Abstract:
The present invention provides an electro-optical sensing device for detecting the presence or concentration of an analyte. More particularly, the invention relates to (but is not in all cases necessarily limited to) optical-based sensing devices which are characterized by being totally self-contained, with a smooth and rounded oblong, oval, or elliptical shape (e.g., a bean- or pharmaceutical capsule-shape) and a size which permits the device to be implanted in humans for in-situ detection of various analytes.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of application Ser. No. 11/106,481, filed on Apr. 15, 2005, the contents of which are hereby incorporated by reference in their entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The invention relates to electro-optical sensing devices for detecting the presence or concentration of an analyte in a liquid or gaseous medium. More particularly, the invention relates to (but is not in all cases necessarily limited to) optical-based sensing devices which are characterized by being totally self-contained, with a smooth and rounded oblong, oval, or elliptical shape (e.g., a bean- or pharmaceutical capsule-shape) and a size which permit the device to be implanted in humans for in-situ detection of various analytes. 
     2. Discussion of the Background 
     U.S. Pat. No. 5,517,313, the disclosure of which is incorporated herein by reference, describes a fluorescence-based sensing device comprising indicator molecules and a photosensitive element, e.g., a photodetector. Broadly speaking, in the context of the field of the present invention, indicator molecules are molecules one or more optical characteristics of which is or are affected by the local presence of an analyte. In the device according to U.S. Pat. No. 5,517,313, a light source, e.g., a light-emitting diode (“LED”), is located at least partially within a layer of material containing fluorescent indicator molecules or, alternatively, at least partially within a wave guide layer such that radiation (light) emitted by the source strikes and causes the indicator molecules to fluoresce. A high-pass filter allows fluorescent light emitted by the indicator molecules to reach the photosensitive element (photodetector) while filtering out scattered light from the light source. 
     The fluorescence of the indicator molecules employed in the device described in U.S. Pat. No. 5,517,313 is modulated, i.e., attenuated or enhanced, by the local presence of an analyte. For example, the orange-red fluorescence of the complex tris(4,7-diphenyl-1,10-phenanthroline)ruthenium(II) perchlorate is quenched by the local presence of oxygen. Therefore, this complex can be used advantageously as the indicator molecule in an oxygen sensor. Indicator molecules whose fluorescence properties are affected by various other analytes are known as well. 
     Furthermore, indicator molecules which absorb light, with the level of absorption being affected by the presence or concentration of an analyte, are also known. See, for example, U.S. Pat. No. 5,512,246, the disclosure of which is incorporated by reference, which discloses compositions whose spectral responses are attenuated by the local presence of polyhydroxyl compounds such as sugars. It is believed, however, that such light-absorbing indicator molecules have not been used before in a sensor construct like that taught in U.S. Pat. No. 5,517,313 or in a sensor construct as taught herein. 
     In the sensor described in U.S. Pat. No. 5,517,313, the material which contains the indicator molecules is permeable to the analyte. Thus, the analyte can diffuse into the material from the surrounding test medium, thereby affecting the fluorescence of the indicator molecules. The light source, indicator molecule-containing matrix material, high-pass filter, and photodetector are configured such that fluorescent light emitted by the indicator molecules impacts the photodetector such that an electrical signal is generated that is indicative of the concentration of the analyte in the surrounding medium. 
     The sensing device described in U.S. Pat. No. 5,517,313 represents a marked improvement over devices which constitute prior art with respect to U.S. Pat. No. 5,517,313. There has, however, remained a need for sensors that permit the detection of various analytes in an extremely important environment—the human body. Moreover, further refinements have been made in the field, which refinements have resulted in smaller and more efficient devices. 
     U.S. Pat. Nos. 6,400,974 and 6,711,423, the disclosures of which are incorporated herein by reference, each describe a fluorescence-based sensing device comprising indicator molecules and a photosensitive element that is designed for use in the human body. 
     SUMMARY OF THE INVENTION 
     In one aspect, the present invention provides an electro-optical sensing device. In one particular embodiment, the sensing device includes: a housing having an outer surface; a plurality of indicator molecules located on at least a portion of the outer surface of the housing; a circuit board housed within the housing; a support member having a side that lies on a plane that is substantially perpendicular to a plane on which a top side of the circuit board lies; a radiation source attached to the side of the support member and positioned a distance above the top side of the circuit board; and a photodetector connected to the circuit board for detecting a response of the indicator molecules. 
