JP2005535411A - Devices and methods for in vitro determination of analyte concentration in body fluids - Google Patents

Abstract

A reagentless whole blood analyte detection system that can be placed near a patient has a source capable of emitting a beam of radiation having a spectral band. The whole blood system also has a detector in the optical path of the beam. The whole blood system also has a housing configured to contain the source and the detector. The whole blood system also has a sample element located in the optical path of the beam. The sample element has a sample cell and a sample cell wall that does not exclude the transmission of the beam of radiation within the spectral band.

Description

  The present invention generally relates to the determination of analyte concentrations in a material sample.

  Millions of diabetics take samples of bloody fluids on a daily basis to monitor the level of glucose in their bloodstream ( draw). This practice is called self-monitoring and is usually done using one of a number of reagent-based glucose monitors. These monitors measure glucose concentration by observing certain aspects of the chemical reaction between the reagent and the glucose in the fluid sample. The reagent is a chemical compound known to react with glucose in a predictable manner, allowing the monitor to determine the glucose concentration in the sample. For example, the monitor is configured to measure a voltage or current generated by a reaction between the glucose and the reagent. Often a small test strip is used to hold the reagent and to host the reaction between the glucose and the reagent. Reagent-based monitors and test strips suffer from various problems and have limited performance.

  Problems and costs associated with reagents arise during the manufacture, transport, storage, and use of test strips containing the reagents. Expensive and stringent quality control strategies must be incorporated into the test strip manufacturing process to ensure that the strip will function properly at the end. For example, a manufacturing lot-specific calibration code must be determined through blood or equivalent testing before the strip can be released for consumer sale. Diabetic patients using reagent-based monitors often have to put this calibration code in the monitor to ensure that the monitor is accurately reading the glucose concentration in the sample on the strip. Of course, this requirement leads to errors in reading and entering the calibration code, which can cause the monitor to produce inaccurate readings of glucose concentration.

  Reagent-based monitor test strips also require special packaging during shipping and storage to avoid hydration of the reagent. Premature hydration affects the way the reagent reacts with glucose and can cause false readings. Once the test strips are transported, they must be stored within a storage temperature range controlled by the vendor and user. Unfortunately, many users are often unable to follow these protocols. If the test strips and their reagents are not properly handled and stored, false monitor readings can occur. Even if all necessary processes, packaging, and storage management are followed, the reagents on the strip will still degrade over time and thus the strip will have only a limited shelf-life. All these factors have led consumers to make reagent-based monitors and test strips expensive and cumbersome. In fact, reagent-based test strips will still be expensive even if they are designed to be simpler and completely failsafe.

  The performance of reagent-based glucose monitors is limited in many aspects related to reagents. As discussed above, the accuracy of such a monitor is limited by the sensitive nature of the reagent, and thus any breaks in strict protocols related to manufacturing, packaging, storage, and usage. A breakdown reduces the accuracy of the monitor. The time at which the reaction occurs between glucose and the reagent is limited by the amount of reagent on the strip. Accordingly, the time for measuring the glucose concentration in the sample is similarly limited. The confidence of the reagent-based blood glucose monitor output can only be increased by taking more fluid samples and making additional measurements. This is undesirable because it doubles or triples the number of painful fluid withdrawals. At the same time, reagent-based monitoring performance is limited in that the reaction rate limits the rate at which individual measurements are obtained. The reaction time is considered too long by most users.

In general, reagent-based monitors are too complex for most users and have limited performance. In addition, such monitors require the user to collect fluids multiple times a day using a sharp lance that must be carefully handled.
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  In one embodiment, the present invention is a reagentless whole-blood analyte detection system that can be deployed near a patient. The whole blood system includes a source capable of emitting a beam of radiation having a spectral band, and a detector in the optical path of the beam. Prepare. The whole blood system also has a housing configured to contain the source and the detector. The whole blood system also has a sample element located in the optical path of the beam. The sample element has a sample cell and a sample cell wall that does not exclude transmission of the radiation beam in the spectral band.

  In another embodiment, the present invention includes a reagentless whole blood analyte detection system. The whole blood system comprises a radiation generating system having a radiation source and a filter that together generate electromagnetic radiation in at least one spectral band between about 4.2 μm and about 12.2 μm. system). The whole blood system also includes an optical detector positioned in the optical path of the spectral band radiation and responsive to the spectral band radiation to generate a signal. The whole blood system also has a signal processor that receives and processes the signal. The signal processor also generates an output. The whole blood system also has a display and a sample extractor. A portable housing is configured to at least partially contain at least one of the radiation generating system, the optical detector, the signal processor, and the sample extractor. The housing is adapted to receive a sample element having at least one optically transmissive portion.

  In yet another embodiment, the present invention includes a reagentless whole blood analyte detection system. The whole blood system has a source, an optical detector, and a sample element. The source is configured to emit electromagnetic radiation. The optical detector is positioned in the optical path of radiation. The sample element is located in the optical path of the radiation. The whole blood system performs optical analysis on a sample of whole blood to assess at least one characteristic of the whole blood.

  In another embodiment, a reagentless whole blood analyte detection system for analyzing a sample of whole blood comprises an optical calibration system and an optical analysis system. The optical calibration system is adapted to calibrate the whole blood system substantially simultaneously with the optical analysis system analyzing a sample of whole blood.

  In another embodiment, a method for performing whole blood analyte detection is provided. A reagent-free whole blood analyte detection system that can be positioned near a patient and includes an optical calibration system, an optical analysis system, and a sample cell is provided. A substantial portion of the sample cell is filled with the sample. A first calibration measurement of the sample cell is performed. An analytical measurement of a sample of whole blood in the sample cell is performed.

  In another embodiment, the invention includes a method for reagent-free whole blood analyte detection. A sample element having a source, a detector in the optical path of the source, a portable housing configured to receive the source and the detector, and a sample cell is provided. A fluid sample is taken from a portion of tissue. The opening of the sample element is positioned adjacent to the sample of fluid such that fluid is drawn into the sample element. The sample element is positioned within the housing such that the sample cell is in the optical path of the source. A emitted radiation beam having at least one spectral band is emitted from the source to the sample cell of the sample element. A transmitted radiation beam containing radiation exiting the sample element is detected by the detector.

  In another embodiment, the present invention includes a method for reagent-free whole blood analyte detection that can be performed near a patient. A source configured to emit electromagnetic radiation and an optical detector positioned in the optical path of the radiation are provided. A portable housing configured to at least partially contain the source and the optical detector and a sample element are also provided. The sample element is located in the optical path of the radiation within the housing and contains a sample of whole blood. A radiation beam of electromagnetic radiation is emitted from the source. A transmitted beam of radiation transmitted through the sample of whole blood is detected to evaluate at least one characteristic of the sample of whole blood.

  In another embodiment, the present invention includes a method of operating a reagentless whole blood detection system that may be placed near a patient. The detection system includes an optical calibration system and an optical analysis system. A sample element comprising a calibration portion and an analysis portion having a sample of whole blood is advanced into the whole blood analysis system. A first beam of electromagnetic radiation is transmitted through the analysis portion of the sample element to determine the optical properties of the whole blood sample and the sample element.

  In another embodiment, an automatic reagentless whole-blood analyte detection system has a source, an optical detector, a sample extractor, a sample cell, and a signal processor. . The source can generate radiation having at least a wavelength of electromagnetic radiation. The optical detector is positioned in the optical path of the radiation. The optical detector responds to the radiation by generating at least one signal. The sample extractor is configured to sample fluid from a portion of tissue. The sample cell is positioned in the optical path of the radiation and is configured to receive a fluid sample. The signal processor processes the signal. The test system is configured to take a fluid sample, receive the fluid sample, generate the radiation, detect the radiation, and process the signal without any intervention from the patient. The

Although certain preferred embodiments and examples are described below, the present invention goes beyond the specifically disclosed embodiments to other alternative embodiments and / or uses of the present invention and its obviousness. It will be understood by those skilled in the art that this extends to various variants and equivalents. Thus, it is intended that the scope of the invention disclosed herein should not be limited by the specific disclosed embodiments described below.
I. Overview of analyte detection systems (OVERVIEW OF ANALYTE DETECTOIN SYSTEMS)
An analyte detection system is disclosed herein, which has a non-invasive system that is primarily discussed in Part A below, and a whole blood system that is primarily discussed in Part B below. Various methods are also disclosed, including methods for detecting the concentration of an analyte in a material sample. The non-invasive system / method and the whole blood system / method are related in that they can both use optical measurements. As used herein with reference to measurement devices and methods, “optical” is a broad term and is used in its ordinary sense, without limitation, without the need for a chemical reaction to occur, a material sample Refers to the identification of the presence or concentration of an analyte within. As discussed in more detail below, the two approaches can each operate independently to perform an optical analysis of a material sample. The two approaches can also be combined in the device, or the two approaches can be used together to perform different process steps.

  In one embodiment, the two approach devices are combined to calibrate, for example, a device that uses a non-invasive approach. In another embodiment, an advantageous combination of the two approaches provides a non-invasive measurement that achieves higher accuracy and a whole blood measurement that minimizes patient discomfort. For example, the whole blood technique is more precise than non-invasive techniques at certain times of the day, for example, after a meal has been consumed or after a drug has been administered.

  However, it should be understood that any of the disclosed devices may be operated by any suitable detection methodology, and any disclosed method may be used in the operation of any suitable device. Further, the disclosed devices and methods include invasive, non-invasive, intermittent or continuous measurements, subcutaneous implantation, wearable detection systems or any combination thereof, The present invention is not limited thereto, and can be applied in a wide variety of operation situations or modes.

Any method described and illustrated herein is not limited to the precise sequence of acts described, but is not necessarily limited to the practices of all actions expressed. Other sequences of events or actions, or less than all of the events, or a simultaneous occurrence of the events, may be used to perform the method (s) in question.
A. Noninvasive system
1. Monitor structure
FIG. 1 depicts a currently preferred configuration of a noninvasive optical detection system {hereinafter “noninvasive system”} 10. The depicted non-invasive system 10 non-invasively determines the concentration of an analyte in a material sample S by observing the infrared energy emitted by the sample, as discussed in more detail below. It is particularly suitable for detecting noninvasively.

  As used herein, the term “noninvasive” is a broad term and is used in its ordinary sense to limit, without limitation, the ability to determine the concentration of an analyte in an extracorporeal tissue sample or fluid. The analyte detection device and method is referred to. However, the non-invasive system 10 disclosed herein is non-invasive because the non-invasive system 10 may be used to analyze extracorporeal fluids or tissue samples obtained invasively or non-invasively. It should be understood that the usage is not limited to specific usage. As used herein, the term “invasive” is a broad term and is used in its ordinary sense to include, without limitation, analyte detection methods that include removal of a fluid sample through the skin. Call it. As used herein, the term “material sample” is a broad term, used in its ordinary sense, and without limitation, any collection of materials suitable for analysis by the non-invasive system 10. of material). For example, the material sample S may include a tissue sample, such as a human forearm, placed against the non-invasive system 10. The material sample S may also be whole blood, blood component (s) {blood component (s)}, non-invasively obtained interstitial fluid or intercellular fluid. ) Or non-invasively obtained saliva or urine, or some collection of organic or inorganic materials, or a volume of bodily fluid. As used herein, the term “analyte” is a broad term, used in its ordinary sense, and without limitation, the non-invasive system 10 looks for presence or concentration in a material sample S. It refers to some chemical species. For example, the analyte (s) detected by the non-invasive system 10 include glucose, ethanol, insulin, water, carbon dioxide, blood oxygen, cholesterol, bilirubin, ketones, fatty acids. ), Lipoproteins, albumin (albumin), urea (urea), creatinine, leukocytes, red blood cells, hemoglobin, oxygenated hemoglobin, carboxyhemoglobin, organic molecules, inorganic molecules, Including, but not limited to, pharmaceuticals, cytochrome, various proteins and chromephores, microcalcifications, electrolytes, sodium, potassium, chlorine, bicarbonate, and hormones Not. As used herein to describe a measurement technique, the term “continuous” is a broad term and is used in its ordinary sense, and without limitation, an individual more frequently about once every 10 minutes. Taking measurements and / or a flow of measurements or other data over any suitable time, such as over 1 to a few seconds, minutes, hours, days, or longer, or Call to take a series. As used herein to describe a measurement technique, the term “intermittent” is a broad term, used in its ordinary sense, and without limitation, measured less frequently than about once every 10 minutes. Refers to taking a value.

  The non-invasive system 10 preferably includes a window assembly 12, although in some embodiments a window assembly 12 is omitted. One function of the window 12 is to allow infrared energy E to enter the non-invasive system 10 from the sample S when the sample S is placed against the top surface 12a of the window assembly 12. is there. The window assembly 12 has a heater layer (see discussion below) that is used to heat the material sample S and stimulate the emission of infrared energy therefrom. The cooling system 14 preferably includes a Peltier-type thermoelectric device so that the window assembly 12 and the material sample S can be operated according to the detection methodology discussed in more detail below. The window assembly 12 is in heat conduction relationship. The cooling system 14 has a cold surface 14 a in thermal communication with the cold reservoir 16 and the window assembly 12 and a hot surface 14 b in thermal communication with the heat sink 18.

  As the infrared energy E enters the non-invasive system 10, it first passes through the window assembly 12, then through an optical mixer 20, and then through a collimator 22. The optical mixer 20 preferably includes a light pipe having a highly reflective inner surface that randomizes the direction of the infrared energy E as it passes and reflects off the mixer wall. It is good to prepare. The collimator 22 also includes a light pipe with a highly reflective inner wall that diverges as it extends away from the mixer 20. The divergent wall causes the infrared energy E to tend to straighten as it travels toward the wider end of the collimator 22, but it is infrared when reflected to the collimator wall. This is because of the angle of incidence of energy.

  From the collimator 22, the infrared energy E passes through a filter array 24, each of which allows only a selected wavelength or band of wavelengths to pass therethrough. These wavelengths / bands are selected to highlight or separate the absorption effects of the analyte of interest in the detection methodology discussed in detail below. Each filter 24 is preferably in optical communication with a concentrator 26 and an infrared detector 28. The concentrator 26 has a highly reflective, converging inner wall that concentrates the infrared energy as it travels toward the detector 28, the detector The density of energy incident on 28 is increased.

  The detector 28 is in electrical communication with a control system 30 that receives an electrical signal from the detector 28 and calculates the concentration of the analyte in the sample S. The control system 30 is also electrically connected to the window 12 and the cooling system 14 to monitor the temperature of the window 12 and / or the cooling system 14 and to control the supply of power to the window 12 and the cooling system 14. To contact.

a. Window Assembly
A preferred configuration of the window assembly 12 is shown in perspective view in FIG. 2, as viewed from the underside (in other words, the side of the window assembly 12 opposite the sample S). The window assembly 12 generally includes a main layer 32 formed of a highly infrared transmissive material and a heater layer 34 attached to the underside of the main layer 32. And having. The main layer 32 has a preferred thickness of about 0.25 mm, preferably diamond, and most preferably chemically-vapor-deposited (“CVD”) diamond. . In other embodiments, alternative materials that are highly infrared transparent, such as silicon or germanium, may be used in forming the main layer 32.

  The heater layer 34 preferably has bus bars 36 disposed at opposite ends of an array of heater elements 38. The bus bar 36 is connected to the element 38 such that when the bus bar 36 is connected to a suitable power source (not shown), a current generating heat in the window assembly 12 is routed through the element 38. Electrically connected. The heater layer 34 also measures the temperature of the window assembly 12 and provides temperature feedback to the control system 30 in order to provide thermistors or resistance temperature devices {RTDs. )} May be included (see FIG. 1).

  Referring to FIG. 2, the heater layer 34 is a first adhesion layer of gold or platinum deposited on the alloy layer attached to the main layer 32 (hereinafter referred to as a “gold” layer). } Is preferably included. The alloy layer may be a material suitable for implementation of the heater layer 34, such as 10/90 titanium / tungsten, titanium / platinum, nickel / chromium, or other similar materials, according to examples. Including. The gold layer preferably has a thickness of about 4000 mm and the alloy layer preferably has a thickness ranging between about 300 mm and about 500 mm. The gold layer and / or the alloy layer may be vapor deposition, liquid deposition, plating, laminating, casting, sintering or other known to those skilled in the art. It may be deposited on the main layer 32 by chemical deposition, including but not necessarily limited to formation or deposition methodology. If desired, the heater layer 34 may be covered with an electrically insulating coating, which also improves adhesion to the main layer 32. One preferred coating material is aluminum oxide. Other acceptable materials include but are not limited to titanium oxide or zinc selenide.

  The heater layer 34 may incorporate a variable pitch distance between the centerlines of adjacent heater elements 38 in order to maintain a constant power density throughout the layer 34 and promote a uniform temperature. If constant pitch spacing is used, the preferred spacing is at least about 50-100 micrometers. The heater elements 38 generally have a preferred width of about 25 micrometers, but their widths may be varied as necessary for the same reasons described above.

  Alternative structures suitable for use as the heater layer 34 include thermoelectric heaters, radiofrequency {RF} heaters, infrared radiant heaters, optical heaters, heat exchangers, electrical resistance heating grids. (Electrical resistance heater grids), wire bridge heating grids, or laser heaters. Whatever type of heater layer is used, it is preferred that the heater layer cover up to about 10% or less of the window assembly 12.

  In the preferred embodiment, the window assembly 12 has substantially only the main layer 32 and the heater layer 34. Thus, when installed in an optical detection system, such as the non-invasive system 10 shown in FIG. An optical path that is blocked to the minimum by the infrared detector 28 is realized. The optical path 32 within the preferred non-invasive system 10 includes the main layer 32 and the heater layer 34 of the window assembly 12 (any antireflective, refractive index attached to or placed within it). (Including matching, electrical insulation, or protective coatings), through the optical mixer 20 and collimator 22, and only to the detector 28.

