f, so that the integration is independent of f.

WIRELESS INTERFACE [0022] The wireless interface serves to provide power input and clock generation, and to collect data output. Wireless interface 22 comprises an antenna, such as inductor coil 26 made of any combination of metal or other conductive layers, voltage rectifier, voltage regulator, and clock generator. Inductor coil 26 can be an integrated inductor coil, (for microarray applications), or an external inductor coil (for implantable applications). In cases where inductor coil 26 is an external inductor, it can be bonded to the chip, and may further be embedded in an outer layer. For implantable applications, the external inductor may be in contact with a stent or other implantable device, or the device {i.e. stent} itself may act as the inductor. Inductor coil 26 is designed so that its resonant frequency is near the needed clock frequency of the chip. In one embodiment, the chip uses a 30 loop, square coil with 4μm width, and lμm spacing. The metal 3 layer is only 2μ wide to reduce capacitance. It should be readily apparent that the specific parameters may vary with chip size and manufacturing process. Inductor coil 26 connects to a rectifier and is connected between RFP and RFN. The rectifier is diode clamped to ensure that high voltages do not affect circuitry on chip. The series of diode connected FETs are designed to ensure that voltage on the coil does not get too high and destroy the chip. The FETs used may be double gate FETs, which should better shield the circuitry from high voltages. The signal from the rectifier, V^.^, then feeds into voltage regulator 28. Voltage regulator 28 supplies approximately 200 μ Amps, at 1.5V, and additionally provides several reference voltages.

[0023] In another embodiment, the diode clamps are made with high threshold voltage devices to shield the clamp itself from high voltages. In some embodiments, separate power supplies are used: one for the analog and one for the digital circuitry, to avoid noise coupling. Each power supply has its own inductor, rectifier and voltage regulator. In some embodiments, all of the components are integrated on the chip. Inductor 26 loops around the chip. In cases where two coils are used, the inductor coils may be concentric. In some embodiments, multiple coils are used, wherein the power contribution from each of the multiple coils can be summed. [0024] In one embodiment, wireless interface 22 is used to power an external LED for visualization of smaller intracellular features, or optical density measurements.

DIGITAL CIRCUITRY [0025] Reference is now made to FIG. 8, which is a graphical illustration of a clock signal that is generated from the sine wave (RF). A digital block called RESBLK outputs a signal called RESB. This signal is a logic 0 when the chip begins to power up. When V_βO/?, the regulated voltage output, reaches a predetermined number of threshold voltages (for example, =3 V ). RESB becomes a logic 1 , and the digital circuitry on the chip is activated. Much of the digital circuitry begins to function only when RESB = 1, preventing high power loss intermediate states in the logic circuits. The CKGEN circuit block generates the clock signal. The RF signal from the coil is passed to a capacitive voltage divider, which then feeds into a series of inverters. The clock signal is at the same frequency of the RF signal. The clock is then divided down by a series of D-flip-flops to provide the counter. The memory elements are a series of flip flops that load data in parallel, and then serially shift it out. Power consumption is large in blocks that contain rapidly switching D-flip-flops (i.e. the counter) because of the momentary path from V_nn to GND as the states switch. The TX circuit block is responsible for the transmission of data. During readout, the bits are passed to the TX block. The bits are then multiplied by a digital signal that is 1/N times the frequency of the clock (where N=integer). Thus the data is modulated at fclk/N, and can be separated from the excitation RF signal via a low pass filter.

[0026] Reference is now made to FIGS. 9A and 9B, which are diagrammatic illustrations of a light source in accordance with embodiments of the present invention. Light source 20 is configured to provide light to sample 18 and chip 14. One goal of the present invention is to eliminate the need for lenses by placing the sensor adjacent to the sample surface, so that the emitted light cannot spread too far before it intersects the sensor. Therefore a lens is not needed to gather the light. To implement this, the pixel must be as large or larger than the imaging spot (for maximum signal), and must be on the order of the spot size (for example, if the spot is 100 micrometers, the sensor should be between 0 and several hundred micrometers away from the surface). The maximum pixel size is dictated by the spot size and pitch. Furthermore, by eliminating bond wires (via wireless interface, as shown in FIG. 9A, or via use of flip chip bonding, as shown in FIG. 9B), the sensor may be placed extremely close to the surface, maximizing signal reception. As shown in FIG. 9A, chip 12 is placed in close proximity to sample 18. In one embodiment, chip 12 is in contact with sample 18. In another embodiment, chip 12 is within a few micrometers of sample 18. The proximity of sample 18 to chip 12 may be dependent on the spot size of sample 18 and may be, for example, within a distance which is several times the spot size. Light detection side of chip 12 faces sample 12. In this embodiment, all bond wires have been eliminated, and a wireless interface is present. In cases where a wireless interface is not included, bond wires can be avoided by using flip-chip bonding, as shown in FIG. 9B. In this embodiment, as in the embodiment shown in FIG. 9A, chip 12 is placed in close proximity to sample 18. In one embodiment, chip 12 is in contact with sample 18. In another embodiment, chip 12 is within a few micrometers of sample 18. However, a thin transparent substrate 52 is placed beneath sample 18, and metallic connecting element 54 connects chip 12 to a processor, such as a PC board. In one embodiment, substrate 52 is a glass cover slip with microfabricated wire traces. In another embodiment, substrate 52 is a flexible polymer. In one embodiment, metallic connecting element 54 is gold, and may be a ball or bump. In another embodiment, metallic connecting element 54 is a lump of solder. [0027] In one embodiment, light source 20 is a prism 48 configured to provide evanescent lighting. Traditional imaging systems (epi-fluorescent) utilize filters and lenses to guide light to the sample and focused the re-emitted light. By implementing an evanescent system of illumination, the sample can be illuminated from underneath, allowing for the imaging sensor to be placed close to the surface. Evanescent lighting allows for measurement of binding kinetics, which is important for protein microarrays. In this embodiment, sample 18 is patterned on a transparent substrate, such as glass or plastic. The substrate with the sample inside is placed on the top, flat surface of prism 48. Light, depicted by arrows 50, is directed into the prism at an angle such that a layer approximately 50 nm (approximately 1/10* of the wavelength) above the surface is illuminated. The minimum angle is θ_c = arcsin ( — ) , determined by the critical angle, which is ^ ^l ' where nl is the index of refraction of the prism, and n2 is the index of refraction of the medium {i.e. our sample, or water} thetaC is given with respect to the normal (i.e. the perpendicular line going through the surface of the prism). This light causes sample 18 to be illuminated with an evanescent wave. Light detection side of chip 12 is positioned adjacent to sample 18, and light emitted from sample 18 is transmitted to sensor 14. This configuration allows for samples which are close to the surface to be illuminated, while those greater than a few tens of nm away are not.

[0028] An additional way to eliminate optical components, such as filters, is by the use of quantum dots instead of fluorophores. Quantum dots can be conjugated to DNA or protein, and/or used as a secondary label. Typical fluorophores absorb and reemit light with a Stoke's shift of typically between 15 and 30 nanometers. In order to separate the excitation light from the emitted light, an optical filter is needed. Quantum dots, however, absorb exceedingly well at deep UV wavelengths and emit at a constant visible wavelength, while silicon absorbs UV light poorly. Thus, if a quantum dot is used as a marker instead of a fluorophore, UV light can be used as the excitation light, and no optical filter is needed since the silicon cannot "see" the UV light. The quantum dot will emit a visible wavelength of light, which can be detected by the CMOS sensor. An additional advantage of quantum dots is that they do not bleach, allowing long integration times to see extremely small signals. Quantum dots are available from www.qdots.com, and can be conjugated with a variety of proteins (i.e. streptavidin) or functionalized chemical linkers, (i.e. Nh2 or COOH).

[0029] Reference is now made to FIG. 10, which is an illustration of direct UV illumination of a commercial CMOS camera. Results are shown for no illumination (frame 60), illumination with UV light (frame 62), illumination with UV light plus quantum dots (frame 64) and illumination with UV plus quantum dots plus background (frame 66). No optical filters were used.

