Patent Publication Number: US-2006004267-A1

Title: Layered spectroscopic sample element with microporous membrane

Description:
PRIORITY APPLICATION  
      This application is a continuation of U.S. patent application Ser. No. 10/337,226 (filed 6 Jan. 2003), the entire disclosure of which is hereby incorporated by reference herein. 
    
    
     BACKGROUND OF THE INVENTION  
      1. Field of the Invention  
      This invention relates generally to determining analyte concentrations in material samples.  
      2. Description of the Related Art  
      Millions of diabetics draw samples of bodily fluid such as blood on a daily basis to monitor the level of glucose in their bloodstream. This practice is called self monitoring, and is commonly performed using one of a number of reagent based glucose monitors. These monitors measure glucose concentration by observing some aspect of a chemical reaction between a reagent and the glucose in the fluid sample. The reagent is a chemical compound that is known to react with glucose in a predictable manner, enabling the monitor to determine the concentration of glucose in the sample. For example, the monitor can be configured to measure a voltage or a current generated by the reaction between the glucose and the reagent. A small test strip is often used to hold the reagent and to host the reaction between the glucose and the reagent. Reagent based monitors and test strips suffer from a variety of problems and also have limited performance.  
      Problems and costs relating to reagent arise during manufacture, shipment, storage and use of the reagent containing test strips. Costly and demanding quality control strategies must be incorporated into the test strip manufacturing processes to assure that the strips ultimately function properly. For example, a manufacturing lot specific calibration code must be determined through blood or equivalent testing before the strips can be released for consumer sale. The diabetics using the reagent based monitors must often enter this calibration code into the monitor to ensure that the monitor accurately reads the concentration of glucose in a sample placed on the strip. Naturally, this requirement leads to errors in reading and entering the calibration code, which can cause the monitor to make dangerously inaccurate readings of glucose concentration.  
      Reagent based monitor test strips also require special packaging during shipment and storage to prevent hydration of the reagent. Premature hydration affects the manner in which the reagent reacts with glucose and can cause erroneous readings. Once the test strips have been shipped, they must be stored by the vendor and user within a controlled storage temperature range. Unfortunately, the multitude of users are often unable to follow these protocols. When test strips and their reagents are not properly handled and stored, erroneous monitor readings can occur. Even when all necessary process, packaging and storage controls are followed, the reagents on the strips still degrade with time, and thus the strips have a limited shelf life. All these factors have led consumers to view reagent based monitors and test strips as expensive and troublesome. Indeed, reagent based test strips would be even more expensive if they were designed to be made simpler and completely fail safe.  
      The performance of reagent based glucose monitors is limited in a number of respects related to reagents. As discussed above, the accuracy of such monitors is limited by the sensitive nature of the reagent, and thus any breakdown in the strict protocols relating to manufacture, packaging, storage and use reduces the accuracy of the monitor. The time during which the reaction occurs between the 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 limited as well. Confidence in the reagent based blood glucose monitor output can be increased only by taking more fluid samples and making additional measurements. This is undesirable because it doubles or triples the number of painful fluid removals. At the same time, reagent based monitor performance is limited in that the reaction rate limits the speed with which an individual measurement can be obtained. The reaction time is regarded as too long by most users.  
      Generally, reagent based monitors are too complex for must users, and have limited performance. Additionally, such monitors require users to draw fluid multiple times per day using sharp lances which must be disposed of carefully.  
     SUMMARY OF THE INVENTION  
      In one embodiment, a spectroscopic sample holder comprises a microporous sheet. The microporous sheet has a top surface, a bottom surface substantially parallel to the top surface, and at least one side surface oriented substantially perpendicular to the top and bottom surfaces. The side surface forms an exposed transit opening configured to contact a material sample and distribute the contacted material sample into the microporous sheet. The spectroscopic sample holder further comprises a first planar support member positioned on, and substantially parallel to, the top surface of the microporous sheet. The spectroscopic sample holder further comprises a second planar support member positioned on the bottom surface of the microporous sheet, and oriented substantially parallel to the first planar support member.  
      In another embodiment, an apparatus comprises a microporous sheet positioned between first and second support members. At least a portion of the microporous sheet is an exposed transit opening configured to receive and distribute a material sample into the microporous sheet.  
      In another embodiment, a method comprises providing a microporous sheet disposed between first and second support members. At least a portion of the microporous sheet is left exposed. The method further comprises contacting the exposed portion of the microporous sheet with a material sample. At least a portion of the material sample is drawn into the microporous sheet. The method further comprises transmitting electromagnetic radiation through the material sample in the microporous sheet. The method further comprises analyzing the electromagnetic radiation transmitted through the material sample in a spectral region of interest.  
      In another embodiment, a method comprises providing a microporous sheet disposed between first and second support members. At least a portion of the microporous sheet is left exposed. The method further comprises contacting the exposed portion of the microporous sheet with a material sample. At least a portion of the material sample is drawn into the microporous sheet. The method further comprises transmitting electromagnetic radiation emitted from the material sample in the microporous sheet to a detector. The method further comprises analyzing the electromagnetic radiation emitted from the material sample in a spectral region of interest.  
      In another embodiment, a reagentless analyte detection system comprises a source configured to emit electromagnetic radiation. The reagentless analyte detection system further comprises a detector positioned in an optical path of the radiation. The reagentless detection system further comprises a microporous sheet situated in the optical path of the radiation. The microporous sheet is also positioned between first and second support members. At least a portion of the microporous sheet is an exposed transit opening configured to receive and distribute a material sample into the microporous sheet. The analyte detection system performs optical analysis on the material sample to assess at least one constituent of the material sample. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1  is a schematic view of a noninvasive optical detection system.  
       FIG. 2  is a perspective view of a window assembly for use with the noninvasive detection system.  
       FIG. 2A  is a plan view of another embodiment of a window assembly for use with the noninvasive detection system.  
       FIG. 3  is an exploded schematic view of another embodiment of a window assembly for use with the noninvasive detection system.  
       FIG. 4  is a plan view of the window assembly connected to a cooling system.  
       FIG. 5  is a plan view of the window assembly connected to a cold reservoir.  
       FIG. 6  is a cutaway view of a heat sink for use with the noninvasive detection system.  
       FIG. 6A  is a cutaway perspective view of a lower portion of the noninvasive detection system of  FIG. 1 .  
       FIG. 6B  is an exploded perspective view of a window mounting system for use with the noninvasive optical detection system.  
       FIG. 6C  is a partial plan view of the window mounting system of  FIG. 6B .  
       FIG. 6D  is a sectional view of the window mounting system of  FIG. 6C .  
       FIG. 7  is a schematic view of a control system for use with the noninvasive optical detection system.  
       FIG. 8  depicts a first methodology for determining the concentration of an analyte of interest.  
       FIG. 9  depicts a second methodology for determining the concentration of an analyte of interest.  
       FIG. 10  depicts a third methodology for determining the concentration of an analyte of interest.  
       FIG. 11  depicts a fourth methodology for determining the concentration of an analyte of interest.  
       FIG. 12  depicts a fifth methodology for determining the concentration of an analyte of interest.  
       FIG. 13  is a schematic view of a reagentless whole-blood detection system.  
       FIG. 14  is a perspective view of one embodiment of a cuvette for use with the reagentless whole-blood detection system.  
       FIG. 15  is a plan view of another embodiment of a cuvette for use with the reagentless whole-blood detection system.  
       FIG. 16  is a disassembled plan view of the cuvette of  FIG. 15 .  
       FIG. 16A  is an exploded perspective view of the cuvette of  FIG. 15 .  
       FIG. 17  is a side view of the cuvette of  FIG. 15 .  
       FIG. 18  is a perspective view of a sample holder according to a preferred embodiment of the present invention.  
       FIG. 19A  is an exploded perspective view of a sample holder comprising a circumferential open mesh surrounding the microporous sheet.  
       FIG. 19B  is a perspective view of a sample holder having a removable protective flap disposed thereon.  
       FIG. 20A  is an exploded perspective view of a sample holder comprising a shield that forms an aperture.  
       FIG. 20B  is a cross-sectional view of the sample holder of  FIG. 20A .  
       FIG. 21A  is a perspective view of a sample holding having a skin-piercing structure.  
       FIG. 21B  is a cross-sectional view of the sample holding of  FIG. 21A  taken along line  21 B- 21 B. 
    
    
      These figures, which are idealized, are not to scale and are intended to be merely illustrative and non-limiting.  
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
      Although certain preferred embodiments and examples are disclosed below, it will be understood by those skilled in the art that the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses of the invention and obvious modifications and equivalents thereof. Thus, it is intended that the scope of the invention herein disclosed should not be limited by the particular disclosed embodiments described below.  
     I. Overview of Analyte Detection Systems  
      Disclosed herein are analyte detection systems, including a noninvasive system discussed largely in part A below and a whole-blood system discussed largely in part B below. Also disclosed are various methods, including methods for detecting the concentration of an analyte in a material sample. Both the noninvasive system/method and the whole-blood system/method can employ optical measurement. As used herein with reference to measurement apparatus and methods, “optical” is a broad term and is used in its ordinary sense and refers, without limitation, to identification of the presence or concentration of an analyte in a material sample without requiring a chemical reaction to take place. As discussed in more detail below, the two approaches each can operate independently to perform an optical analysis of a material sample. The two approaches can also be combined in an apparatus, or the two approaches can be used together to perform different steps of a method.  
      In one embodiment, the two approaches are combined to perform calibration of an apparatus, for example, of an apparatus that employs a noninvasive approach. In another embodiment, an advantageous combination of the two approaches performs an invasive measurement to achieve greater accuracy and a whole-blood measurement to minimize discomfort to the patient. For example, the whole-blood technique may be more accurate than the noninvasive technique at certain times of the day, for example, at certain times after a meal has been consumed, or after a drug has been administered.  
      It should be understood, however, that any of the disclosed devices may be operated in accordance with any suitable detection methodology, and that any disclosed method may be employed in the operation of any suitable device. Furthermore, the disclosed devices and methods are applicable in a wide variety of situations or modes of operation, including but not limited to invasive, noninvasive, intermittent or continuous measurement, subcutaneous implantation, wearable detection systems, or any combination thereof.  
      Any method which is described and illustrated herein is not limited to the exact sequence of acts described, nor is it necessarily limited to the practice of all of the acts set forth. Other sequences of events or acts, or less than all of the events, or simultaneous occurrence of the events, may be used in practicing the method or methods in question.  
      A. Noninvasive System  
      1. Monitor Structure  
       FIG. 1  depicts a noninvasive optical detection system (hereinafter “noninvasive system”)  10  in a presently preferred configuration. The depicted noninvasive system  10  is particularly suited for noninvasively detecting the concentration of an analyte in a material sample S, by observing the infrared energy emitted by the sample, as will be discussed in further detail below.  
      As used herein, the term “noninvasive” is a broad term and is used in its ordinary sense and refers, without limitation, to analyte detection devices and methods which have the capability to determine the concentration of an analyte in in-vivo tissue samples or bodily fluids. It should be understood, however, that the noninvasive system  10  disclosed herein is not limited to noninvasive use, as the noninvasive system  10  may be employed to analyze an in-vitro fluid or tissue sample which has been obtained invasively or noninvasively. As used herein, the term “invasive” (or, alternatively, “traditional”) is a broad term and is used in its ordinary sense and refers, without limitation, to analyte detection methods which involve the removal of fluid samples through the skin. As used herein, the term “material sample” is a broad term and is used in its ordinary sense and refers, without limitation, to any collection of material which is suitable for analysis by the noninvasive system  10 . For example, the material sample S may comprise a tissue sample, such as a human forearm, placed against the noninvasive system  10 . The material sample S may also comprise a volume of a bodily fluid, such as whole blood, blood component(s), interstitial fluid or intercellular fluid obtained invasively, or saliva or urine obtained noninvasively, or any collection of organic or inorganic material. As used herein, the term “analyte” is a broad term and is used in its ordinary sense and refers, without limitation, to any chemical species the presence or concentration of which is sought in the material sample S by the noninvasive system  10 . For example, the analyte(s) which may be detected by the noninvasive system  10  include but are not limited to glucose, ethanol, insulin, water, carbon dioxide, blood oxygen, cholesterol, bilirubin, ketones, fatty acids, lipoproteins, albumin, urea, creatinine, white blood cells, red blood cells, hemoglobin, oxygenated hemoglobin, carboxyhemoglobin, organic molecules, inorganic molecules, pharmaceuticals, cytochrome, various proteins and chromophores, microcalcifications, electrolytes, sodium, potassium, chloride, bicarbonate, and hormones. As used herein to describe measurement techniques, the term “continuous” is a broad term and is used in its ordinary sense and refers, without limitation, to the taking of discrete measurements more frequently than about once every 10 minutes, and/or the taking of a stream or series of measurements or other data over any suitable time interval, for example, over an interval of one to several seconds, minutes, hours, days, or longer. As used herein to describe measurement techniques, the term “intermittent” is a broad term and is used in its ordinary sense and refers, without limitation, to the taking of measurements less frequently than about once every 10 minutes.  
      The noninvasive system  10  preferably comprises a window assembly  12 , although in some embodiments the window assembly  12  may be omitted. One function of the window assembly  12  is to permit infrared energy E to enter the noninvasive system  10  from the sample S when it is placed against an upper surface  12   a  of the window assembly  12 . The window assembly  12  includes a heater layer (see discussion below) which is employed to heat the material sample S and stimulate emission of infrared energy therefrom. A cooling system  14 , preferably comprising a Peltier-type thermoelectric device, is in thermally conductive relation to the window assembly  12  so that the temperature of the window assembly  12  and the material sample S can be manipulated in accordance with a detection methodology discussed in greater detail below. The cooling system  14  includes a cold surface  14   a  which is in thermally conductive relation to a cold reservoir  16  and the window assembly  12 , and a hot surface  14   b  which is in thermally conductive relation to a heat sink  18 .  
      As the infrared energy E enters the noninvasive 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 comprises a light pipe having highly reflective inner surfaces which randomize the directionality of the infrared energy E as it passes therethrough and reflects against the mixer walls. The collimator  22  also comprises a light pipe having highly-reflective inner walls, but the walls diverge as they extend away from the mixer  20 . The divergent walls cause the infrared energy E to tend to straighten as it advances toward the wider end of the collimator  22 , due to the angle of incidence of the infrared energy E when reflecting against the collimator walls.  