     Advantageously, to facilitate attachment of the support member to the circuit board, the circuit board may have a groove in the top side thereof and the support member may have an end inserted into the groove. 
     The sensing device may further include a reflector that is spaced apart from the radiation source and that has a reflective side that faces the radiation source. The photodetector may be positioned in a location beneath a region between the radiation source and the reflective side of the reflector. 
     In another embodiment, the sensing device includes: a housing having an outer surface; a plurality of indicator molecules located on at least a portion of the outer surface of the housing; a circuit board housed within the housing; a photodetector having a top side and a bottom side, wherein the photodetector is electrically connected to a circuit on the circuit board and at least a top side of the photodetector is photosensitive; a filter having a top side and a bottom side, the bottom side being positioned over the top side of the photodetector; and a radiation source positioned over the top side of the filter. 
     In some embodiments, the sensing device may further include a base having a top side and a bottom side, with the bottom side being attached to an end of the circuit board, and with the bottom side of the photodetector being mounted on the top side of the base. Preferably, the top side of the base lies in a plane that is substantially perpendicular to a plane on which a top side of the circuit board lies and the top side of the photodetector is generally parallel with the top side of the base. To facilitate attachment of the base to the circuit board, the bottom side of the base may have a groove therein, and an end of the circuit board may be inserted into the groove. 
     In other configurations, the top side of the photodetector lies in a plane that is substantially parallel with a plane on which a top side of the circuit board lies. Additionally, an opaque base may be disposed between the radiation source and the filter. The base may be made from molybdenum. 
     The above and other features and advantages of the present invention, as well as the structure and operation of preferred embodiments of the present invention, are described in detail below with reference to the accompanying drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The accompanying drawings, which are incorporated herein and form part of the specification, help illustrate various embodiments of the present invention and, together with the description, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention. In the drawings, like reference numbers indicate identical or functionally similar elements. Additionally, the left-most digit(s) of a reference number identifies the drawing in which the reference number first appears. 
         FIG. 1  is a schematic, section view of a fluorescence-based sensor according to an embodiment of the invention. 
         FIG. 2  is a schematic, section view of a fluorescence-based sensor according to another embodiment of the invention. 
         FIG. 3  is a perspective, top view of a circuit board according to an embodiment of the invention. 
         FIG. 4  is a schematic, section view of a fluorescence-based sensor according to another embodiment of the invention. 
         FIG. 5  is a schematic, section view of an assembly according to an embodiment of the invention. 
         FIG. 6  is a schematic, section view of a fluorescence-based sensor according to another embodiment of the invention. 
     
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
       FIG. 1  is a schematic, section view of an optical-based sensor (“sensor”)  110 , according to an embodiment of the invention, that operates based on the fluorescence of fluorescent indicator molecules  116 . As shown, sensor  110  includes a sensor housing  112 . Sensor housing  112  may be formed from a suitable, optically transmissive polymer material. Preferred polymer materials include, but are not limited to, acrylic polymers such as polymethylmethacrylate (PMMA). 
     Sensor  110  may further include a matrix layer  114  coated on at least part of the exterior surface of the sensor housing  112 , with fluorescent indicator molecules  116  distributed throughout the layer  114  (layer  114  can cover all or part of the surface of housing  112 ). 
     Sensor  110  further includes a radiation source  118 , e.g. a light emitting diode (LED) or other radiation source, that emits radiation, including radiation over a range of wavelengths which interact with the indicator molecules  116 . For example, in the case of a fluorescence-based sensor, radiation sensor  118  emits radiation at a wavelength which causes the indicator molecules  116  to fluoresce. Sensor  110  also includes a photodetector  120  (e.g. a photodiode, phototransistor, photoresistor or other photosensitive element) which, in the case of a fluorescence-based sensor, is sensitive to fluorescent light emitted by the indicator molecules  116  such that a signal is generated by the photodetector  120  in response thereto that is indicative of the level of fluorescence of the indicator molecules. Two photodetectors  120   a  and  120   b  are shown in  FIG. 1  to illustrate that sensor  110  may have more than one photodetector. Source  118  may be implemented using, for example, LED model number EU-U32SB from Nichia Corporation (www.nichia.com). Other LEDs may be used depending on the specific indicator molecules applied to sensor  110  and the specific analytes of interested to be detected. 