APPLICATIONS [0030] Some of the many potential applications for a wireless CMOS biosensor such as the ones described above include applications for microarrays as well as for implantable biosensors. Microarrays may include DNA, RNA, protein and other biological applications. Implantable biosensors may be useful in measuring cellular signals, signals involving viruses, bacteria, or other small molecules. In some embodiments, the implantable biosensor may also be a drug delivery device. DNA μ-arrays for diagnostics

[0031] Genetic diagnostic and screening applications are growing as the relationship between genetics and disease pathology is being elucidated. In addition, personalized medicine, the emerging field whereby drug treatment is partially determined by a patient's genetic makeup (i.e. Iressa, Herceptin, Bidil, etc.) will rely extensively on large scale genetic analysis. Drug trials are now beginning to include genetic screening, to determine the most effective patient profile. A biosensor such as the ones described herein may be useful for large scale genetic screening and analysis and for small scale genetic/diagnostic applications whereby arrays on the order of 10-100 are assayed.

[0032] The biosensor of the present invention is useful for both traditional microarray reader applications (e.g. cy3/cy5 labeled DNA), as well as GFP labeled protein. Since GFP labeling requires immersion in solution, a sensor such as the one described herein can be useful for this type of application. RNA binding proteins (RNAbp) can be fused to GFP to allow in-vivo tracking, immunoprecipitation, and also function as a label for microarray applications. The immunoprecipitated complex will be RNA + RNAbp + GFP and can be directly applied to an array, without the need for exogenously labeling with Cy3/Cy5.

[0033] Another way to use a CMOS sensor such as the ones described herein is to label DNA with Qdots (e.g., biotinylated DNA + streptavidin Qdots), rather than Cy3/Cy5 dyes. The quantum dots can be illuminated at any wavelength below their emission wavelength, and still fluoresce at a specific emission wavelength, as described above. Streptavidin labeled Qdots have been used on both protein and DNA microarrays. Applicants have shown that Qdots can be illuminated with UV and this UV light is not readily absorbed by the sensor. The Qdots then emit visible light, which can be detected by the sensor. This eliminates the need for an excitation filter. Protein u-arrays for drug development and basic research

[0034] Although DNA μ-arrays provide a wealth of information, proteins are the final effectors of physiological function, and provide the key to the vast majority of in-vitro diagnostics. Large scale protein arrays may enable advances in drug screening and interactions - by panning a drug against every protein in the system, both intended and potential side effects can be visualized and in basic research. Understanding protein-protein interactions helps elucidate key biological pathways and mechanisms of action. Furthermore, by knowing the binding kinetics of specific protein-protein interactions, the binding strength and specificity can be determined. These are characteristics that are relevant to both basic research and determining drug kinetics. Unlike DNA μarrays, which can be synthesized, proteins must be cloned and purified in a time consuming process. A biosensor such as the one described herein, could be combined with a method for patterning proteome arrays and used for studying binding kinetics.

[0035] After patterning of proteins on a surface, a GFP label sample is introduced. An evanescent wave only illuminates fluorophores within l/lO* of a wavelength from the surface. Therefore, only fluorophores that are bound to the surface are illuminated. By monitoring the amount of light as a function of time, protein binding kinetics can be ascertained. Using GFP labeled proteins (or proteins labeled with a fluorophore), one can eliminate the need for labeled antibodies and multiple step procedures for imaging protein arrays. Kinetics can be visualized as well, since only one binding event is required, and real-time data can be taken in a hydrated environment. Since GFP must be hydrated, a fluid compatible sensor must be used. The biosensor of the present invention includes an outer layer to provide a fluid barrier and as such, can be placed in solution and used for assaying binding kinetics in a high throughput format. Additionally, chemical labeling (such as with FITC, or CY3/Cy5), can be used instead of GFP. Implantable diagnostics/monitoring devices [0036] Traditionally, flow cytometry or microscopy has been used for imaging cellular biosensors (cells with a reporter gene). In order to use these imaging techniques, cells must be placed into an in-vitro environment. The optimal biosensor for some applications would be a highly sensitive, real-time, continuous sensor of an organism, constantly circulating and being exposed to potential targets. For example, a cell could act as a living biosensor. The cellular sensors would then report back to a device which would relay information about the cells to the outside world. In order to accomplish this, the interfacing element (that communicates with the cellular sensors and relays the information) must be in the same environment as the cell, thus giving rise to the need for an implantable sensor. B cell / T cell sensors: Cells can be used as living biosensors, since they have highly specific detection machinery in the form of antibodies and transmembrane receptors, internal signal amplification through a variety of signal transduction pathways, and reporting of the event via protein activation (e.g. phosphorylation) or gene activation through transcription factors. All cells can detect specific ligands, and certain cells lend themselves well to being engineered to bind to a specific target. The procedure of generating monoclonal antibodies is one in which cells are selected that bind to a specific target. The B cell hybridomas that produce antibodies also carry the antibodies on their surface. When the B cell receptors (BCR) bind to their target, the BCR complex activates an intracellular signaling pathway. This pathway activates an intracellular pathway, resulting in intracellular calcium release, and activation of transcription factors, such as API , NF-AT and NF-KB. T cells work in a similar fashion, although the T cell receptor must have the target presented by an MHC II complex. B cell hybridomas capable of antigen specific binding are engineered with a stable transfection of a reporter gene. Hybridomas are generated by fusing a myeloma cell line (AG8) with a B cell population from an immunized mouse. Of course cells can be transfected with nucleic acid constructs encoding a receptor or cell surface protein of interest.

[0037] Similar approaches can be applied to any biomarker that needs to be constantly sensed (i.e., glucose, insulin, cancer biomarkers, cardiac enzymes, etc), and may include sensing of optical biological signals, or signals obtained from an external dye marker.

[0038] The biosensor of the present invention is small and wireless, making it a potential candidate for implantable applications. In one embodiment, the biosensor can detect and measure a reporter gene that produces GFP when the cell encounters a specific target. In another embodiment, cells may be labeled or filled with quantum dots (Qdots). The cells loaded with Qdots can migrate across a CMOS image sensor and be illuminated with light, e.g., UV light, and a picture taken. This can be used to track migration of cells. As pixel size and spacing becomes smaller and smaller, intracellular features may also be visualized. In some embodiments for in vitro or in vivo use, a labeled binding agent such as an antibody or ligand is used. The binding agent specifically binds to one or more entities of interest. The entity could be an organic or inorganic substance, also referred to as an "analyte" or a cell that expresses a molecule on the cell surface, wherein the binding agent binds to the molecule. The binding agent may be labeled with a fluorescent or luminescent moiety. Such moieties are well known in the art and include small molecules (e.g., fluorescent dyes), polypeptides, quantum dots, etc. See, e.g., The Handbook — A Guide to Fluorescent Probes and Labeling Technologies (Invitrogen Corp.).

[0039] Certain embodiments of the invention are particularly suited for in vivo applications such as determining the concentration of an analyte in a body fluid of a mammal though of course they can be used for in vitro applications as well. The uses of the system include applications such as determining whether an analyte of interest is present, determining the identity of an analyte, etc. Thus the output of the system may simply indicate that a substance is present or provide the identity of a substance. For purposes of brevity the system is described in terms of determining concentration but it is understood that these additional applications are encompassed within that phrase. In some embodiments the system stores spectral information for a plurality of substances, which information is of use to identify a substance.

[0040] The invention provides a system comprising a light emitting source, a wireless-powered optical sensor that is optionally implantable into the body of a mammalian subject, and a wireless communication and power system. In some embodiments part or all of the system utilizes optical power and communication. In some embodiments the light emitting source is outside the body, and the detection system comprising the sensor is inside the body (implantable). In some embodiments the system further comprises a receiver for receiving a signal from the sensor. The sensor is implantable and contained in a biocompatible, optically transparent material. In some embodiments the receiver is located in a unit external to the body. A wireless subsystem is present on both sensor and the receiver unit allowing communication therebetween. Also provided is a method of determining the concentration of an analyte in a body fluid, the method comprising providing a sensor located in proximity to a sample comprising the fluid, illuminating the sample, obtaining a signal indicative of the interaction of light with the sample, and analyzing the signal to determine the concentration of the analyte. [0041] The system and method can be applied to any analyte which has spectral properties that cause it to differ from its surroundings (i.e. distinct absorption spectra). In some embodiments the system comprises an external unit comprising one or more light emitting sources, power transmission circuitry, and wireless receiver circuitry. The components of the external unit are suitably housed, e.g., in a plastic housing. Optionally the external unit is attachable to a garment or wearable around a limb, e.g., around the wrist. In some embodiments the external unit comprises a processor capable of analyzing the signal and outputting results. In some embodiments the external unit comprises a display for the results. The light emitting sources are, e.g., LEDS and /or laser diodes. The light they emit may be modulated so as to distinguish it from background / ambient light as well as to modulate it to place the signal frequency above the low frequency flicker noise present in the sensor circuitry. The LED/laser diode output can be synchronized to the sensor circuitry. The light emitting source can be covered by an optical filter to provide a narrower bandwidth of light.