  FIG. 3 depicts an exploded side view of an alternative configuration for the window assembly 12 that may be used in place of the configuration shown in FIG. The window assembly 12 depicted in FIG. 3 has a highly infrared transmissive and thermally conductive spreader layer 42 near its top surface (the surface intended to contact the sample S). Below the spreader layer 42 is a heater layer 44. A thin electrically insulating layer (not shown) such as aluminum oxide, titanium dioxide, or zinc selenide may be disposed between the heater layer 44 and the spreader layer 42 (the aluminum oxide layer may also be the heater layer). 44 to increase adhesion to the spreader layer 42). Adjacent to the heater layer 44 is a thermal insulation and impedance matching layer 46. Adjacent to the thermal insulation layer 46 is an internal thermal conduction layer 48. The spreader layer 42 is coated with a thin protective coating layer 50 on its top surface. The bottom surface of the inner layer 48 is coated with a thin overcoat layer 52. Preferably, the protective coating 50 and the overcoat layer 52 have antireflection properties.

  The spreader layer 42 has a high thermal conductivity sufficient to facilitate uniform heat transfer from the heater layer into the material sample S when the material sample S is placed against the window assembly 12. It is preferably formed of a highly infrared transmissive material. Other useful materials include, but are not limited to, CVD diamond, diamond-like carbon, gallium arsenide, germanium, and other infrared transparent materials with sufficiently high thermal conductivity. The preferred dimensions for the spreader layer 42 are about 25.4 mm (1 inch) in diameter and about 0.254 mm (0.010 inch) thick. As shown in FIG. 3, the preferred embodiment of the spreader layer 42 incorporates a beveled edge. Although not necessary, a bevel of about 45 degrees is preferred.

  The protective layer 50 is intended to protect the top surface of the spreader layer 42 from breakage. Ideally, the protective layer should be highly infrared transparent and highly resistant to mechanical breaks such as scratching or abrasion. The protective layer 50 and the overcoat layer 52 preferably have high thermal conductivity and antireflection and / or refractive index matching characteristics. A satisfactory material for use as the protective layer 50 and overcoat 52 is a multi-layer broadband manufactured by Deposition Research Laboratories, Inc. of St. Charles, Missouri, Missouri. Anti-reflection coating (multi-layer Broad Band Anti-Reflective Coating). Diamondlike carbon coatings are also suitable.

  Except as noted below, the heater layer 44 is generally similar to the heater layer 34 used in the window assembly shown in FIG. Alternatively, the heater layer 44 may have a doped infrared transparent material, such as a doped silicon layer, having regions of higher and lower resistivity. The heater layer 44 preferably has a resistance of about 2 ohms and has a preferred thickness of about 1,500 mm. A preferred material for forming the heater layer 44 is a gold alloy, but other acceptable materials include, but are not limited to, platinum, titanium, tungsten, copper, and nickel.

  The thermal insulation layer 46 prevents the release of heat from the heater element 44 while allowing the cooling system 14 to effectively cool the material sample S (see FIG. 1). This layer 46 comprises a material that is thermally insulating (e.g., has a lower thermal conductivity than the spreader layer 42) and has an infrared transmissive quality. A preferred material is the calcogenide glass family known as AMTIR-1 manufactured by Amorphous Materials, Inc. of Garland, Texas. family) germanium-arsenic-selenium compound. The depicted embodiment has a diameter of about 21.6 mm (about 0.85 inches) and a preferred thickness in the range of about 0.127 to about 0.254 mm (about 0.005 to about 0.010 inches). When the heat generated by the heater layer 44 passes through the spreader layer 42 and into the material sample S, the thermal insulation layer 46 insulates this heat.

  The inner layer 48 may be formed of a thermally conductive material, preferably crystalline silicon formed using a conventional conventional float zone crystal growth method. The purpose of the inner layer 48 is to serve as a cold-conducting mechanical base for the entire stratified window assembly.

  The overall optical transmission of the window assembly 12 shown in FIG. 3 should preferably be at least 70%. The window assembly 12 of FIG. 3 is preferably held together by a retention bracket (not shown) and attached to the non-invasive system 10. The bracket is preferably formed of glass-filled plastic, for example Ultem 2300, manufactured by General Electric. Ultem 2300 has a low thermal conductivity that prevents heat transfer from the stratified window assembly 12.

b. Cooling system
The cooling system 14 (see FIG. 1) preferably has a Peltier-type thermoelectric device. Thus, application of current to the preferred cooling system 14 causes the cold surface 14a to cool and the opposite hot surface 14b to heat up. The cooling system 14 cools the window assembly 12 through the situation of the window assembly 12 in heat transfer relationship with the cold surface 14 a of the cooling system 14. The cooling system 14, the heater layer 34, or both may be used to create an oscillating thermal gradient in the sample S, depending on the various analyte-detection methodologies discussed herein. The window assembly 12 can be manipulated to induce a desired time-varying temperature.

  Preferably, the cold reservoir 16 is positioned between the cooling system 14 and the window assembly 12 and functions as a heat conductor between the system 14 and the window assembly 12. The cold reservoir 16 may be formed of a suitable heat conducting material, preferably brass. Alternatively, the window assembly 12 can be located in direct contact with the cold surface 14 a of the cooling system 14.

  In an alternative embodiment, the cooling system 14 may be a heat exchanger that is pumped through a coolant such as air, nitrogen or chilled water, or a passive conduction cooler such as a heat sink. ). As a further alternative, a gaseous coolant such as nitrogen is circulated through the interior of the non-invasive system 10 to contact the underside of the window assembly 12 (see FIG. 1) and conduct heat therefrom. Also good.

  FIG. 4 is a schematic plan view of a preferred arrangement of the window assembly 12 (of the type shown in FIG. 2) and the cold reservoir 16, and FIG. 5 shows an alternative for the window assembly 12 to be in direct contact with the cooling system 14. It is a schematic plan view of arrangement | positioning. The cold reservoir 16 / cooling system 14 preferably contacts the underside of the window assembly 12 along its opposite edge on either side of the heater layer 34. With the thermal conductivity established between the window assembly 12 and the cooling system 14, the window assembly can be cooled as needed during operation of the non-invasive system 10. In order to promote the formation of a substantially uniform or isothermal temperature profile on the upper surface of the window assembly 12, the pitch distance between the centerlines of adjacent heater elements 38 is determined by the window assembly. May be smaller (and thereby increase the density of the heater elements 38) near the contact area (s) between 12 and the cold reservoir 16 / cooling system 14. As a supplement or alternative, the heater element 38 itself may be made wider near these contact areas. As used herein, “isothermal” is a broad term and is used in its ordinary sense, and without limitation, the window assembly 12 or other structure at a given point in time. Of the material sample S is referred to as a condition that is substantially uniform across the surface intended to be placed in a heat transfer relationship. Thus, although the temperature of the structure or surface varies over time, the structure or surface is nevertheless isothermal at any given point in time.

  The heat sink 18 drains waste heat from the hot surface 14 b of the cooling system 16 and stabilizes the operating temperature of the non-invasive system 10. A preferred heat sink 18 (see FIG. 6) comprises a hollow structure formed of brass or any other suitable material having a relatively high specific heat and high thermal conductivity. The heat sink 18 has a conductive surface 18a that enters a heat transfer relationship with the hot surface 14b of the cooling system 14 when the heat sink 18 is installed in the non-invasive system 10 (see FIG. 1). A cavity 54 is formed in the heat sink 18 and preferably includes a phase-change material (not shown) to increase the capacity of the sink 18. A preferred phase change material is calcium chloride hexahydrate available from PCM Thermal Solutions, Inc., Naperville, Illinois, under the name T29 (TH29). Hydrate salt such as Alternatively, the cavity 54 may be removed to create a heat sink 18 with a solid, unitary mass. The heat sink 18 also forms a number of fins 56 to further increase heat conduction from the sink 18 to the ambient air.

  Alternatively, the heat sink 18 may be integrally formed with the optical mixer 20 and / or collimator 22 as a unit mass of a hard, thermally conductive material such as copper or aluminum. In such a heat sink, the mixer 20 and / or collimator 22 extends axially through the heat sink 18 and the heat sink defines an inner wall of the mixer 20 and / or collimator 22. These inner walls are coated and / or polished to have appropriate reflectivity and non-absorption at infrared wavelengths, as further described below. When such a unit heat sink-mixer-collimator is used, it is desirable to thermally insulate the detector array from the heat sink.

  As long as the material sample S is provided with a suitable degree of cycled heating and / or cooling, any suitable structure may be provided instead of or in addition to the window assembly 12 / cooling system 14 disclosed above. It should be understood that the material sample S may be used for heating and / or cooling. In addition, other types of heat may be used to heat the material sample S, such as but not limited to radiation, chemically induced heat, friction and vibration. Furthermore, it will be appreciated that heating of the sample can be accomplished by any suitable method such as convection, conduction, radiation, etc.

c. Optical equipment (Optics)
As shown in FIG. 1, the optical mixer 20 comprises a light pipe with an internal coating, which coating is highly reflective, exhibits minimal absorption at infrared wavelengths, and is preferably a polished gold coating. However, if other wavelengths of electromagnetic radiation are used, other suitable coatings may be used. The pipe itself may be made of another rigid material such as aluminum or stainless steel, so long as the inner surface is coated or otherwise treated to be highly reflective. Preferably, the optical mixer 20 has a rectangular cross-section, although other polygonal shapes or other cross-sectional shapes such as circle or ellipse shapes may be used in alternative embodiments. When taken perpendicular to the longitudinal axis AA of the mixer 20 and the collimator 22). The inner wall of the optical mixer 20 is substantially parallel to the longitudinal axis AA of the mixer 20 and collimator 22. The highly reflective and substantially parallel inner wall of the mixer 20 maximizes the number of times that the infrared energy E is reflected between the walls of the mixer 20, when the energy propagates through the mixer 20. , The infrared energy E is thoroughly mixed. In the presently preferred embodiment, the mixer 20 is about 3.05 cm to 6.1 cm (about 1.2 inches to 2.4 inches) long and has a cross-section of about 1.02 cm × 1.52 cm (about 0 inches). .4 inches x about 0.6 inches). Of course, other dimensions may be used to make the mixer 20. In particular, it is advantageous to downsize the mixer or otherwise make it as small as possible.

  Still referring to FIG. 1, the collimator 22 may comprise a tube having an inner coating, preferably a polished gold coating, that is highly reflective and has minimal absorption at infrared wavelengths. As long as the inner surface is coated to be highly reflective or otherwise treated, the tube itself may be made of another hard material such as aluminum, nickel or stainless steel. Preferably, the collimator 22 has a rectangular cross-section, although other embodiments may use other cross-sectional shapes, such as other polygonal shapes or circles, parabolic or elliptical shapes. It may be broken. The inner walls of the collimator 22 diverge as they extend away from the mixer. Preferably, the inner wall of the collimator 22 is substantially straight and forms an angle of about 7 degrees with respect to the longitudinal axis AA. The collimator 22 propagates in a direction generally parallel to the longitudinal axis AA of the mixer 20 and collimator 22 so that the infrared energy E strikes the surface of the filter 24 at an angle as close to 90 degrees as possible. Match the infrared energy E.

  In the presently preferred embodiment, the collimator 22 is about 7.5 inches in length. At its narrow end 22a, the cross-section of the collimator 22 is a rectangle about 1.02 cm × about 1.52 cm (about 0.4 inch × about 0.6 inch). At its wide end, the collimator 22 has a rectangular cross section of about 4.57 cm × about 6.60 cm (about 1.8 inches × 2.6 inches). Preferably, the collimator 22 aligns the infrared energy E to an incident angle of about 0-15 degrees (relative to the longitudinal axis AA) before the energy E impinges on the filter 24. . Of course, other dimensions and angles of incidence may be used to make and operate the collimator 22.

  With further reference to FIGS. 1 and 6A, each concentrator 26 is adapted so that its wide end 26a is adapted to receive infrared energy exiting the corresponding filter 24 and its narrow end 26b is associated with a corresponding detector. Adjacent to 28, it has an oriented tapered surface. The inwardly facing surface of the concentrator 26 should have a highly reflective inner coating with minimal absorption at infrared wavelengths, preferably a polished gold coating. The concentrator 26 itself may be made of another hard material such as aluminum, nickel or stainless steel, so long as their inner surfaces are highly reflectively coated or otherwise treated.

  Preferably, the concentrator 26 has a rectangular cross-section, although other embodiments may use other polygonal shapes or other cross-sectional shapes such as circles, parabolas or ellipses. It may be broken. The inner walls of the concentrator converge as they extend toward the narrow end 26b. Preferably, the inner wall of the concentrator 26 is substantially straight and forms an angle of about 8 degrees with respect to the longitudinal axis AA. Such a shape is adapted to concentrate infrared energy as it passes through the concentrator 26 from the wide end 26a to the narrow end 26b before it reaches the detector 28.

  In the presently preferred embodiment, each concentrator 26 is about 1.5 inches in length. At its wide end 26a, the cross-section of each concentrator 26 is a rectangle measuring about 0.62 × 0.57 inches. At its narrow end 26b, each concentrator 26 has a rectangular cross section of about 0.177 inches x 0.177 inches. Of course, other dimensions or angles of incidence may be used to make the concentrator 26.

d. Filters
Filter 24 is preferably widely available from manufacturers such as Optical Coating Laboratory, Inc. {"OCLI"} of Santa Rosa, Calif. It may have standard interference-type infrared filters. In the embodiment illustrated in FIG. 1, a 3 × 4 array of filters 24 is positioned on a 3 × 4 array of detectors 28 and concentrators 26. As used in this embodiment, the filters 24 are arranged in four groups of three filters having the same wavelength sensitivity. These four groups have bandpass center wavelengths of 7.15 μm ± 0.03 μm, 8.40 μm ± 0.03 μm, 9.48 μm ± 0.04 μm, and 11.10 μm ± 0.04 μm, respectively. , They correspond to the wavelengths at which water and glucose absorb electromagnetic radiation in the vicinity. Typical bandwidths for these filters range from 0.20 μm to 0.50 μm.

  In an alternative embodiment, the wavelength-specific array of filters 24 may be replaced by a single Fabry-Perot interferometer, which is configured to take a sample of infrared energy from the material sample S. Provides varying wavelength sensitivity. Thus, this embodiment allows the use of only one detector 28 whose output signal varies with wavelength specificity over time. The output signal can be de-multiplexed based on the wavelength sensitivity induced by the Fabry-Perot interferometer to provide a multiple wavelength profile of infrared energy emitted by the material sample S. . In this embodiment, since only one detector 28 needs to be used, the optical mixer 20 may be omitted.

  In still other embodiments, the arrangement of filters 24 has a filter wheel in which various filters with varying wavelength sensitivity rotate on one detector 24. Alternatively, an electronically tunable infrared filter to provide wavelength sensitivity that changes during the detection process may be used in a manner similar to the Fabry-Perot interferometer discussed above. In either of these embodiments, the optical mixer 20 may be omitted because only one detector 28 needs to be used.

e. Detectors
The detector 28 may comprise any detector type adapted to detect infrared energy, preferably at mid-infrared wavelength. For example, the detector 28 may comprise a mercury-cadmium-telluride {MCT} detector. Detectors such as Fermiionics {Simi Valley, Calif.} With a pre-amplifier PVA481-1 (Model PV-9.1) Acceptable. Similar units from other manufacturers such as Graseby {Tampa, Fla.} Can be replaced. Other suitable components for use as the detector 28 are pyroelectric detectors, thermopiles, bolometers, silicon microbolometers and red salt Includes lead-salt focal plane arrays.

f. Control system
FIG. 7 depicts not only the detailed control system 30, but also the interconnection between the control system and other relevant parts of the non-invasive system. The control system has a temperature control subsystem and a data acquisition subsystem.

  In the temperature control subsystem, a temperature sensor (such as RTDs and / or thermistors) located within the window assembly 12 asynchronously synchronizes the window temperature signal with the synchronous analog-to-digital conversion system 70. Type analog-to-digital conversion system 72. The A / D systems 70, 72 in turn provide digital window temperature signals to a digital signal processor {DSP} 74. The processor 74 executes a window temperature control algorithm and determines appropriate control inputs for the heater layer 34 and / or the cooling system 14 of the window assembly 12 based on information contained in the window temperature signal. To do. The processor 74 outputs one or more digital control signals to a digital-to-analog conversion system 76, which in turn provides one or more analog control signals to the current driver 78. In response to the control signal (s), the current driver 78 regulates the power supplied to the heater layer 34 and / or the cooling system 14. In one embodiment, the processor 74 provides a control signal through a digital I / O device 77 to a pulse-width modulator (PWM) controller 80, which controls the current driver 78. Provides a signal to control the operation. Instead, a low pass filter (not shown) at the output of the PWM provides continuous operation of the current driver 78.

  In another embodiment, a temperature sensor is located in the cooling system 14 and is suitably connected to the A / D system (s) and processor, as well as providing closed loop control of the cooling system.

  In yet another embodiment, the detector cooling system 82 is placed in a heat transfer relationship with one or more of the detectors 28. The detector cooling system 82 comprises any of the devices disclosed above including the cooling system 14, and preferably comprises a Peltier-type thermoelectric device. The temperature control subsystem may also include temperature sensors, such as RTDS and / or thermistors, located in or adjacent to the detector cooling system 82, and these asynchronous sensors. / D system 72 may be included. The temperature sensor of the detector cooling system 82 provides a detector temperature signal to the processor 74. In one embodiment, the detector cooling system 82 operates independently from the window temperature control system, and the detector cooling system temperature signal is sampled using the asynchronous A / D system 72. According to the temperature control algorithm, the processor 74 determines an appropriate control input for the detector cooling system 82 based on information contained in the detector temperature signal. The processor 74 outputs a digital control signal to the D / A system 76, which in turn provides an analog control signal to the current driver 78. In response to the control signal, the current driver 78 regulates the power supplied to the detector cooling system 14. In one embodiment, the processor 74 also provides a control signal through the digital I / O device 77 and the PWM controller 80 to control the operation of the detector cooling system 82 by the current driver 78. To do. Instead, a low pass filter (not shown) at the output of the PWM provides continuous operation of the current driver 78.