     The indicator molecules  116  may be coated on the surface of the sensor body or they may be contained within matrix layer  114  (as shown in  FIG. 1 ), which comprises a biocompatible polymer matrix that is prepared according to methods known in the art and coated on the surface of the sensor housing  112 . Suitable biocompatible matrix materials, which preferably are permeable to the analyte, include some methacrylates (e.g., HEMA) and hydrogels which, advantageously, can be made selectively permeable—particularly to the analyte—i.e., they perform a molecular weight cut-off function. 
     Sensor  110  may be wholly self-contained. In other words, the sensor is preferably constructed in such a way that no electrical leads extend into or out of the sensor housing  112  to supply power to the sensor (e.g., for driving the source  118 ) or to transmit signals from the sensor. Rather, sensor  110  may be powered by an external power source (not shown), as is well known in the art. For example, the external power source may generate a magnetic field to induce a current in inductive element  142  (e.g., a copper coil or other inductive element). Additionally, circuitry  166  may use inductive element  142  to communicate information to an external data reader. Circuitry  166  may include discrete circuit elements, an integrated circuit (e.g., an application specific integrated circuit (ASIC), and/or other electronic components). The external power source and data reader may be the same device. 
     In an alternative embodiment, the sensor  110  may be powered by an internal, self-contained power source, such as, for example, microbatteries, micro generators and/or other power sources. 
     As shown in  FIG. 1 , many of the electro-optical components of sensor  110  are secured to a circuit board  170 . Circuit board  170  provides communication paths between the various components of sensor  110 . 
     As further illustrated in  FIG. 1 , optical filters  134   a  and  134   b , such as high pass or band pass filters, may cover a photosensitive side of photodetectors  120   a  and  120   b , respectively. Filter  134   a  may prevent or substantially reduce the amount of radiation generated by the source  118  from impinging on a photosensitive side  135  of the photodetector  120   a . At the same time, filter  134   a  allows fluorescent light emitted by fluorescent indicator molecules  116  to pass through to strike photosensitive side  135  of the photodetector  120   a . This significantly reduces “noise” in the photodetector signal that is attributable to incident radiation from the source  118 . 
     According to one aspect of the invention, an application for which the sensor  110  was developed—although by no means the only application for which it is suitable—is measuring various biological analytes in the human body. For example, sensor  110  may be used to measure glucose, oxygen, toxins, pharmaceuticals or other drugs, hormones, and other metabolic analytes in the human body. The specific composition of the matrix layer  114  and the indicator molecules  116  may vary depending on the particular analyte the sensor is to be used to detect and/or where the sensor is to be used to detect the analyte (i.e., in the blood or in subcutaneous tissues). Preferably, however, matrix layer  114 , if present, should facilitate exposure of the indicator molecules to the analyte. Also, it is preferred that the optical characteristics of the indicator molecules (e.g., the level of fluorescence of fluorescent indicator molecules) be a function of the concentration of the specific analyte to which the indicator molecules are exposed. 
     To facilitate use in-situ in the human body, the housing  112  is preferably formed in a smooth, oblong or rounded shape. Advantageously, it has the approximate size and shape of a bean or a pharmaceutical gelatin capsule, i.e., it is on the order of approximately 500 microns to approximately 0.85 inches in length L and on the order of approximately 300 microns to approximately 0.3 inches in diameter D, with generally smooth, rounded surfaces throughout. This configuration permits the sensor  110  to be implanted into the human body, i.e., dermally or into underlying tissues (including into organs or blood vessels) without the sensor interfering with essential bodily functions or causing excessive pain or discomfort. 
     In some embodiments, a preferred length of the housing is approx. 0.5 inches to 0.85 inches and a preferred diameter is approx. 0.1 inches to 0.11 inches. 
     In the embodiment shown in  FIG. 1 , source  118  is elevated with respect to a top side  171  of circuit board  170 . More specifically, in the embodiment shown, source  118  is fixed to a support member  174 , which functions to elevate source  118  above side  171  and to electrically connect source  118  to circuitry on board  170  so that power can be delivered to source  118 . The distance (d) between source  118  and side  171  generally ranges between 0 and 0.030 inches. Preferably, the distance (d) ranges between 0.010 and 0.020 inches. Support member  174  may be a circuit board. Circuit board  170  may have a groove  180  for receiving a proximal end  173  of member  174 . This feature is further illustrated in  FIG. 3 , which is a perspective, top view of board  170 . 