[0042] In some embodiments the external unit is a handheld device of a suitable size to fit comfortably in a human hand, e.g., having dimensions up to approximately 15 x 15 x 2.5 cm. Devices such as personal digital assistants (PDAs), Blackberry®, Palm Pilot®, or cell phones are examples of handheld devices having suitable dimensions. In one embodiment the device houses the light emitting source and has an optically transparent "window" through which light of a wavelength suitable for interacting with an analyte of interest can pass. The device is held close to the skin (e.g., directly on the surface of the skin or at a distance up to .1 mm - 5 cm from the skin) at a position where the implantable sensor is known to be located. The device may be waved over the approximate location overlying the sensor. Light from the source passes through the skin and impinges on the sample and sensor as described further below. The sensor detects a signal indicative of the interaction of light with the sample and transmits the signal, optionally after processing) to the external unit which displays the results (optionally after processing). In some embodiments the sensor and/or receiver is either physically or wirelessly connected to an implanted or external device that responds to the signal by delivering a substance to the body (e.g., a medication) or altering the dose of a delivered substance. For example, the sensor and/or receiver may be connected to an insulin pump, a pump that delivers a pain medication, an alarm, etc. In some embodiments portions of the system communicate with one another via optical fiber(s).

[0043] In some embodiments the sensor comprises an implantable platform onto which a plurality of sensor modules are integrated (e.g., they may be fabricated substantially at the same time as the sensor modules) or the sensor modules are fabricated separately and attached to the platform, e.g., by flip chip bonding or wire bonding. The platform comprises a substrate that supports the wireless interface circuitry as well as circuitry to interact with the sensor modules. In some embodiments the implementation is silicon-based CMOS (complementary metal oxide semiconductor). The sensor module comprises an array of optical detectors. Optionally the sensor comprises detectors capable of detecting non-optical parameters as described further below. In some embodiments each optical detector measures a specific wavelength or optical property. The intensity of light at each wavelength is used to determine the concentration and/or identity of an analyte of interest as further described below.

[0044] The sensor processes (e.g., amplifies and/or filters) the sensor output, digitizes the data (e.g., using an analog to digital converter) and transmits the data, e.g., to a receiver unit. In this instance, the data may be modulated at a frequency different from the carrier RF wave. In one implementation, the data is modulated at Vi the frequency of the carrier wave.

[0045] In some embodiments the platform wirelessly receives power and data, and includes on chip signal processing and analog to digital conversion.

[0046] In some embodiments the sensor utilizes silicon-based CMOS technology wherein circuitry is fabricated on chip. The circuitry in this instance comprises an on-chip inductor coil, a rectifier, and a voltage regulator. These elements allow power to be transmitted to the chip. Digital circuitry generates a clock, decoder for accessing each pixel, an amplifier to magnify the signal, and an analog to digital converter. The digital data is then modulated and transmitted through the RF coil. Any component mentioned, e.g., coil, sensor, amplifier etc, can be attached to the chip rather than integrated. [0047] In some embodiments the sensor comprises CMOS (complementary metal oxide semiconductor) detectors on a silicon substrate. In some embodiments the substrate allows IR light of a desired wavelength or range of wavelengths (e.g., 2-10 μm) to pass through. For example at least 50%, at least 80%, at least 90% or more of the intensity of the IR light may be transmitted. In some embodiments the substrate does not substantially transmit visible light. For example, the total intensity of visible light may be attenuated by at least 90% by the substrate. In some embodiments the sensor comprises CMOS (complementary metal oxide semiconductor) detectors on a glass substrate. Glass allows both visible and IR light to pass through.

[0048] In some embodiments the sensor and method of the invention measure the concentration of an analyte in a body fluid in vivo by directing light containing a plurality of different IR wavelengths through the body fluid. In some embodiments the light of the plurality of different wavelengths travel in substantially the same direction with respect to each other as they pass through the fluid, e.g., they are directed parallel to one another and have essentially the same optical path. In other embodiments, the light of different wavelengths does not have the same optical path. In some embodiments the light is emitted from discrete sources each of which emits within a discrete range of wavelengths. In some embodiments one or more sources emits across a range of wavelengths. For example, a source may emit light comprising a plurality of wavelengths. [0049] Some embodiments of the sensor comprise at least two sensor modules, each comprising a plurality of detectors. Light of a given wavelength is sensed by a detector on each of at least two sensor modules. Thus variations in absorption, scattering, or differences in path length may be corrected for, and the desired spectral information extracted. Some of the detectors may be devoted specifically to calibrating and correcting for such differences. The differential detection approach of these embodiments allows robust detection and provides a way to overcome certain limitations associated with prior efforts to reliably detect analyte concentrations in vivo. Calibrating wavelengths may also be measured, for example, to account for factors such as blood volume, vessel wall thickness, tissue or other material between the vessel and the sensor modules, as well as components in the blood such as hemoglobin, albumin, globulins, lipids, etc. The detectors could be, e.g., photodiodes. For example, a CMOS photodiode array is used in certain embodiments of the invention.

[0050] The differential detection aspects of the invention and implementation thereof are applicable to a broad range of in vivo and in vitro uses and are in no way limited to implantable sensor applications. For example, such aspects could be used to measure substances present in fluids (e.g., oil, water, gas) flowing in pipes or conduits buried underground, under water, within structures, or otherwise separated from a light source used for such measurement by material that could scatter and/or absorb light. Furthermore it will be appreciated that the device could be implemented in a variety of technologies including but not limited to CMOS-based technologies.

[0051] In some embodiments the body fluid is blood located in a blood vessel such as a vein. In other embodiments the body fluid is interstitial fluid located outside a blood vessel, e.g., within a membrane or body structure. In some embodiments the light is emitted and detected within a short period of time, e.g., within a time less than or equal to the average interval between heartbeats of the subject (e.g., within a time less than or equal to 1%, 10%, or 50% of the average time interval between heartbeats, or within less than about 1, 5, 10, 20, 50, or 100 ms. In some embodiments between 5 and 100 different wavelengths are detected. In some embodiments between 5 and 20 or between 10 and 20 different wavelengths are detected. In some embodiments a complete spectrum across a range of wavelengths is gathered. In some embodiments at least some wavelengths are used for purposes of normalization and/or calibration. In some embodiments at least some wavelengths are used to account for baseline offset. The wavelengths may bracket or span the spectral region of interest, i.e., the region containing wavelengths at which the substance or substances of interest characteristically absorbs and/or transmits light and which are of use to detect the substance. The differential detection embodiments of the invention obviate the need for at least some of these corrections. Thus in some embodiments since each intensity at each wavelength is measured twice, once before the light enters the sample and once after the unabsorbed light leaves the sample, baseline correction, etc., is not needed. Furthermore, such differential detection embodiments obviate the need to account for scattering and absorption of the tissue located between the sensor modules and the light source. Thus the invention provides an implantable sensor device wherein analytes in the blood or interstitial fluid are measured using an external (i.e., outside the body) light source, without needing to account for scattering and absorption due to tissues located between the light source and the implanted sensor modules. The inventive method focuses on making measurements on the sample itself (e.g., blood) thereby offering increased sensitivity by excluding other components that add significant noise to the measurement (e.g., skin, fat, interstitial fluid, bone).