      From the collimator  22  the infrared energy E passes through an array of filters  24 , each of which allows only a selected wavelength or band of wavelengths to pass therethrough. These wavelengths/bands are selected to highlight or isolate the absorptive effects of the analyte of interest in the detection methodology discussed in greater detail below. Each filter  24  is preferably in optical communication with a concentrator  26  and an infrared detector  28 . The concentrators  26  have highly reflective, converging inner walls which concentrate the infrared energy E as it advances toward the detectors  28 , increasing the density of the energy incident upon the detectors  28 .  
      The detectors  28  are in electrical communication with a control system  30  which receives electrical signals from the detectors  28  and computes the concentration of the analyte in the sample S. The control system  30  is also in electrical communication with the window  12  and cooling system  14 , so as to monitor the temperature of the window  12  and/or cooling system  14  and control the delivery of electrical power to the window  12  and cooling system  14 .  
      a. Window Assembly  
      A preferred configuration of the window assembly  12  is shown in perspective, as viewed from its underside (in other words, the side of the window assembly  12  opposite the sample S), in  FIG. 2 . The window assembly  12  generally comprises a main layer  32  formed of a highly infrared-transmissive material and a heater layer  34  affixed to the underside of the main layer  32 . The main layer  32  is preferably formed from diamond, most preferably from chemical-vapor-deposited (“CVD”) diamond, with a preferred thickness of about 0.25 millimeters. In other embodiments alternative materials which are highly infrared-transmissive, such as silicon or germanium, may be used in forming the main layer  32 .  
      The heater layer  34  preferably comprises bus bars  36  located at opposing ends of an array of heater elements  38 . The bus bars  36  are in electrical communication with the elements  38  so that, upon connection of the bus bars  36  to a suitable electrical power source (not shown) a current may be passed through the elements  38  to generate heat in the window assembly  12 . The heater layer  34  may also include one or more temperature sensors (not shown), such as thermistors or resistance temperature devices (“RTDs”), to measure the temperature of the window assembly  12  and provide temperature feedback to the control system  30  (see  FIG. 1 ).  
      Still referring to  FIG. 2 , the heater layer  34  preferably comprises a first adhesion layer of gold or platinum (hereinafter referred to as the “gold” layer) deposited over an alloy layer which is applied to the main layer  32 . The alloy layer comprises a material suitable for implementation of the heater layer  34 , such as, by way of example, 10/90 titanium/tungsten, titanium/platinum, nickel/chromium, or other similar material. The gold layer preferably has a thickness of about 4000 Å, and the alloy layer preferably has a thickness ranging between about 300 Åand about 500 Å. The gold layer and/or the alloy layer may be deposited onto the main layer  32  by chemical deposition including, but not necessarily limited to, vapor deposition, liquid deposition, plating, laminating, casting, sintering, or other forming or deposition methodologies well known to those of ordinary skill in the art. If desired, the heater layer  34  may be covered with an electrically insulating coating which also enhances adhesion to the main layer  32 . One preferred coating material is aluminum oxide. Other acceptable materials include, but are not limited to, titanium dioxide or zinc selenide.  
      The heater layer  34  may incorporate a variable pitch distance between centerlines of adjacent heater elements  38  to maintain a constant power density, and promote a uniform temperature, across the entire heater layer  34 . Where a constant pitch distance is employed, the preferred distance is at least about 50-100 microns. Although the heater elements  38  generally have a preferred width of about 25 microns, their width may also be varied as needed for the same reasons stated above.  
      Alternative structures suitable for use as the heater layer  34  include, but are not limited to, thermoelectric heaters, radiofrequency (“RF”) heaters, infrared radiation heaters, optical heaters, heat exchangers, electrical resistance heating grids, wire bridge heating grids, or laser heaters. Whichever type of heater layer is employed, it is preferred that the heater layer obscures about 10% or less of the window assembly  12 .  
      In a preferred embodiment, the window assembly  12  comprises substantially only the main layer  32  and the heater layer  34 . Thus, when installed in an optical detection system such as the noninvasive system  10  shown in  FIG. 1 , the window assembly  12  will facilitate a minimally obstructed optical path between a (preferably flat) upper surface  12   a  of the window assembly  12  and the infrared detectors  28  of the noninvasive system  10 . The optical path  40  in the preferred noninvasive system  10  proceeds only through the main layer  32  and heater layer  34  of the window assembly  12  (including any antireflective, index-matching, electrical insulating or protective coatings applied thereto or placed therein), through the optical mixer  20  and collimator  22  and to the detectors  28 .  
       FIG. 2A  shows another embodiment of the window assembly  12 , that may be used in place of the window assembly  12  depicted in  FIG. 2 . The window assembly  12  shown in  FIG. 2A  may be similar to that shown in  FIG. 2 , except as described below. In the embodiment of  FIG. 2A  the main layer  32  has a preferred thickness of up to about 0.012″ and more preferably about 0.010″ or less. The heater layer  34  may also include one or more resistance temperature devices (“RTDs”)  55  to measure the temperature of the window assembly  12  and provide temperature feedback to a control system  30 . The RTDs  55  terminate in RTD connection pads  57 .  
      In the embodiment of  FIG. 2A , the heater elements  38  are typically provided with a width of about 25 microns. The pitch distance separating centerlines of adjacent heater elements  38  may be reduced, and/or the width of the heater elements  38  may be increased, in the regions of the window assembly  12  near the point(s) of contact with the thermal diffuser  410  (see  FIGS. 6B through 6D  and discussion below). This arrangement advantageously promotes an isothermal temperature profile at the upper surface of the main layer  32  despite thermal contact with the thermal diffuser.  
      The embodiment shown in  FIG. 2A  includes a plurality of heater elements  38  of substantially equal width which are variably spaced across the width of the main layer  32 . In the embodiment of  FIG. 2A , the centerlines of the heater elements  38  are spaced at a first pitch distance of about 0.0070″ at peripheral portions  34   a  of the heater layer  34 , and at a second pitch distance of about 0.015″ at a central portion  34   b  of the main layer  32 . The heater elements  38  closest to the center are preferably sufficiently spaced to allow the RTDs  55  to extend therebetween. In the embodiment of  FIG. 2A , the main layer  32  includes peripheral regions  32   a  which extend about 0.053″ from the outermost heater element on each side of the heater layer  34  to the adjacent edge of the main layer  32 . As shown, the bus bars  36  are preferably configured and segmented to allow space for the RTDs  55  and the RTD connection pads  57 , in intermediate gaps  36   a . The RTDs  55  preferably extend into the array of heater elements  38  by a distance that is slightly longer than half of the length of an individual heater element  38 . In alternative embodiments, the RTDs  55  may be located at the edges of the main layer  32 , or at other locations as desired for a particular noninvasive system.  
      With continued reference to  FIG. 2A , the peripheral regions  32   a  of the main layer  32  may include metallized edge portions  35  for facilitating connection to the diffuser  410  (discussed below in connection with  FIGS. 6B through 6D ). The metallized edge portions  35  may be formed by the same or similar processes used in forming the heater elements  38  and RTDs  55 . In the embodiment of  FIG. 2A , the edge portions  35  are typically between about 0.040″ and about 0.060″ wide by between about 0.450″ and about 0.650″ long, and in one embodiment, they are about 0.050″ by about 0.550″. Other dimensions may be appropriately used so long as the window assembly  12  may be joined in thermal communication with the diffuser  410  as needed.  
      In the embodiment shown in  FIG. 2A , the main layer  32  is about 0.690″ long by about 0.571″ wide, and the heater layer  34  (excluding the metallized edge portions  35 ) is about 0.640″ long by about 0.465″ wide. The main layer  32  is about 0.010″-0.012″ thick, and is advantageously thinner than about 0.010″ where possible. Each heater element  38  is about 0.570″ long, and each peripheral portion  34   a  is about 0.280″ wide. These dimensions are merely exemplary; of course, other dimensions may be used as desired.  
       FIG. 3  depicts an exploded side view of an alternative configuration for the window assembly  12 , which may be used in place of the configuration shown in  FIG. 2 . The window assembly  12  depicted in  FIG. 3  includes near its upper surface (the surface intended for contact with the sample S) a highly infrared-transmissive, thermally conductive spreader layer  42 . Underlying the spreader layer  42  is a heater layer  44 . A thin electrically insulating layer (not shown), such as layer of aluminum oxide, titanium dioxide or zinc selenide, may be disposed between the heater layer  44  and the spreader layer  42 . (An aluminum oxide layer also increases adhesion of the heater layer  44  to the spreader layer  42 .) Adjacent to the heater layer  44  is an impedance matching and thermal insulating layer  46 . Adjacent to the thermal insulating layer  46  is a thermally conductive inner layer  48 . The spreader layer  42  is coated on its top surface with a thin layer of protective coating  50 . 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 antireflective properties.  
      The spreader layer  42  is preferably formed of a highly infrared-transmissive material having a high thermal conductivity sufficient to facilitate heat transfer from the heater layer  44  uniformly into the material sample S when it is placed against the window assembly  12 . Other effective materials include, but are not limited to, CVD diamond, diamond-like carbon, gallium arsenide, germanium, and other infrared-transmissive materials having sufficiently high thermal conductivity. Preferred dimensions for the spreader layer  42  are about one inch in diameter and about 0.010 inch thick. As shown in  FIG. 3 , a preferred embodiment of the spreader layer  42  incorporates a beveled edge. Although not required, an approximate 45-degree bevel is preferred.  
      The protective coating  50  is intended to protect the top surface of the spreader layer  42  from damage. Ideally, the protective coating  50  is highly infrared-transmissive and highly resistant to mechanical damage, such as scratching or abrasion. It is also preferred that the protective coating  50  and the overcoat layer  52  have high thermal conductivity and antireflective and/or index-matching properties. A satisfactory material for use as the protective coating  50  and the overcoat layer  52  is the multi-layer Broad Band Anti-Reflective Coating produced by Deposition Research Laboratories, Inc. of Saint Charles, Mo. Diamond-like carbon coatings are also suitable.  
      Except as noted below, the heater layer  44  is generally similar to the heater layer  34  employed in the window assembly shown in  FIG. 2 . Alternatively, the heater layer  44  may comprise a doped infrared-transmissive material, such as a doped silicon layer, with 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 1500 angstroms. 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 insulating layer  46  prevents the dissipation of heat from the heater layer  44  while allowing the cooling system  14  to effectively cool the material sample S (see  FIG. 1 ). The thermal insulating layer  46  comprises a material having thermally insulative (for example, lower thermal conductivity than the spreader layer  42 ) and infrared transmissive qualities. A preferred material is a germanium-arsenic-selenium compound of the calcogenide glass family known as AMTIR-1 produced by Amorphous Materials, Inc. of Garland, Tex. The illustrated embodiment has a diameter of about 0.85 inches and a preferred thickness in the range of about 0.005 to about 0.010 inches. As heat generated by the heater layer  44  passes through the spreader layer  42  into the material sample S, the thermal insulating layer  46  insulates this heat.  
      The inner layer  48  is formed of thermally conductive material, preferably crystalline silicon formed using a conventional floatzone crystal growth method. The purpose of the inner layer  48  is to serve as a cold-conducting mechanical base for the entire layered window assembly.  
      The overall optical transmission of the window assembly  12  shown in  FIG. 3  is preferably at least 70%. The window assembly  12  of  FIG. 3  is preferably held together and secured to the noninvasive system  10  by a holding bracket (not shown). The bracket is preferably formed of a glass-filled plastic, for example Ultem 2300, manufactured by General Electric. Ultem 2300 has low thermal conductivity which prevents heat transfer from the layered window assembly  12 .  
      b. Cooling System  
      The cooling system  14  (see  FIG. 1 ) preferably comprises a Peltier-type thermoelectric device. Thus, the application of an electrical current to the preferred cooling system  14  causes the cold surface  14   a  to cool and causes the opposing hot surface  14   b  to heat up. The cooling system  14  cools the window assembly  12  via the situation of the window assembly  12  in thermally conductive relation to the cold surface  14   a  of the cooling system  14 . It is contemplated that the cooling system  14 , the heater layer  34 , or both, can be operated to induce a desired time-varying temperature in the window assembly  12  to create an oscillating thermal gradient in the sample S, in accordance with various analyte-detection methodologies discussed herein.  
      Preferably, the cold reservoir  16  is positioned between the cooling system  14  and the window assembly  12 , and functions as a thermal conductor between the cooling system  14  and the window assembly  12 . The cold reservoir  16  is formed from a suitable thermally conductive material, preferably brass. Alternatively, the window assembly  12  can be situated in direct contact with the cold surface  14   a  of the cooling system  14 .  
      In alternative embodiments, the cooling system  14  may comprise a heat exchanger through which a coolant, such as air, nitrogen or chilled water, is pumped, or a passive conduction cooler such as a heat sink. As a further alternative, a gas coolant such as nitrogen may be circulated through the interior of the noninvasive system  10  so as to contact the underside of the window assembly  12  (see  FIG. 1 ) and conduct heat therefrom.  
       FIG. 4  is a top schematic view of a preferred arrangement of the window assembly  12  (of the types shown in  FIG. 2  or  2 A) and the cold reservoir  16 .  FIG. 5  is a top schematic view of an alternative arrangement in which the window assembly  12  directly contacts the cooling system  14 . The cold reservoir  16 /cooling system  14  preferably contacts the underside of the window assembly  12  along opposing edges thereof, on either side of the heater layer  34 . With thermal conductivity thus established between the window assembly  12  and the cooling system  14 , the window assembly can be cooled as needed during operation of the noninvasive system  10 . To promote a substantially uniform or isothermal temperature profile over the upper surface  12   a  of the window assembly  12 , the pitch distance between centerlines of adjacent heater elements  38  may be made smaller (thereby increasing the density of heater elements  38 ) near the region(s) of contact between the window assembly  12  and the cold reservoir  16 /cooling system  14 . As a supplement or alternative, the heater elements  38  themselves may be made wider near these regions of contact. As used herein, “isothermal” is a broad term and is used in its ordinary sense and refers, without limitation, to a condition in which, at a given point in time, the temperature of the window assembly  12  or other structure is substantially uniform across a surface intended for placement in thermally conductive relation to the material sample S. Thus, although the temperature of the structure or surface may fluctuate over time, at any given point in time the structure or surface may nonetheless be isothermal.  
      The heat sink  18  drains waste heat from the hot surface  14   b  of the cooling system  14  and stabilizes the operational temperature of the noninvasive system  10 . The preferred heat sink  18  (see  FIG. 6 ) comprises a hollow structure formed from brass or any other suitable material having a relatively high specific heat and high heat conductivity. The heat sink  18  has a conduction surface  18   a  which, when the heat sink  18  is installed in the noninvasive system  10 , is in thermally conductive relation to the hot surface  14   b  of the cooling system  14  (see  FIG. 1 ). A cavity  54  is formed in the heat sink  18  and preferably contains a phase-change material (not shown) to increase the capacity of the heat sink  18 . A preferred phase change material is a hydrated salt, such as calcium chloride hexahydrate, available under the name TH29 from PCM Thermal Solutions, Inc., of Naperville, Ill. Alternatively, the cavity  54  may be omitted to create a heat sink  18  comprising a solid, unitary mass. The heat sink  18  also forms a number of fins  56  to further increase the conduction of heat from the heat sink  18  to surrounding air.  