     In some embodiments, support member  174  may include an electrical contact  158  (e.g., a conductive pad or other device for conducting electricity) disposed on a surface thereof and electrically connected to source  118 . The contact  158  electrically connects to a corresponding electrical contact  157  that may be disposed in groove  180  through an electrical interconnect  159  (e.g., a circuit trace or other transmission line). Contact  157  may be electrically connected to circuit  166  or other circuit on circuit board  170 . Accordingly, in some embodiments, there is an electrical path from circuit  166  to source  118 . 
     As further shown in  FIG. 1 , a reflector  176  may be attached to board  170  at an end thereof. Preferably, reflector  176  is attached to board  170  so that a face portion  177  of reflector  176  is generally perpendicular to side  171  and faces source  118 . Preferably, face  177  reflects radiation emitted by source  118 . For example, face  177  may have a reflective coating disposed thereon or face  177  may be constructed from a reflective material. 
     Referring now to photodetectors  120 , photodetectors  120  are preferably disposed below a region of side  171  located between source  118  and reflector  176 . For example, in some embodiments, photodetectors  120  are mounted to a bottom side  175  of board  170  at a location that is below a region between source  118  and reflector  176 . In embodiments where the photodetectors  120  are mounted to bottom side  175  of board  170 , a hole for each photodetector  120  is preferably created through board  170 . This is illustrated in  FIG. 3 . As shown in  FIG. 3 , two holes  301   a  and  301   b  have been created in board  170 , thereby providing a passageway for light from indicator molecules  116  to reach photodetectors  120 . The holes in circuit board  170  may be created by, for example, drilling, laser machining and the like. Preferably, each photodetector  120  is positioned such that light entering the hole is likely to strike a photosensitive side of the photodetector  120 , as shown in  FIG. 1 . This technique also diminishes the amount of ambient light striking photodetector  120 . 
     As further illustrated in  FIG. 1 , each hole in board  170  may be contain a filter  134  so that light can only reach a photodetector  120  by passing through the corresponding filter  134 . The bottom side and all sides of the photodetectors  120  may be covered with black light blocking epoxy  190  to further diminish the amount of ambient light striking photodetector  120 . 
     In one embodiment, photodetector  120   a  is used to produce a signal corresponding to the light emitted or adsorbed by indicator molecules  116  and photodetector  120   b  is used to produce a reference signal. In this embodiment, a fluorescent element  154  may be positioned on top of filter  134   b . Preferably, fluorescent element  154  fluoresces at a predetermined wavelength. Element  154  may be made from terbium or other fluorescent element that fluoresces at the predetermined wavelength. In this embodiment, filter  134   a  and filter  134   b  filter different wavelengths of light. For example, filter  134   a  may filter wavelengths below 400 nm and filter  134   b  may filter wavelengths below 500 nm. 
     Referring now to  FIG. 2 ,  FIG. 2  illustrates a sensor  210  according to another embodiment of the invention. As shown in  FIG. 2 , sensor  210  is similar to sensor  110 . A primary difference being that reflector  176  is replaced by a support member  202 , which is connected to end  194  of board  170  and to which source  118  is fixed. In this embodiment, and support member  174  is replaced with a reflector  209 . Like reflector  176 , reflector  209  has a reflective face  211  that faces source  118 . Additionally, so that photodetector  120   a  remains closer to source  118 , photodetector  120   a  may switch places with photodetector  120   b  and filter  134   a  may switch places with filter  134   b . Fluorescent element  154  may also be re-positioned so that it remains on top of filter  134   b.    
     As shown in  FIGS. 1 and 2 , in some embodiments, indicator molecules  116  may be positioned only in a region that is above a region  193 , which region is between source  118  and reflector  176 . 
     Referring now to  FIG. 4 ,  FIG. 4  is a schematic, section view of an optical-based sensor  410 , according to another embodiment of the invention. Sensor  410  includes many of the same components as sensor  110 . However, the positioning of source  118 , photodetector  120   a  and filter  134   a  in sensor  410  is different than the positioning in sensor  110 . 
     As shown in  FIG. 4 , a base  412  is mounted to an end  413  of circuit board  170 . A top side  414  and bottom side  416  of base  412  each may lie in a plane that is generally perpendicular to a plane in which side  171  of board  170  lies. Bottom side  416  may have a groove  418  therein that receives end  413  of board  170 . Groove  418  facilitates fixing base  412  to board  170 . 
     Photodetector  120   a  may be mounted on top side  414  of base  412 . Preferably, photodetector  120   a  is mounted on base  412  so that photosensitive side  135  of photodetector  120   a  lies in a plane that is generally perpendicular to the plane in which side  171  of board  170  lies and faces in the same direction as top side  414 . 