  In the data acquisition subsystem, the detector 28 responds to infrared energy E incident thereon by sending one or more analog detector signals to a preamplifier 84. The preamplifier 84 amplifies the detector signals and sends them to the synchronous A / D system 70, which converts the detector signals to digital form and sends them to the processor 74. The processor 74 is based on the detector signal and a concentration-analysis algorithm and / or a phase / concentration regression model stored in the memory module 88. To determine the concentration of the analyte (s) of interest. The concentration-analysis algorithm and / or phase / concentration regression model may be developed by any of the analytical methodologies discussed herein. The processor communicates the concentration result and / or other information to a display controller 86, which displays a display (not shown) such as an LCD display to present the information to the user. Make it work.

  A watchdog timer 94 may be used to ensure that the processor 74 is operating correctly. If the watchdog timer 94 does not receive a signal from the processor 74 within a specified time, the watchdog timer resets the processor. The control system may also include a JTAG interface 96 to allow testing of the non-invasive system 10.

  In one embodiment, the synchronous A / D system 70 includes a 20-bit, 14 channel system and the asynchronous A / D system 72 includes a 16-bit, 16 channel system. The preamplifier may include a 12 channel preamplifier corresponding to an array of 12 detectors 28.

  The control system may also have a serial port 90 or other conventional data port to allow connection to a personal computer 92. The personal computer updates the algorithm (s) stored in the memory module 88 and / or the phase / concentration regression model (s) or analyte-concentration from the non-invasive system. Can be used to download data compilation. A real time clock or other timing device may be accessible by the processor 74 to perform any time-dependent calculations desired by the user.

2. Analysis methodology
The detector (s) 28 of the non-invasive system 10 are used to detect infrared energy emitted by the material sample S at various desired wavelengths. At each measured wavelength, the material sample S emits infrared energy with an intensity that varies over time. The time-varying intensity is primarily in response to the use of the window assembly 12 (including its heater layer 34) and the cooling system 14 inducing a thermal gradient within the material sample S. Occur. As used herein, “thermal gradient” is a broad term and is used in its ordinary sense to increase temperature and / or thermal energy at one or more locations in the sample without limitation. It refers to the difference in temperature and / or thermal energy between various locations, such as various depths, of a material sample that can be induced by any suitable method of reducing. As discussed in detail below, the concentration of the analyte of interest (such as glucose) in the material sample S is determined by comparing the time-varying intensity profile of the various measured wavelengths with the non-invasive property. It can be determined by a device such as system 10.

  Here, analytical methodologies are discussed in the context of detecting the concentration of glucose in a material sample, such as a tissue sample, which contains a large proportion of water. However, it is clear that these methodologies are not limited to this background and may be applied to the detection of a wide variety of analytes within a wide variety of sample types. It should also be understood that other suitable analytical methodologies and a wide variety of the disclosed methodologies may be used to operate an analyte detection system, such as the non-invasive system 10. .

  As shown in FIG. 8, a first reference signal P is measured at a first reference wavelength. The first reference signal P is measured at a wavelength that is strongly absorbed by water (for example, 2.9 μm or 6.1 μm). Since water strongly absorbs radiation at these wavelengths, the detector signal intensity is reduced at those wavelengths. In addition, at these wavelengths, water absorbs photon emissions emanating from the deep interior of the sample. The net effect is that signals emitted at these wavelengths from deep inside the sample are not easily detected. The first reference signal P is thus a good indicator of thermal gradient effects near the sample surface. This signal may be calibrated and normalized to a baseline value of 1 if there is no heating or cooling applied to the sample. More than one first reference wavelength may be measured for higher accuracy. For example, both 2.9 μm and 6.1 μm may be selected as the first reference wavelength.

  Further, as shown in FIG. 8, the second reference signal R may also be measured. The second signal R may be measured at a wavelength where water has very low absorption (eg, 3.6 μm or 4.2 μm). Thus, this second reference signal R provides the analyte with information about the deeper region of the sample, while the first reference signal P provides information about the sample surface. This signal may also be calibrated and normalized to a baseline value of 1 in the absence of heating or cooling applied to the sample. By using more than one second (deep) reference signal, as in the first (surface) reference signal P, higher accuracy is obtained.

  A third (analytical) signal Q is also measured to determine the analyte concentration. This signal is measured at the IR absorption peak of the selected analyte. The IR absorption peak for glucose is in the range of about 6.5 μm to 11.0 μm. This detector signal may also be calibrated and normalized to a baseline value of 1 in the absence of heating or cooling applied to the material sample S. As in the reference signals P, R, the analysis signal Q may be measured with more than one absorption peak.

  Optionally or additionally, a reference signal may be measured at a wavelength that brackets the analyte absorption peak. These signals are advantageously monitored at a reference wavelength that does not overlap with the analyte absorption peak. Furthermore, it is advantageous to measure the reference wavelength of the absorption peak that does not overlap with the absorption peaks of other possible components contained in the sample.

a. Basic thermal gradient
As further shown in FIG. 8, the signal strengths P, Q, and R are initially shown with a normalized baseline signal strength of 1. Of course, this reflects the baseline radiation behavior of the test sample in the absence of applied heating or cooling. At time t _C, the sample surface is subjected to a thermal event (Temperature event) to induce thermal gradients within the sample. The gradient can be induced by heating or cooling the sample. The example shown in FIG. 8 uses cooling using, for example, a 10 ° C. cooling event. In response to the cooling event, the intensity of the detector signals P, Q, R decreases over time.

Since the cooling of the sample is neither uniform nor instantaneous, the surface cools before the deeper region of the sample cools. As each of the signals P, Q, and R decreases in intensity, a pattern appears. The signal strength decreases as expected, but when the signal P, Q, R reaches a given amplitude value (or series of amplitude values: 150, 152, 154, 156, 158), a certain temporal result Notice. After the cooling event is triggered at t _C , the first (surface) reference signal P decays the fastest and arrives at checkpoint 150 first at time t _P. This is due to the fact that the first reference signal P reflects the radiation characteristics of the sample close to the surface of the sample. Since the sample surface cools before the underlying region, the surface (first) reference signal P first drops in intensity.

At the same time, the second reference signal R is monitored. Since the second reference signal R does not cool as fast as the surface (due to the time required for surface cooling to propagate into the deeper region of the sample), it corresponds to the radiation characteristics of the deeper region of the sample. The strength does not decrease until a little later. As a result, the signal R does not reach the magnitude 150 until some lag time t _R. In other words, there is a time delay (time delay) between the time t _P and time t _R of the second reference signal R reaches the same checkpoint 150 where the amplitude of the first reference signal P reaches the checkpoint 150. This time delay can be expressed as a phase difference Φ (λ). In addition, the phase difference may be measured between the analysis signal Q and either or both of the reference signals P, R.

As the analyte concentration increases, the amount of absorption at the analysis wavelength increases. This reduces the intensity of the analysis signal Q in a concentration dependent manner. As a result, the analytical signal Q reaches intensity 150 at some intermediate time t _Q. The higher the analyte concentration, the more the analysis signal Q shifts to the left in FIG. As a result, with increasing analyte concentration, the phase difference Φ (λ) decreases with respect to the first (surface) reference signal P and increases with respect to the second (deep tissue) reference signal R. The phase difference (s) Φ (λ) is directly related to the analyte concentration and can be used to make an accurate determination of the analyte concentration.

  The phase difference Φ (λ) between the first (surface) reference signal P and the analysis signal Q is expressed by the following equation.

Φ (λ) = | t _P −t _Q |
The magnitude of this phase difference decreases with increasing analyte concentration.

  The phase difference Φ (λ) between the second (deep tissue) reference signal R and the analysis signal Q is expressed by the following equation.

Φ (λ) = | t _Q −t _R |
The magnitude of this phase difference increases with increasing analyte concentration.

Accuracy is improved by selecting several checkpoints, eg 150, 152, 154, 156 and 158, and averaging the phase differences observed at each checkpoint. The accuracy of this method is further improved by integrating the phase difference (s) continuously over the entire test time. In only one thermal event (in this case, the cooling event) This example because is induced, the sample reaches the lower equilibrium temperature than the new, the signal is stabilized at a new constant level I _F. Of course, the method was induced by heating or by the application or introduction of other types of energy such as but not limited to radiation, chemically induced heat, friction and vibration. It works equally well with thermal gradients.

This methodology is not limited to determining phase differences. And whether the time given what (e.g., at time t _X), the amplitude reference signal P of the analytical signal Q, may be compared with the amplitude of either or both of R. The difference in amplitude is observed and processed to determine the analyte concentration.

  This method, variants disclosed herein, and devices disclosed as suitable for application of the method (s) are not limited to the detection of in-vivo glucose concentration. The methods and disclosed variants and devices may be used in organic or inorganic compositions in human, animal, or even plant subjects, or in non-medical settings. The method may be used to make measurements of virtually any type of in-vivo or extra-corporeal sample. The method includes glucose, ethanol, insulin, water, carbon dioxide, blood oxygen, cholesterol, bilirubin, ketones, fatty acids, lipoproteins, albumin (urebumin), urea (urea), creatinine , White blood cells, red blood cells, hemoglobin, oxygenated hemoglobin, carbon monoxide hemoglobin, organic molecules, inorganic molecules, pharmaceuticals, cytochromes, various proteins and chromophores, microcalcifications, only hormones It is useful for measuring the concentration of a wide range of additional chemical analytes, including but not limited to other chemical compounds. To detect a given analyte, one only needs to select the appropriate analysis wavelength and reference wavelength.

  The method is adaptable and may be used to determine the chemical concentration in a body fluid (eg, blood, urine or saliva) sample once extracted from the patient. In fact, the method may be used for measuring virtually any type of extracorporeal sample.

b. Modulated Thermal Gradient
In a variation on the methodology described above, a periodically modulated thermal gradient can be used to make an accurate determination of the analyte concentration.

  As previously shown in FIG. 8, once a thermal gradient is introduced into the sample, the reference and analysis signals P, Q, R fall out of phase with respect to each other. This phase difference Φ (λ) exists even when the thermal gradient is induced by heating or cooling. By alternately subjecting the test sample to a cyclic pattern of heating and cooling, or alternatively heating and cooling, an oscillating thermal gradient is induced in the sample for an extended period of time.

The oscillating thermal gradient is illustrated using a sinusoidally modulated gradient. FIG. 9 depicts the detector signal emanating from the test sample. As in the methodology shown in FIG. 8, one or more reference signals J, L are measured. One or more analysis signals K are also monitored. These signals are calibrated to one baseline and normalized in the absence of heating or cooling applied to the sample. FIG. 9 shows the signal after normalization. At some time t _C , a temperature event (eg, cooling) is induced on the sample surface. This causes a detector signal decline. As shown in FIG. 8, the signal (P, Q, R) is reduced to a thermal gradient disappears and reach a new equilibrium detector signal I _F. In the illustrated method in FIG. 9, slope and start off the signal intensity 160, a heating event at time t _W is induced in the sample surface. As a result, the detector output signals J, K, L increase as the sample temperature increases. At some later time t _C2 , another cooling event is triggered, reducing the temperature and detector signal. This cycle of cooling and heating may be repeated over any length of time interval. Furthermore, if the cooling and heating events are properly timed, a periodically modulated thermal gradient is induced in the test sample.

  As previously discussed in the discussion regarding FIG. 8, the phase difference Φ (λ) is measured and used to determine the analyte concentration. FIG. 9 shows that the intensity of the first (surface) reference signal J first decreases and increases. The second (deep tissue) reference signal L falls and rises in a time delayed manner with respect to the first reference signal. Analytical signal K indicates the analyte concentration dependent time / phase delay. With increasing concentration, the analysis signal K shifts to the left in FIG. As in FIG. 8, the phase difference Φ (λ) may be measured. For example, the phase difference Φ (λ) between the second reference signal L and the analysis signal K may be measured with the set amplitude 162 shown in FIG. Again, the magnitude of the phase signal reflects the analyte concentration of the sample.

  To determine the analyte concentration in the sample, the phase difference information compiled by any of the methodologies disclosed herein is correlated with the phase difference information previously determined by the control system 30 (see FIG. 1). (Correlated) is taken. This correlation is a comparison of the phase difference information received from the analysis of the sample with a data set containing phase difference profiles observed from a standard analysis of a wide variety of known analyte concentrations. Including. In one embodiment, a phase / concentration curve or regression model is established by applying regression techniques to a set of phase difference data observed with a standard of known analyte concentration. This curve is used to estimate the analyte concentration in the sample based on the phase difference information received from the sample.

  Advantageously, the phase difference Φ (λ) may be measured continuously throughout the test period. The phase difference measurement may be integrated over the entire test period for extremely precise measurement of the phase difference Φ (λ). The accuracy may be improved by using more than one reference signal and / or more than one analysis signal.

  As an alternative or supplement to the phase difference (s) measurement, the amplitude difference between the analysis and the reference signal (s) may be measured and used to determine the analyte concentration. Additional details relating to this technology and not needing to be repeated here are found in the assignee's patent application, which is hereby incorporated by reference below.

  In addition, these methods are advantageously used to simultaneously measure the concentration of one or more analytes. By selecting non-overlapping reference and analyte wavelengths, the phase difference can be measured simultaneously and processed to determine the analyte concentration. Although FIG. 9 illustrates the method used in conjunction with a sinusoidally modulated thermal gradient, the principle applies to a thermal gradient that is conforming to any periodic function. In more complex cases, analysis using signal processing with a Fourier transform or other techniques allows for precise determination of the phase difference Φ (λ) and analyte concentration.

  As shown in FIG. 10, the magnitude of the phase difference is determined by measuring the time interval between the amplitude peaks {or toughs} of the reference signals J, L and the analysis signal K. . Instead, the time interval between “zero crossings” (the point at which the signal amplitude changes from positive to negative, or from negative to positive) depends on the position between the analytic signal K and the reference signals J, L. It may be used to determine the phase difference. This information is then processed to determine the analyte concentration. This particular method has the advantage of not requiring normalized signals.

  As a more advanced alternative, more than one driving frequency may be used to determine the analyte concentration at a selected depth within the sample. A slow (eg, 1 Hz) drive frequency creates a thermal gradient that penetrates deeper into the sample than a gradient created by a fast (eg, 3 Hz) drive frequency. This is because individual heating and / or cooling events have a longer duration when the drive frequency is low. Thus, the use of a slow drive frequency provides analyte concentration information from a deeper “slice” of the sample than the use of a fast drive frequency.

  When analyzing human skin samples, a temperature event of 10 ° C. was found to create a thermal gradient that penetrates to a depth of about 150 μm after an exposure of about 50 ms. As a result, a 1 Hz cooling / heating cycle or drive frequency provides information up to a depth of about 150 μm. It was determined that exposure to a 10 ° C. temperature event for about 167 ms creates a thermal gradient that penetrates to a depth of about 50 μm. Thus, a 3 Hz cooling / heating cycle provides information up to a depth of about 50 μm. By subtracting the detector signal information measured at 3 Hz drive frequency from the detector signal information measured at 1 Hz drive frequency, the analyte concentration (s) in the skin region between 50 and 150 μm can be determined. . Of course, a similar approach can be used to determine analyte concentrations in any desired depth range within any suitable type of sample.

As shown in FIG. 11, alternating deep and shallow thermal gradients are induced by alternating slow and fast drive frequencies. As in the method described above, this variation also includes detection and measurement of the phase difference Φ (λ) between the reference signals G, G ′ and the analysis signals H, H ′. The phase difference is measured at both fast (eg, 3 Hz) and slow (eg, 1 Hz) drive frequencies. The slow drive frequency may last for an arbitrarily chosen number of cycles (region SL ₁ ), eg, two full cycles. Then, the speed had driving frequency during the selected duration, used in region F _1. The phase difference data is compiled in the same manner as disclosed above. In addition, to provide a precise determination of the analyte concentration in the region of the sample between the gradient penetration depth associated with the fast drive frequency and that associated with the slow drive frequency The fast frequency (shallow sample) phase difference data is subtracted from the slow frequency (deep sample) data.

  The drive frequencies (eg, 1 Hz and 3 Hz) can be multiplexed as shown in FIG. Fast (3 Hz) and slow (1 Hz) drive frequencies are superimposed rather than being implemented sequentially. During analysis, the data may be separated by frequency (using Fourier transforms or other techniques) and independent measurements of phase delay may be calculated at each of the drive frequencies. Once separated, the two sets of phase delay data are processed to determine absorption and analyte concentration.

Additional details that need not be repeated here are described in U.S. Pat. 19 found. The above patents, patent applications and publications are hereby incorporated by reference in their entirety and form part of this specification.
B. Whole-Blood Detection System
FIG. 13 is a schematic diagram of a preferred configuration of a reagentless whole blood analyte detection system 200 (hereinafter referred to as a “whole-blood system”). The whole blood system 200 includes a radiation source 220, a filter 230, a cuvette 240 having a sample cell 242, and a radiation detector 250. The whole blood system 200 preferably also includes a signal processor 260 and a display 270. Although cuvette 240 is shown here, other sample elements may also be used in the system 200, as described below. The whole blood system 200 can also have a sample extractor 280, which can be used to remove bodily fluids from the appendage, such as a finger 290, forearm, or some other suitable location. fluid).

  As used herein, the terms “whole-blood analyte detection system” and “whole-blood system” are broad, synonymous terms and their Used in the normal sense, and without limitation, refers to an analyte detection device that can determine the concentration of an analyte in a material sample by passing electromagnetic radiation through the sample and detecting absorption of the radiation by the sample. As used herein, the term “whole-blood” is a broad term and is used in its ordinary sense, and without limitation, has been extracted from a patient, but after being removed from the patient, others Refers to blood that has never been processed, eg, hemolysed, lyophilized under reduced pressure, centrifuged, or otherwise separated. Whole blood has entered some amount of other fluids, such as interstitial fluid or intercellular fluid, that entered or naturally existed in the sample during the withdrawal process May be included. However, the whole blood system 200 disclosed herein is such that the whole blood system 10 is saliva, urine, sweat, interstitial fluid, intercellular fluid, hemolyzed, lyophilized under reduced pressure or centrifuged. It should be understood that it is not limited to the analysis of whole blood as it is used to analyze other substances, such as blood or some other organic or inorganic material.