      Alternatively, the heat sink  18  may be formed integrally with the optical mixer  20  and/or the collimator  22  as a unitary mass of rigid, heat-conductive material such as brass or aluminum. In such a heat sink, the mixer  20  and/or collimator  22  extend axially through the heat sink  18 , and the heat sink defines the inner walls of the mixer  20  and/or collimator  22 . These inner walls are coated and/or polished to have appropriate reflectivity and non-absorbance in infrared wavelengths as will be further described below. Where such a unitary heat sink-mixer-collimator is employed, it is desirable to thermally insulate the detector array from the heat sink.  
      It should be understood that any suitable structure may be employed to heat and/or cool the material sample S, instead of or in addition to the window assembly  12 /cooling system  14  disclosed above, so long a proper degree of cycled heating and/or cooling are imparted to the material sample S. In addition other forms of energy, such as but not limited to light, radiation, chemically induced heat, friction and vibration, may be employed to heat the material sample S. It will be further appreciated that heating of the sample can achieved by any suitable method, such as convection, conduction, radiation, and so forth.  
      c. Window Mounting System  
       FIG. 6B  illustrates an exploded view of a window mounting system  400  which, in one embodiment, is employed as part of the noninvasive system  10  disclosed above. Where employed in connection with the noninvasive system  10 , the window mounting system  400  supplements or, where appropriate, replaces any of the window assembly  12 , cooling system  14 , cold reservoir  16  and heat sink  18  shown in  FIG. 1 . In one embodiment, the window mounting system  400  is employed in conjunction with the window assembly  12  depicted in  FIG. 2A ; in alternative embodiments, the window assemblies shown in  FIGS. 2 and 3  and described above may also be used in conjunction with the window mounting system  400  illustrated in  FIG. 6B .  
      In the window mounting system  400 , the window assembly  12  is physically and electrically connected (typically by soldering) to a first printed circuit board (“first PCB”)  402 . The window assembly  12  is also in thermally conductive relation (typically by contact) to a thermal diffuser  410 . The window assembly may also be fixed to the diffuser  410  by soldering.  
      The thermal diffuser  410  generally comprises a heat spreader layer  412  which, as mentioned, preferably contacts the window assembly  12 , and a conductive layer  414  which is typically soldered to the heat spreader layer  412 . The conductive layer  414  may then be placed in direct contact with a cold side  418   a  of a thermoelectric cooler (“TEC”)  418  or other cooling device. The TEC  418 , which in one embodiment comprises a 25 watt TEC manufactured by MELCOR, is in electrical communication with a second PCB  403 , which includes TEC power leads  409  and TEC power terminals  411  for connection of the TEC  418  to an appropriate power source (not shown). The second PCB  403  also includes contacts  408  for connection with RTD terminals  407  (see  FIG. 6C ) of the first PCB  402 . A heat sink  419 , which may take the form of the illustrated water jacket, the heat sink  18  shown in  FIG. 6 , any other heat sink structures mentioned herein, or any other appropriate device, is in thermal communication with a hot side  418   b  of the TEC  418  (or other cooling device), in order to remove any excess heat created by the TEC  418 .  
       FIG. 6C  illustrates a plan view of the interconnection of the window assembly  12 , the first PCB  402 , the diffuser  410  and the thermoelectric cooler  418 . The first PCB  402  includes RTD bonding leads  406  and heater bonding pads  404  which permit attachment of the RTDs  55  and bus bars  36 , respectively, of the window assembly  12  to the first PCB  402  via soldering or other conventional techniques. Electrical communication is thus established between the heater elements  38  of the heater layer  34 , and heater terminals  405  formed in the heater bonding pads  404 . Similarly, electrical communication is established between the RTDs  55  and RTD terminals  407  formed at the ends of the RTD bonding leads  406 . Electrical connections can be established with the heater elements  38  and the RTDs  55  via simple connection to the heater terminals  405  and the RTD terminals  407  of the first PCB  402 .  
      With further reference to  FIGS. 2A and 6B  through  6 C, the heat spreader layer  412  of the thermal diffuser  410  contacts the underside of the main layer  32  of the window assembly  12  via a pair of rails  416 . The rails  416  may contact the main layer  32  at the metallized edge portions  35 , or at any other appropriate location. The physical and thermal connection between the rails  416  and the window main layer  32  may be achieved by soldering, as indicated above. Alternatively, the connection may be achieved by an adhesive such as epoxy, or any other appropriate method. The material chosen for the window main layer  32  is preferably sufficiently thermally conductive that heat may be quickly removed from the main layer  32  through the rails  416 , the diffuser  410 , and the TEC  418 .  
       FIG. 6D  shows a cross-sectional view of the assembly of  FIG. 6C  through line  6 D- 6 D. As can be seen in  FIG. 6D , the window assembly  12  contacts the rails  416  of the heat spreader layer  412 . The conductive layer  414  underlies the heat spreader layer  412  and may comprise protrusions  426  configured to extend through openings  424  formed in the spreader layer  412 . The openings  424  and protrusions  426  are sized to leave sufficient expansion space therebetween, to allow expansion and contraction of the conductive layer  414  without interference with, or causing deformation of, the window assembly  12  or the heat spreader layer  412 . Moreover, the protrusions  426  and openings  424  coact to prevent displacement of the spreader layer  412  with respect to the conductive layer  414  as the conductive layer  414  expands and contracts.  
      The thermal diffuser  410  provides a thermal impedance between the TEC  418  and the window assembly  12 , which impedance is selected to drain heat from the window assembly at a rate proportional to the power output of the heater layer  34 . In this way, the temperature of the main layer  32  can be rapidly cycled between “hot” and a “cold” temperatures, thereby allowing a time-varying thermal gradient to be induced in a sample S placed against the window assembly  12 .  
      The heat spreader layer  412  is preferably made of a material which has substantially the same coefficient of thermal expansion as the material used to form the window assembly main layer  32 , within the expected operating temperature range. Preferably, both the material used to form the main layer  32  and the material used to form the heat spreader layer  412  have substantially the same, extremely low, coefficient of thermal expansion. For this reason, CVD diamond is preferred for the main layer  32  (as mentioned above); with a CVD diamond main layer  32  the preferred material for the heat spreader layer  412  is Invar. Invar advantageously has an extremely low coefficient of thermal expansion and a relatively high thermal conductivity. Because Invar is a metal, the main layer  32  and the heat spreader layer  412  can be thermally bonded to one another with little difficulty. Alternatively, other materials may be used for the heat spreader layer  412 ; for example, any of a number of glass and ceramic materials with low coefficients of thermal expansion may be employed.  
      The conductive layer  414  of the thermal diffuser  410  is typically a highly thermally conductive material such as copper (or, alternatively, other metals or non-metals exhibiting comparable thermal conductivities). The conductive layer  414  is typically soldered or otherwise bonded to the underside of the heat spreader layer  412 .  
      In the illustrated embodiment, the heat spreader layer  412  may be constructed according to the following dimensions, which are to be understood as exemplary; accordingly the dimensions may be varied as desired. The heat spreader layer  412  has an overall length and width of about 1.170″, with a central opening of about 0.590″ long by 0.470″ wide. Generally, the heat spreader layer  412  is about 0.030″ thick; however, the rails  416  extend a further 0.045″ above the basic thickness of the heat spreader layer  412 . Each rail  416  has an overall length of about 0.710″; over the central 0.525″ of this length each rail  416  is about 0.053″ wide. On either side of the central width each rail  416  tapers, at a radius of about 0.6″, down to a width of about 0.023″. Each opening  424  is about 0.360″ long by about 0.085″ wide, with corners rounded at a radius of about 0.033″.  
      In the illustrated embodiment, conductive layer  414  may be constructed according to the following dimensions, which are to be understood as exemplary; accordingly the dimensions may be varied as desired. The conductive layer  414  has an overall length and width of about 1.170″, with a central opening of about 0.590″ long by 0.470″ wide. Generally, the conductive layer  414  is about 0.035″ thick; however, the protrusions  426  extend a further 0.075″-0.085″ above the basic thickness of the conductive layer  414 . Each protrusion  426  is about 0.343″ long by about 0.076″ wide, with corners rounded at a radius of about 0.035″.  
      As shown in  FIG. 6B , first and second clamping plates  450  and  452  may be used to clamp the portions of the window mounting system  400  to one another. For example, the second clamping plate  452  is configured to clamp the window assembly  12  and the first PCB  402  to the diffuser  410  with screws or other fasteners extending through the openings shown in the second clamping plate  452 , the heat spreader layer  412  and the conductive layer  414 . Similarly, the first clamping plate  450  is configured to overlie the second clamping plate  452  and clamp the rest of the window mounting system  400  to the heat sink  419 , thus sandwiching the second clamping plate  452 , the window assembly  12 , the first PCB  402 , the diffuser  410 , the second PCB  403 , and the TEC  418  therebetween. The first clamping plate  450  prevents undesired contact between the sample S and any portion of the window mounting system  400 , other than the window assembly  12  itself. Other mounting plates and mechanisms may also be used as desired.  
      d. Optics  
      As shown in  FIG. 1 , the optical mixer  20  comprises a light pipe with an inner surface coating which is highly reflective and minimally absorptive in infrared wavelengths, preferably a polished gold coating, although other suitable coatings may be used where other wavelengths of electromagnetic radiation are employed. The pipe itself may be fabricated from a another rigid material such as aluminum or stainless steel, as long as the inner surfaces are coated or otherwise treated to be highly reflective. Preferably, the optical mixer  20  has a rectangular cross-section (as taken orthogonal to the longitudinal axis A-A of the mixer  20  and the collimator  22 ), although other cross-sectional shapes, such as other polygonal shapes or circular or elliptical shapes, may be employed in alternative embodiments. The inner walls of the optical mixer  20  are substantially parallel to the longitudinal axis A-A of the mixer  20  and the collimator  22 . The highly reflective and substantially parallel inner walls of the mixer  20  maximize the number of times the infrared energy E will be reflected between the walls of the mixer  20 , thoroughly mixing the infrared energy E as it propagates through the mixer  20 . In a presently preferred embodiment, the mixer  20  is about 1.2 inches to 2.4 inches in length and its cross-section is a rectangle of about 0.4 inches by about 0.6 inches. Of course, other dimensions may be employed in constructing the mixer  20 . In particular it is advantageous to miniaturize the mixer or otherwise make it as small as possible  
      Still referring to  FIG. 1 , the collimator  22  comprises a tube with an inner surface coating which is highly reflective and minimally absorptive in infrared wavelengths, preferably a polished gold coating. The tube itself may be fabricated from a another rigid material such as aluminum, nickel or stainless steel, as long as the inner surfaces are coated or otherwise treated to be highly reflective. Preferably, the collimator  22  has a rectangular cross-section, although other cross-sectional shapes, such as other polygonal shapes or circular, parabolic or elliptical shapes, may be employed in alternative embodiments. The inner walls of the collimator  22  diverge as they extend away from the mixer  20 . Preferably, the inner walls of the collimator  22  are substantially straight and form an angle of about 7 degrees with respect to the longitudinal axis A-A. The collimator  22  aligns the infrared energy E to propagate in a direction that is generally parallel to the longitudinal axis A-A of the mixer  20  and the collimator  22 , so that the infrared energy E will strike the surface of the filters  24  at an angle as close to  90  degrees as possible.  
      In a presently preferred embodiment, the collimator is about 7.5 inches in length. At its narrow end  22   a , the cross-section of the collimator  22  is a rectangle of about 0.4 inches by 0.6 inches. At its wide end  22   b , the collimator  22  has a rectangular cross-section of about 1.8 inches by 2.6 inches. Preferably, the collimator  22  aligns the infrared energy E to an angle of incidence (with respect to the longitudinal axis A-A) of about 0-15 degrees before the energy E impinges upon the filters  24 . Of course, other dimensions or incidence angles may be employed in constructing and operating the collimator  22 .  
      With further reference to  FIGS. 1 and 6 A, each concentrator  26  comprises a tapered surface oriented such that its wide end  26   a  is adapted to receive the infrared energy exiting the corresponding filter  24 , and such that its narrow end  26   b  is adjacent to the corresponding detector  28 . The inward-facing surfaces of the concentrators  26  have an inner surface coating which is highly reflective and minimally absorptive in infrared wavelengths, preferably a polished gold coating. The concentrators  26  themselves may be fabricated from a another rigid material such as aluminum, nickel or stainless steel, so long as their inner surfaces are coated or otherwise treated to be highly reflective.  
      Preferably, the concentrators  26  have a rectangular cross-section (as taken orthogonal to the longitudinal axis A-A), although other cross-sectional shapes, such as other polygonal shapes or circular, parabolic or elliptical shapes, may be employed in alternative embodiments. The inner walls of the concentrators converge as they extend toward the narrow end  26   b . Preferably, the inner walls of the concentrators  26  are substantially straight and form an angle of about 8 degrees with respect to the longitudinal axis A-A. Such a configuration is adapted to concentrate infrared energy as it passes through the concentrators  26  from the wide end  26   a  to the narrow end  26   b , before reaching the detectors  28 .  
      In a presently preferred embodiment, each concentrator  26  is about 1.5 inches in length. At the wide end  26   a , the cross-section of each concentrator  26  is a rectangle of about 0.6 inches by 0.57 inches. At the narrow end  26   b , each concentrator  26  has a rectangular cross-section of about 0.177 inches by 0.177 inches. Of course, other dimensions or incidence angles may be employed in constructing the concentrators  26 .  
      e. Filters  
      The filters  24  preferably comprise standard interference-type infrared filters, widely available from manufacturers such as Optical Coating Laboratory, Inc. (“OCLI”) of Santa Rosa, Calif. In the embodiment illustrated in  FIG. 1 , a 3×4 array of filters  24  is positioned above a 3×4 array of detectors  28  and concentrators  26 . As employed 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, which correspond to wavelengths around which water and glucose absorb electromagnetic radiation. Typical bandwidths for these filters range from 0.20 μm to 0.50 μm.  