[0052] In some embodiments of the invention a blood vessel having a diameter between about 0.3-1.0 mm is selected, although vessels having larger or smaller dimensions could be used. In some embodiments the sensor modules are positioned so that the shortest straight line distance between the sensor module and the exterior surface of the vessel is less than 5 mm, e.g., less than 1 mm. In some embodiments the sensor is implanted into the outer wall of the vessel. In some embodiments the sensor modules are positioned so that the shortest straight line distance between the sensor module and the interior surface of the vessel is less than 5 mm, e.g., less than 1 mm. Furthermore, modules may be positioned to have multiple vessels therebetween. [0053] One of skill in the art will be aware of wavelengths at which analytes of interest have significant absorption and transmission. The particular wavelengths and spectral regions chosen for any given embodiment and analyte may be selected empirically and/or using known spectral features of analytes of interest optionally guided by experimental results. The intensity of light detected at each of a plurality of wavelengths is used to determine the concentration and/or identity of an entity of interest using multivariate analysis. It will be appreciated that the sample, e.g., blood, may contain other analytes that have a spectrum overlapping with that of the analyte of interest. Furthemore, blood vessel walls, cells, and tissues will absorb. The sensor, with its individual detectors, measures at least several different wavelengths at key points in the spectrum for an analyte of interest and other substances found in the sample. From this information, the amounts of each substance that contribute to each spectra can be determined. It may be assumed that the concentration of different substances contribute to the total measured spectrum in a linear manner. It will be appreciated that components with concentrations significantly below (e.g., two to several orders of magnitude below) that of the analyte(s) of interest may be excluded as they will not significantly affect the measurements. Any of a variety of techniques and algorithms known in the art can be used to ascertain concentrations of individual analyte(s). Examples include partial least squares analysis, principal component analysis, linear regression, neural networks, multivariate analysis, etc. Spectral deconvolution methods are known in the art. See, e.g., K.H. Hazen, et al. Analyήca Chimica Acta, Vol. 371, pp. 255-267, 1998; .R. A. Shaw and H. H. Mantsch. Infrared Spectroscopy in Clinical and Diagnostic Analysis. Encyclopedia of Analytical Chemistry.; Y. C. Shen, et al., Phys Med Biol 48 (2003) 2023-2032; H. Heise, et al., Anal. Chem., 61 , 2009-2015 (1989); P. Bhandare, et al., Appl. Spectrosc, 8,1214-1221 (1993); K.J. Ward, D.M. et al. Appl. Spectrosc, 46, 959-965 (1992); D.M. Haaland, et al., Appl. Spectrosc, 46, 1575-1578 (1992). [0054] The table below presents a nonlimiting list of substances present in blood and their approximate concentrations. Other substances, e.g., ethanol, pharmaceutical agents, if present, may be accounted for as well.

[0055] In some embodiments multiple measurements are made within a short period of time, e.g., within a time less than or equal to the average interval between heartbeats of the subject (e.g., within a time less than or equal to 1%, 10%, or 50% of the average time interval between heartbeats, or within less than about 1, 5, 10, 20, 50, or 100 ms. Said multiple measurements may each be made at multiple wavelengths. [0056] In some embodiments the sensor comprises two sensor modules that are positionable in a functional relationship to each other and to a sample comprising an entity of interest to be detected. "Positioned in a functional relationship" in this context means that the sensor modules are positioned so that light that passes through a first sensor module will be incident on the sample, and light that is not absorbed or significantly scattered by the sample will be incident on the second sensor module. "Incident on the second sensor module" means that at least some of the detectors will be illuminated by the light that passes through the sample. For example, in some embodiments all of the sensors of the second module are illuminated. In some embodiments at least 25%, 50%, 75% or more of the sensors of the second module are illuminated. In another embodiment, a ring comprising at least two sensor modules is arranged around the sample, such as from any angle, a ray of light passes through two sensor modules. The sensor modules are connected via a series of wires or can wirelessly communicate with each other and/or the receiver. The signals from each photodetector can be analyzed sequentially or differentially (e.g., subtract the signals and amplify). For example, each of two sensor modules comprises a photodetector that detects light having a wavelength "X". The signals from these two photodetectors are subtracted, thereby providing a measurement of the absorption (or transmission) of the sample at that wavelength without interference due, e.g., to absorption (or transmission) from materials outside the sample of interest (e.g., tissues located between the light source and the blood vessel). This arrangement allows only the sample of interest to be measured.

[0057] FlG. 17 is an illustration of an implantable sensor comprising two sensor modules each comprising an array of photodetectors. The sensor modules are positioned on opposite sides of a blood vessel. They need not be directly opposite one another. The positioning need only be such that light passing through one of the sensor modules will pass through at least a portion of the fluid-filled region of the vessel and light not absorbed or scattered by the contents of the vessel and/or vessel walls will pass through at least a portion of the second array of photodetectors allowing detection to take place. The sensor modules may, but need not be, be physically connected to one another. They may be flexibly connected to allow the sensor to encircle at least a portion of a cross-section of a blood vessel. The connecting material is a biocompatible substance.

[0058] FIG. 18 is an illustration of another embodiment of an implantable sensor in which two sensor modules each comprising an array of photodetectors are attached to and electrically coupled to a substrate, which is a component of a platform that may house additional components such as processor, transmitter, etc. FIG. 19 is a schematic illustration showing powering of the sensor by inductive coupling. FIG. 20 is a schematic illustration of light illuminating and passing through both sensor modules and a vessel positioned between the sensor modules. FIG. 21 is an illustration of a sensor module comprising multiple photodetectors, each capable of detecting light of a different wavelength. [0059] The formula for determining absorption is [0060] I_abs = I_o exp{- εeb)

[0061] If I_abs , the light that leaves the sample, and I₀ , the light that enters the sample, one can determine the concentration c by knowing the path length b (the absorption ε is a known constant for each material). [0062] In some embodiments, the sensor is implantable for use in detecting a substance present in a body fluid of a subject, e.g., a mammalian and, optionally determining the concentration of the component. The body fluid may be, for example, blood, lymph, aqueous humor, or interstitial fluid. The substance may be a metabolite, nutrient, hormone, enzyme, etc. It may be a protein, a small molecule, lipid, or sugar such as glucose. In some embodiments the substance is a toxin. In some embodiments the substance is a pharmaceutical agent, e.g., a drug approved by the U.S. Food & Drug Administration or being studied with a view to such approval. In some embodiments the substance is ethanol. In some embodiments the substance is a biomarker whose presence is indicative that the subject has an illness, e.g., cancer or infection. For example, the substance may be a bacterial product. In some embodiments the substance is hemoglobin or bilirubin. [0063] In some embodiments the substance has an absorption spectrum in the infrared (IR) region. To this end, the array comprises photodetectors that detect infrared (IR) light. In certain embodiments the array comprises photodetectors that detect IR in the near, mid, and/or far IR ranges. For example, wavelengths of interest range between 700 nm and 1 mm. In some embodiments the wavelengths of interest are between 2-5 um, e.g., between 2-2.5 um, and/or between 5-10 um or in some embodiments as low as 1-1.5 um. Infrared detectors may be fabricated by placing an infrared absorbing material, e.g., a thermocouple material with a high coefficient of thermal expansion comprising for example, nickel, silicon, germanium, or another material with an appropriately high coefficient of thermal expansion as known in the art. In some embodiments the detectors are composed at least in part of silicon (Si), germanium (Ge), silicon-germanium (SiGe), or combinations thereof. Silicon as used herein includes polysilicon and such other forms of silicon as known in the art. Other materials known to absorb in the IR region such as InGaAs, lead sulfide (PbS), lead selenide (PbSe), indium arsenide (InAs), etc., could be used. The material changes properties, such as resistance, size, or junction potential in response to absorbing the infrared light. In some embodiments the sensor comprises SiGe detectors grown on a Si substrate. [0064] In an embodiment of particular interest a substance to be detected is glucose. The need for glucose monitoring in diabetic patients is known in the art, and the advantages of an implantable glucose sensor are well recognized. See, e.g., U.S. Pat. No. 6,049,727, which is incorporated herein by reference. The '727 patent extensively reviews prior approaches to noninvasive detection of glucose and the challenges encountered. The present invention, in certain embodiments, allows the monitoring of glucose and/or other substance(s) present in a body fluid such as blood (e.g., urea, cholesterol), without the need to implant a light source in the subject. Furthermore, embodiments of the invention allow such monitoring without the need to implant power source, lens, optical filters, etc., in the subject.