  The whole blood system 200 may comprise a near-patient testing system. As used herein, “near-patient testing system” is used in its ordinary sense and is, without limitation, configured to be used where the patient is not exclusively in the laboratory. Other test systems, such as systems that can be used in a patient's home, clinic, hospital, or even in a mobile environment. Users of the test system near the patient include a patient, a patient family member, a clinician, a nurse, or a doctor. “Patient close test system” also includes a “point-of-care” system.

  The whole blood system 200 may be configured to be easily operated by a patient or user in one embodiment. As such, the system 200 is preferably a portable device. As used herein, “portable” is used in its ordinary sense, and without limitation, means that the system 200 is easily carried by the patient and used at a convenient location. For example, the system 200 is advantageously small. In one preferred embodiment, the system 200 is small enough to fit within a purse or backpack. In another embodiment, the system 200 is small enough to fit in a pant pocket. In another embodiment, the system 200 is small enough to be held in the palm of a hand.

  Some of the embodiments described herein use sample elements that hold material samples, such as biological fluid samples. As used herein, “sample element” is a broad term and is used in its ordinary sense, without limitation, a sample cell and at least one sample cell wall. More generally, but can hold, support or contain a material sample and thereby allow electromagnetic radiation to pass through the contained, supported or contained sample. Including, for example, cuvettes, test strips, and the like. As used herein, the term “disposable” when applied to a component such as a sample element is a broad term, used in its ordinary sense, and without limitation, the component in question is finite. Means used once and then discarded. Some disposable parts are used only once and then discarded. Other disposable parts are used more than once and then discarded.

  The source 220 of the whole blood system 200 has any of a number of spectral ranges, for example, in the infrared wavelengths, in the mid-infrared wavelengths above about 0.8 μm, about 5.0 μm and Radiate electromagnetic radiation between about 20.0 μm and / or between 5.25 μm and about 12.0 μm. However, in other embodiments, the whole blood system 200 is somewhere from the visible spectrum to the microwave spectrum, such as from about 0.4 μm to greater than about 100 μm. Thus, a radiation source 220 that emits at the wavelengths found may be used. In still further embodiments, the radiation source is between about 3.5 μm and about 14 μm, or between about 0.8 μm and about 2.5 μm, or between about 2.5 μm and about 20 μm, or It emits electromagnetic radiation of a wavelength between about 20 μm and about 100 μm, or between about 6.85 μm and about 10.10 μm.

  The radiation emitted from the source 220 is at a frequency between about one-half Hz and about 100 Hz in one embodiment, and between about 2.5 Hz and about 7.5 Hz in another embodiment. In yet another embodiment, it is modulated at about 50 Hz and in yet another embodiment about 5 Hz. With a modulated radiation source, ambient light sources, such as flickering fluorescent lamps, can be easily identified and rejected when analyzing radiation incident on the detector 250. One source suitable for this application is made by ION OPTICS, INC. And sold under part number NL5LNC.

  Filter 230 allows selected wavelengths of electromagnetic radiation to pass and impinge on cuvette / sample element 240. Preferably, the filter 230 has at least approximately the following wavelengths: 3.9, 4.0 μm, 4.05 μm, 4.2 μm, 4.75, 4.95 μm, 5.25 μm, 6.12 μm, 7.4 μm, 8 Allows 0.0, 8.45, 9.25, 9.5, 9.65, 10.4, 12.2 [mu] m radiation to pass to the cuvette / sample element. In another embodiment, the filter 230 has at least approximately the following wavelengths: 5.25 μm, 6.12 μm, 6.8 μm, 8.03 μm, 8.45 μm, 9.25 μm, 9.65 μm, 10.4 μm, Allows 12 μm of radiation to pass to the cuvette / sample element. In yet another embodiment, the filter 230 has at least approximately the following wavelengths: 6.85 μm, 6.97 μm, 7.39 μm, 8.23 μm, 8.62 μm, 9.02 μm, 9.22 μm, 9.43 μm. , 9.62 μm, and 10.10 μm of radiation are allowed to pass to the cuvette / sample element. The set of wavelengths listed above corresponds to a particular embodiment within the scope of this disclosure. Furthermore, other subsets of the set or other wavelength combinations can be selected. Finally, the cost, manufacturability, and commercial availability of the filters used to generate production, development time, availability and selected wavelengths and / or reduce the total number of filters required Other wavelength sets may be selected within the scope of this disclosure based on other factors with respect to time to date.

  In one embodiment, the filter 230 can cycle through its various narrow spectral bands or its passbands in various selected wavelengths. The filter 230 may thus comprise a solid-state tunable infrared filter, such as that available from Ion Optics. The filter 230 is also implemented as a filter wheel having a plurality of fixed-passband filters installed on the wheel and generally perpendicular to the direction of radiation emitted by the source 220. It can also be done. The rotation of the filter wheel alternately turns out a filter that passes a certain wavelength of radiation, but the wavelength varies with the filter as it passes through the field of view of the detector 250.

  The detector 250 includes a pyroelectric detector having a length of 3 mm and a width of 3 mm. Appropriate samples are available from DIAS Angewandte Sensorik GmbH in Dresden, Germany, or from BAE Systems (its TGS model (TGS)). model) like a detector. The detector 250 may alternatively be a thermopile, a bolometer, a silicon bolometer, a lead-salt focal plane array, or a mercury-cadmium telluride. (MCT) detectors may be included. Whatever structure is used as the detector, it is preferably configured to respond to radiation incident on its active surface 254 to produce an electrical signal corresponding to the incident radiation.

  In one embodiment, the sample element includes a cuvette 240, which in turn has tissue and / or fluid (whole blood, blood components, interstitial fluid, intercellular fluid, saliva, A sample cell 242 configured to hold a sample (such as urine, sweat and / or organic or inorganic material). The cuvette 240 is placed in the whole blood system 200 and the sample cell 242 is at least partially disposed in the optical path 243 between the radiation source 220 and the detector 250. Thus, when radiation is emitted from the source 220 through the filter 230 and the sample cell 242 of the cuvette 240, the detector 250 emits radiation signal intensity (radiation) of the wavelength (s) of interest. signal strength). Based on this signal strength, signal processor 260 determines the degree to which the sample in cell 242 absorbs radiation at the detected wavelength (s). The concentration of the analyte of interest is then determined from the absorption data via any suitable spectroscopic technique.

  As shown in FIG. 13, the whole blood system 200 can also have a sample extractor 280. As used herein, the term “sample extractor” is a broad term and is used in its ordinary sense, without limitation, tissue, such as whole blood or other body fluids through the patient's skin. Any device suitable for drawing a fluid sample from is referred to. In various embodiments, the sample extractor is a lance, a laser lance, an iontophoretic sampler, a gas jet, a fluid jet or a particle jet perforator. -jet perforator), ultrasonic enhancer {used with or without chemical enhancer}, or any other suitable device.

As shown in FIG. 13, the sample extractor 280 can form an opening in the appendage, such as a finger 290, to make whole blood available to the cuvette 240. It should be understood that other outer limbs, including but not limited to forearms, can be used to take samples. Using one embodiment of the sample extractor 280, the user forms a tiny hole or slice through the skin through which a sample of bodily fluid such as whole blood flows. If the sample extractor 280 includes a lance (see FIG. 14), the sample extractor 280 includes a sharp cutting implement made of metal or other rigid material. One suitable laser lance is the Lasette Plus ^(R) made by Cell Robotics International, Inc., Albuquerque, New Mexico. If a laser lance, iontophoretic sampler, gas jet or fluid jet perforator is used as the sample extractor 280, can it be integrated into the whole blood system 200 (see FIG. 13) or it can be You can also

  Additional information regarding laser lances can be found in US Pat. No. 6,057,034, the entirety of which is hereby incorporated by reference herein and made a part of this specification. One suitable gas jet, fluid jet, or particle jet perforator is disclosed in US Pat. No. 6,057,096, the entirety of which is incorporated herein by reference and made a part of this specification. One suitable iontophoretic sampler is disclosed in U.S. Patent No. 6,057,096, the entirety of which is hereby incorporated by reference herein and made a part of this specification. One suitable ultrasonic enhancer, and a chemical enhancer suitable for use therewith, is disclosed in US Pat. No. 6,057,086, the entire disclosure of which is hereby incorporated by reference and is incorporated herein by reference. Become.

FIG. 14 shows an example of a sample element in the form of a cuvette 240 in great detail. The cuvette 240 further includes a sample supply passage 248, a pierceable portion 249, a first window 244, and a second window 246, the sample cell 242 being between the windows 244, 246. It extends. In one embodiment, cuvette 240 does not have a second window 246. The first window 244 (or second window 246) is a type of sample cell wall, and in other embodiments of the sample elements and cuvettes disclosed herein, a material sample such as a biological fluid sample is at least partially Any sample cell that contains, holds or supports, and is transparent to at least some bands of electromagnetic radiation, and may be transparent to electromagnetic radiation in the visible range, but need not Walls may be used. The perforated portion 249 is an area of the sample supply passage 248 that can be perforated by a suitable embodiment of the sample extractor 280. In order to create a wound in the outer limb 290 and provide an entrance for blood or other fluid from the wound to enter the cuvette 240, a suitable embodiment of the sample extractor 280 pierces the portion 249 and the outer limb 290. I can do it. (The sample extractor 280 is shown on the opposite side of the sample element in FIG. 14 compared to FIG. 13 because it punctures the portion 249 from either side.)
The windows 244, 246 are preferably optically transmissive in the range of electromagnetic radiation emitted by the source 220 and allowed to pass through the filter 230. In one embodiment, the material comprising the windows 244, 246 is completely transparent, i.e. it does not absorb any electromagnetic radiation from the source 220 and the filters incident thereon. In another embodiment, the window 244,246 material has some absorption in the electromagnetic range of interest, but the absorption is negligible. In yet another embodiment, the absorption of the windows 244, 246 is not negligible, but it is known and stable for a relatively long period of time. In another embodiment, the absorption of the windows 244, 246 is only stable for a relatively short period of time, but the whole blood system 200 observes the absorption of the material and the material properties change measurable. Is configured to exclude it from the analyte measurement before it can.

  The windows 244, 246 are made of polypropylene in one embodiment. In another embodiment, the windows 244, 246 are made of polyethylene. Polyethylene and polypropylene are materials having particularly advantageous properties for handling and manufacturing, as is known in the art. Polypropylene can also be arranged in a number of structures within the sample element that improve the flow properties of the sample, such as isotactic, atactic and syndiotactic. Preferably, the windows 244, 246 are made of a durable and easily manufacturable material, such as the polypropylene or polyethylene described above, or silicone or any other suitable material. The windows 244, 246 can be made of any suitable polymer whose structure can be isotactic, atactic or syndiotactic.

  The spacing between the windows 244 and 246 includes the optical path length and can be between about 1 μm and about 100 μm. In one embodiment, the optical path length is between about 10 μm and about 40 μm, or between about 25 μm and about 60 μm, or between about 30 μm and about 50 μm. In yet another embodiment, the optical path length is about 25 μm. The transverse size of each of the windows 244, 246 is preferably approximately equal to the size of the detector 250. In one embodiment, the window is round and has a diameter of about 3 mm. In this embodiment where the optical path length is about 25 μm, the volume of the sample cell 242 is about 0.177 μl. In one example, the length of the sample supply passage 248 is about 6 mm, the height of the sample supply passage 248 is about 1 mm, and the thickness of the sample supply passage 248 is approximately equal to the thickness of the sample cell, for example 25 μm. The volume of the sample supply passage is about 0.150 μl. Thus, the total volume of cuvette 240 in one embodiment is about 0.327 μl. Of course, the cuvette 240 / sample cell 242 / other volume depends on the size and sensitivity of the detector 250, the intensity of the radiation emitted by the source 220, the expected flow characteristics of the sample, and the flow enhancer (discussed below). It can vary depending on many variables such as whether it is incorporated in the cuvette 240 or not. The transport of fluid to the sample cell 242 is preferably accomplished through capillary action, but may also be accomplished through wicking or a combination of wicking and capillary action.

  FIGS. 15-17 depict another embodiment of a cuvette 305 that can be used in conjunction with the whole blood system 200. The cuvette 305 has a sample cell 310, a sample supply passage 315, an air vent passage 320, and a vent 325. As best seen in FIGS. 16, 16A and 17, the cuvette also has a first sample cell window 330 having an inner side 332 and a second sample cell window having an inner side 337. 335. As discussed above, in some embodiments the window (s) 330/335 also has a sample cell wall (s). The cuvette 305 also has an opening 317 at the end of the sample supply passage 315 opposite the sample cell 310. The cuvette 305 is preferably about 1 / 4-1 / 8 inch wide and about 3/4 inch long, however, the cuvette 305 Other dimensions are possible while still achieving the benefits of 305.

  The sample cell 310 is defined between an inner side 332 of the first sample cell window 330 and an inner side 337 of the second sample cell window 335. The vertical distance T between the two inner sides 332, 337 includes the optical path length, which can be between about 1 μm and about 1.22 mm. The optical path length can alternatively be between about 1 μm and about 100 μm. The optical path length can still be alternatively about 80 μm, but is preferably between about 10 μm and about 50 μm. In another embodiment, the optical path length is about 25 μm. The windows 330, 335 are preferably formed of any of the materials discussed above as retaining sufficient radiation transmission. The thickness of each window is preferably as small as possible without undue weakening of the sample cell 310 or cuvette 305.

  Once a wound is created in the outer limb 290, the opening 317 of the sample supply passage 315 of the cuvette 305 is placed in contact with the fluid flowing from the wound. In another embodiment, the sample is obtained without creating a wound, for example, as is done with a saliva sample. In that case, the opening 317 of the sample supply passage 315 of the cuvette 305 is placed in contact with the obtained fluid without creating a wound. The fluid is then transported through the sample supply passage 315 and into the sample cell 310 via capillary action. The air vent passage 320 prevents the build-up of air pressure in the cuvette and improves the capillary action by allowing the blood to displace the air as it flows into it.

  Other mechanisms may be used to transport the sample to the sample cell 310. For example, wicking can be used by providing wicking material in at least a portion of the sample supply passage 315. As another variation, wicking and capillary action can be used together to transport the sample to the sample cell 310. Membranes can also be positioned in the sample supply passage 315 to move blood while simultaneously filtering components that may complicate optical measurements made by the whole blood system 200. .

  16 and 16a depict one strategy for making the cuvette 305. In this manner, the cuvette 305 has a first layer 350, a second layer 355, and a third layer 360. The second layer 355 is positioned between the first layer 350 and the third layer 360. The first layer 350 forms the first sample cell window 330 and the vent 325. As described above, the vent 325 provides an escape for the air in the sample cell 310. Although the vent 325 is shown on the first layer 350, it can also be positioned on the third layer 360, or be a cutout in the second layer, and then the first layer 350 and the first layer 350. It is also possible to arrange between the three layers 360. The third layer 360 forms a second sample cell window 335.

  The second layer 355 may be entirely formed of an adhesive that joins the first and third layers 350 and 360. In other embodiments, the second layer may be formed of the same material as the first and third layers, or any other suitable material. The second layer 355 may also be formed as a carrier with an adhesive deposited on both sides thereof. The second layer 355 forms a sample supply passage 315, an air vent passage 320, and a sample cell 310. The thickness of the second layer 355 can be between about 1 μm and about 1.22 μm. The thickness can alternatively be between about 1 μm and about 100 μm. This thickness can alternatively be about 80 μm, but is preferably between about 10 μm and about 50 μm. In another embodiment, the second layer thickness is about 25 μm.

  In other embodiments, the second layer 355 can be made as an adhesive film having a cutout portion defining the passages 315, 320, or as a cutout surrounded by an adhesive.

  Further information can be found in US Pat. No. 6,057,086, the entirety of which is hereby incorporated by reference herein and forms part of this specification.

II. REAGENTLESS WHOLE-BLOOD ANALYTE DETECTION SYSTEM
A. Detection systems
FIG. 18 shows a schematic diagram of a reagentless whole blood analyte detection system 400 similar to the whole blood system 200 discussed above, except for the following details. The whole blood system 400 can be configured for use near a patient. One example configured for use near a patient is a near-patient, or point-of-care test system. Such systems offer several advantages over more complex laboratory systems, but they include convenience to the patient or doctor, ease of use, and the relatively low cost of analysis performed. .

  The whole blood system 400 includes a housing 402, a communication port 405, and a communication line 410 for connecting the whole blood system 400 to an external device 420. One such external device 420 is another analyte detection system, such as the non-invasive system 10. The communication port 405 and line 410 are preferably connected to the whole blood system 400 to transmit data to the external device 420 in a manner that is preferably seamless, secure, and organized. Connect. For example, the data is communicated in an organized fashion such that data corresponding to a first user of the whole blood system 400 is segregated from data corresponding to other users. And via line 410. This is preferably done without intervention by the user. In this manner, the first user's data is not misapplied to other users of the whole blood system 400. Other external devices 420 may be used, for example, to further process the data produced by the monitor, or make the data available to a network such as the Internet. This makes the output of the whole blood system 400 available to remotely located health-care professionals, as is known. Although the device 420 is labeled as an “external” device, the device 420 and the whole blood system 400 may be permanently connected in some embodiments.