      In an alternative embodiment, the array of wavelength-specific filters  24  may be replaced with a single Fabry-Perot interferometer, which can provide wavelength sensitivity which varies as a sample of infrared energy E is taken from the material sample S. Thus, this embodiment permits the use of only one detector  28 , the output signal of which varies in wavelength specificity over time. The output signal can be de-multiplexed based on the wavelength sensitivities induced by the Fabry-Perot interferometer, to provide a multiple-wavelength profile of the infrared energy E emitted by the material sample S. In this embodiment, the optical mixer  20  may be omitted, as only one detector  28  need be employed.  
      In still other embodiments, the array of filters  24  may comprise a filter wheel that rotates different filters with varying wavelength sensitivities over a single detector  24 . Alternatively, an electronically tunable infrared filter may be employed in a manner similar to the Fabry-Perot interferometer discussed above, to provide wavelength sensitivity which varies during the detection process. In either of these embodiments, the optical mixer  20  may be omitted, as only one detector  28  need be employed.  
      f. Detectors  
      The detectors  28  may comprise any detector type suitable for sensing infrared energy, preferably in the mid-infrared wavelengths. For example, the detectors  28  may comprise mercury-cadmium-telluride (“MCT”) detectors. A detector such as a Fermionics (Simi Valley, Calif.) model PV-9.1 with a PVA481-1 pre-amplifier is acceptable. Similar units from other manufacturers such as Graseby (Tampa, Fla.) can be substituted. Other suitable components for use as the detectors  28  include pyroelectric detectors, thermopiles, bolometers, silicon microbolometers and lead-salt focal plane arrays.  
      g. Control System  
       FIG. 7  depicts the control system  30  in greater detail, as well as the interconnections between the control system  30  and other relevant portions of the noninvasive system  10 . The control system  30  includes a temperature control subsystem and a data acquisition subsystem.  
      In the temperature control subsystem, temperature sensors (such as RTDs and/or thermistors) located in the window assembly  12  provide a window temperature signal to a synchronous analog-to-digital (“A/D”) conversion system  70  and an asynchronous A/D conversion system  72 . The A/D systems  70 ,  72  in turn provide a digital window temperature signal 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  of the window assembly  12  and/or for the cooling system  14 , based on the information contained in the window temperature signal. The processor  74  outputs one or more digital control signals to a digital-to-analog (“D/A”) conversion system  76  which in turn provides one or more analog control signals to current drivers  78 . In response to the control signal(s), the current drivers  78  regulate the power supplied to the heater layer  34  and/or to the cooling system  14 . In one embodiment, the processor  74  provides a control signal through a digital input/output (“I/O”) device  77  to a pulse-width modulator (“PWM”) control  80 , which provides a signal that controls the operation of the current drivers  78 . Alternatively, a low-pass filter (not shown) at the output of the PWM provides for continuous operation of the current drivers  78 .  
      In another embodiment, temperature sensors may be located at the cooling system  14  and appropriately connected to the A/D system(s) and processor to provide closed-loop control of the cooling system as well.  
      In yet another embodiment, a detector cooling system  82  is located in thermally conductive relation to one or more of the detectors  28 . The detector cooling system  82  may comprise any of the devices disclosed above as comprising 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 electrical connections between these sensors and the asynchronous A/D system  72 . The temperature sensors of the detector cooling system  82  provide detector temperature signals to the processor  74 . In one embodiment, the detector cooling system  82  operates independently of the window temperature control system, and the detector cooling system temperature signals are sampled using the asynchronous A/D system  72 . In accordance with the temperature control algorithm, the processor  74  determines appropriate control inputs for the detector cooling system  82 , based on the information contained in the detector temperature signal. The processor  74  outputs digital control signals to the D/A conversion system  76  which in turn provides analog control signals to the current drivers  78 . In response to the control signals, the current drivers  78  regulate 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 control  80 , to control the operation of the detector cooling system  82  by the current drivers  78 . Alternatively, a low-pass filter (not shown) at the output of the PWM provides for continuous operation of the current drivers  78 .  
      In the data acquisition subsystem, the detectors  28  respond to the infrared energy E incident thereon by passing one or more analog detector signals to a preamp  84 . The preamp  84  amplifies the detector signals and passes them to the synchronous A/D system  70 , which converts the detector signals to digital form and passes them to the processor  74 . The processor  74  determines the concentrations of the analyte(s) of interest, based on the detector signals and a concentration-analysis algorithm and/or phase/concentration regression model stored in a memory module  88 . The concentration-analysis algorithm and/or phase/concentration regression model may be developed according to any of the analysis methodologies discussed herein. The processor  74  may communicate the concentration results and/or other information to a display controller  86 , which operates a display (not shown), such as a liquid crystal display (“LCD”), to present the information to the user.  
      A watchdog timer  94  may be employed 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  94  resets the processor  74 . The control system may also include a joint test action group (“JTAG”) interface  96  to enable testing of the noninvasive system  10 .  
      In one embodiment, the synchronous A/D system  70  comprises a 20-bit, 14 channel system, and the asynchronous A/D system  72  comprises a 16-bit, 16 channel system. The preamp  84  may comprise a 12-channel preamp corresponding to an array of 12 detectors  28 .  
      The control system may also include a serial port  90  or other conventional data port to permit connection to a personal computer  92 . The personal computer  92  can be employed to update the algorithm(s) and/or phase/concentration regression model(s) stored in the memory module  88 , or to download a compilation of analyte-concentration data from the noninvasive system  10 . A real-time clock or other timing device may be accessible by the processor  74  to make any time-dependent calculations which may be desirable to a user.  
      2. Analysis Methodology  
      The detector(s)  28  of the noninvasive system  10  are used to detect the infrared energy E emitted by the material sample S in various desired wavelengths. At each measured wavelength, the material sample S emits infrared energy at an intensity which varies over time. The time-varying intensities arise largely in response to the use of the window assembly  12  (including its heater layer  34 ) and the cooling system  14  to induce a thermal gradient in the material sample S. As used herein, “thermal gradient” is a broad term and is used in its ordinary sense and refers, without limitation, to a difference in temperature and/or thermal energy between different locations, such as different depths, of a material sample, which can be induced by any suitable method of increasing or decreasing the temperature and/or thermal energy in one or more locations of the sample. As will be discussed in detail below, the concentration of an analyte of interest (such as glucose) in the material sample S can be determined with a device such as the noninvasive system  10 , by comparing the time-varying intensity profiles of the various measured wavelengths.  
      Analysis methodologies are discussed herein within the context of detecting the concentration of glucose within a material sample, such as a tissue sample, which includes a large proportion of water. However, it will evident that these methodologies are not limited to this context 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 analysis methodologies and suitable variations of the disclosed methodologies may be employed in operating an analyte detection system, such as the noninvasive system  10 .  
      As shown in  FIG. 8 , a first reference signal P may be measured at a first reference wavelength. The first reference signal P is measured at a wavelength where water strongly absorbs (for example, 2.9 μm or 6.1 μm). Because water strongly absorbs radiation at these wavelengths, the detector signal intensity is reduced at those wavelengths. Moreover, at these wavelengths water absorbs the photon emissions emanating from deep inside the sample. The net effect is that a signal emitted at these wavelengths from deep inside the sample is not easily detected. The first reference signal P is thus a good indicator of thermal-gradient effects near the sample surface and may be known as a surface reference signal. This signal may be calibrated and normalized, in the absence of heating or cooling applied to the sample, to a baseline value of  1 . For greater accuracy, more than one first reference wavelength may be measured. For example, both 2.9 μm and 6.1 μm may be chosen as first reference wavelengths.  
      As further shown in  FIG. 8 , a second reference signal R may also be measured. The second signal R may be measured at a wavelength where water has very low absorbance (for example, 3.6 μm or 4.2 μm). This second reference signal R thus provides the analyst with information concerning the deeper regions of the sample, whereas the first signal P provides information concerning the sample surface. This signal may also be calibrated and normalized, in the absence of heating or cooling applied to the sample, to a baseline value of 1. As with the first (surface) reference signal P, greater accuracy may be obtained by using more than one second (deep) reference signal R.  
      To determine analyte concentration, a third (analytical) signal Q is also measured. This signal is measured at an infrared absorbance peak of the selected analyte. The infrared absorbance peaks for glucose are in the range of about 6.5 μm to 11.0 μm. This detector signal may also be calibrated and normalized, in the absence of heating or cooling applied to the material sample S, to a baseline value of 1. As with the reference signals P, R, the analytical signal Q may be measured at more than one absorbance peak.  
      Optionally, or additionally, reference signals may be measured at wavelengths that bracket the analyte absorbance peak. These signals may be advantageously monitored at reference wavelengths which do not overlap the analyte absorbance peaks. Further, it is advantageous to measure reference wavelengths at absorbance peaks which do not overlap the absorbance peaks of other possible constituents contained in the sample.  
      a. Basic Thermal Gradient  
      As further shown in  FIG. 8 , the intensities of the signals P, Q, R are shown initially at the normalized baseline signal intensity of 1. This of course reflects the baseline radiative behavior of a test sample in the absence of applied heating or cooling. At a time t C , the surface of the sample is subjected to a temperature event which induces a thermal gradient in the sample. The gradient can be induced by heating or cooling the sample surface. The example shown in  FIG. 8  uses cooling, for example, using a 10° C. cooling event. In response to the cooling event, the intensities of the detector signals P, Q, R decrease over time.  
      Since the cooling of the sample is neither uniform nor instantaneous, the surface cools before the deeper regions of the sample cool. As each of the signals P, Q, R drop in intensity, a pattern emerges. Signal intensity declines as expected, but as the signals P, Q, R reach a given amplitude value (or series of amplitude values:  150 ,  152 ,  154 ,  156 ,  158 ), certain temporal effects are noted. After the cooling event is induced at t C , the first (surface) reference signal P declines in amplitude most rapidly, reaching a checkpoint  150  first, at time t P . This is due to the fact that the first reference signal P mirrors the sample&#39;s radiative characteristics near the surface of the sample. Since the sample surface cools before the underlying regions, the surface (first) reference signal P drops in intensity first.  
      Simultaneously, the second reference signal R is monitored. Since the second reference signal R corresponds to the radiation characteristics of deeper regions of the sample, which do not cool as rapidly as the surface (due to the time needed for the surface cooling to propagate into the deeper regions of the sample), the intensity of signal R does not decline until slightly later. Consequently, the signal R does not reach the magnitude  150  until some later time t R . In other words, there exists a time delay between the time t P  at which the amplitude of the first reference signal P reaches the checkpoint  150  and the time t R  at which the second reference signal R reaches the same checkpoint  150 . This time delay can be expressed as a phase difference Φ(λ). Additionally, a phase difference may be measured between the analytical signal Q and either or both reference signals P, R.  
      As the concentration of analyte increases, the amount of absorbance at the analytical wavelength increases. This reduces the intensity of the analytical signal Q in a concentration-dependent way. Consequently, the analytical signal Q reaches intensity  150  at some intermediate time t Q . The higher the concentration of analyte, the more the analytical signal Q shifts to the left in  FIG. 8 . As a result, with increasing analyte concentration, the phase difference Φ(λ) decreases relative to the first (surface) reference signal P and increases relative to the second (deep tissue) reference signal R. The phase difference(s) Φ(λ) are directly related to analyte concentration and can be used to make accurate determinations of analyte concentration.  
      The phase difference Φ(λ) between the first (surface) reference signal P and the analytical signal Q is represented by the 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 analytical signal Q signal is represented by the equation: 
 
Φ(λ)= 51   t   Q   −t   R |
 
 The magnitude of this phase difference increases with increasing analyte concentration. 
 
      Accuracy may be enhanced by choosing several checkpoints, for example,  150 ,  152 ,  154 ,  156 , and  158  and averaging the phase differences observed at each checkpoint. The accuracy of this method may be further enhanced by integrating the phase difference(s) continuously over the entire test period. Because in this example only a single temperature event (here, a cooling event) has been induced, the sample reaches a new lower equilibrium temperature and the signals stabilize at a new constant level l F . Of course, the method works equally well with thermal gradients induced by heating or by the application or introduction of other forms of energy, such as but not limited to light, radiation, chemically induced heat, friction and vibration.  
      This methodology is not limited to the determination of phase difference. At any given time (for example, at a time t X ) the amplitude of the analytical signal Q may be compared to the amplitude of either or both of the reference signals P, R. The difference in amplitude may be observed and processed to determine analyte concentration.  
      This method, the variants disclosed herein, and the apparatus disclosed as suitable for application of the method(s), are not limited to the detection of in-vivo glucose concentration. The method and disclosed variants and apparatus may be used on human, animal, or even plant subjects, or on organic or inorganic compositions in a non-medical setting. The method may be used to take measurements of in-vivo or in-vitro samples of virtually any kind. The method is useful for measuring the concentration of a wide range of additional chemical analytes, including but not limited to, glucose, ethanol, insulin, water, carbon dioxide, blood oxygen, cholesterol, bilirubin, ketones, fatty acids, lipoproteins, albumin, urea, creatinine, white blood cells, red blood cells, hemoglobin, oxygenated hemoglobin, carboxyhemoglobin, organic molecules, inorganic molecules, pharmaceuticals, cytochrome, various proteins and chromophores, microcalcifications, hormones, as well as other chemical compounds. To detect a given analyte, one needs only to select appropriate analytical and reference wavelengths.  
      The method is adaptable and may be used to determine chemical concentrations in samples of body fluids (for example, blood, urine or saliva) once they have been extracted from a patient. In fact, the method may be used for the measurement of in-vitro samples of virtually any kind.  
      b. Modulated Thermal Gradient  
      In some embodiments of the methodology described above, a periodically modulated thermal gradient can be employed to make accurate determinations of analyte concentration.  
      As previously shown in  FIG. 8 , once a thermal gradient is induced in the sample, the reference and analytical signals P, Q, R fall out of phase with respect to each other. This phase difference Φ(λ) is present whether the thermal gradient is induced through heating or cooling. By alternatively subjecting the test sample to cyclic pattern of heating, cooling, or alternately heating and cooling, an oscillating thermal gradient may be induced in a sample for an extended period of time.  
      An oscillating thermal gradient is illustrated using a sinusoidally modulated gradient.  FIG. 9  depicts detector signals emanating from a test sample. As with the methodology shown in  FIG. 8 , one or more reference signals J, L are measured. One or more analytical signals K are also monitored. These signals may be calibrated and normalized, in the absence of heating or cooling applied to the sample, to a baseline value of 1.  FIG. 9  shows the signals after normalization. At some time t C , a temperature event (for example, cooling) is induced at the sample surface. This causes a decline in the detector signal. As shown in  FIG. 8 , the signals (P, Q, R) decline until the thermal gradient disappears and a new equilibrium detector signal l F  is reached. In the method shown in  FIG. 9 , as the gradient begins to disappear at a signal intensity  160 , a heating event, at a time t W , is induced in the sample surface. As a result the detector output signals J, K, L will rise as the sample temperature rises. At some later time t C2 , another cooling event is induced, causing the temperature and detector signals to decline. This cycle of cooling and heating may be repeated over a time interval of arbitrary length. Moreover, if the cooling and heating events are timed properly, a periodically modulated thermal gradient may be induced in the test sample.  