     Filter  134   a  is preferably disposed above side  135  of photodetector  120   a  so that most, if not all, light that strikes side  135  must first pass through filter  134   a . Filter  134   a  may be fixedly mounted to photodetector  120   a . For example, a reflective index (RI) matching epoxy  501  (see  FIG. 5 ) may be used to fix filter  134   a  to photodetector  120   a.    
     In some embodiments, base  412  may include at least two electrical contacts disposed thereon (e.g., on side  414 ). For example, as shown in  FIG. 4 , a first electrical contact  471  and a second electrical contact  472  are disposed on side  414  of base  412 . A wire  473  (or other electrical connector) preferably electrically connects photodetector  120   a  to electrical contact  471  and a wire  474  (or other electrical connector) preferably electrically connects source  118  to electrical contact  472 . Contact  471  electrically connects to a corresponding contact  475  via an electrical interconnect  476 . Similarly, contact  472  electrically connects to a corresponding contact  477  via an electrical interconnect  478 . Contacts  475 ,  477  are preferably disposed on the end of board  170  that is inserted into groove  418 . Contacts  475 ,  477  may be electrically connected to circuit  166  or other circuit on circuit board  170 . Accordingly, in some embodiments, base  412  provides a portion of an electrical path from circuit  166  to source  118  and/or photodetector  120   a.    
     Referring now to  FIG. 5 ,  FIG. 5  further illustrates the arrangement of photodetector  120   a , filter  134   a  and source  118 . As shown in  FIGS. 4 and 5 , source  118  is mounted on a top side  467  of filter  134   a . Accordingly, as shown in  FIGS. 4 and 5 , photodetector  120   a , filter  134   a  and source  118  are aligned. That is, as shown in  FIG. 5 , both filter  134   a  and source  118  are each disposed in an area that is over at least a portion of photosensitive side  135  of photodetector  120   a.    
     Preferably, a non-transparent, non-translucent base  431  is disposed between source  118  and filter  134 . Opaque base  431  functions to prevent light emitted from source  118  from striking side  467  of filter  134   a . Base  431  may be a gold-clad-molybdenum tab (molytab) or other opaque structure. Epoxy  555  may be used to fix source  118  to base  431  and base  431  to filter  134   a.    
     Preferably, in this embodiment, source  118  is configured and oriented so that most of the light transmitted therefrom is transmitted in a direction away from side  467 , as shown in  FIGS. 4 and 5 . For example, in the embodiment shown, the light is primarily directed towards an end  491  of housing  102 . Preferably, indicator molecules  116  are located on end  491  so that they will receive the radiation emitted from source  118 . As discussed above, indicator molecules  116  will respond to the received radiation, and the response will be a function of the concentration of the analyte being measured in the region of the indicator molecules  116 . Photodetector  120   a  detects the response. 
     Referring now to  FIG. 6 ,  FIG. 6  is a schematic, section view of an optical-based sensor  610 , according to another embodiment of the invention. Sensor  610  includes many of the same components as sensor  110 . Also, sensor  610  is similar to sensor  410  in that, in sensor  610 , photodetector  120   a , filter  134   a  and source  118  are preferably aligned. Further, like in sensor  410 , in sensor  610  filter  134   a  may be fixedly mounted on side  135  of photodetector  120   a  and source  118  may be fixedly mounted on side  467  of filter  134   a , and the photodetector  120   a , filter  134   a , source  118  assembly may be located adjacent an end  491  of housing  102 , as illustrated in  FIG. 6 . 
     However, the orientation of source  118 , photodetector  120   a  and filter  134   a  in sensor  610  is different than the orientation in sensor  410 . For example, in sensor  610 , side  135  of photodetector  120   a  faces in a direction that is substantially perpendicular to the longitudinal axis of housing  102 . Additionally, in sensor  610 , filter  134   a  and/or photodetector  120   a  are directly fixed to board  170  such that base  412  may be removed. In the embodiment shown, filter  134   a  and/or photodetector  120   a  are directly fixed to end  413  of board  170 . 
     In one or more of the above described embodiments, housing  102  may be filled with a material to keep the components housed in housing  102  from being able to move around. For example, housing  102  may be filled with an optical epoxy either before or after board  170  and the components attached thereto are inserted into housing  120 . EPO-TEK 301-2 Epoxy from Epoxy Technology of Billerica, Mass. and/or other epoxies may be used. 
     While various embodiments/variations of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.