  The whole blood system 400 is configured to be easily operated by a patient or user. As such, the whole blood system 400 is preferably a portable device. As used herein, “portable” means that the whole blood system 400 is easily carried by the patient and can be used where convenient. For example, the housing 402 configured to accommodate at least a portion of the source 220 and detector 250 is small. In one preferred embodiment, the housing 402 of the whole blood system 400 is small enough to fit within a purse or backpack. In another embodiment, the housing 402 of the whole blood system 400 is small enough to fit in a pant pocket. In yet another embodiment, the housing 402 of the whole blood system 400 is small enough to be held in the user's palm. In addition to being compact in size, the whole blood system 400 has other features that make it easier for patients or end users to use it. Such features can be easily filled by a patient, clinician, nurse or doctor and inserted into the whole blood system 400 without intervention of the sample. Contains various sample elements discussed herein. FIG. 18 shows that once the sample element, eg, the cuvette shown, has been filled by the patient or user, it can be inserted into the housing 402 of the whole blood system 400 for analyte detection. Also, the whole blood systems described herein, including the whole blood system 400, are designed for durability and are configured for patient use in that they have, for example, very few moving parts. .

  In one embodiment of the whole blood system 400, the radiation source 220 emits electromagnetic radiation having a wavelength between about 3.5 μm and about 14 μm. The spectral band contains a number of wavelengths corresponding to the primary vibration of the molecule of interest. In another embodiment, the radiation source 220 emits electromagnetic radiation having a wavelength between about 0.8 μm and about 2.5 μm. In another embodiment, the radiation source 220 emits electromagnetic radiation having a wavelength between about 2.5 μm and about 20 μm. In another embodiment, the radiation source 220 emits electromagnetic radiation having a wavelength between about 20 μm and about 100 μm. In another embodiment, the radiation source 220 emits radiation between about 5.25 μm and about 12 μm. In yet another embodiment, the radiation source 220 emits infrared radiation between about 6.85 μm and about 10.10 μm.

  As discussed above, the radiation source 220 is modulated between about 1.5 Hz and about 10 Hz in one embodiment. In another embodiment, the source 220 is modulated between about 2.5 Hz and about 7.5 Hz. In another embodiment, the source 220 is modulated at about 5 Hz. In another variant, the radiation source 220 can emit radiation with a constant intensity, ie as a direct current source (D.C.).

  Transport of the sample to the sample cell 242 is preferably accomplished by capillary action, but may also be accomplished by wicking or a combination of wicking and capillary action. As discussed below, one or more flow enhancers may be incorporated into a sample element, such as cuvette 240, to improve blood flow into sample cell 242. A flow enhancer is any of a number of physical treatments, chemical treatments, or any topological features on one or more surfaces of the sample supply passage that aids sample flow into the sample cell 242. is there. In one embodiment of the flow enhancer, the sample supply passage 248 is made to have one very smooth surface and an opposing surface with small pores or dimples. These features are formed by a spread process of granulated detergent on one surface. The detergent is then washed away, creating the pores or dimples. The flow enhancer is discussed in more detail below. By incorporating one or more flow enhancers in the cuvette 240, the volume of the sample supply passage 248 is reduced, the filling time of the cuvette 240 is reduced, or the volume and filling time of the cuvette 240 are reduced. Both can be reduced.

  If the filter 230 has an electronically tunable filter, a solid state tunable infrared filter, such as one made by ION OPTICS INC., May be used. . The Ion Optics device is a commercial adaptation of the device described in Non-Patent Document 1. The entire contents of this article are hereby incorporated by reference and form part of this specification. The use of an electronically tunable filter is advantageous because it allows monitoring of multiple wavelengths within a relatively small spatial volume.

  As discussed above, the filter 230 may also be implemented as the filter wheel 530 shown in FIG. As in the filter 230, the filter wheel 530 is positioned between the source 220 and the cuvette 240. The filter wheel 530 can similarly be used in conjunction with any other sample element. The filter wheel 530 has a generally planar structure 540 that is rotatable about an axis A. At least a first filter 550A is placed on the planar structure 540 and is therefore also rotatable. The filter wheel 530 and the filter 550A are coupled to the source 220 and the cuvette 240 such that when the filter wheel 530 rotates, the filter 550A rotates periodically into the optical path of radiation emitted by the source 220. Positioned against. Thus, the filter 550A periodically allows a specified wavelength of radiation to strike the cuvette 240. In the embodiment illustrated in FIG. 19, the filter wheel 530 also has a second filter 550B that is also periodically rotated into the optical path of the radiation emitted by the source 220. FIG. 19 further shows that the filter file 530 can be made with as many filters as necessary (ie, up to n-th filter, up to 550N).

  As discussed above, the filters 230, 530 allow selected wavelengths of electromagnetic radiation to pass and strike the cuvette 240. Preferably, the filters 230, 530 have at least approximately the following wavelengths: 4.2 μm, 5.25 μm, 6.12 μm, 7.4 μm, 8.0 μm, 8.45 μm, 9.25 μm, 9.65 μm, 10 Allow 4 μm, 12.2 μm radiation to pass to the cuvette. In another embodiment, the filters 230, 530 have at least approximately the following wavelengths: 5.25 μm, 6.12 μm, 6.8 μm, 8.03 μm, 8.45 μm, 9.25 μm, 9.65 μm, 10. Allows 4 μm, 12 μm radiation to pass through the cuvette. In yet another embodiment, the filters 230, 530 have at least approximately the following wavelengths: 6.85 μm, 6.97 μm, 7.39 μm, 8.23 μm, 8.62 μm, 9.02 μm, 9.22 μm, 9.43 μm, 9.62 μm, and 10.10 μm of radiation are allowed to pass through the cuvette. The set of wavelengths quoted above corresponds to specific examples within the scope of this disclosure. Other wavelength sets are based on production cost, development time, availability, and other factors related to the cost of the filter used to generate the selected wavelength, manufacturability, and time to market May be selected within the scope of this disclosure.

  The whole blood system 400 also includes a signal processor 260 that is electrically connected to the detector 250. As discussed above, the detector 250 responds to radiation incident on the working surface 254 by generating an electrical signal that can be manipulated to analyze the radiation spectrum. In one embodiment, as described above, the whole blood system 400 has a source 220 to be modulated and a filter wheel 530. In that embodiment, the signal processor 260 has a synchronous demodulation circuit to process the electrical signal generated by the detector 250. After processing the detector 250 signal, the signal processor 260 provides an output signal to the display 448.

  In one embodiment of the whole blood system 400, the display 448 is a digital display, as illustrated in FIG. In another embodiment, the display 448 is an audible display. This type of display is particularly advantageous for users with limited vision, mobility or blindness. In another embodiment, the display 448 is not a part of the whole blood system 400, but rather a separate device. As another device, the display may be permanently connected to the whole blood system 448 or may be temporarily connectable. In one embodiment, the display is made by Palm Corporation (PALM, INC.) Under the names PalmPilot, Palm III (PalIII), Palm V (PalmV), and Palm VII (PalmVII). It is a portable computing device commonly known as a personal data assistant {"PDA"}.

  FIG. 18A illustrates a reagentless detection system 450 (“no-removal”) having a housing 452 that at least partially surrounds a reagent-free whole blood analyte detection subsystem 456 (“whole blood subsystem”) and a non-invasive subsystem 460. 1 is a schematic representation of a reagent system “)”. As discussed above, the whole blood subsystem 456 is configured to obtain a sample of whole blood. This is done using the sample extractor 280 discussed above in connection with FIG. As discussed above, other biological fluid samples may also be used in conjunction with the whole blood system 450. Once extracted, the sample is positioned in the sample cell 242 as discussed above. An optical analysis of the sample can then be performed. The non-invasive subsystem 460 is configured to function as described above in connection with FIGS. 1-12. In one mode of operation, the reagentless system 450 can be operated to use either the whole blood subsystem 456 or the non-invasive subsystem 460 separately. The reagentless system 450 may be configured to select one subsystem or another, depending on the environment, for example, depending on whether the user has recently eaten or an extremely accurate test is desired. In another mode of operation, the reagentless system 450 can operate the whole blood subsystem 456 and the non-invasive subsystem 460 in a coordinated manner. For example, in one embodiment, the reagentless system 450 coordinates the use of the subsystems 456, 460 when calibration is required. In another embodiment, the reagentless system 450 passes through a first selectable sample supply passage to the whole blood subsystem 456 or through a second selection sample supply passage after a sample is obtained. The non-invasive subsystem 460 is configured to track the sample to either. The subsystem 460 may be configured with an adapter to position the whole blood sample on the window for measurement.

  20A-20C illustrate another approach to making a cuvette for use with the whole blood system 200. FIG. In this embodiment, the first portion 655 is formed using an injection molding process. The first portion 655 includes a sample cell 610, a sample supply passage 615, an air vent passage 620, and a second sample cell window 335. The cuvette 605 also includes a second portion 660 configured to be attached to the first portion 655 to enclose at least the sample cell 610 and the sample supply passage 615. The second portion 660 includes a first sample cell window 330 and preferably also surrounds at least a portion of the air vent passage 620. The first portion 655 and the second portion 660 are preferably joined together by a welding process at weld joint 665. Although four weld joints 665 are shown, it should be understood that fewer or more than four weld joints may be used. As will be appreciated, other techniques may be used to secure the portions 655,660.

  Yet another approach to making cuvette 240 is to make it using a wafer fabrication process. FIG. 21 illustrates one embodiment of the process of making a cuvette 755 using micro-electromechnical system machining techniques, such as wafer fabrication techniques. In step 710, a wafer made of a material having acceptable electromagnetic radiation transmission characteristics is provided, as discussed above. The wafer is preferably made of silicon or elmanium. Preferably, in a subsequent step 720, a second wafer made of a material having acceptable electromagnetic radiation transmission properties is provided. The second wafer may be a simple planar portion of the selected material. Preferably, in the next step 730, an etching process is used to create multiple cuvette subassemblies, each subassembly comprising a sample supply passage, an air vent passage, and Has a sample cell. Although conventional etching processes are used to etch these structures in the wafer, the individual etched subassembly has an appearance similar to the first portion 655 shown in FIG. 20C. Preferably, in a next step 740, the second wafer is attached to the first wafer, bonded and sealed to create a wafer assembly surrounding each of the sample supply passage, the sample cell, and the air vent passage. It is better. This process creates a large number of cuvettes coupled together. Preferably, in the next step 750, the wafer assembly is processed to separate the multiple cuvettes into individual cuvettes 755, i.e., machined, diced, sliced, or the like. Or sawed. Although the steps 710-750 are expressed in a particular order, it should be understood that the steps may be performed in other orders within the scope of the method.

  In one embodiment, the cuvette 755 made in the process of FIG. 21 is relatively small. In another embodiment, the cuvette 755 is approximately the size of the cuvette 305. If the cuvettes 755 are small, they can be made easy to use by incorporating them in a disposable sample element handler 780 shown in FIG. The disposable sample element handler 780 has an unused sample element portion 785 and a used sample element portion 790. When new, the unused cuvette portion 785 may include any number of sample elements 757. For the first use of the sample element handler 780 by the user, the first sample element 757 A is advanced to the sample taking location 795. The user then takes a sample as described above. Optical measurements are made using a whole blood system, such as system 200. Once the measurement is complete, the used sample element 757A can be advanced toward the used sample element portion 790 of the disposable sample element handler 780 when the next sample element 757B is advanced to the sample removal position 795. Is possible. Once the last sample element 757N has been used, the disposable sample element handler 780 is discarded and biohazardous material is contained within the used sample element portion 790. In another embodiment, once the sample has been taken, the sample element 757A is advanced into the housing 402 of the test system 400. In some embodiments, the sample element handler 780 can be automatically advanced to the sample pick position 795 and then automatically advanced into the housing 402.

  As discussed above in connection with FIGS. 15-17, the air vent 325 allows air in the cuvette 305 to escape, thereby improving sample flow from the outer limb 290 into the sample cell 310. Other structures, referred to herein as “flow enhancers”, can also be used to enhance the flow of samples into the sample cell 310. FIG. 23A illustrates one embodiment of a cuvette 805 with a flow enhancer. The cuvette 805 has a sample cell 810, a sample supply passage 815, and a seal 820. Sample extractor 880 can also be incorporated into or separated from cuvette 805.

  The seal 820 of the cuvette 805 holds the vacuum in the sample cell 810 and the sample supply passage 815. The seal 820 also provides a barrier that prevents contaminants from entering the cuvette 805, but can be penetrated by the sample extractor 880. The seal 820 is advantageous because it creates a bond between the tissue and the cuvette 805 to remove extraneous sample loss and other biological contamination. Although many different materials can be used to prepare the seal 820, one special material that can be used is the DuPont's TYVEK material. The cuvette 805 not only improves sample flow, but also eliminates the sample spillage problem found in capillary assembly systems that rely on vents to induce collective flow. The flow enhancement efforts applied to the cuvette 805 can be applied to other sample elements.

  FIG. 23B is a schematic illustration of a cuvette 885 similar to that shown in FIG. 23A, except as described below. The cuvette 885 has one or more small pores that allow the passage of air from the interior of the cuvette 885 to the ambient atomsphere. These small holes function similarly to the vent 325 but are small enough to prevent a sample (eg, whole blood) from spilling out of the cuvette 885. The cuvette 885 further comprises a mechanical intervention blood acquisition system 890 having an external vacuum source (ie pump), diaphragm, plunger, or mechanical means to improve sample flow within the cuvette 885. The system 890 is placed in contact with the small ostium and vents the air in the cuvette 885 from the cuvette 885. The system 890 also tends to draw the blood into the cuvette 885. The flow enhancement technique applied to the cuvette 885 can be applied to other sample elements as well.

  Another example of a flow enhancer is shown in FIGS. 24A and 23B. The cuvette 905 is similar to the cuvette 305 and includes a sample cell 310 and windows 330 and 335. As discussed above, the window may have a sample cell wall. The cuvette also has a sample supply passage 915 extending between the first opening 917 at the outer edge of the cuvette 905 and the second opening 919 of the sample cell 310 of the cuvette 905. As shown in FIG. 24B, the sample supply passage 915 has one or more ridges 940 formed on the top and bottom of the sample supply passage 915. In one variation, the ridge 940 is formed only on the top or only on the bottom of the sample supply passage 915. The undulating shape of the ridge 940 advantageously improves the flow of the sample into the sample supply passage 915 of the cuvette 905 and advantageously encourages the sample to flow into the sample cell 310.

  Other variations of the flow enhancer are also conceivable. For example, various embodiments of the flow enhancer may include physical changes such as scoring the passage surface. In another variation, one or more surfaces of the sample supply passage are subjected to a chemical treatment, such as a surface-active chemical treatment, in order to reduce the surface tension of the sample drawn into the passage. May be applied. As discussed above, the flow enhancer disclosed herein can be applied to other sample elements in addition to the various cuvettes described herein.

  As discussed above, materials that have some electromagnetic radiation absorption within the spectral range used by the whole blood system 200 can be used to make portions of the cuvette 240. FIG. 25 shows a whole blood analyte detection system 1000, which is similar to the whole blood system 200 discussed above, except as detailed below. The whole blood system 1000 is configured to determine the amount of absorption depending on the material used to make the sample element, such as the cuvette 1040. To accomplish this, the whole blood system 1000 has an optical calibration system 1002 and an optical analysis system 1004. As shown, the whole blood system 1000 has a source 220 similar to that of the whole blood system 200. The whole blood system 1000 has a filter 1030 similar to the filter 230. The filter 1030 also splits the radiation into two parallel beams, ie creates a split beam 1025. The split beam 1025 has a calibration beam 1027 and an analyte transmission beam 1029. In another variation, two sources 220 may be used to create two parallel beams, or a separate beam splitter may be positioned between the source 220 and the filter 1030. . A beam splitter is also downstream of the filter 1030 but may be positioned in front of the cuvette 1040. In any of the above variations, a calibration beam is directed through the calibration portion 1042 of the cuvette 1040 and an analyte transmitted beam is directed through the sample cell 1044 of the cuvette 1040.

  In the embodiment of FIG. 25, the calibration beam 1027 passes through the calibration portion 1042 of the cuvette 1040 and is incident on the operating surface 1053 of the detector 1052. The analyte transmitted beam 1029 passes through the sample cell 1044 of the cuvette 1040 and is incident on the working surface 1055 of the detector 1054. The detectors 1052, 1054 are of the same type and may use any of the detection techniques discussed above. As explained above, detectors 1052 and 1054 generate electrical signals in response to radiation incident on their working surfaces 1053 and 1055. The generated signal is sent to a digital signal processor 1060, which processes both signals to verify the radiative absorption of the cuvette 1040 and an electrical signal from the detector 1054 to remove the absorption of the cuvette 1040. Correct the signal and provide the result to the display 484. In one embodiment, the optical calibration system 1002 includes the calibration beam 1027 and the detector 1052, and the optical analysis system 1004 includes the analyte transmitted beam 1029 and the detector 1054. In another embodiment, the optical calibration system 1002 also has a calibration portion 1042 of the cuvette 1040, and the optical analysis system 1004 also has an analysis portion 1044 of the cuvette 1040.

  FIG. 26 is a schematic illustration of another embodiment of a reagentless whole blood analyte detection system 1100 (“whole blood system”). FIG. 26 shows that a similar calibration procedure can be performed with one detector 250. In this embodiment, source 220 and filter 230 together generate beam 1125 as described above in connection with FIG. An optical router 1170 is provided in the optical path of the beam 1125. The router 1170 directs the beam 1125 alternately as a calibration beam 1127 and as an analyte transmission beam 1129. The calibration beam 1127 is directed by the router 1170 through the calibration portion 1042 of the cuvette 1040. In the embodiment of FIG. 26, the calibration beam 1127 is then detected by a first calibration beam optical director 1180 and a second calibration beam optical director 1190. To the operating surface 254 of the vessel 250. In one embodiment, the optical directors 1180, 1190 are reflective surfaces. In another variation, the optical directors 1180, 1190 are collection lenses. Of course, other numbers of optical directors can be used to direct the beam onto the working surface 254.