      As previously explained in the discussions relating to  FIG. 8 , the phase difference Φ(λ) may be measured and used to determine analyte concentration.  
       FIG. 9  shows that the first (surface) reference signal J declines and rises in intensity first. The second (deep tissue) reference signal L declines and rises in a time-delayed manner relative to the first reference signal J. The analytical signal K exhibits a time/phase delay dependent on the analyte concentration. With increasing concentration, the analytical signal K shifts to the left in  FIG. 9 . As with  FIG. 8 , the phase difference Φ(λ) may be measured. For example, a phase difference Φ(λ) between the second reference signal L and the analytical signal K, may be measured at a set amplitude  162  as shown in  FIG. 9 . Again, the magnitude of the phase signal reflects the analyte concentration of the sample.  
      The phase-difference information compiled by any of the methodologies disclosed herein can correlated by the control system  30  (see  FIG. 1 ) with previously determined phase-difference information to determine the analyte concentration in the sample. This correlation could involve comparison of the phase-difference information received from analysis of the sample, with a data set containing the phase-difference profiles observed from analysis of wide variety of standards of known analyte concentration. In one embodiment, a phase/concentration curve or regression model is established by applying regression techniques to a set of phase-difference data observed in standards of known analyte concentration. This curve is used to estimate the analyte concentration in a 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 measurements may be integrated over the entire test period for an extremely accurate measure of phase difference Φ(λ). Accuracy may also be improved by using more than one reference signal and/or more than one analytical signal.  
      As an alternative or as a supplement to measuring phase difference(s), differences in amplitude between the analytical and reference signal(s) may be measured and employed to determine analyte concentration. Additional details relating to this technique and not necessary to repeat here may be found in U.S. patent application Ser. No. 09/538,164, incorporated by reference below.  
      Additionally, these methods may be advantageously employed to simultaneously measure the concentration of one or more analytes. By choosing reference and analyte wavelengths that do not overlap, phase differences can be simultaneously measured and processed to determine analyte concentrations. Although  FIG. 9  illustrates the method used in conjunction with a sinusoidally modulated thermal gradient, the principle applies to thermal gradients conforming to any periodic function. In more complex cases, analysis using signal processing with Fourier transforms or other techniques allows accurate determinations of phase difference Φ(λ) and analyte concentration.  
      As shown in  FIG. 10 , the magnitude of the phase differences may be determined by measuring the time intervals between the amplitude peaks (or troughs) of the reference signals J, L and the analytical signal K. Alternatively, the time intervals between the “zero crossings” (the point at which the signal amplitude changes from positive to negative, or negative to positive) may be used to determine the phase difference between the analytical signal K and the reference signals J, L. This information is subsequently processed and a determination of analyte concentration may then be made. This particular method has the advantage of not requiring normalized signals.  
      As a further alternative, two or more driving frequencies may be employed to determine analyte concentrations at selected depths within the sample. A slow (for example, 1 Hz) driving frequency creates a thermal gradient which penetrates deeper into the sample than the gradient created by a fast (for example, 3 Hz) driving frequency. This is because the individual heating and/or cooling events are longer in duration where the driving frequency is lower. Thus, the use of a slow driving frequency provides analyte-concentration information from a deeper “slice” of the sample than does the use of a fast driving frequency.  
      It has been found that when analyzing a sample of human skin, a temperature event of 10° C. creates a thermal gradient which penetrates to a depth of about 150 μm, after about 500 ms of exposure. Consequently, a cooling/heating cycle or driving frequency of 1 Hz provides information to a depth of about 150 μm. It has also been determined that exposure to a temperature event of 10° C. for about 167 ms creates a thermal gradient that penetrates to a depth of about 50 μm. Therefore, a cooling/heating cycle of 3 Hz provides information to a depth of about 50 μm. By subtracting the detector signal information measured at a 3 Hz driving frequency from the detector signal information measured at a 1 Hz driving frequency, one can determine the analyte concentration(s) in the region of skin between 50 and 150 μm. Of course, a similar approach can be used to determine analyte concentrations at any desired depth range within any suitable type of sample.  
      As shown in  FIG. 11 , alternating deep and shallow thermal gradients may be induced by alternating slow and fast driving frequencies. As with the methods described above, this variation also involves the detection and measurement of phase differences Φ(λ) between reference signals G, G′ and analytical signals H, H′. Phase differences are measured at both fast (for example, 3 Hz) and slow (for example, 1 Hz) driving frequencies. The slow driving frequency may continue for an arbitrarily chosen number of cycles (in region SL 1 ), for example, two full cycles. Then the fast driving frequency is employed for a selected duration, in region F 1 . The phase difference data is compiled in the same manner as disclosed above. In addition, the fast frequency (shallow sample) phase difference data may be subtracted from the slow frequency (deep sample) data to provide an accurate determination of analyte concentration in the region of the sample between the gradient penetration depth associated with the fast driving frequency and that associated with the slow driving frequency.  
      The driving frequencies (for example, 1 Hz and 3 Hz) can be multiplexed as shown in  FIG. 12 . The fast (3 Hz) and slow (1 Hz) driving frequencies can be superimposed rather than sequentially implemented. During analysis, the data can be separated by frequency (using Fourier transform or other techniques) and independent measurements of phase delay at each of the driving frequencies may be calculated. Once resolved, the two sets of phase delay data are processed to determine absorbance and analyte concentration.  
      Additional details not necessary to repeat here may be found in U.S. Pat. No. 6,198,949, titled SOLID-STATE NON-INVASIVE INFRARED ABSORPTION SPECTROMETER FOR THE GENERATION AND CAPTURE OF THERMAL GRADIENT SPECTRA FROM LIVING TISSUE, issued Mar. 6, 2001; U.S. Pat. No. 6,161,028, titled METHOD FOR DETERMINING ANALYTE CONCENTRATION USING PERIODIC TEMPERATURE MODULATION AND PHASE DETECTION, issued Dec. 12, 2000; U.S. Pat. No. 5,877,500, titled MULTICHANNEL INFRARED DETECTOR WITH OPTICAL CONCENTRATORS FOR EACH CHANNEL, issued on Mar. 2, 1999; U.S. patent application Ser. No. 09/538,164, filed Mar. 30, 2000 and titled METHOD AND APPARATUS FOR DETERMINING ANALYTE CONCENTRATION USING PHASE AND MAGNITUDE DETECTION OF A RADIATION TRANSFER FUNCTION; U.S. Provisional Patent Application No. 60/336,404, filed Oct. 29, 2001 and titled WINDOW ASSEMBLY; U.S. Provisional Patent Application No. 60/340,435, filed Dec. 12, 2001 and titled CONTROL SYSTEM FOR BLOOD CONSTITUENT MONITOR; U.S. Provisional Patent Application No. 60/340,654, filed Dec. 12, 2001 and titled SYSTEM AND METHOD FOR CONDUCTING AND DETECTING INFRARED RADIATION; U.S. Provisional Patent Application No. 60/336,294, filed Oct. 29, 2001 and titled METHOD AND DEVICE FOR INCREASING ACCURACY OF BLOOD CONSTITUENT MEASUREMENT; and U.S. Provisional Patent Application No. 60/339,116, filed Nov. 7, 2001 and titled METHOD AND APPARATUS FOR IMPROVING CLINICALLY SIGNIFICANT ACCURACY OF ANALYTE MEASUREMENTS. The entire disclosure of all of the above-mentioned patents, patent applications and publications (less any appendices thereto) are hereby incorporated by reference herein and made a part of this specification.  
      B. Whole-Blood Detection System  
       FIG. 13  is a schematic view of a reagentless whole-blood analyte detection system  200  (hereinafter “whole-blood system”) in a preferred configuration. The whole-blood system  200  may comprise a radiation source  220 , a filter  230 , a cuvette  240  that includes a sample cell  242 , and a radiation detector  250 . The whole-blood system  200  preferably also comprises a signal processor  260  and a display  270 . Although a cuvette  240  is shown here, other sample elements, as described below, could also be used in the system  200 . The whole-blood system  200  can also comprise a sample extractor  280 , which can be used to access bodily fluid from an appendage, such as the finger  290 , forearm, or any other suitable location.  
      As used herein, the terms “whole-blood analyte detection system” and “whole-blood system” are broad, synonymous terms and are used in their ordinary sense and refer, without limitation, to analyte detection devices which can determine the concentration of an analyte in a material sample by passing electromagnetic radiation into the sample and detecting the absorbance 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 refers, without limitation, to blood that has been withdrawn from a patient but that has not been otherwise processed, for example, it has not been hemolyzed, lyophilized, centrifuged, or separated in any other manner, after being removed from the patient. Whole-blood may contain amounts of other fluids, such as interstitial fluid or intracellular fluid, which may enter the sample during the withdrawal process or are naturally present in the blood. It should be understood, however, that the whole-blood system  200  disclosed herein is not limited to analysis of whole-blood, as the whole-blood system  200  may be employed to analyze other substances, such as saliva, urine, sweat, interstitial fluid, intracellular fluid, hemolyzed, lyophilized, or centrifuged blood or any other organic or inorganic materials.  
      The whole-blood system  200  may comprise a near-patient testing system. As used herein, “near-patient testing system” is a broad term and is used in its ordinary sense, and includes, without limitation, test systems that are configured to be used where the patient is rather than exclusively in a laboratory, for example, systems that can be used at a patient&#39;s home, in a clinic, in a hospital, or even in a mobile environment. Users of near-patient testing systems can include patients, family members of patients, clinicians, nurses, or doctors. A “near-patient testing system” could also include a “point-of-care” system.  
      The whole-blood system  200  may in one embodiment be configured to be operated easily by the patient or user. As such, the system  200  is preferably a portable device. As used herein, “portable” is a broad term and is used in its ordinary sense and means, without limitation, that the system  200  can be easily transported by the patient and used where convenient. For example, the system  200  is advantageously small. In one preferred embodiment, the system  200  is small enough to fit into a purse or backpack. In another embodiment, the system  200  is small enough to fit into a pants pocket. In still another embodiment, the system  200  is small enough to be held in the palm of a hand of the user.  
      Some of the embodiments described herein employ a sample element to hold a material sample, such as a sample of biological fluid. As used herein, “sample element” is a broad term and is used in its ordinary sense and includes, without limitation, structures that have a sample cell and at least one sample cell wall, but more generally includes any of a number of structures that can hold, support or contain a material sample and that allow electromagnetic radiation to pass through a sample held, supported or contained thereby; for example, a cuvette, test strip, and so forth. As used herein, the term “disposable” when applied to a component, such as a sample element, is a broad term and is used in its ordinary sense and means, without limitation, that the component in question is used a finite number of times and then discarded. Some disposable components are used only once and then discarded. Other disposable components are used more than once and then discarded.  
      The radiation source  220  of the whole-blood system  200  emits electromagnetic radiation in any of a number of spectral ranges, for example, within infrared wavelengths; in the mid-infrared wavelengths; above about 0.8 μm; between about 5.0 μm and about 20.0 μm; and/or between about 5.25 μm and about 12.0 μm. However, in other embodiments the whole-blood system  200  may employ a radiation source  220  which emits in wavelengths found anywhere from the visible spectrum through the microwave spectrum, for example anywhere from about 0.4 μm to greater than about 100 μm. In still further embodiments the radiation source emits electromagnetic radiation in wavelengths 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 between about 20 μm and about 100 μm, or between about 6.85 μm and about 10.10 μm. As used herein, “source” is a broad term, and is used in its ordinary sense and further refers, without limitation, to anything that emits electromagnetic radiation, or that causes electromagnetic radiation to be emitted.  
      The radiation emitted from the source  220  is in one embodiment modulated at a frequency between about one-half hertz and about one hundred hertz, in another embodiment between about 2.5 hertz and about 7.5 hertz, in still another embodiment at about 50 hertz, and in yet another embodiment at about 5 hertz. With a modulated radiation source, ambient light sources, such as a flickering fluorescent lamp, can be more easily identified and rejected when analyzing the radiation incident on the detector  250 . One source that is suitable for this application is produced by Ion Optics, Inc., and sold under the part number NL5LNC.  
      The filter  230  permits electromagnetic radiation of selected wavelengths to pass through and impinge upon the cuvette/sample element  240 . Preferably, the filter  230  permits radiation at least at about the following wavelengths to pass through to the cuvette/sample element: 3.9 μm, 4.0 μm, 4.05 μm, 4.2 μm, 4.75 μm, 4.95 μm, 5.25 μm, 6.12 μm, 7.4 μm, 8.0 μm, 8.45 μm, 9.25 μm, 9.5 μm, 9.65 μm, 10.4 μm, 12.2 μm. In another embodiment, the filter  230  permits radiation at least at about the following wavelengths to pass through to the cuvette/sample element: 5.25 μm, 6.12 μm, 6.8 μm, 8.03 μm, 8.45 μm, 9.25 μm, 9.65 μm, 10.4 μm, 12 μm. In still another embodiment, the filter  230  permits radiation at least at about the following wavelengths to pass through to the cuvette/sample element: 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. The sets of wavelengths recited above correspond to specific embodiments within the scope of this disclosure. Furthermore, other subsets of the foregoing sets or other combinations of wavelengths can be selected. Finally, other sets of wavelengths can be selected within the scope of this disclosure based on cost of production, development time, availability, and other factors relating to cost, manufacturability, and time to market of the filters used to generate the selected wavelengths, and/or reduction of the total number of filters needed.  
      In one embodiment, the filter  230  is capable of cycling its passband among a variety of narrow spectral bands or a variety of selected wavelengths. The filter  230  may thus comprise a solid-state tunable infrared filter, such as that available from Ion Optics, Inc. The filter  230  could also be implemented as a filter wheel with a plurality of fixed-passband filters mounted on the wheel, generally perpendicular to the direction of the radiation emitted by the source  220 . Rotation of the filter wheel alternately presents filters that pass radiation at wavelengths that vary in accordance with the filters as they pass through the field of view of the detector  250 .  