[0065] One aspect of the invention is a novel method of measuring the concentration of an analyte of interest present in a mixture with one or more additional analytes. The method finds use in a variety of contexts including but not limited to, that of an implantable device of the present invention. The invention may be of particular use when the analyte of interest represents only a small proportion of the total mixture. For example, in the case of measuring analytes such as glucose present in the blood, the most significant component is water, which is four orders of magnitude greater in concentration than glucose. See the table below for approximate concentrations of many components present in blood. [0066] The method of measuring the absorption due to a second substance in a sample comprising first and second substances comprises (a) largely or completely eliminating the absorption due to the second substance from a measurement of the absorption due to the second substance by (i) obtaining a first absorption measurement at a first wavelength and a second absorption measurement at a second wavelength, wherein the absorption due to the second substance at the first wavelength is substantially identical to the absorption due to the second substance at the second wavelength and wherein the absorption due to the first substance at the first wavelength is substantially different to the absorption due to the first substance at the second wavelength; and (ii) subtracting the first and second measurements from each other, thereby resulting in a measurement of the absorption due to the first substance. The method involves largely or completely eliminating the absorption of the second substance from the measurement of the absorption of the first substance by making at least first and second measurements around a local minimum or maximum in the spectrum of the second substance, i.e., in a region where the spectrum assumes a parabolic shape. "Substantially identical" absorptions may be within, e.g., 1, 2, 5, 10, or 20% of one another in various embodiments of the invention. "Substantially different" absorptions may differ from one another by, e.g., at least 1.5, 2, 2.5-fold, or more, in various embodiments of the invention.

[0067] The method is illustrated in FIG. 22 for the case of removing the absorption due to water from a signal so as to accurately measure absorption due to glucose, but it will be understood that the method is applicable to any two substances wherein at least one of the substances (i.e., the substance whose absorption is to be removed from the signal) has a spectrum that assumes a suitable, e.g., approximately parabolic or similar shape in a wavelength range of interest. It will also be understood that the method is applicable to spectra of any type, e.g., transmission, reflectance, scattering, etc., as well as absorption spectra, and is of broad utility to measuring analytes present in mixtures. In certain embodiments, the method is used to remove absorption due to a solvent from measurement of absorption due to a solute. Furthermore, the method can be used to isolate the signal due to a single analyte present in a complex mixture of substances by making multiple measurements as described herein, wherein measurements are made at two different wavelengths for each substance whose absorption is to be removed from the signal, wherein the absorptions due to that substance at each of the two different wavelengths are approximately equal. Appropriate mathematical techniques and algorithms, e.g., partial least squares analysis, principal component analysis, linear regression, neural networks, etc., as known to those of skill in the art, may be employed to process the measurement data and solve for the individual concentrations.

[0068] Turning to FIG. 22, the absorption spectrum of water is shown with a dashed line and the absorption spectrum of glucose is shown with a solid line. Measurements are made at two wavelengths Λ, and X₁ that will have approximately identical water absorption, but significantly different glucose absorption (e.g., differing by a factor of at least 1.5-2, although smaller fold differences are within the scope of the method. If one subtracts the absorption at A₁ from A₂ , the absorption due to water cancels out, leaving only the absorption due to glucose. The expression using the water and glucose absorption can be written as:

[0069] If it is assumed that one illuminates with the same intensity at both wavelengths, and that one can match the water absorption at the two wavelengths with an error of Δε_w , and the intensity of light at each wavelength ( A₁ and A₂ ) is equal, the difference in absorption at each wavelength can be written as:

[0070] Furthermore one could correct for any changes in the path length between the sensor modules that may occur over time, if desired. The absorption of protein (e.g., albumin, globulin) follows a similar pattern as does water, with a parabolic spectra around 2.2μm, and can be subtracted out from the glucose measurement. The absorption of urea, lactate and cholesterol can also be eliminated or measured by using the same strategy as for glucose by appropriate selection of wavelengths. The inventive approach can provide the opportunity for monitoring analytes relevant to kidney function (e.g., urea) and coronary artery disease (e.g., cholesterol), two key components to mortality caused by diabetes.

[0071] Further nonlimiting details of certain embodiments of the invention are provided in FIG. 23, which depicts side and front views of a differential optical sensor assembly, including two optical sensor modules (referred to as detectors in the figure) wire bonded onto metallized quartz substrates. Of course other materials sufficiently transparent to light in the wavelength range of interest could be used instead of quartz, and other means of establishing electrical connection could be used. The sensor assembly is implantable and includes data processing circuitry and transmits data to an external unit. In certain embodiments the host substrate houses data processing and transmission circuitry. FIG. 24 shows a schematic diagram of a glucose sensing system of the present invention, including a differential sensor assembly as in FIG. 23. The external unit houses a light source (e.g., LED), appropriate optical components (e.g., one or more lenses) and appropriate filters to selectively transmit light falling within wavelength ranges of interest. In certain embodiments a filter assembly allows automated selection of narrowband (e.g., ~10nm) optical filters. The external unit may house a power source (e.g., RF power source) that transmits power to the sensor modules. Interface circuitry controls the light source and filter assembly and receives electrical signals from the detectors. [0072] FlG. 25 shows implementation details of the optical emission and detection in an exemplary embodiment of the glucose sensor. The LED is modulated at a low frequency, e.g., between 1 and 100 kHz. The photodiode is incorporated into an integrator circuit with a reset mechanism. The signal at the output of the integrator is captured and processed. [0073] In some embodiments the detector comprises a structure comprising thermocouple material. Thermocouple materials are in some embodiments materials that are microfabrication compatible and have a high coefficient of thermal expansion. Examples are nickel and copper. Materials such as SiGe can also be used. In some embodiments the detector is in the shape of a beam. The beam may be an elongated structural member having substantially parallel sides and a square or rectangular cross-section. In other embodiments the beam may have a circular cross-section and be shaped as a cylinder. The beam resonates according to its size and effective spring constant. Changes in temperature affect the change in size, which also change the resonant frequency. In some embodiments the sensor independently measures the change in resistance and resonant frequency. In some embodiments the sensor output is based on individual parameters, or combination of at least two parameters. In some embodiment the structure is made at least in part of nickel and/or SiGe. In some embodiments the beam is coated with a thin layer of absorbing metal, e.g., gold. In some embodiments the structure is made of a material suitable for microfabrication such as silicon or polysilicon, and coated with a thermocouple material (i.e. material with a high coefficient of thermal expansion)

[0074] In some embodiments the detector comprises a beam of material that absorbs infrared light that is suspended, increasing thermal isolation by means of etching away a supporting sacrificial layer. In some embodiments the structure is made on a silicon on insulator (SOI) wafer, and the oxide is etched away. In some embodiments another sacrificial material is used, e.g., polysilicon, photoresist, polimide, silicon nitride, SiO2, MgO. In some embodiments the sensor module is fabricated separately and bonded to the chip. In some embodiments the structure (e.g., resonator beam) is formed from a structural material that is easily microfabricated, such as silicon, poly silicon, or silicon on oxide, and the beam is then coated with a material that has a high coefficient of thermal expansion, such as nickel or copper. The material absorbs infrared light, increases temperature and expands, causing the resonant frequency of the beam to change. This change in frequency is measured, and correlated to the amount of incident light. [0075] In some embodiments the light emitting source (LED/Laser diode) and transmission circuitry operate in a closed loop with a sensor module, wherein the signal from the sensor module is used to guide the output from the light emitting source. For example, if the detectors are not receiving sufficient signal, the power output from the light emitting source is increased until an adequate signal is detected. [0076] In regards to a suitable light source, commercial LEDs are available that emit light from the UV to near or mid IR. In some embodiments the light source emits at a plurality of discrete wavelengths. In some embodiments the light source emits light having a broad range of wavelengths. In some embodiments, to achieve transmission in the far-IR, an appropriate additional element is added. The element receives light from a source such as an LED that emits in the UV and in turn emits light of a different wavelength. For example, in one embodiment a layer or "film" of quantum dots that emit at the wavelength of interest is used. The quantum dots can absorb at energies greater than their emission (such as the UV or mid IR emitted by commercial LEDs), but emit at a wavelength determined by their properties such as composition and size. Therefore, quantum dots of the appropriate composition and size to emit in the wavelengths of interest (e.g., near-mid IR 2-5 urn), far IR (e.g., 5-10 um) are fabricated into a layer and placed between the LED (emitting a shorter wavelength) and the sensor module. In one embodiment the layer is included in the implantable portion of the apparatus. For example, it may be patterned on the sensor module. In other embodiments it is positioned on the light emitting source itself or in close proximity thereto and housed within the same housing such that light from the light source passes through the layer. Suitable quantum dots are commercially available. Other elements capable of modifying the spectrum of light emitted from commercially available LEDs or other light sources could also be used. It will be appreciated that LEDs that emit with suitable power (mW) having wavelengths in the far IR would also be of use as would a variety of other light sources that emit in the mid to far IR region. Thus there are a variety of ways to provide light incident on the sample wherein the light comprises wavelengths at which the analyte(s) of interest absorb.