  As discussed above, the analyte transmitted beam 1129 is directed into the sample cell 1044 of the cuvette 1040, passes through the sample, and is incident on the working surface 254 of the detector 250. A signal processor 1160 compares the signal generated by the detector 250 when the calibration beam 1127 is incident on the working surface 254 and when the analyte transmitted beam 1129 is incident on the working surface. This comparison causes the signal processor 1160 to generate a signal representative of the absorption of the sample only in the sample cell 1044, ie, excluding the absorption contribution of the cuvette 1040. This signal is provided to display 484 in the manner described above. Thus, the absorption of the cuvette 1040 itself can be removed from the absorption of the cuvette-plus-sample that is observed when the beam 1029 passes through the sample cell and is detected by the detector 250. As discussed above in connection with FIG. 25, the whole blood system 1100 includes an optical calibration 1196 and an optical analysis system 1198. The optical calibration system 1196 includes the router 1170, the optical directors 1180, 1190, and the detector 250. The optical analysis system 1198 includes the router 1170 and the detector 250. In another embodiment, the optical analysis system 1198 also has the analysis portion 1044 of the cuvette 1040 and the optical calibration system 1196 also has a calibration portion 1042 of the cuvette 1040. The cuvette 1040 is just one type of sample element used in conjunction with the systems of FIGS.

  FIG. 27 is a schematic illustration of a cuvette 1205 configured for use with the whole blood system 1000, 1100. The calibration portion 1242 is configured to allow the whole blood system 1000, 1100 to estimate the absorption of only the windows 330, 335 without reflection or refraction. The cuvette 1205 includes a component 1242 and a sample cell 1244 having a first sample cell window 330 and a second sample cell window 335. The component 1242 includes a window 1250 having the same electromagnetic transmission characteristics as the window 330, and a window 1255 having the same electromagnetic transmission characteristics as the window 335. As discussed above, the windows 1250, 1255 are formed in the form of sample cell walls, and in some embodiments, there need not be two windows. In one embodiment, the calibration portion 1242 has a separation on the inner surface of the windows 1250, 1255 where the separation between the inner surface 332 of the window 330 and the surface 337 of the window 335 (ie, dimension T shown in FIG. 17). ) Necked-down from the sample cell 1244 to be much smaller. The calibration portion 1242 is narrowed, but the thickness of the windows 1250, 1255 is preferably the same as the windows 330, 335.

  By reducing the cracks in the windows 1250, 1255 of the calibration portion 1242, errors in estimating the absorption contribution by the windows 330, 335 of the sample cell 1240 can be reduced. Such errors are caused, for example, by scattering of the electromagnetic radiation of the beam 1027 or beam 1127 by molecules located between the windows 1250, 1255 as the radiation passes through the calibration portion 1242. . Such scattering is interpreted by the signal processors 1060, 1160 as absorption by the windows 1250, 1255.

  In another variation, the space between the windows 1250, 1255 can be completely removed. In yet another variation, the signal processor 1060, 1160 may include a module configured to estimate any error induced by having a space between the windows 1250, 1255. In that case, the calibration portion 1242 need not be necked down at all, and not only the cuvette but also the windows 1250, 1255 can have a generally constant thickness along their length.

  FIG. 28 is a plan view of one embodiment of a cuvette 1305 having a single motion lance 1310 and a sample supply passage 1315. The lance 1310 can be a lance made of sharpened plastic, or any other suitable rigid material. The lance 1310 is a small razor blade that creates very small slices or microlacerations in a finger-like outer limb, forearm, or some other outer limb as discussed above. miniature razor-blade). The lance 1310 is positioned within the cuvette 1305 so that a single motion used to create the slice in the outer limb places the opening 1317 of the sample supply passage 1315 in the wound. This eliminates the process of aligning the opening 1317 of the sample supply passage 1315 with the flaw. This is advantageous for all users because the cuvette 1305 is configured to receive a very small volume of the sample and the lance is configured to create a very small slice. As a result, it may be difficult to separately align the opening 1317 and the whole blood sample that exits the slice. This is especially true for users with limited fine power control, such as elderly users or people suffering from muscular diseases.

  FIG. 28A is a plan view of another embodiment of a cuvette 1355 having a single motion lance 1360, a sample supply passage 1315, and an opening 1317. As discussed above, the single motion lance can be a metal lance, a sharpened plastic, or any other suitable rigid material lance. As with the lance 1310, the lance 1360 works like a small razor that creates a minute slice or laceration in the outer limb. The single motion lance 1360 also has an outer limb perforation end which includes a first cutting implement 1360 that converges at a distal end 1375, a second cutting implement 1370, Have A diverging portion 1380 is formed between the distal end 1375 and the inlet 1317. The single motion lance 1360 is positioned within the cuvette 1305 so that a single motion creates a slice in the outer limb and places the opening 1317 of the sample supply passage 1315 in the wound. The diverging portion 1380 creates a wound that is small enough to minimize the pain experienced by the user, but large enough to produce enough whole blood to fill the cuvette 1355. Composed. As discussed above in connection with cuvette 1305, the cuvette 1355 separately creates slices and eliminates the need to align openings 1317 in the cuvette 1355.

  FIG. 29 is a plan view of another embodiment of a cuvette 1405 having a single motion lance 1410 made in any suitable manner discussed above. In this example, the single motion lance 1410 is positioned adjacent to the sample supply passage 1415. The opening 1417 of the sample supply passage 1415 is positioned so that the cuvette 1405 can be placed adjacent to the outer limb, moved laterally and aligned to create a slice in the outer limb. As can be seen, the width of the lance 1410 is small compared to the width of the sample supply passage 1415. This also ensures that movement of the cuvette 1405 creating a slice in the outer limb positions the opening of the sample supply passage 1415 at the wound. As discussed above in connection with cuvette 1305, cuvette 1405 creates separate slices, eliminating the need to align opening 1417 of cuvette 1405.

  FIGS. 31-32A illustrate another embodiment of a reagentless sample element 1502 that can be used in conjunction with or separate from the whole blood systems 200, 400, 450, 1000 and 1100. FIG. The reagentless sample element 1502 is configured for reagentless measurement of an analyte concentration performed near the patient. While this provides several advantages over more complex laboratory systems, they include convenience to the patient or doctor, ease of use, and the relatively low cost of analysis performed. Additional information regarding reagentless sample elements can be found in US Pat. No. 6,057,086, the entirety of which is hereby incorporated by reference herein and made a part of this specification.

  Sample element 1502 has a cuvette 1504 held within a pair of channels 1520, 1522 of housing 1506. As shown in FIG. 31, the housing 1506 further comprises an integrated lance 1507 having a resilient bendable strip 1508 and a distal lancing member 1524. The distal lance member 1524 has a sharp cutting implement made of metal or other rigid material, which allows an external limb such as a finger 290 to make the cuvette 1504 available to the whole blood. An opening can be formed. It should be understood that other outer limbs can be used to collect the sample, including but not limited to the forearm, abdomen or some other hand on the fingertip. It will be appreciated that the integrated lance 1507 facilitates one-handed operation of the sample element 1502 while simultaneously requiring less movement of the sample element 1502 during the sample extraction procedure.

In various other embodiments, the integrated lance 1507 may include a laser lance, iontophoretic sampler, gas jet, fluid jet or particle jet perforator, or any other suitable device. . One suitable laser lance is Lasette Plus ^(R) made by Cell Robotics International, Inc., Albuquerque, New Mexico. Further, when a laser lance, iontophoretic sampler, gas jet or fluid jet perforator is used, the integrated lance 1507 can be incorporated into the whole blood system 200, incorporated into the housing 1506, or It may be used as a separate device. Additional information regarding laser lances can be found in US Pat. One suitable gas jet, fluid jet, or particle jet perforator is disclosed in the above-mentioned US Pat. No. 6,057,028 and one suitable iontophoretic sampler is disclosed in the above-mentioned US Pat.

  The cuvette 1504 has a first plate 1510, a second plate 1512, and a pair of spacers 1514, 1514 '. As most clearly shown in FIGS. 32A and 33, the spacers 1514, 1514 ′ have a sample supply passage 1518 defined therebetween and an opening 1519 at the distal end 1503 of the cuvette 1504 (see FIG. 32). Is disposed between the first and second plates 1510 and 1512. The plates 1510, 1512 and the spacers 1514, 1514 'are glued, welded or otherwise fastened together by the use of any suitable technique. The housing provides mechanical support to the plates 1510, 1512 and the spacers 1514, 1514 ′ and retains the cuvette 1504 when used separately from the whole blood system 200/400/450/1000/1100. To make it easier.

  The spacers 1514 and 1514 'may be entirely formed of an adhesive that joins the first and second plates 1510 and 1512. In other embodiments, the spacers 1514, 1514 'may be formed from the same material as the plates 1510, 1512 or any other suitable material. The spacers 1514, 1514 'may also be formed as carriers having adhesive deposited on both sides thereof.

  As shown in FIG. 33, the first plate 1510 has a first window 1516, and the second plate 1512 has a second window 1516 '. The first and second windows 1516, 1516 'are preferably optically transmissive within the range of electromagnetic radiation emitted by the source 220 and allowed to pass through the filter. In one embodiment, the material comprising the windows 1516, 1516 'is completely transmissive, i.e., the material does not absorb any incident electromagnetic radiation from the source 220 and filter 230. In another embodiment, the material, including the windows 1516, 1516 ', exhibits negligible absorption within the electromagnetic range of interest. In yet another embodiment, the absorption of the material comprising the windows 1516, 1516 'is not negligible, but rather the absorption is known and stable for a relatively long period of time. In another embodiment, the absorption of the windows 1516, 1516 ′ is stable for a relatively short period of time, but the whole blood system 200 detects the absorption of the material and the material properties can be measured in any way. It may be configured to remove it from the analyte measurement before undergoing a change.

  In one embodiment, the first and second windows 1516, 1516 'are made of polypropylene. In another embodiment, the windows 1516, 1516 'are made of polyethylene. As noted above, polyethylene and polyethylene are materials that have particularly advantageous properties for handling and manufacturing, as is known in the art. In addition, these plastics can be deployed in a number of structures, such as isotactic, atactic and syndiotactic structures, which improve the flow characteristics of the sample within the sample element 1502. Preferably, the windows 1516, 1516 'are made of a durable, easily manufacturable material such as the polypropylene or polyethylene, silicone, or any other suitable material described above. Further, the windows 1516, 1516 'can be made of any suitable polymer whose structure can be isotactic, atactic or syndiotactic.

  Alternatively, the entire first and second plates 1510, 1512 may be made of a transparent material such as polypropylene or polyethylene as discussed above. In this example, each of the plates 1510, 1512 is formed of a single piece of transparent material, and the windows 1516, 1516 ′ are positioned between the plates 1510, 1512 with spacers 1514, 1514 ′ and the sample being analyzed. Defined by the vertical distance along the supply passage 1518. It will be appreciated that forming the entire plate 1510, 1512 with a transparent material advantageously simplifies the manufacture of the cuvette 1504.

  As illustrated in FIGS. 32A and 32B, the first and second windows 1516, 1516 ′ are placed on the plates 1510, 1512 such that the windows 1516, 1516 ′ and spacers 1514, 1514 ′ define a chamber 1534. Positioned. The chamber 1534 is defined not only on the inner surface 1517 of the first window 1516 and the inner surface 1517 ′ of the second window 1516 ′, but also on the inner surface 1515 of the spacer 1514 and the inner surface 1515 ′ of the spacer 1514 ′ when spacers are used. Is done. Distal to chamber 1534 is a sample supply passage 1518 and proximal to chamber 1534 is a vent 1536. It will be appreciated that the chamber 1534 and the vent 1536 are formed by a distal extension of the sample supply passage 1518 along the length of the spacers 1514, 1514 '. As illustrated in FIG. 32B, the dashed line indicates the boundary between the chamber 1534, the sample supply passage 1518, and the vent 1536. The vertical distance T between the inner surfaces 1517, 1517 'includes the optical path length, which in one embodiment can be between about 1 μm and less than about 1.22 mm. Alternatively, the optical path length can be between about 1 μm and about 100 μm. The optical path length can still alternatively be about 80 μm, or between about 10 μm and about 50 μm. In another embodiment, the optical path length is about 25 μm. The thickness of each window is preferably as thin as possible without making the chamber 1534 or the cuvette 1504 too weak.

  The sample elements depicted in FIGS. 31-35 are reagent-free and are intended for use in reagent-free measurements of analyte concentration, thus defining the volume of the chamber 1534 and / or the chamber 1534 itself. Inner surfaces 1515, 1515 ′, 1517, 1517 ′ are inert to any of the body fluids collected therein for analyte concentration measurement. In other words, the material forming the inner surface 1515, 1515 ′, 1517, 1517 ′ and / or any material contained within the chamber 1534 may be present for about 15-30 minutes following entry into the chamber 1534. The body fluid in a manner that significantly affects any measurement made at the analyte concentration in the sample of body fluid in the whole blood system 200/400/450/1000/1100 or any other suitable system. Will not react. Thus, the chamber 1534 has a reagentless chamber.

  In one embodiment, the plates 1510, 1512 and spacers 1514, 1514 'are sized such that the chamber 1534 has a volume of about 0.5 μl. In another embodiment, the plates 1510, 1512 and spacers 1514, 1514 'are dimensioned such that the total volume of body fluid collected into the cuvette 1504 is at most 1 μl. In yet another embodiment, the chamber 1534 may be configured to hold about 1 μl or less of bodily fluid. As will be appreciated by those skilled in the art, the volume of the cuvette 1504 / chamber 1534, etc., by way of example, passes through the size and sensitivity of the detector used in conjunction with the cuvette 1504, the windows 1516, 1516 ′. It may vary depending on several variables, such as the intensity of the radiation, the expected flow characteristics of the sample, and whether a flow enhancer (discussed above) is incorporated into the cuvette 1504. The transport of bodily fluids into the chamber 1534 may be accomplished by capillary action, but may also be accomplished by wicking or a combination of wicking and capillary action.

  In operation, the distal end 1503 of the cuvette 1504 is placed in contact with the outer limb 290 or other site on the patient's body suitable for obtaining body fluid 1560 (FIG. 32C). The body fluid 1560 may include whole blood, blood components, interstitial fluid, intercellular fluid, saliva, urine, sweat, and / or other organic or inorganic materials from the patient. The elastic bendable strip 1508 is then pressurized and released to momentarily push the lancing member distally into the outer limb 290, thereby creating a small wound. Once the wound is created, contact between the cuvette 1504 and the wound is maintained so that fluid flowing from the wound enters the sample supply passage 1518. In another embodiment, the bodily fluid 1560 may be obtained without creating a wound, as is done, for example, in a saliva sample. In that case, the distal end of the sample supply passage 1518 is placed in contact with the body fluid 1560 without creating a wound. As illustrated in FIG. 32C, the bodily fluid 1560 is then transported through the sample supply passage 1518 and into the chamber 1534. The bodily fluid 1560 may be transported through the sample supply passage 1518 and into the chamber 1534 via capillary action and / or wicking, depending on the precision structure (s) used. Will be appreciated. Vent 1536 allows air to exit proximally from the cuvette 1504 as the body fluid 1560 displaces air in the sample supply passage 1518 and chamber 1534. This prevents the formation of air pressure in the cuvette 1504 as the body fluid 1560 flows into the chamber 1534.

  Other mechanisms may be used to transport body fluid 1560 to the chamber 1534. For example, wicking may be used by providing wicking material within at least a portion of the sample supply passage 1518. In another embodiment, wicking and capillary action may be used in connection with the transport of bodily fluid 1560 to the chamber 1534. A membrane may also be positioned in the sample supply passage 1518 to move the body fluid 1560 while simultaneously filtering components that complicate optical measurements performed by the whole blood system 200.

  As shown in FIG. 32C, once bodily fluid 1560 enters the chamber 1534, a cuvette 1504 is placed in the whole blood system 200/400/450/1000/1100 or any one of the other similar optical measurement systems. Installed. When the cuvette 1504 is installed in the whole blood system 200, the chamber 1534 is at least partially disposed in the optical path 243 between the radiation source 220 and the detector 250. Thus, when radiation is emitted from the source 220 through the filter 230 (FIG. 13) and the chamber 1534 of the cuvette 1504, the detector 250 detects the radiation signal intensity at the wavelength (s) of interest. Based on this signal strength, the signal processor 260 determines the degree to which the body fluid 1560 in the chamber 1534 absorbs radiation at the detected wavelength (s). The concentration of the analyte of interest is then determined from the absorption data via any suitable spectroscopic technique.

  In one embodiment, a method for measuring an analyte concentration in a patient's tissue comprises placing a distal end 1503 of the sample element 1502 against a withdrawal site on the patient's body. . In one embodiment, the removal site is the fingertip of the outer limb 290. In another embodiment, the removal site is on a patient's body suitable for analyte concentration measurements, such as, for example, on the forearm, abdominal cavity, or somewhere else on the fingertip. Any alternate-site location may be used.

  Once the distal end 1503 is placed in contact with a suitable removal site, the integrated lance 1507 shown in FIG. 31 is used to lance to the removal site, thereby creating a small wound. While the sample element 1502 is held in stationary contact with the removal site, the bodily fluid 1560 (FIG. 32C) flows from the removal site and moves the sample supply without moving the distal end 1503 or the cuvette 1504. It enters the opening of passage 1518 and is transported into sample chamber 1534. Transport of bodily fluid 1560 into the chamber 1534 is accomplished by capillary action, but may also be wicked, or wicked and capillaryed by specific structures and / or enhancers utilized in conjunction with the sample element 1502. It may be achieved by a combination of actions. In one embodiment, the cuvette 1504 is configured to remove no more than about 1 μl of the body fluid 1560. In another embodiment, the chamber 1534 is configured to hold at most about 0.5 μl of the body fluid 1560. In yet another embodiment, the chamber 1534 may be configured to hold about 1 μl or less of the body fluid 1560.