      The detector  250  preferably comprises a 3 mm long by 3 mm wide pyroelectric detector. Suitable examples are produced by DIAS Angewandte Sensorik GmbH of Dresden, Germany, or by BAE Systems (such as its TGS model detector). The detector  250  could alternatively comprise a thermopile, a bolometer, a silicon microbolometer, a lead-salt focal plane array, or a mercury-cadmium-telluride (“MCT”) detector. Whichever structure is used as the detector  250 , it is desirably configured to respond to the radiation incident upon its active surface  254  to produce electrical signals that correspond to the incident radiation.  
      In one embodiment, the sample element comprises a cuvette  240  which in turn comprises a sample cell  242  configured to hold a sample of tissue and/or fluid (such as whole-blood, blood components, interstitial fluid, intercellular fluid, saliva, urine, sweat and/or other organic or inorganic materials) from a patient within its sample cell. The cuvette  240  is installed in the whole-blood system  200  with the sample cell  242  located at least partially 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  detects the radiation signal strength at the wavelength(s) of interest. Based on this signal strength, the signal processor  260  determines the degree to which the sample in the 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 comprise a sample extractor  280 . As used herein, the term “sample extractor” is a broad term and is used in its ordinary sense and refers, without limitation, to any device which is suitable for drawing a sample material, such as whole-blood, other bodily fluids, or any other sample material, through the skin of a patient. In various embodiments, the sample extractor may comprise a lance, laser lance, iontophoretic sampler, gas-jet, fluid-jet or particle-jet perforator, ultrasonic enhancer (used with or without a chemical enhancer), or any other suitable device.  
      As shown in  FIG. 13 , the sample extractor  280  could form an opening in an appendage, such as the finger  290 , to make whole-blood available to the cuvette  240 . It should be understood that other appendages could be used to draw the sample, including but not limited to the forearm. With some embodiments of the sample extractor  280 , the user forms a tiny hole or slice through the skin, through which flows a sample of bodily fluid such as whole-blood. Where the sample extractor  280  comprises a lance (see  FIG. 14 ), the sample extractor  280  may comprise a sharp cutting implement made of metal or other rigid materials. One suitable laser lance is the Lasette Plus® produced by Cell Robotics International, Inc. of Albuquerque, N. Mex. If a laser lance, iontophoretic sampler, gas-jet or fluid-jet perforator is used as the sample extractor  280 , it could be incorporated into the whole-blood system  200  (see  FIG. 13 ), or it could be a separate device.  
      Additional information on laser lances can be found in U.S. Pat. No. 5,908,416, issued Jun. 1, 1999, titled LASER DERMAL PERFORATOR; the entirety of this patent 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 U.S. Pat. No. 6,207,400, issued Mar. 27, 2001, titled NON- OR MINIMALLY INVASIVE MONITORING METHODS USING PARTICLE DELIVERY METHODS; the entirety of this patent is hereby incorporated by reference herein and made a part of this specification. One suitable iontophoretic sampler is disclosed in U.S. Pat. No. 6,298,254, issued Oct. 2, 2001, titled DEVICE FOR SAMPLING SUBSTANCES USING ALTERNATING POLARITY OF IONTOPHORETIC CURRENT; the entirety of this patent is hereby incorporated by reference herein and made a part of this specification. One suitable ultrasonic enhancer, and chemical enhancers suitable for use therewith, are disclosed in U.S. Pat. No. 5,458,140, issued Oct. 17, 1995, titled ENHANCEMENT OF TRANSDERMAL MONITORING APPLICATIONS WITH ULTRASOUND AND CHEMICAL ENHANCERS; the entire disclosure of this patent is hereby incorporated by reference and made a part of this specification.  
       FIG. 14  shows one embodiment of a sample element, in the form of a cuvette  240 , in greater detail. The cuvette  240  further comprises a sample supply passage  248 , a pierceable portion  249 , a first window  244 , and a second window  246 , with the sample cell  242  extending between the first and second windows  244 ,  246 . In one embodiment, the cuvette  240  does not have a second window  246 . The first window  244  (or second window  246 ) is one form of a sample cell wall; in other embodiments of the sample elements and cuvettes disclosed herein, any sample cell wall may be used that at least partially contains, holds or supports a material sample, such as a biological fluid sample, and which is transmissive of at least some bands of electromagnetic radiation, and which may but need not be transmissive of electromagnetic radiation in the visible range. The pierceable portion  249  is an area of the sample supply passage  248  that can be pierced by suitable embodiments of the sample extractor  280 . Suitable embodiments of the sample extractor  280  can pierce the portion  249  and the appendage  290  to create a wound in the appendage  290  and to provide an inlet for the blood or other fluid from the wound to enter the cuvette  240 . (The sample extractor  280  is shown on the opposite side of the sample element in  FIG. 14 , as compared to  FIG. 13 , as it may pierce the pierceable portion  249  from either side.)  
      The windows  244 ,  246  are preferably optically transmissive in the range of electromagnetic radiation that is emitted by the source  220 , or that is permitted to pass through the filter  230 . In one embodiment, the material that makes up the windows  244 ,  246  is completely transmissive, that is, it does not absorb any of the electromagnetic radiation from the source  220  and filter  230  that is incident upon it. In another embodiment, the material of the windows  244 ,  246  has some absorption in the electromagnetic range of interest, but its absorption is negligible. In yet another embodiment, the absorption of the material 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 stable for only a relatively short period of time, but the whole-blood system  200  is configured to observe the absorption of the material and eliminate it from the analyte measurement before the material properties can change measurably.  
      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. Also, polypropylene can be arranged in a number of structures, for example, isotactic, atactic and syndiotactic, which may enhance the flow characteristics of the sample in the sample element. Preferably the windows  244 ,  246  are made of durable and easily manufactureable materials, such as the above-mentioned polypropylene or polyethylene, or silicon or any other suitable material. The windows  244 ,  246  can be made of any suitable polymer, which can be isotactic, atactic or syndiotactic in structure.  
      The distance between the windows  244 ,  246  comprises an optical pathlength and can be between about 1 μm and about 100 μm. In one embodiment, the optical pathlength 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 still another embodiment, the optical pathlength is about 25 μm. The transverse size of each of the windows  244 ,  246  is preferably about equal to the size of the detector  250 . In one embodiment, the windows are round with a diameter of about 3 mm. In this embodiment, where the optical pathlength is about 25 μm the volume of the sample cell  242  is about 0.177 μL. In one embodiment, 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 about 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 the cuvette  240  in one embodiment is about 0.327 μL. Of course, the volume of the cuvette  240 /sample cell  242  can vary, depending on many variables, such as the size and sensitivity of the detectors  250 , the intensity of the radiation emitted by the source  220 , the expected flow properties of the sample, and whether flow enhancers (discussed below) are incorporated into the cuvette  240 . The transport of fluid to the sample cell  242  is achieved preferably through capillary action, but may also be achieved through wicking, or a combination of wicking and capillary action.  
       FIGS. 15 through 17  depict another embodiment of a cuvette  305  that could be used in connection with the whole-blood system  200 . The cuvette  305  comprises 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 comprises a first sample cell window  330  having an inner side  332 , and a second sample cell window  335  having an inner side  337 . As discussed above, the first and second sample cell windows  330 ,  335  in some embodiments also comprise sample cell walls. The cuvette  305  also comprises an opening  317  at the end of the sample supply passage  315  opposite the sample cell  310 . The cuvette  305  is preferably about ¼-⅛ inch wide and about ¾ inch long; however, other dimensions are possible while still achieving the advantages of the cuvette  305 .  
      The sample cell  310  is defined between the inner side  332  of the first sample cell window  330  and the inner side  337  of the second sample cell window  335 . The perpendicular distance T between the two inner sides  332 ,  337  comprises an optical pathlength that can be between about 1 μm and about 1.22 mm. The optical pathlength can alternatively be between about 1 μm and about 100 μm. The optical pathlength could still alternatively be about 80 μm, but is preferably between about 10 μm and about 50 μm. In another embodiment, the optical pathlength is about 25 μm. The first and second windows  330 ,  335  are preferably formed from any of the materials discussed above as possessing sufficient radiation transmissivity. The thickness of each window is preferably as small as possible without overly weakening the sample cell  310  or cuvette  305 .  
      Once a wound is made in the appendage  290 , the opening  317  of the sample supply passage  315  of the cuvette  305  is placed in contact with the fluid that flows 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 fluid obtained 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  improves the capillary action by preventing the buildup of air pressure within the cuvette and allowing the blood to displace the air as the blood flows therein.  
      Other mechanisms may be employed to transport the sample to the sample cell  310 . For example, wicking could be used by providing a wicking material in at least a portion of the sample supply passage  315 . In another variation, wicking and capillary action could be used together to transport the sample to the sample cell  310 . Membranes could also be positioned within the sample supply passage  315  to move the blood while at the same time filtering out components that might complicate the optical measurement performed by the whole-blood system  200 .  
       FIGS. 16 and 16 A depict one approach to constructing the cuvette  305 . In this approach, the cuvette  305  comprises 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 mentioned above, the vent  325  provides an escape for the air that is in the sample cell  310 . While the vent  325  is shown on the first layer  350 , it could also be positioned on the third layer  360 , or could be a cutout in the second layer  355 , and would then be located between the first layer  350  and the third layer  360  The third layer  360  forms the second sample cell window  335 .  
      The second layer  355  may be formed entirely of an adhesive that joins the first and third layers  350 ,  360 . In other embodiments, the second layer  355  may be formed from similar materials as the first and third layers  350 ,  360 , 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 the sample supply passage  315 , the air vent passage  320 , and the sample cell  310 . The thickness of the second layer  355  can be between about 1 μm and about 1.22 mm. This thickness can alternatively be between about 1 μm and about 100 μm. This thickness could 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 constructed as an adhesive film having a cutout portion to define the sample supply and air vent passages  315 ,  320 , or as a cutout surrounded by adhesive.  
      Further information can be found in U.S. patent application Ser. No. 10/055,875, filed Jan. 21, 2002, titled REAGENT-LESS WHOLE-BLOOD GLUCOSE METER. The entire contents of this patent application are hereby incorporated by reference herein and made a part of this specification.  
     II. Layered Spectroscopic Sample Element with Microporous Membrane  
      Disclosed in this section are various embodiments of a sample holder that can be used with the noninvasive system  10  and the whole-blood system  200  described above. Specifically, the sample holders disclosed in this section can be used in place of the cuvette  240  described above in connection with the whole-blood system  200 . Additionally, any of the sample holders disclosed in this section can also be affixed to the window assembly  12  of the noninvasive system  10  described above for measurement of a sample contained in the sample holder by the noninvasive system  10 . In particular, placement of any of the sample holders disclosed in this section on the window assembly  12  allows thermal energy to be delivered to, and infrared energy E to be received from, the material sample S.  
      As described above, to obtain an infrared absorbance spectrum of a material sample S, the material sample S is typically applied to or contained in a sample holder (also referred to hereafter as a “sample cell” or “cell”). This sample holder or cell holds the sample in an optical path between a radiation source and a radiation detector. It is desired that the material used for the sample holder be highly transmissive in the region of the electromagnetic spectrum which is of interest. In addition, the sample holder should not be soluble in, or reactive with, either the sample or the solvent (if any).  
      A sample holder according to a preferred embodiment of the present invention comprises a microporous sheet disposed between two planar support surfaces or faces which facilitate mounting the sample holder on the noninvasive system  10  or in the whole-blood system  200 , both of which are described above. In a modified embodiment, the sample holder further comprises an aperture shield.  
      A. Structural Properties  
       FIG. 18  illustrates a sample holder  500  comprising a microporous sheet  512  disposed between two substantially planar support members  514 . Preferably, the microporous sheet  512  is exposed edgewise along its entire periphery, thus forming a transit opening  518  through which a material sample S can be applied to the microporous sheet  512 . In other embodiments, the microporous sheet  512  is exposed edgewise along only a portion of its periphery, such as along only one edge of a sample holder  500  having a square, rectangular, triangular or other configuration; or such as along one or more arcuate portions of a sample holder  500  having a circular, elliptical or other configuration having one or more curved edges; or such as intermittently along one or more edges of the sample holder  500 . One or more transit openings  518  are thus formed at each such exposed portion. The microporous sheet  512  is configured to hold the material sample S during a spectroscopic analysis. The support members  514  preferably provide the sample holder  500  with a rigid structure, prevent contamination of the material sample S and the spectroscopic equipment, and facilitate the mounting of the sample holder  500  in or on an analyte detection system, including but not limited to a whole-blood system such as the system  200  disclosed herein, or a noninvasive system such as the noninvasive system disclosed herein, or any other suitable whole-blood system or noninvasive system.  
      As used herein, “microporous sheet” is a broad term and is used in its ordinary sense, and further refers, without limitation, to any non-solid material having a network of voids through which a material sample, for example a bodily fluid, can propagate. As used herein, “transit opening” is a broad term and is used in its ordinary sense, and further refers, without limitation, to any region at which a fluid can enter a microporous sheet. As used herein, “planar support member” is a broad term and is used in its ordinary sense, and further refers, without limitation, to any member having structural rigidity greater than or equal to the structural rigidity of the microporous sheet.  
      The microporous sheet  512  is preferably thin, typically being less than about 150 μm thick, and is preferably between about 2.5 μm and about 25 μm thick. Thicker films may be used in some instances, but may tend to lead to greater interference due to the stronger spectral absorbances associated with thicker films. Both the microporous sheet  512  and the support members  514  are preferably inert (that is, non-reactive) with respect to any material sample S, such as any of the bodily fluids or other material sample types disclosed herein, to be applied thereto.  
      The sample holder  500  can have any dimensions sufficient to accommodate a material sample applied thereto and to permit mounting on the analyte detection system in question. For example, in one preferred embodiment, the area of the sample holder is preferably small, ranging from less than 1.0 cm 2  to about 6.0 cm 2  per each face in many instances. It will be understood by one of ordinary skill in the art that larger or smaller sample holders can be used. The increase in sensitivity of modern instruments enables the taking of spectra of small material samples, and therefore small sizes of sample holders can be used.  
      In a preferred embodiment, the microporous sheet  512  and the support members  514  comprise polymeric sheets. In such embodiments, the polymeric sheets preferably have a basis weight between about 0.03 g m −2  and 1.0 g m 2 . Polymeric sheets with lower basis weights may be used in some instances, but may tend to be too weak to support the material sample S. Polymeric sheets with higher basis weights may be used in some instances, but may tend to interfere undesirably with material composition analysis.  
      B. Sample Holder Optical Properties  
      Selection of appropriate components for the microporous sheet  512  and the support members  514  for a particular application will partially depend on the composition of the material sample and on the analysis to be performed thereon. Polymeric films typically scatter a portion of the light incident thereto. Components of the sample holder can be evaluated for use in particular applications by measuring the aggregate baseline transmittance or absorbance of the sample holder  500 . The transmittance T is the ratio of the power of the radiation passed through the sample holder to the power of the radiation incident to the sample holder. Transmittance T is typically expressed as a percentage. Absorbance A is the negative of the log of transmittance. That is, 
 
 A =−log( T ). 