[0077] In some embodiments the light is filtered before it comes into contact with the detectors. The light can be filtered by an optical interference filter, or by a cavity which only allows certain wavelengths of light to resonate. These filters are optical bandpass or bandstop filters, some of which may be integrated with the detectors (e.g., as part of a sensor module) and some of which may be attached. In some embodiments the photodetectors are coated with a material that serves as an optical filter. The optical filter allows only a narrow wavelength of light to pass through, allowing selective detection of light of different wavelengths by the detectors. The thickness and/or composition of the material can be altered to achieve substantial transmission of only a desired range of wavelengths.

[0078] In some embodiments the sensor comprises an optical filter for a wavelength of interest. In some embodiments the filter is located between the light source and the detectors. For example, the filter is located between the light source and a sensor module. In some embodiments the filter is an interference filter. The filter is made, for example, from a layers of films stacked on top of each other such that only a specific wavelength may pass through. In some embodiments the filter is a cavity sized such that one wavelength is resonant. The cavity is formed by putting the detectors, e.g., a sensor module or one or more detectors, between reflective surfaces. The surfaces reflect the light back and forth. Only light of a wavelength corresponding to the dimensions of the cavity is trapped, thereby filtering the light. In some embodiments the cavity dimensions are adjusted by electrical bias to alter the resonant wavelength. In some embodiments the sensor is positioned between two surfaces that reflect the wavelength of light.

[0079] In some embodiments at least some of the photodetectors are capable of detecting light in the visible range (400 - 700 nm wavelength). In some embodiments the photodetectors are fabricated at least in part of silicon.

[0080] In some embodiments the sensor allows the monitoring of variables that provide information about the physiological status of a subject. Examples include temperature and pressure. Temperature can affect the spectral characteristics of a substance in a body fluid, and in some embodiments the measurements are corrected or normalized to account for changes in temperature. For example, concentration values could be normalized to a subject's normal body temperature, to a temperature of -98 degrees F, etc. In some embodiments, changes in temperature are measured to determine whether the subject is suffering from an infection. Pressure can be an indicator of blood volume and flow rate and thus is a parameter useful for monitoring the physiological status of a subject. Such environmental variables as pressure and temperature affect properties of the detectors such as resistance, size, or junction potential and can thus be measured in an analogous fashion to light. In some embodiments, a PTAT circuit is incorporated on chip using, e.g., a CMOS process. This functions as a temperature sensor. A pressure sensor can be made from etching underneath a film, or by bonding a MEMS (micro-electromechanical system) pressure sensor to an area on the chip, which then can interrogate the sensor. MEMS pressure sensors are commercially available. In some embodiments the pressure sensor is attached to, e.g., bonded to, the array of photodetectors.

[0081] In some embodiments, one or more of the sensors detects polarized light. The polarization information may be incorporated into the calibration routine. In some embodiments the polarized light sensor is implemented by either fabricating or bonding a polarized light filter onto the optical sensor module. Glucose is known to polarize light. Thus incorporating a sensor of polarized light can give another data point to determine the concentration of glucose from the environment (e.g., blood or interstitial fluid).

[0082] Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following non- limiting examples. EXAMPLES

[0083] Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting fashion.

[0084] An LED was used to test the prototype sensor with 515nm light. Reference is now made to FIG. 11, which is a calibration curve showing the number of photons incident on the sensor versus applied voltage. The LED emits light at around 2.7V of forward bias. At around 3V, the equivalent number of photons is about 40/um^Λ2/2.

[0085] Reference is now made to FIG. 12, which is a graphical illustration of pixel output from ramping LED voltage. The LED was taken from 0-4V (indices 0-40), and then ramped down from 4V to 0 V (indices 40-80). This shows a response to light. Additionally, a signal of 40 photons/um^Λ2/s can be clearly seen.

[0086] Reference is now made to FIG. 13A and 13B, which are graphical illustrations of amplifier output versus incident light. The output of the amplifier is shown for different pixel types.

Clearly the Nwell/Psub diodes have the greatest response. [0087] Reference is now made to FIG. 14, which is a graphical illustration of digital values from the amplifier output. Signals as low as 10 photons/um2/s can be detected.

[0088] Reference is now made to FTG. 15, which is a graphical illustration of differential output with noise (noise = 0.34 bits). On the X axis, 0-40 corresponds to 0-4 V, 41 to 80 corresponds to 3.9 V to 0 V. At index 30, approximately 40 photons/um²/s are imaged. [0089] Reference is now made to FIG. 16, which is a graphical illustration comparing varying concentrations of GFP using the CMOS sensor of the present invention versus a CCD camera. Serial dilutions of GFP were made and imaged with both a CCD and the CMOS sensor. The CCD output is the digital output (1 to 4096), and the wireless CMOS sensor output is the amplifier output (before digital conversion). For the CCD, the higher the amount of light, the greater the digital value. For the wireless sensor, the greater the amount of light, the greater the deviation form baseline (i.e. lower voltage). PBS is added as a negative control. Serial dilutions of GFP are then imaged. Both sensors can image GFP to about 10^Λ7 molecules. For reference, a 125 x 125 um^Λ2 area on a microarray slide can contain up to 10^Λ8 molecules, so the sensitivity of the sensor of the present invention approaches the sensitivity needed to detect spots on a microarray. [0090] PCT Publication WO2007008864 (PCT/US2006/026830) and United States Serial

Number 60/921 ,478 are incorporated herein by reference. For example and without limitation, the following embodiments as recited in United States Serial Number 60/921 ,478 are included herein: 1. A system for measuring a biological sample, the system comprising: a sensor which provides an electrical output; an analog to digital converter in electrical communication with said sensor for converting said output into a digital signal, wherein at least said sensor and said analog to digital converter form a CMOS circuit; and a processor for processing said digital signal.

2. The system of claim 1 , wherein the sensor comprises a photodiode for converting photons obtained from interaction with the sample into electrons.

3. The system of claim 1, further comprising a wireless interface in communication with said sensor and said processor, said wireless interface configured to provide power to said sensor, and further configured to transmit and receive data from said processor.

4. The system of claim 3, wherein said wireless interface comprises an external antenna.

5. The system of claim 3, wherein said wireless interface comprises an integrated antenna, said integrated antenna integrated into a physical structure of said system. 6. The system of claim 1, wherein the sensor is integrated with an implantable device.

7. The system of claim 6, wherein said implantable device is a stent, and wherein said sensor is integrated with said stent.

8. The system of claim 6, wherein said implantable device is a drug delivery device, and said sensor is integrated with said drug delivery device. 9. The system of claim 1 , wherein said sensor further comprises a flip-chip bonding scheme.

10. The system of claim 2, wherein said sensor further comprises multiple photodiodes arranged in a pixel array of photodiodes.

11. The system of claim 10, wherein said pixel array of photodiodes comprises a one-to-one correspondence with an array of the biological sample.