  Once the body fluid 1560 has been removed into the chamber 1534 as described above, the sample element 1502 is removed from the removal site and the cuvette 1504 is removed from the housing 1506. The cuvette 1504 is then inserted into the whole blood system 200/400/450/1000/1100, or any other similar system, such that the chamber 1534 is positioned in the optical path 243. Is done. Preferably, the chamber 1534 is located in the optical path 243 such that the windows 1516, 1516 'are oriented substantially perpendicular to the optical path 243, as shown in FIG. 32C. When the cuvette 1504 is inserted into the whole blood system 200, the chamber 1534 is disposed between the radiation source 220 and the detector 250. The analyte concentration in the body fluid 1560 is then measured using the whole blood system 200 as discussed in detail above with reference to FIG.

  Figures 34A-34B are perspective views illustrating another embodiment of a cuvette 1530 having an integrated lancing member. The cuvette 1530 is substantially similar to the cuvette 1504 of FIGS. 31-33, except that the cuvette 1530 includes a first plate 1532 having a channel 138 that receives a lancing member 1524. The channel 1538 serves as a longitudinal guide for the lance member 1524, which ensures that the lance member does not move sideways when the lance member 1524 is used to create a wound, as described above. To do. The channel 1538 also places the lancing member 1524 near the opening of the sample supply passage 1518. This facilitates entry of bodily fluid into the sample supply passage 1518 when the lancing member 1524 is used to create a wound, but the cuvette 1530 need not be moved around on the wound site.

  FIG. 35 illustrates another embodiment of a reagentless sample element 1550 used in conjunction with or separate from the whole blood system 200/400/450/1000/1100. The sample element 1550 includes a cuvette 1504 that is retained within a pair of channels 1520, 1522 of the housing 1556. The sample element 1550 is substantially similar to the sample element 1502 of FIGS. 31-32B, with the exception that the housing 1556 has a sample extractor 1552. In various embodiments, the sample extractor 1552 is used with a lance, laser lance, iontophoretic sampler, gas jet, fluid jet or particle jet perforator, ultrasonic enhancer (with or without chemical enhancer). Or any other suitable device may be included. Accordingly, the lance 1524 shown in FIG. 31 should be considered a sample extractor as well. Further, it should be understood that the sample element 1550 of FIG. 35 is configured to remove at most about 1 μl of bodily fluid 1560, as in the sample element 1502 illustrated in FIG. Similarly, chamber 1534 of sample element 1550 is configured to hold no more than about 0.5 μl of body fluid 1560. In another example, the chamber 1534 may be configured to hold about 1 μl or less of the bodily fluid 1560.

  As shown in FIG. 35, when the sample extractor 1552 acts on an outer limb such as a finger 290 to allow the whole blood and / or other fluid to be acquired in the cuvette 1504, the sample extractor 1552 The sample extraction mechanism (eg, laser beam, fluid jet, particle jet, lance tip, current) has an associated operating path 1554 along which it operates. It should be understood that other outer limbs, including but not limited to the forearm, can be used to take the sample.

  As shown in FIG. 35, the sample extractor 1552 includes a portion of the housing 1556, so that the opening 1519 of the supply passage 1518 and the chamber 1534 are positioned when the cuvette 1504 is installed in the housing 1556. Located near the operating path 1554. This arrangement allows fluid extracted by the action of the sample extractor 1552 along the working passage 1554 to flow into the supply passage 1518 and the chamber 1534 without having to move the cuvette 1504 to the patient removal site. Guarantee. If a laser lance, iontophoretic sampler, gas jet or fluid jet perforator is used as the sample extractor 1552, it may instead be incorporated into the whole blood system 200.

  In one embodiment, a method of using the sample element 1550 to measure an analyte concentration in patient tissue includes placing a distal end 1503 of the sample element 1502 against a removal site of the patient's body. It comprises. In one embodiment, the removal site is the finger tip of the outer limb 290. In another embodiment, the removal site may be anything on the patient's body suitable for analyte concentration measurement, such as by way of example, somewhere on the forearm, abdominal cavity, or other hand on the fingertip. May be an alternate site location.

  Once the distal end 1503 is placed in contact with a suitable removal site, the sample extractor 1552 is used to cause a sample of body fluid to flow from the removal site. As described above, body fluid 1560 extracted by use of sample extractor 1552 may include whole blood, blood components, interstitial fluid, or intercellular fluid.

  While the sample element 1550 is held in stationary contact with the removal site, the body fluid 1560 flows from the removal site without moving the distal end 1503 or the cuvette 1504, and the sample supply passage 1518 opens. Part 1519 is entered and transferred to the sample chamber 1534. In one embodiment, transport of bodily fluid 1560 into the chamber 1534 is accomplished by capillary action, but may also be wicked or wicked by a particular structure and / or enhancer utilized in connection with the sample element 1550. And a combination of capillary action. As in the cuvette 1504 (FIG. 31), the cuvette 1550 is configured to remove 1 μl or less of the bodily fluid 1560 and the chamber 1534 is configured to hold at most about 0.5 μl of the bodily fluid 1560. In another embodiment, the chamber 1534 is configured to hold about 1 μl or less of bodily fluid 1560.

Once the body fluid 1560 is removed into the chamber 1534, the sample element 1550 is removed from the removal site and the cuvette 1504 is removed from the housing 1556. The cuvette 1504 is then inserted into the whole blood system 200/400/450/1000/1100 or any other similar system such that the optical path 243 passes through the chamber 1534. Preferably, the chamber 1534 is located in the optical path 243 such that the windows 1516, 1516 ′ are oriented substantially perpendicular to the optical path 243, as shown in FIG. 32C. The chamber 1534 is positioned between the radiation source 220 and the detector 250 when the cuvette 1504 is inserted into the whole blood system 200. The analyte concentration in the body fluid 1560 is then measured using the whole blood system 200 as discussed in detail above with reference to FIG.
B. Advantages and Other Uses
The whole blood system described herein has several advantages and uses in addition to those already discussed above. The whole blood systems described here are very precise because they optically measure the analyte of interest. Also, the accuracy of the whole blood system can be further improved without the need to collect a large number of blood samples. In reagent-based techniques, a blood sample is brought into contact with a reagent on a test strip, a prescribed chemical reaction occurs, and certain aspects of the reaction are observed. The test strip that hosts the reaction has a limited amount of reagent and can only accommodate a limited amount of blood. As a result, reagent-based analytical techniques observe only one reaction per test strip, which corresponds to a single measurement. In order to make a second measurement to improve the accuracy of the reagent-based technique, a second test strip must be prepared, which requires a second removal of blood from the patient. In contrast, the whole blood system described herein optically observes the sample response to incident radiation. This observation can be made multiple times for each blood sample removed from the patient.

  In the whole blood system discussed herein, the optical measurements of the analyte can be integrated over a number of measurements, allowing a more accurate estimate of the analyte concentration. FIG. 30 shows the root mean square error (RMS Error) in mg / dl on the y-axis versus the measurement time on the x-axis. Measurement time is shown on the x-axis, but more measurement time represents more measurements made. FIG. 30 shows the root mean square error for three different samples when more measurements were taken. Lines representing each of the following samples are shown: a phantom, a sample with a known analyte concentration, a combination of glucose and water, and a human sample. Each line on the graph of FIG. 30 shows a trend of increasing accuracy (decreasing error) as more measurements (corresponding to more measurement times) are made.

  In addition to providing improved accuracy, the whole blood system disclosed herein also has a lower manufacturing cost. For example, the sample elements used in the whole blood system can be made at a lower manufacturing cost. Unlike systems that require reagents, the sample elements of the whole blood system disclosed herein are not subject to limited shelf-life limitations. Also, unlike reagent-based systems, the sample elements do not need to be packaged to avoid reagent hydration. Many other expensive quality assurance measures designed to preserve reagent viability are not required. In summary, the components of the whole blood system disclosed herein are easier to make and can be made at a lower cost than reagent-based components.

  The whole blood systems are also more convenient to use because they can perform relatively rapid analyte detection. As a result, the user does not need to wait for a long time to obtain the result. The accuracy of the whole blood system can be tailored to the user's needs or environment to add further convenience. In one embodiment, the whole blood system calculates and displays a running estimate of the accuracy of the reported analyte concentration value based on the number of measurements made (and the integration of those measurements). . In one embodiment, the user can terminate the measurement when he concludes that the accuracy is sufficient. In one embodiment, the whole blood system can measure and apply a “confidence” level for the analyte concentration measurement. The confidence reading may be in the form of a percentage, a plus or minus series, or any other appropriate measurement that increases as more measurements are made. In one embodiment, the whole blood system is configured to determine if more measurements should be taken to increase accuracy and automatically inform the user of the estimated necessary measurement time. The Also, as described above, the accuracy of the whole blood system is improved without the need for multiple sample removals from the user.

  The cost of the sample elements described above is low because at least no reagents are used. Although the user cost for each use is further reduced in some embodiments by incorporating a sample extractor, it eliminates the need for another sample extractor. Another advantage of the sample element discussed above is that the opening of the sample supply passage for taking the sample into the sample element can be pre-positioned at the site of the wound created by the sample extractor. Thus, the action of moving the sample element to position the sample supply passage over the wound is eliminated. Further cost reduction of the sample elements described above can be achieved by using optical calibration of the sample cell wall (s).

  As described above, the measurements performed by the whole blood system described herein are faster because no chemical reaction needs to occur. More precise results can be achieved if the user or whole blood system simply allows more integration time during the measurement. The cost and size of the instrument can be reduced by incorporating an electronically tunable filter. The whole blood system works well with very small amounts of blood that allows measurements at lower perfused sites such as the forearm.

  In one embodiment, the reagentless whole blood system is configured to operate automatically. In this embodiment, any of the whole blood systems disclosed herein, such as the whole blood system 200 of FIG. 13, is configured as an automatic reagentless whole-blood system. The automated system can be placed close to the patient, as is the case with a near-patient testing system. In this embodiment, the automated system includes a source 220, an optical detector 250, a sample extractor 280, a sample cell 254, and a signal processor 260 as described in connection with FIG. In one embodiment, the automated test system is configured to operate with minimal intervention from the user or patient. For example, in one embodiment, the user or patient simply inserts the sample cell 254 into the automated test system and initiates the test. The automated test system is configured to form a slice, receive a sample from the slice, generate radiation, detect the radiation, and process the signal without any intervention from the patient. In another embodiment, there is no intervention from the user. One way in which this is accomplished relies on providing a sample element handler, as discussed above in connection with FIG. 22, where the sample element is automatically placed in the optical path of radiation from the source 220. Advanced. In another embodiment, the whole blood system is configured to provide intermittent or continuous monitoring without user or patient intervention.

  As will be appreciated by those skilled in the art, conventional reagent-based analyte detection systems can be used to transfer a volume of analyte (eg, glucose) along with a volume of body fluid (eg, blood) to a reagent {eg, glucose It is reacted with an enzyme glucose oxidase} and the current produced by the reaction {ie, electron flow} is measured. Generating a current large enough to overcome noise in the electronic measurement circuit requires a substantial amount of analyte to be considered, thus establishing a minimum amount that can be measured. Those skilled in the art will appreciate that with such a system, the signal to noise ratio decreases with decreasing sample volume, as the electronic noise level remains constant while the current produced by the reaction decreases. You will recognize it. Modern electronic circuits are approaching the theoretical {ie quantum} minimum noise limit. Thus, the current state of the art requiring about 0.5 μl of blood represents the low volume limit of this technique.

As disclosed herein, spectroscopic measurements that do not require reagents depend on (1) the absorption of electromagnetic energy by the analyte molecules in the sample and (2) the ability of the measurement system to measure the absorption by these molecules. To do. The sample volume required for the measurement is substantially determined by the optical components, most importantly the physical dimensions of the detector 250. In one embodiment, the detector 250 is about 2 mm in diameter, and thus the chamber 1534 can also be about 2 mm in diameter. These dimensions result in a sample volume as small as about 0.3 μl. The size of the detector 250 establishes a minimum sample volume because the total electromagnetic signal incident on the detector 250 must be modulated by the absorption of the sample. On the other hand, the dimensions of the radiation source 220 are such that the intensity (W / cm ² ) distribution of the optical beam supplied by the source 220 is substantially uniform within essentially the entire range of the sample and the detector 250. As long as it is not a limiting factor.

  In another embodiment where a smaller 1 mm diameter detector {such as a detector manufactured by DIAS GmbH) is used, a smaller sample volume is accommodated accordingly. obtain. Detector dimensions that allow sample volumes of about 0.1 μl or less are commercially available from manufacturers such as DIAS, InfraTec, Eltec, and others. One advantageous feature of reagentless, optical / spectroscopic measurements is that as detector size decreases, the intrinsic detector noise level decreases as well. Thus, in an optical / spectroscopic measurement system, the signal to noise ratio remains relatively constant as the sample volume is reduced. This achieves the use of a smaller detector and thus a smaller sample volume, which is not the case with the reagent-based systems discussed above.

1 is a schematic illustration of a non-invasive optical detection system. 1 is a perspective view of a window assembly for use with a non-invasive detection system. FIG. FIG. 6 is an exploded schematic view of an alternative window assembly for use in a non-invasive detection system. FIG. 3 is a plan view of a window assembly coupled to a cooling system. FIG. 6 is a plan view of a window assembly coupled to a cryogenic reservoir. FIG. 3 is a cutaway view of a heat sink for use with a non-invasive detection system. FIG. 2 is a cutaway perspective view of a lower portion of the noninvasive detection system of FIG. 1. 1 is a schematic diagram of a control system for use with a non-invasive optical detection system. Describes a first methodology for determining the concentration of an analyte of interest. Describes a second methodology for determining the concentration of an analyte of interest. Draw a third methodology for determining the concentration of the analyte of interest. Draw a fourth methodology to determine the concentration of the analyte of interest. Draw a fifth methodology for determining the concentration of the analyte of interest. 1 is a schematic diagram of a reagentless whole blood detection system. 1 is a perspective view of one embodiment of a cuvette for use in a reagentless whole blood detection system. FIG. FIG. 6 is a plan view of another embodiment of a cuvette for use in a reagentless whole blood detection system. FIG. 16 is an exploded plan view of the cuvette shown in FIG. 15. FIG. 16 is an exploded perspective view of the cuvette of FIG. 15. FIG. 16 is a side view of the cuvette of FIG. 15. 1 is a schematic diagram of a reagentless whole blood detection system having a communication port for connecting the system to another device or network. 1 is a schematic diagram of a reagentless whole blood detection system having a non-invasive subsystem and a whole blood subsystem. FIG. 14 is a schematic view of a filter wheel incorporated in an embodiment of the whole blood system of FIG. FIG. 6 is a plan view of another embodiment of a whole blood strip cuvette. FIG. 20B is a side view of the whole blood strip cuvette of FIG. 20A. FIG. 20B is an exploded view of the example of the whole blood strip cuvette of FIG. 20A. FIG. 6 is a process flow diagram illustrating a method of making another embodiment of a whole blood strip cuvette. FIG. 22 is a schematic illustration of a cuvette handler for packaging a whole blood strip cuvette made according to the process of FIG. 21 for the system of FIG. 1 is a schematic illustration of a whole blood strip cuvette with one type of flow enhancer. 1 is a schematic illustration of a whole blood strip cuvette with another type of flow enhancer. FIG. 6 is a side view of a whole blood strip cuvette with another type of flow enhancer. FIG. 24B is a cross-sectional view of the whole blood strip cuvette of FIG. 24A showing the structure of one type of flow enhancer. 2 is a schematic illustration of another embodiment of a reagentless whole blood detection system. 2 is a schematic illustration of another embodiment of a reagentless whole blood detection system. 2 is a schematic illustration of a cuvette configured for calibration. 1 is a plan view of one embodiment of a cuvette having an integrated lance. FIG. FIG. 6 is a plan view of another embodiment of a cuvette having an integrated lance. FIG. 6 is a plan view of another embodiment of a cuvette having an integrated lance. It is a graph of the measurement accuracy of the whole blood analyte detection system with respect to measurement time. FIG. 6 is a perspective view of another embodiment of a sample element having an integrated lancing member. FIG. 32 is a perspective view of the distal end of the sample element of FIG. 31. FIG. 33 is a cross-sectional view of the distal end of FIG. 32 taken along line 32A-32A. FIG. 33 is a cross-sectional view of the distal end of FIG. 32 taken along line 32B-32B. FIG. 32C is a cross-sectional view of the portion of the distal end of FIG. 32B illustrating the optical path through a chamber located at the distal end. FIG. 32 is an exploded perspective view of the sample element of FIG. 31. FIG. 6 is a perspective view of another example of a sample element having an integrated lansing member. FIG. 6 is a perspective view of another example of a sample element having an integrated sample extractor.