 
      The observed transmittance of the sample holder  500  is a function of overall thickness, porosity of the microporous sheet  512 , light scattering characteristics, and composition. Observed transmittance can also partially depend upon the particular wavelength or wavenumber of interest. In a preferred embodiment, the average baseline transmittance of the sample holder  500  in some or all of the wavelength ranges disclosed above for analysis of bodily fluids is greater than about 1%, is preferably greater than about 10%, and is more preferably greater than about 50%. Expressed in terms of absorbance units, the absorbance of the sample holder  500  is less than about 2, is preferably less than about 1, and is more preferably less than about 0. The average baseline absorbance of the sample holder  500  is readily determined by averaging the absorbance of the sample holder  500  at various points within the wavelength range of interest.  
      The standard deviation (n=20) of the sample holder transmittance variability is a measure of the variation in transmittance of the sample holder at (n=20) different locations on the surface of the sample holder. Sample holder transmittance variability is preferably less than about 25 percent relative, and is more preferably less than about 10 percent relative. To ensure highly probative evaluation of sample holder transmittance variability, it is typically measured at a wavenumber at which the sample holder has an absorbance of about 0.7 to about 1.0 absorbance units. For example, for a sample holder  500  having a polyethylene microporous sheet  512 , sample holder transmittance variability is preferably measured at approximately 6.85 μm. When using a dual beam (dispersive) instrument, a small standard deviation in sample holder variability facilitates more accurate subtraction of the absorbances of the sample holder from those of the material sample S. Similarly, with Fourier transform infrared (“FTIR”) instruments, a small standard deviation in variability permits subtraction of a standard reference spectrum from those of later analyses.  
      Although any microporous polymeric film can be used as a microporous sheet  512  in the sample holder  500 , the microporous sheet  512  preferably is selected to reduce spectral interference caused by the inherent absorbances of the polymer with the absorbance bands being analyzed in the material sample. Likewise, the support members  514  are also preferably selected to reduce spectral interference caused by the inherent absorbances of the support member  514  with the absorbance bands being analyzed in the material sample. Characteristic absorbances of the microporous sheet  512  and the support members  514  are preferably in regions of the infrared spectrum that do not interfere with the absorbances of the material sample. In other words, the sample holder  500  is preferably highly transmissive in the spectral region or regions of interest. For example, as discussed below, except for the region of about 3.33 μm to about 3.57 μm, where its aliphatic carbon-hydrogen stretching is evident as strong absorbances, sheets of polyethylene can be used in sample holders to perform infrared spectroscopic analysis across the wavelength ranges disclosed above for analysis of bodily fluids. Polyethylene exhibits a limited number of other absorbances in other portions of this range, but these are typically narrow, well-defined absorbances that are easily taken into account. For example, TEFLON™ films and KEL-F™ films (chlorotrifluoroethylene polymers and copolymers) are also useful as constituents of the microporous sheet  512  and the support members  514  for spectroscopic analysis in the wavelength ranges disclosed above for analysis of bodily fluids.  
      It should be noted that certain spectroscopic instruments have the capacity to “subtract” background absorbances due to solvents, the cell, the atmosphere, and so forth. In a dispersive-type instrument, the infrared beam is split into two parallel beams. One beam is passed through the sample, and the other reference beam is passed through a “blank” cell. When measuring a spectrum of a material sample dissolved in solvent, a cell containing only pure solvent is placed in the reference beam so that the instrument can subtract the spectrum of the solvent from that of the dissolved sample. Additionally, the spectrum of the background of a blank or reference cell can be scanned and electronically stored so that it can be subtracted from sample spectra collected later.  
      However, the process of subtraction of background absorbances may be imperfect because absorbances may not be cleanly subtracted and may interfere with the absorbances of the material sample, particularly when the sample exhibits subtle absorbances which can be inadvertently masked or lost by the subtraction process. Accordingly, the materials comprising the sample holder  500  are preferably selected to minimize, and more preferably to eliminate, interference due to absorbances of such components with absorbances of the material sample. Because the infrared spectra of many polymer films are well known, it is straightforward to select appropriate materials for the microporous sheet  512  and the support members  514 .  
      In certain embodiments of the sample holder  500 , the microporous sheet  512  comprises microporous polyethylene and the support members  514  comprise polyethylene. Polyethylene exhibits a relatively simple spectrum consisting of only four distinctive absorbances in the region of interest: at 3.43 μm, 3.51 μm, 6.83 μm, and 13.9 μm, the latter two being of relatively low intensity. This simple spectrum can be easily subtracted from the spectrum of the material sample S. Polyethylene having a degree of substantial crystallinity has two additional absorbances caused by the splitting of the latter two absorbances into pairs of peaks. Advantageously, polyethylene is inert to many chemicals, is insensitive to moisture, and provides strong, (for example, tear- and puncture-resistant) films at low thicknesses.  
      In other embodiments, particularly in embodiments wherein the carbon-hydrogen bond (C—H) stretching region is of significant interest, the microporous sheet  512  comprises microporous polytetrafluoroethylene (“PTFE”) and the support members  514  comprise polytetrafluoroethylene. PTFE has no absorbances above about 6.67 μm, so the C—H stretching region which is at about 3.33 μm to about 3.57 μm is not subject to interfering absorbances.  
      C. Microporous Sheet Properties  
      The void volume of the microporous sheet  512  is typically greater than about 20 percent and is preferably greater than about 50 percent. Many useful microporous polymer films are open structures wherein only a fraction of the total volume is occupied by the polymer material. In sample holders  500  comprising such films, a greater portion of the material in the optical path  40  (see  FIG. 18 ) is the material sample S itself.  
      When a material sample S is applied to the microporous sheet  512 , such as through the transit opening  518  on the edgewise exposed portion(s) of the microporous sheet  512 , the material sample will be conducted into and occupy most or all of the microporous sheet  512 , thereby containing the material sample in the sample holder  500 , and enabling the sample to be analyzed in an appropriate analyte detection system.  
      By using microporous sheets as provided herein, it is possible to obtain acceptable spectra of material samples that readily crystallize when put on a flat surface for a time. It has previously been considered difficult to obtain spectra of crystalline samples due to the dispersive and reflective effects of the crystal lattice. Applying such a material sample to a microporous sheet retards crystallization and/or limits crystal growth due to the constraint of the pore size. This reduces the previously encountered unwanted dispersive and reflective effects of the crystal lattice, thereby permitting effective spectroscopic analysis.  
      Microporous polymer sheets can be characterized as having a plurality of interconnecting microscopic pores. Preferably, the pore size distribution across the microporous sheet is substantially uniform so as to provide a low sheet transmittance variability as discussed above. Pore sizes typically range from about 0.1 μm to about 50 μm in their “average characteristic width”. For example, in applications wherein the material sample S comprises whole blood, the pore sizes are preferably greater than about 20 μm. Preferably, the support members  514  are not microporous, thereby preventing the material sample S from contacting elements of the analyte detection system to be employed with the holder  500 , which could lead to undesirable contamination of both the material sample and the analyte detection system.  
      As used herein, “average characteristic width” means the average of the largest of the cross-sectional dimension of the pores. For example, if the pores are substantially circular in cross-section, the average characteristic width is the average pore diameter. The pore density is such that the void volume of the microporous sheet  512 , as measured by ASTM D4197-82, is typically greater than about 20 percent, is preferably in the range of about 50 percent to about 98 percent, and is more preferably between about 70 percent and about 85 percent. In general, as void volume increases, the inherent absorbances of the microporous sheet  512  are less likely to interfere with the absorbances of the material sample S. The pore configuration is not critical. For instance, the microporous sheet  512  can comprise, for example, a sheet with uniform, substantially circular pores formed by laser ablation or nuclear etching; a sheet made of fibrillated masses with openings of varying size and configuration; a sheet made of non-woven materials; or a sheet made of strands having uniform diameter of material defining a tortuous path (for example, random or fixed) through the sheet. Uniformity of pore size along the transit openings reduces or prevents coagulation of the material sample S at the transit openings, thus enhancing the accuracy of analyte concentration measurements. In addition, uniformity of pore size along the support structures enhances uniform distribution of the material sample S within the microporous sheet. As used herein, “microporous” describes sheets having any such openings.  
      In a modified embodiment, the porosity of the microporous sheet has a porosity gradient between the edges of the sample holder and the center of the sample holder. For example, if the microporous sheet has a greater porosity in central regions of the sample holder than in the edge regions of the sample holder (that is, near the transit openings), greater capillary forces can be created, thus facilitating the drawing of the material sample into the sample holder.  
      As used herein, “microporous sheet” also further includes polymeric sheets having at least one structured surface wherein the surface has surface voids, grooves, depressions, and so forth, having a minimum depth of about 0.1 μm and a minimum width of about 0.1 μm therein, and typically having an average characteristic dimension of at least between about 0.1 μm and about 50 μm, sometimes even substantially larger. As described above, in applications wherein the material sample S comprises whole blood, the pore sizes are preferably greater than about 20 μm. As used in this context, “average characteristic dimension” means the average of the largest dimension of the structure element in a plane parallel to the transit opening  518  of the sample holder  500 . Such sheets can be formed from solid polymeric sheets by a variety of surface modifying and replication techniques, including but not limited to laser ablation, molding, embossing, extrusion, and the like. Such surface features can increase the sample holder&#39;s retention of the material sample, especially material samples containing particulate materials. Structured surface features can also be formed on microporous sheets having a plurality of pores as described above.  
       FIG. 19A  is an exploded perspective view of a sample holder  500  that further comprises a circumferential open mesh  516  bonded to and surrounding the microporous sheet  514 . The open mesh  516  facilitates collection and retention of the material sample. In such embodiments, the sample holder  500  preferably meets the transmittance criteria described herein. However, because the open mesh  516  is open, and because the open mesh  516  can be positioned outside of the optical path  40 , the bulk properties of the open mesh  516  may or may not meet those transmittance criteria.  
      U.S. Pat. No. 4,539,256 (Shipman) discloses microporous sheet materials and methods for making the same. Many of these materials can be used with the embodiments disclosed herein. In addition, U.S. Pat. Nos. 3,953,566, 3,962,153, 4,096,227, 4,110,392, 4,187,390 and 4,194,041 describe the preparation of porous articles, including microporous sheets, from polytetrafluoroethylene. All of these patents are hereby incorporated herein by reference. Many of the polymeric materials described in these patents can be used with the embodiments disclosed herein.  
      Many types of microporous polymer sheets useful in the various embodiments disclosed herein are commercially available in a variety of polymers, thicknesses and void volumes. Among these are: ADVENT film (a microporous polyethylene film available from 3M, Saint Paul, Minn.); CELGARD™ films (hydrophobic or hydrophilic microporous polyethylene or polypropylene films available from Hoechst Celanese, Charlotte, N.C.); GORE-TEX™ film (a microporous polytetrafluoroethylene film available from W.L. Gore Associates); ZITEX™ film (a microporous polytetrafluoroethylene film available from Norton Performance Plastics, Wayne, N.J.); and DURAPORE™ film (a microporous hydrophilic film available from Millipore Products Division, Bedford, Mass.). Other illustrative examples include microporous sheets of polyolefins such as ethylene/propylene copolymers, polyvinylidene fluoride, polyester and nylon. In other embodiments, the microporous sheet can consist of one or more of the chosen polymeric films. The microporous sheet can comprise special agents such as the hydrophilic or hydrophobic coatings discussed below.  
      In a modified embodiment, illustrated in  FIG. 19B , the sample holder  500  further comprises a protective cover or flap  540  that covers at least a portion of the transit opening(s)  518  during storage. Preferably, the flap  540  is secured to the sample holder  500  using a removable adhesive  542 , thereby allowing the flap to be moved clear of the transit opening  518  when a material sample S is to be applied thereto. Such a configuration reduces the likelihood of contamination of the microporous sheet  512  when not in use.  
      D. Support Member Properties  
      As described above, the support members  514  are configured to provide the sample holder  500  with a rigid structure, to prevent contamination of the material sample S and the analyte detection system, and to facilitate the mounting of the sample holder  500  in or on an analyte detection system. Support members  514  having appropriate optical properties, as described above, can be formed by a wide variety of processes, such as but not limited to, injection molding, stamping of bulk sheet stock, and growth of materials having a crystalline structure.  
      In a preferred embodiment, the microporous sheet  512  is bonded to the support members  514  using an adhesive (not shown) applied outside the optical path  40 . For example, the adhesive can be applied around the circumference of the sample holder  500 . Suitable adhesives include, for example, pressure-sensitive adhesives and hot-melt adhesives. Placement of the adhesive outside the optical path reduces the likelihood that the adhesive will interfere with the absorbance spectra obtained during analysis of the material sample S. In certain applications, it may be desirable to configure the adhesive to be repositionable, non-outgassing, or the like. Those of ordinary skill in the art will be able to readily identify and select many suitable adhesives appropriate for a particular application, such as for example press-fitting, heat-activation or tacking characteristics. In other embodiments, different bonding mechanisms can be used, such as for example, lamination, sonic welding or mechanical techniques. In still other embodiments, a thin film of the material comprising the microporous sheet can be applied to the support members  514  using a sputtering process. The layered support members can be constructed in bulk dimensions, and then cut or stamped to appropriate dimensions after the assembly steps have been completed.  
      The support members  514  are preferably sufficiently stiff, and the microporous sheet  512  is preferably mounted sufficiently tightly therein, that the microporous sheet  512  is held flat across the sample holder  500 . Due to the material properties of the microporous sheet  512  discussed above, the microporous sheet  512  is often thin and thus may be subject to creasing or crinkling. It is generally desired that the microporous sheet  512  be maintained substantially flat when mounted on the spectroscopic device, thereby providing a substantially constant microporous sheet thickness along the optical path  40 . A substantially constant microporous sheet thickness causes the infrared energy E to pass through a substantially constant amount of material sample S, and minimizes reflectance and scattering of the infrared energy by the microporous sheet. Reflectance and scattering are generally undesirable effects that can cause interference in spectra obtained using the sample holder. As discussed above, the support members  514  can comprise any suitable film that is relatively rigid compared to the microporous sheet  512  and that is preferably not microporous, such as polymeric films.  