12. The system of claim 1 1, wherein a size of each pixel in said pixel array is less than 150 micrometers.

13. The system of claim 12, wherein a size of each pixel of said pixel array is approximately 120 micrometers x 120 micrometers. 14. The system of claim 10, wherein said sensor further comprises an outer layer substantially surrounding said pixel array, said outer layer providing a fluid barrier between electrical components of said sensor and the biological sample.

15. The system of claim 2, further comprising an evanescent illumination system said illumination system comprising a prism positioned beneath said sensor for introducing light, wherein said at least one photodiode is configured for receiving photons via said evanescent illumination system.

16. The system of claim 2, wherein said at least one photodiode is selected from the group consisting of an N-plus P-sub diode, an N-well P-sub diode, a P-plus N-well P-sub diode, and an N-plus P-well diode.

17. The system of claim 16, wherein all of said diodes are used. 18. The system of claim 10, wherein each pixel of said pixel array comprises a sensor photodiode and a reference photodiode. 19. The system of claim 18, wherein said reference photodiode is covered with metal.

20. The system of claim 18, wherein each pixel of said pixel array further comprises a first source follower, a second source follower, and a hold capacitor, and wherein said first source follower is for applying a sample and hold operation onto said hold capacitor for storage, said second source follower is for transmitting said stored hold operation to said processor.

21. The system of claim 1, further comprising a microarray of the biological sample, wherein said sensor is positionable in close proximity with said microarray.

22. The system of claim 21 , further comprising multiple photodiodes arranged in a pixel array of photodiodes wherein a size of each pixel ranges from less than the size of a spot on the microarray to a maximum of the pitch between spots on the microarray.

23. The system of claim 21, wherein said microarray is selected from the group consisting of: a protein array, a DNA array, an RNA array, a cellular array, an array including a virus, an array including a bacteria, and an array including small molecules.

24. The system of claim 1, wherein the biological sample is tagged with quantum dots, the system further comprising a UV illuminator, said obtained photons obtained from illumination of said quantum dots by said UV illuminator.

25. The system of claim 1, wherein said sensor is implantable in a human body.

26. The system of claim 25, wherein said obtained photons are obtained from optical signals in the body. 27. The system of claim 26, wherein said optical signals include cellular signals.

28. The system of claim 26, wherein said optical signals include signals from a biological marker.

29. The system of claim 25, wherein said obtained photons are obtained from an external dye marker. 30. The system of claim 3, further comprising a light source powered by said wireless interface.

31. The system of claim 14, wherein said outer layer is a biocompatible material.

32. A sensor for identifying an interaction in a microarray, the sensor comprising: a pixel array of photodiodes, wherein a size of each pixel of said pixel array corresponds to said microarray; and an outer layer substantially surrounding said pixel array, said outer layer providing a fluid barrier between electrical components of said sensor and said biological sample.

33. The sensor of claim 32, wherein a size of each pixel ranges from less than the size of a spot on the microarray to a maximum of the pitch between spots on the microarray. 34. The sensor of claim 32, wherein a size of each pixel is less than 150 micrometers. 35. The sensor of claim 34, wherein each pixel of said pixel array is approximately 120 micrometers x 120 micrometers in size.

36. The sensor of claim 32, wherein said sensor is implantable within a human body.

37. The sensor of claim 32, wherein said outer layer is a biocompatible material. 38. The sensor of claim 32, wherein said pixel array of photodiodes comprises at least one photodiode selected from the group consisting of an N-plus P-sub diode, an N-well P-sub diode, and a P-plus N-well P-sub diode.

39. The system of claim 38, wherein all of said diodes are used.

40. The sensor of claim 32, wherein each pixel of said pixel array comprises a sensor photodiode and a reference photodiode.

41. The sensor of claim 40, wherein said reference photodiode is covered with metal.

42. The sensor of claim 32, further comprising an analog/digital converter in electrical communication with said photodiodes.

43. The sensor of claim 42, wherein each pixel of said pixel array further comprises a first source follower, a second source follower, and a hold capacitor, and wherein said first source follower is for applying a sample and hold operation onto said hold capacitor for storage, said second source follower is for transmitting said stored hold operation to said processor.

44. The sensor of claim 42, wherein said photodiodes and at least said analog/digital converter form a CMOS circuit on said sensor. 45. A method for measuring a sample, comprising: providing a wireless CMOS biosensor comprising a pixel array of photodiodes; providing a biological sample; tagging said biological sample with a fluorescent label; placing said biosensor proximal to said biological sample; illuminating said biosensor and said biological sample, wherein said illuminating causes said tagged biological sample to emit photons; converting said photons into an electrical signal using said CMOS biosensor; and wirelessly receiving said electrical signal, said electrical signal being representative of an amount of said tagged biological sample. 46. The method of claim 45, wherein said sample is a biological sample.

47. The method of claim 46, wherein said biological sample is a DNA sample.

48. The method of claim 46, wherein said biological sample is a protein sample.

49. The method of claim 45, wherein said placing said biosensor proximal to said biological sample comprises placing said biosensor in solution. 50. The method of claim 45, wherein said placing said biosensor proximal to said biological sample comprises placing said biosensor in contact with said biological sample. 51. The method of claim 45, wherein said placing said biosensor proximal to said biological sample comprises providing said biological sample as a microarray, and placing said biosensor within a distance which is several times a spot size of the microarray.

52. The method of claim 45, wherein said tagging comprises tagging with quantum dots. 53. The method of claim 45, wherein said illuminating comprises evanescently illuminating.

54. The sensor, system, or method of any of claims 1-53, wherein the sensor, system, or method detects infrared light.

55. The sensor, system, or method of any of claims 1-53, wherein the sensor, system, or method measures glucose concentration in a body fluid. 56. The sensor or system of any of claims 1-44, wherein the sensor comprises two or more sensor modules that are functionally positionable with respect to each other and with respect to a sample.

57. The sensor system of claim 56, wherein each sensor module comprises a plurality of photodetectors 58. A method of determining the concentration of an analyte comprising directing light at a sensor comprising two or more sensor modules each comprising a plurality of photodetectors positionable with respect to each other and with respect to a sample, so that light that passes through the first sensor module and the sample is incident on the second sensor module.

59. A system comprising (i) an implantable sensor comprising at least two sensor modules each comprising an array of photodetectors; and (ii) an external unit that houses a light source and, optionally at least one item selected from a display, a processor, and a receiver.

60. The system of claim 59, wherein the sensor modules communicate wirelessly with each other and/or with the receiver.

[0091] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents may occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention. All patents, unpublished and published patent applications, and other publications mentioned herein are incorporated herein by reference. [0092] The articles "a", "an", and "the" as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to include the plural referents. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention also includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, it is to be understood that the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the listed claims is introduced into another claim dependent on the same base claim (or, as relevant any other claim) unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise. Where elements are presented as lists, e.g., in Markush group or similar format, it is to be understood that each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements, features, etc., certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements, features, etc. For purposes of simplicity those embodiments have not in every case been specifically set forth herein. It should also be understood that any embodiment of the invention, e.g., any embodiment found within the prior art, can be explicitly excluded from the claims, regardless of whether the specific exclusion is recited in the specification. [0093] Where ranges are given herein, the invention includes embodiments in which the endpoints are included, embodiments in which both endpoints are excluded, and embodiments in which one endpoint is included and the other is excluded. It should be assumed that both endpoints are included unless indicated otherwise. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. It is also understood that where a series of numerical values is stated herein, the invention includes embodiments that relate analogously to any intervening value or range defined by any two values in the series, and that the lowest value may be taken as a minimum and the greatest value may be taken as a maximum. Numerical values, as used herein, include values expressed as percentages. For any embodiment of the invention in which a numerical value is prefaced by "about" or "approximately", the invention includes an embodiment in which the exact value is recited. For any embodiment of the invention in which a numerical value is not prefaced by "about" or "approximately", the invention includes an embodiment in which the value is prefaced by "about" or "approximately". "Approximately" or "about" generally includes numbers that fall within a range of 1% or in some embodiments 5% of a number in either direction (greater than or less than the number) unless otherwise stated or otherwise evident from the context (except where such number would impermissibly exceed 100% of a possible value).