Claims (189)

A sample element for use in determining the concentration of an analyte in a patient's body fluid, said sample element comprising:
A sample extractor configured to cause a flow of bodily fluid from a site on the patient, and a chamber close to an operating passage of the sample extractor, the chamber being defined by at least one inner surface All of the at least one inner surface has a material that is inert to the body fluid, and the chamber is configured to hold 0.5 μl or less of the body fluid,
The sample element characterized in that when the patient is lanced with the sample extractor, the body fluid flows from the lanced site into the chamber without displacement of the chamber.   2. The sample element of claim 1, wherein the chamber comprises a volume and the volume is inert to the body fluid.   2. The sample element of claim 1, wherein the chamber is further defined by at least one window.   The sample element of claim 1, wherein the sample extractor has a lance.   The sample element of claim 1 wherein the sample extractor has a laser lance.   The sample element of claim 1 wherein the sample extractor comprises an iontophoretic sampler.   The sample element of claim 1 wherein the sample extractor comprises a gas jet perforator.   The sample element of claim 1 wherein the sample extractor comprises a fluid jet perforator.   The sample element of claim 1 wherein the sample extractor comprises a particle jet perforator.   The sample element of claim 1, wherein the bodily fluid comprises whole blood.   The sample element of claim 1, wherein the bodily fluid has a blood component.   The sample element of claim 1, wherein the bodily fluid comprises an interstitial fluid.   The sample element of claim 1, wherein the bodily fluid comprises an intercellular fluid. A sample element for use in determining the concentration of an analyte in a patient's body fluid, said sample element comprising:
A sample extractor configured to cause fluid flow from a site on the patient, and a chamber near an operating path of the sample extractor, the chamber being incompatible with the fluid. Active and the chamber is configured to hold 0.5 μl or less of the bodily fluid;
The sample element wherein when the patient is lanced by the sample extractor, the body fluid flows from the lanced site into the chamber without displacement of the chamber.   15. The sample element of claim 14, wherein the chamber is further defined by at least one window. A sample element for use in determining the concentration of an analyte in a patient's body fluid, said sample element comprising:
A sample extractor configured to cause a flow of bodily fluid from a site on the patient, and a reagent-free chamber near an operating passage of the sample extractor, the chamber being in the body fluid Configured to hold 0.5 μl or less,
The sample element wherein when the patient is lanced by the sample extractor, the body fluid flows from the lanced site into the chamber without displacement of the chamber.   The sample element of claim 16, wherein the chamber is further defined by at least one window. A sample element for use in determining the concentration of an analyte in a patient's body fluid, said sample element comprising:
A sample extractor configured to cause fluid flow from a site on the patient; and a chamber near an operating passage of the sample extractor, the chamber being defined by at least one inner surface. All of the at least one inner surface comprises a material that is inert to the bodily fluid, and the chamber is configured to hold no more than 1 μl of the bodily fluid;
The sample element characterized in that when the patient is lanced by the sample extractor, the body fluid flows from the lanced site into the chamber without displacement of the chamber.   19. The sample element of claim 18, wherein the chamber comprises a volume and the volume is inert to the body fluid.   The sample element of claim 18, wherein the chamber is further defined by at least one window.   19. The sample element of claim 18, wherein the sample extractor has a lance.   19. The sample element of claim 18, wherein the sample extractor has a laser lance.   19. The sample element of claim 18, wherein the sample extractor comprises an iontophoretic sampler.   The sample element of claim 18 wherein the sample extractor comprises a gas jet perforator.   19. The sample element of claim 18, wherein the sample extractor comprises a fluid jet perforator.   The sample element of claim 18, wherein the sample extractor comprises a particle jet perforator.   19. The sample element of claim 18, wherein the bodily fluid comprises whole blood.   19. The sample element of claim 18, wherein the body fluid has a blood component.   19. The sample element of claim 18, wherein the bodily fluid comprises an interstitial fluid.   19. The sample element of claim 18, wherein the bodily fluid comprises an intercellular fluid. A sample element for use in determining the concentration of an analyte in a patient's body fluid, said sample element comprising:
A sample extractor configured to cause fluid flow from a site on the patient, and a chamber near an operating path of the sample extractor, the chamber being incompatible with the fluid. Active and the chamber is configured to hold 1 μl or less of the bodily fluid;
The sample element characterized in that when the patient is lanced by the sample extractor, the body fluid flows from the lanced site into the chamber without displacement of the chamber.   32. The sample element of claim 31, wherein the chamber is further defined by at least one window. A sample element for use in determining the concentration of an analyte in a patient's body fluid, said sample element comprising:
A sample extractor configured to cause a flow of bodily fluid from a site on the patient, and a reagent-free chamber near an operating passage of the sample extractor, the chamber being in the body fluid Configured to hold 1 μl or less,
The sample element characterized in that when the patient is lanced by the sample extractor, the bodily fluid flows from the lanced site into the chamber without displacement of the chamber.   34. The sample element of claim 33, wherein the chamber is further defined by at least one window. A method for determining the concentration of an analyte in a body fluid, the method comprising:
Collecting a sample of bodily fluid having a total volume of less than about 0.5 μl;
Holding the sample in a non-flowing manner and using an optical transmission spectroscopic technique to determine the concentration without the use of reagents.   36. The method of claim 35, wherein the optical transmission spectroscopic technique originates from a source and is a measurement of energy passed through the sample.   36. The method of claim 35, wherein the body fluid includes saliva.   36. The method of claim 35, wherein the body fluid includes urine.   36. The method of claim 35, wherein the bodily fluid includes sweat.   36. The method of claim 35, wherein the collecting step further comprises using a sample extractor to create a small wound in the patient.   41. The method of claim 40, wherein the sample extractor includes a lance.   41. The method of claim 40, wherein the sample extractor includes a laser lance.   41. The method of claim 40, wherein the sample extractor comprises an iontophoretic sampler.   41. The method of claim 40, wherein the sample extractor comprises a gas jet perforator.   41. The method of claim 40, wherein the sample extractor comprises a fluid jet perforator.   41. The method of claim 40, wherein the sample extractor comprises a particle jet perforator.   36. The method of claim 35, wherein the bodily fluid comprises whole blood.   36. The method of claim 35, wherein the body fluid includes a blood component.   36. The method of claim 35, wherein the bodily fluid comprises a void fluid.   36. The method of claim 35, wherein the bodily fluid comprises an intercellular fluid. A method for determining the concentration of an analyte in a body fluid, the method comprising:
Collecting a sample of body fluid of about 0.5 μl or less;
Filling a chamber of sample elements with at least a portion of the sample;
Holding the sample in the chamber in a non-flowing manner, and determining the concentration of the analyte in the sample with a reagentless technique.   52. The method of claim 51, wherein the sample of bodily fluid is about 0.4 [mu] l or less.   52. The method of claim 51, wherein the sample of bodily fluid is about 0.3 [mu] l or less.   52. The method of claim 51, wherein the sample of bodily fluid is about 0.2 [mu] l or less.   52. The method of claim 51, wherein the sample of bodily fluid is about 0.1 [mu] l or less.   52. The method of claim 51, wherein the reagentless technique comprises an optical technique.   57. The method of claim 56, wherein the optical technique comprises a spectroscopic technique.   58. The method of claim 57, wherein the spectroscopic technique is a transmission spectroscopic technique.   59. The method of claim 58, wherein the transmission spectroscopic technique originates from a source and is a measurement of energy passed through the sample.   60. The method of claim 59, wherein the measurement is performed on the same side of the sample as the source.   60. The method of claim 59, wherein the measurement is performed on the opposite side of the sample from the source.   52. The method of claim 51, wherein the body fluid includes saliva.   52. The method of claim 51, wherein the body fluid includes urine.   52. The method of claim 51, wherein the bodily fluid includes sweat.   52. The method of claim 51, wherein the collecting step further comprises using a sample extractor to create a small wound in the patient.   66. The method of claim 65, wherein the sample extractor includes a lance.   66. The method of claim 65, wherein the sample extractor includes a laser lance.   66. The method of claim 65, wherein the sample extractor comprises an iontophoretic sampler.   66. The method of claim 65, wherein the sample extractor comprises a gas jet perforator.   66. The method of claim 65, wherein the sample extractor comprises a fluid jet perforator.   66. The method of claim 65, wherein the sample extractor comprises a particle jet perforator.   52. The method of claim 51, wherein the bodily fluid comprises whole blood.   52. The method of claim 51, wherein the body fluid includes a blood component.   52. The method of claim 51, wherein the body fluid comprises a void fluid.   52. The method of claim 51, wherein the bodily fluid comprises an intercellular fluid.   52. The method of claim 51, wherein the chamber comprises an infrared transmissive material.   77. The method of claim 76, wherein the infrared transmitting material is silicon.   77. The method of claim 76, wherein the infrared transmitting material is polyethylene.   77. The method of claim 76, wherein the infrared transmitting material is polypropylene.   77. The method of claim 76, wherein the infrared transmitting material allows transmission of infrared energy having a specific wavelength.   81. The method of claim 80, wherein the wavelength is between about 0.8 [mu] m and about 2.5 [mu] m.   81. The method of claim 80, wherein the wavelength is between about 2.5 [mu] m and about 20 [mu] m.   81. The method of claim 80, wherein the wavelength is between about 20 [mu] m and about 100 [mu] m.   81. The method of claim 80, wherein the wavelength is between about 3.5 [mu] m and about 14 [mu] m. A method for determining the concentration of an analyte in a body fluid, the method comprising:
Creating an unhelpful flow of the body fluid from the patient;
Transporting a sample containing no more than about 0.5 μl of the bodily fluid into the chamber of the sample element such that at least some of the sample is adjacent to the window of the sample element;
Holding the sample in the chamber of the sample element in a non-flowing manner; and from the sample transported into the sample element without reacting the sample with a reagent, the analyte in the body fluid And determining the concentration of the method.   86. The method of claim 85, wherein the creating step further comprises holding the sample element stationary while the sample enters the sample supply passage of the sample element and moves to the chamber.   86. The method of claim 85, wherein the body fluid comprises saliva.   86. The method of claim 85, wherein the body fluid includes urine.   86. The method of claim 85, wherein the bodily fluid includes sweat.   86. The method of claim 85, wherein the creating step comprises using a sample extractor to create a small wound in the patient.   The method of claim 90, wherein the sample extractor includes a lance.   The method of claim 90, wherein the sample extractor comprises a laser lance.   The method of claim 90, wherein the sample extractor comprises an iontophoretic sampler.   The method of claim 90, wherein the sample extractor comprises a gas jet perforator.   The method of claim 90, wherein the sample extractor comprises a fluid jet perforator.   The method of claim 90, wherein the sample extractor comprises a particle jet perforator.   86. The method of claim 85, wherein the bodily fluid comprises whole blood.   86. The method of claim 85, wherein the bodily fluid includes a blood component.   86. The method of claim 85, wherein the bodily fluid comprises a void fluid.   86. The method of claim 85, wherein the body fluid comprises an intercellular fluid. A method for determining the concentration of an analyte in an animal body fluid, the method comprising:
Using a sample extractor having a working channel near the chamber to cause a flow of bodily fluid from a site on the animal, the chamber being defined by at least one inner surface, wherein the at least one All of the inner surfaces have a material that is inert to the body fluid, and the method also includes
Collecting said at least a portion of said bodily fluid in said chamber without displacement of said chamber, said chamber being configured to hold at most 0.5 μl of said bodily fluid.   102. The method of claim 101, wherein the chamber has a volume and the volume is inert to the body fluid.   102. The method of claim 101, wherein the causing step comprises using the sample extractor to create a small wound in the animal.   104. The method of claim 103, wherein the sample extractor includes a lance.   104. The method of claim 103, wherein the sample extractor includes a laser lance.   104. The method of claim 103, wherein the sample extractor comprises an iontophoretic sampler.   104. The method of claim 103, wherein the sample extractor comprises a gas jet perforator.   104. The method of claim 103, wherein the sample extractor comprises a fluid jet perforator.   104. The method of claim 103, wherein the sample extractor comprises a particle jet perforator.   102. The method of claim 101, wherein the bodily fluid comprises whole blood.   102. The method of claim 101, wherein the body fluid comprises a blood component.   102. The method of claim 101, wherein the body fluid comprises a void fluid.   102. The method of claim 101, wherein the bodily fluid comprises an intercellular fluid. A method for determining the concentration of an analyte in a body fluid, the method comprising:
Collecting a sample of bodily fluid having a total volume less than about 1 μl;
Holding the sample in a non-flowing manner, and using an optical transmission spectroscopic technique to determine the concentration without the use of reagents.   115. The method of claim 114, wherein the optical transmission spectroscopic technique is a measurement of energy emanating from a source and passing through the sample.   115. The method of claim 114, wherein the bodily fluid comprises saliva.   115. The method of claim 114, wherein the body fluid comprises urine.   115. The method of claim 114, wherein the bodily fluid includes sweat.   115. The method of claim 114, wherein the collecting step further comprises using a sample extractor to create a small wound in the patient.   120. The method of claim 119, wherein the sample extractor includes a lance.   120. The method of claim 119, wherein the sample extractor includes a laser lance.   120. The method of claim 119, wherein the sample extractor comprises an iontophoretic sampler.   120. The method of claim 119, wherein the sample extractor comprises a gas jet perforator.   120. The method of claim 119, wherein the sample extractor comprises a fluid jet perforator.   120. The method of claim 119, wherein the sample extractor comprises a particle jet perforator.   115. The method of claim 114, wherein the bodily fluid comprises whole blood.   115. The method of claim 114, wherein the bodily fluid includes a blood component.   115. The method of claim 114, wherein the bodily fluid comprises a void fluid.   115. The method of claim 114, wherein the body fluid comprises an intercellular fluid. A method for determining the concentration of an analyte in a body fluid, the method comprising:
Collecting a sample of bodily fluid having a volume of about 1 μl or less;
Filling a chamber of sample elements with at least a portion of the sample;
Holding the sample in the chamber in a non-flowing manner, and determining the concentration of the analyte in the sample using reagentless techniques.   131. The method of claim 130, wherein the sample of bodily fluid is less than about 1 μl.   131. The method of claim 130, wherein the reagentless technique comprises an optical technique.   135. The method of claim 132, wherein the optical technique comprises a spectroscopic technique.   134. The method of claim 133, wherein the spectroscopic technique comprises a transmission spectroscopic technique.   135. The method of claim 134, wherein the transmission spectroscopic technique originates from a source and is a measurement of energy passing through the sample.   138. The method of claim 135, wherein the measurement is performed on the same side of the sample as the source.   138. The method of claim 135, wherein the measurement is performed on the opposite side of the sample from the source.   131. The method of claim 130, wherein the body fluid comprises saliva.   131. The method of claim 130, wherein the body fluid comprises urine.   131. The method of claim 130, wherein the bodily fluid includes sweat.   131. The method of claim 130, wherein the collecting step further comprises using a sample extractor to create a small wound in the patient.   142. The method of claim 141, wherein the sample extractor includes a lance.   142. The method of claim 141, wherein the sample extractor includes a laser lance.   142. The method of claim 141, wherein the sample extractor comprises an iontophoretic sampler.   142. The method of claim 141, wherein the sample extractor comprises a gas jet perforator.   142. The method of claim 141, wherein the sample extractor comprises a fluid jet perforator.   142. The method of claim 141, wherein the sample extractor comprises a particle jet perforator.   131. The method of claim 130, wherein the bodily fluid comprises whole blood.   131. The method of claim 130, wherein the bodily fluid includes a blood component.   131. The method of claim 130, wherein the body fluid comprises a void fluid.   131. The method of claim 130, wherein the bodily fluid comprises an intercellular fluid.   131. The method of claim 130, wherein the chamber comprises an infrared transmissive material.   153. The method of claim 152, wherein the infrared transmitting material is silicon.   153. The method of claim 152, wherein the infrared transmitting material is polyethylene.   153. The method of claim 152, wherein the infrared transmitting material is polypropylene.   153. The method of claim 152, wherein the infrared transmissive material allows transmission of infrared energy having a particular wavelength.   157. The method of claim 156, wherein the wavelength is between about 0.8 μm and about 2.5 μm.   157. The method of claim 156, wherein the wavelength is between about 2.5 μm and about 20 μm.   157. The method of claim 156, wherein the wavelength is between about 20 μm and about 100 μm.   156. The method of claim 156, wherein the wavelength is between about 3.5 [mu] m and about 14 [mu] m. A method for determining the concentration of an analyte in a body fluid, the method comprising:
Creating an unhelpful flow of the body fluid from the patient;
Transporting a sample containing a volume of about 1 μl or less of the bodily fluid into the chamber of the sample element such that at least some of the sample is adjacent the window of the sample element;
Holding the sample in the chamber of the sample element in a manner that does not flow, and the sample of the analyte in the body fluid from the sample transported into the sample element without reacting the sample with a reagent. Determining the concentration. The method comprising:   164. The method of claim 161, wherein the creating step further comprises holding the sample element stationary while the sample enters the sample supply passage of the sample element and moves into the chamber.   163. The method of claim 161, wherein the body fluid comprises saliva.   162. The method of claim 161, wherein the body fluid comprises urine.   162. The method of claim 161, wherein the bodily fluid includes sweat.   163. The method of claim 161, wherein the creating step comprises using a sample extractor to create a small wound in the patient.   173. The method of claim 166, wherein the sample extractor includes a lance.   173. The method of claim 166, wherein the sample extractor includes a laser lance.   173. The method of claim 166, wherein the sample extractor comprises an iontophoretic sampler.   173. The method of claim 166, wherein the sample extractor comprises a gas jet perforator.   171. The method of claim 166, wherein the sample extractor comprises a fluid jet perforator.   173. The method of claim 166, wherein the sample extractor comprises a particle jet perforator.   163. The method of claim 161, wherein the body fluid comprises whole blood.   164. The method of claim 161, wherein the body fluid includes a blood component.   164. The method of claim 161, wherein the body fluid comprises a void fluid.   164. The method of claim 161, wherein the bodily fluid comprises an intercellular fluid. A method for determining the concentration of an analyte in an animal body fluid, the method comprising:
Using a sample extractor having an operating passage near the chamber to cause a flow of bodily fluid from a site on the animal, the chamber being defined by at least one inner surface, All of one inner surface has a material that is inert to the body fluid, and the method also includes
The method comprising collecting at least a portion of the bodily fluid in the chamber without displacement of the chamber, wherein the chamber is configured to hold at most 1 μl of the bodily fluid.   180. The method of claim 177, wherein the chamber has a volume, and the volume is inert to the body fluid.   178. The method of claim 177, wherein the causing step comprises using a sample extractor to create a small wound in the animal.   180. The method of claim 179, wherein the sample extractor includes a lance.   180. The method of claim 179, wherein the sample extractor includes a laser lance.   180. The method of claim 179, wherein the sample extractor includes an iontophoretic sampler.   180. The method of claim 179, wherein the sample extractor comprises a gas jet perforator.   180. The method of claim 179, wherein the sample extractor comprises a fluid jet perforator.   180. The method of claim 179, wherein the sample extractor comprises a particle jet perforator.   178. The method of claim 177, wherein the bodily fluid comprises whole blood.   178. The method of claim 177, wherein the bodily fluid includes a blood component.   180. The method of claim 177, wherein the body fluid comprises a void fluid.   178. The method of claim 177, wherein the bodily fluid comprises an intercellular fluid.

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