      In some applications it may be desirable for the prepared material sample to be archived or stored for future reference. Accordingly, in such embodiments, it is preferable that support members  514  comprise a material that may be written on or otherwise labeled (preferably near the edges) so that pertinent information relating to the material sample (for example, index number or date/time information) can be noted thereon. In other embodiments, a label or other additional information-bearing media (such as microfilm, magnetic media, or the like) can be included around the perimeter of the support members  514  if desired.  
      E. Aperture Shield  
      In certain applications, it is desired to restrict the area of the microporous membrane through which the emitted radiation passes.  FIG. 20A  illustrates an embodiment wherein sample holder  500  comprises a microporous sheet  512  and support members  514 . The sample holder  500  further comprises a shield  538  which covers a portion of the microporous sheet  512 , thereby forming an aperture  539  that leaves only a portion of microporous sheet  512  exposed. In use, the optical path  40  passes through the aperture  539  and the portion of the material sample located in the aperture  539 . Shield  538  is preferably substantially opaque to the wavelengths of radiation to be used (other than, of course, the aperture  539 ), such that no interfering absorbances are produced and no incident radiation is scattered. In the wavelength ranges disclosed above for analysis of bodily fluids, the shield  539  preferably has a transmittance of less than about 10 percent, and more preferably of less than about 1 percent.  FIG. 20B  is a cross-sectional view of the sample holder  500  of  FIG. 20A . The shield  538  can cover a portion of only one side of microporous sheet  512  as shown in  FIGS. 20A and 20B , or it can cover portions of both sides of microporous sheet  512 , leaving at least one aperture  539 , configured to permit the wavelength(s) of interest to pass through the entire sample holder  500 .  
      In certain embodiments, the shield  538  serves as a target to facilitate arrangement of the material sample S on the microporous sheet  512  for spectroscopic analysis. In other embodiments, the shape, size, and location of the aperture  539  are dependent at least in part upon the characteristics of the analyte detection system being used, particularly on the geometric arrangement of the window assembly (as discussed above). For example, in such embodiments, the presence of the material sample across the entire aperture  539  can serve as a indication that a sufficient amount of material sample has been applied to the sample holder  500 . Also, depending on the configuration of the support members  514  and the shield  538 , the shield  538  can serve to impart greater support stiffness to microporous sheet  532 .  
      The shield  538  can comprise plastic, paperboard, metal, or any other suitable, rigid material with appropriate optical properties. Preferably, the shield  538  is inert and nonabsorbent, so that if the material sample S contacts the shield, waste is minimized. The shield  538  can be secured to the microporous sheet  512  and the support members  514  by any suitable technique, such as for example, adhesives, sonic welding and mechanical closures.  
      One of ordinary skill in the art will understand that the shapes of the support members  514 , and the aperture  539  if used, can be of many different types, depending in part on such things as the construction of the sample holder  500 , the characteristics and specifications of the equipment with which the sample holder  500  will be used, the type of material sample being analyzed, and the preferences of individuals using the sample holder  500 . The same is of course true of the microporous sheet  512 .  
      F. Skin-Piercing Structure  
      In a modified embodiment, the sample holder further comprises a skin-piercing structure configured to facilitate introduction of a bodily fluid into the microporous sheet. As illustrated in  FIGS. 21A and 21B , such a skin-piercing structure comprises one or more tapered prongs  550  mounted on one side of a sample holder  500 . The tapered prongs can be securely attached to the edge of the sample holder  500  with any suitable fixation technique, such as with adhesives or snap fittings. Each of the tapered prongs  550  preferably has a sharpened distal tip  552  capable of easily piercing human skin. In one embodiment, the tapered prongs  550  comprise a polished metal, such as stainless steel or aluminum. Although the sample holder  500  illustrated in  FIGS. 21A and 21B  has one tapered prong  550 , one of ordinary skill in the art will recognize that equivalent structures have a plurality of tapered prongs on one or multiple sides of the sample holder. In addition, distal tips having other shapes, such as conical or tubular shapes, are also equivalent.  
      For example, in one preferred embodiment, the outer diameter of a tapered prong  550  is generally between about 100 μm and 400 μm at its thickest point, and generally less than about 10 μm at the distal tip  552 . The average outer diameter of a tapered prong  550  is generally between about 100 μm and 300 μm, typically between about 120 μm and 200 μm. The length of a tapered prong  550  will depend on the desired depth of insertion. More particularly, a tapered prong  550  will be appropriately dimensioned within certain ranges depending on the type of biological fluid (for example, interstitial fluid, blood or both) desired for sampling and the thickness of the skin layers of the particular patient being tested. As such, target skin layers into which a tapered prong can be inserted include, but are not limited to, the dermis, epidermis and the stratum corneum (that is, the outermost layer of the epidermis). Preferably, a tapered prong  550  has a length of at least about 50 μm and more preferably at least about 100 μm, where the length may be as great as 500 μm or greater, but typically does not exceed about 2000 μm and usually does not exceed about 3000 μm.  
      Still referring to  FIGS. 21A and 21B , the tapered prongs  550  preferably further comprise a passageway  554  that is open at a distal tip window  556 . The passageway  554  is preferably in contact with one of the transit openings  518  of the sample holder, and is preferably filled with a microporous material. While the passageway  554  illustrated in  FIGS. 21A and 21B  is substantially linear, one of ordinary skill in the art will recognize that in equivalent structures the passageway can have any shape or orientation, provided that the passageway contacts at least a portion of one of the transit openings. In modified embodiments, the passageway  554  is filled with a microporous material having a gradient of porosity between a distal passageway region  554   a  and a proximal passageway region  554   b . In such embodiments, the microporous material is preferably more porous at the proximal passageway region  554   b  than at the distal passageway region  554   a , thereby providing greater rigidity at the distal tip  552  for piercing the skin. The change in porosity between the proximal passageway region  554   b  and the distal passageway region  554   a  can be gradual or sharp.  
      The micro-protrusions or the distal tip  552  are preferably configured to be mechanically stable and strong enough to penetrate the stratum corneum without breaking. For example, in one embodiment, such skin-piercing structures comprise a biocompatible material so as not to cause irritation to the skin or an undesirable tissue response. Although certain embodiments of the sample holder may be disposable, for those that are intended to be reusable, it is preferable that the material of the micro-needles is able to withstand sterilization cycles.  
      In other embodiments, the skin-piercing function is accomplished by the surface of the distal tip window. Specifically, the distal tip window is formed with sharp protrusions, such as for example micro-needles. In such embodiments, this surface of the distal tip window is non-porous, wherein the sharp protrusions have a porous central core that extends through the distal tip window, thereby defining a fluid access opening to access a fluid to be analyzed. The fluid transfer medium preferably extends between the access opening of the micro-piercing member to the passageway, and functions to transfer fluid to the microporous sheet.  
      The fluid transfer medium is preferably made of a porous hydrophilic material. The material preferably is not water-absorbent, thus preventing water within a biological fluid from being absorbed by the fluid transfer material, but instead causing such water to be completely passed through the medium along with the other components of the biological fluid. Porous hydrophilic materials usable as the fluid transfer medium include, but are not limited to, polymers, ceramics, glass and silica. Suitable polymers include polyacrylates, epoxies, polyesters, polycarbonate, polyamide-imide, polyaryletherketone, polyetheretherketone, polyphenylene oxide, polyphenylene sulfide, liquid crystalline polyesters, or their composites. Examples of ceramics are aluminum oxide, silicon carbide and zirconium oxide.  
      A hydrophilic gel or the like may also be used in conjunction with the porous material located within the passageway. Suitable gels include natural gels such as agarose, gelatin, mucopolysaccharide, starch and the like, and synthetic gels such as anyone of the neutral water-soluble polymers or polyelectrolytes, such as polyvinyl pyrrolidone, polyethylene glycol, polyacrylic acid, polyvinyl alcohol, polyacrylamide, and copolymers thereof.  
      In embodiments comprising a skin-piercing structure, when the distal tip  552  is pierced through a patient&#39;s skin, a body fluid of the patient (for example, blood) will be drawn through the passageway  554  and into the microporous sheet  512 . For example, in embodiments wherein the passageway comprises a hydrophilic porous material, the pores can provide a capillary action by which fluid can be transferred. This configuration provides a convenient sample holder  500  that can be used in both the collection and analysis of a patient&#39;s bodily fluids.  
      G. Use and Analysis Considerations  
      As mentioned above, the sample holders described herein can be easily used with the analyte detection systems described above, simplify the process of preparing material samples for analysis, and facilitate precise and accurate measurements.  
      Hydrophilic films are useful as sheets in spectroscopic analysis of aqueous samples. Such samples can be applied directly to a hydrophilic film without pre-wetting. In addition to aqueous samples, hydrophilic films are useful in the analysis of biological fluids such as blood, sweat, tears, urine, semen, and other bodily fluids disclosed herein. Such biological fluid samples can be applied directly to the sample holder without the need for lengthy sample preparation, and clear, distinct measurements can be obtained. Microporous sheets comprising materials that are inherently hydrophilic or that are treated (for example, by coating with suitable material or by applying suitable surface treatment) to render them hydrophilic can be used with the various embodiments of the sample holders described herein.  
      In certain embodiments, the microporous sheet is treated to improve sample collection and retention properties. The microporous sheet can be treated before or during fabrication of the sample holder, or before application of the material sample. The timing of the treatment of the microporous sheet depends in part on the material comprising the microporous sheet, the treatment, and intended material sample to be analyzed.  
      For example, in certain embodiments the microporous sheet is exposed to corona treatment to impart an electrostatic charge thereto. Typically, when electrostatically-charged, the microporous sheet has a substantially uniform charge across the surfaces that contact the support members, with a side-to-side potential of at least about 100 V per 0.75 mil thickness. Electrostatic charges can be particularly useful in the collection and retention of greater quantities of fine particulate materials. By increasing retention of sample material in the microporous sheet, the amount of equipment cleaning and maintenance is likewise reduced.  
      In another embodiment, at least a portion of the surface of the microporous sheet is treated by application of a material, such as by coating or graft polymerization, that will modify the interaction of the microporous sheet with the material sample. For example, azlactone materials can be used to concentrate proteins in solution in a sample holder for infrared spectroscopic analysis.  
      The sample holders described herein, while providing good analytical results, are sufficiently inexpensive to be discarded after use. Thus, the need to clean and polish the sample holders for reuse is avoided. Furthermore, the sample holders described herein provide reduced exposure to hazardous samples as well as reduced exposure to potentially harmful solvents such as are used in cleaning and reconditioning conventional sample holders, examples of which include chloroform, methylene chloride, and toluene. Additionally, as described above, the sample holder can be stored or archived for future reference, if desired. For instance, it is sometimes desired to compare the spectra of a material sample with the spectra of one or more known standard samples, and in some instances it is desired to compare various spectra during the course of a chemical reaction or process. The sample holders described herein can be stored with samples present in the microporous sheet, thus permitting such samples to be analyzed at a later date, often with little or no degradation in the spectra. In particular, due to the microporous structure of the sheet, the material sample typically penetrates the pores in the sheet and is securely held within the sheet. Thus, there is typically little tendency to lose material sample from the exposed surfaces of the microporous sheet, and due to the chemical inertness of the microporous sheet, there is little tendency of the material sample to react with the microporous sheet. Accordingly, the sample holders described herein are also well-suited for use in aging and degradation studies of materials.  
      The sample holders described herein can be used to provide a convenient method of performing spectroscopic analysis. For example, one preferred method for spectroscopic analysis provided herein comprises 
          a) providing a sample holder as described herein;     b) applying the material sample to the microporous sheet exposed at the transit opening;     c) transmitting radiation in desired wavelength(s) through the material sample by projecting such radiation on one face of the sample holder; and     d) analyzing the radiation transmitted through or emitted from the material sample and sheet in a spectral region of interest.        

      In one preferred embodiment, a roll of microporous sheet material is fed into a spectroscopic analysis device and secured in position by clamping support member plates on either side of the microporous sheet. In such embodiments, the support member plates engage releasably with the microporous sheet.  
      Given the filling factor and porosity of a polyethylene microporous sheet, it is possible to determine the pathlength and the fraction of radiation scattered by using the known polyethylene peaks as a reference. The height of the absorption peaks will allow the thickness of the polyethylene film to be accurately determined. This technique is often used in thin film technology, where the film thickness is determined by absorption lines in the coatings. It is also possible to spike the polyethylene with a known concentration of an internal standard. One of these standards is potassium potassiumthiocyanate (KSCN). Thus, given the filling factor of the microporous sheet is known, the peaks of the spike will allow the pathlength to be determined in a wet measurement, thus eliminating any need for the dry or blank measurement. The spike wavelengths are preferably outside the water total absorbing bands.  
      In embodiments where a dry measurement is performed, similar principles apply because the microporous material will behave as a scatterer. In particular, the microporous sheet will remove the radiation coherence between the two support members and will provide a more precise measurement of the actual beam intensity in the material sample. Highly scattering material will generally overestimate the absorbance if scattering is not accounted for.  
      As will be appreciated by those of ordinary skill in the art, conventional reagent-based analyte detection systems react an amount of analyte (for example, glucose) with a volume of body fluid (for example, blood) with a reagent (for example, the enzyme glucose oxidase) and measure a current (that is, electron flow) produced by the reaction. Generating a current large enough to overcome noise in the electronic measurement circuitry requires a substantial amount of the analyte under consideration and thus establishes a minimum volume that can be measured. The present state of the art systems require about 0.5 μL of blood represent the lower volume limit of electronic measurement technology.  
      Spectroscopic measurement not requiring a reagent, as taught herein, relies on (1) absorption of electromagnetic energy by analyte molecules in the sample and (2) the ability of the measurement system to measure the absorption by these molecules. The volume of the sample required for measurement is substantially determined by the physical size of the optical components, and is significantly less than the sample volume required using conventional reagent based systems. Specifically, the dimensions of the analyte detection systems disclosed herein can result in a sample volume as low as about 0.3 μL. The presence of the microporous sheet can further reduce the sample volume because the volume of material sample required to fill the microporous sheet is less than the volume of material sample required to fill and empty (that is, non-microporous) cuvette.  
      The examples expounded herein are merely illustrative of the utility of the sample holders described herein, demonstrating that spectra of a wide variety of samples can be obtained using microporous sheets as described herein, and using a wide variety of sample collection and application techniques. One of ordinary skill in the art will appreciate that the apparatuses and the analysis methodologies described herein can incorporate, without being limited by, well known techniques for sample element use and construction, such as some of those set forth in U.S. Pat. No. 5,470,757 and PCT Publication WO 93/00580, the entire contents of both of which are hereby incorporated herein by reference. Various modifications and alternations of the present invention will be apparent to those of ordinary skill in the art without departing from the scope of the present invention, which is defined by the claims that follow.