[0094] Certain claims are presented in dependent form for the sake of convenience, but Applicant reserves the right to rewrite any dependent claim in independent format to include the limitations of the independent claim and any other claim(s) on which such claim depends, and such rewritten claim is to be considered equivalent in all respects to the dependent claim in whatever form it is in (either amended or unamended) prior to being rewritten in independent format. It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one act, the order of the acts of the method is not necessarily limited to the order in which the acts of the method are recited, but the invention includes embodiments in which the order is so limited. It should further be understood that where the description and/or claims disclose an apparatus (e.g., a system, sensor, etc.), the invention includes methods of using the apparatus for any purpose contemplated herein, and methods for making the apparatus according to techniques contemplated herein or known in the art, unless clearly indicated to the contrary or evident to one of skill in the art that such apparatus would not be usable for such purpose or such method of making would not be suitable to make such apparatus.

Claims

1. A system for measuring an analyte in a sample, the system comprising: a first and second sensor module, each of which provides an electrical output; an analog to digital converter in electrical communication with said sensor modules for converting said outputs into digital signals, wherein at least said sensor modules and said analog to digital converter form a CMOS circuit; and a processor for processing said digital signals, wherein said first and second sensor modules are positionable with respect to a sample, so that light that passes through the first sensor module and the sample is incident on the second sensor module.

2. The system of claim 1 , wherein the sensor modules each comprises a photodiode for converting photons obtained from interaction with the sample into electrons.

3. The system of claim 1 , further comprising a wireless interface in communication with said sensor modules and said processor, said wireless interface configured to provide power to said sensor modules, and further configured to transmit and receive data from said processor.

5. The system of claim 3, wherein said wireless interface comprises an integrated antenna, said integrated antenna integrated into a physical structure of said system.

6. The system of claim 1 , wherein the sensor modules are components of an implantable device for sensing analytes in the blood.

7. The system of claim 6, wherein said implantable device is configured so that the sensor modules are positionable on either side of a blood vessel and are optionally connected to one another by a connecting element configured to at least partly surround a blood vessel.

8. The system of claim 6, wherein said implantable device further comprises a drug delivery device, and said sensor modules are integrated with said drug delivery device and said drug delivery device optionally delivers a medication suitable for control of blood sugar in a diabetic subject.

9. The system of claim 1 , wherein said sensor modules are fabricated at least in part using a flip-chip bonding scheme.

10. The system of claim 1, wherein said sensor modules comprise multiple photodetectors arranged in a pixel array, wherein the photodetectors are optionally photodiodes.

1 1. The system of claim 10, wherein said pixel array is capable of detecting light within each a plurality of different wavelength ranges.

13. The system of claim 10, wherein said photodetectors are integrated directly into a CMOS chip.

14. The system of claim 10, wherein said sensor module further comprises an outer layer substantially surrounding said pixel array, said outer layer providing a fluid barrier between electrical components of said sensor module and the surrounding tissue when the device is implanted in the body.

15. The system of claim 14, wherein said outer layer is sufficiently optically transparent at least over the infrared region of the spectrum, or a portion thereof to allow detection of glucose.

16. The system of claim 14, wherein said outer layer is a biocompatible material.

17. The system of claim 1, further comprising a light source.

18. The system of claim 17, wherein said light source emits light in the infrared region of the spectrum.

19. The system of claim 17, wherein the sensor modules are components of an implantable device and the system further comprises an external unit and said light source is housed in said external unit.

20. The system of claim 1 , wherein the sensor modules are components of an implantable device and the system further comprises an external unit comprising a power transmitter that transmits power wirelessly to the sensor modules.

21. The system of claim 1 , wherein the sensor modules are components of an implantable device and the system further comprises an external unit comprising a display.

22. The system of claim 1, wherein said system processes the data according to an algorithm s that determines concentration of at least one analyte in the blood based on measuring absorbance of light by substances in the blood at a plurality of wavelengths.

23. The system of claim 22, wherein said measuring comprises measuring differences between intensity of light incident on the first sensor module and the second sensor module at a plurality of wavelengths.

24. The system of claim 22, wherein said wavelengths are in the infrared portion of the spectrum.

23. The system of claim 22, wherein said wavelengths are between about 2 μm and about 2.5 μm.

24. A method of determining the concentration of an analyte comprising directing light at a sensor assembly comprising two or more sensor modules each comprising a plurality of photodetectors, the modules being positionable with respect to each other and with respect to a sample, so that light that passes through the first sensor module and the sample is incident on the second sensor module.

25. A system comprising (i) an implantable sensor comprising at least two sensor modules each comprising an array of photodetectors; and (ii) an external unit that houses a light source and, optionally houses at least one item selected from a display, a processor, and a receiver.

26. The system of claim 25, wherein the sensor modules communicate wirelessly with each other and/or with the receiver.

27. A system comprising (i) an implantable sensor assembly comprising at least two sensor modules each comprising means for detecting light at a plurality of wavelengths, said means optionally comprising an array of photodetectors; and (ii) an external unit that houses at least one item selected from a light source, a display, a power source, a processor, interface circuitry, and a receiver.

28. The system of claim 27, wherein the sensor assembly communicates wirelessly with the external unit.

29. The system of claim 27, wherein the sensor assembly receives power wirelessly from the external unit.

30. The system of claim 27, wherein the sensor modules are positionable on opposite sides of a blood vessel so that light that travels through the first sensor module is incident on the blood vessel and light transmitted through the blood vessel is incident on the second sensor module.

31. The system of claim 27, wherein the external unit houses a light source, a display, a power source, interface circuitry, and a receiver.

32. The system of claim 27, wherein the implantable sensor assembly comprises data processing circuitry.

33. The system of claim 27, wherein the implantable sensor comprises an analog-to-digital converter. 33. The system of claim 27, wherein the implantable sensor comprises data processing circuitry, and wherein the sensor modules, data processing circuitry, or both, are implemented at least in part using CMOS technology.

34. The system of claim 27, wherein said wavelengths include wavelengths in the infrared region of the spectrum.

35. The system of claim 27, wherein said wavelengths include wavelengths suitable for detecting glucose.

36. A method of determining the concentration of an analyte comprising directing light at a sensor assembly comprising two or more sensor modules each comprising a means for detecting light at a plurality of wavelengths, said means optionally comprising a plurality of photodetectors, the modules being positionable with respect to each other and with respect to a sample, so that light that passes through the first sensor module and the sample is incident on the second sensor module.

37. The method of claim 36, wherein said wavelengths include wavelengths in the infrared region of the spectrum.

38. The method of claim 37, wherein said wavelengths include wavelengths suitable for detecting glucose.

39. The method of claim 36, wherein said sample comprises blood in a blood vessel.

40. The method of claim 36, wherein said method comprises measuring the absorption due to a first substance in a sample comprising first and second substances, the method comprising (a) largely or completely eliminating the absorption due to the second substance from a measurement of the absorption due to the first substance by (i) obtaining a first absorption measurement at a first wavelength and a second absorption measurement at a second wavelength, wherein the absorption due to the second substance at the first wavelength is substantially identical to the absorption due to the second substance at the second wavelength and wherein the absorption due to the first substance at the first wavelength is substantially different to the absorption due to the first substance at the second wavelength; and (ii) subtracting the first and second measurements from each other, thereby resulting in a measurement of the absorption due to the first substance.

41. The method of claim 40, wherein the first substance is glucose and the second substance is water.

42. A method of measuring the absorption due to a first substance in a sample comprising first and second substances, the method comprising (a) largely or completely eliminating the absorption due to the second substance from a measurement of the absorption due to the first substance by (i) obtaining a first absorption measurement at a first wavelength and a second absorption measurement at a second wavelength, wherein the absorption due to the second substance at the first wavelength is substantially identical to the absorption due to the second substance at the second wavelength and wherein the absorption due to the first substance at the first wavelength is substantially different to the absorption due to the first substance at the second wavelength; and (ii) subtracting the first and second measurements from each other, thereby resulting in a measurement of the absorption due to the sfϊrst substance.

43. The method of claim 42, wherein said first and second measurements are made within 10 ms of each other.

44. The method of claim 42, wherein the sample comprises blood.

45. The method of claim 42, wherein the first substance is water.

46. The method of claim 42, wherein the first substance is water and the second substance is glucose, urea, or cholesterol.