WO2014150447A1

WO2014150447A1 - Multiplexing and non-multiplexing noninvasive analyte concentration measurement system and methods

Info

Publication number: WO2014150447A1
Application number: PCT/US2014/023288
Authority: WO
Inventors: Kenneth FLATON; Hannu Harjunmaa
Original assignee: Grove Instruments Inc.
Priority date: 2013-03-15
Filing date: 2014-03-11
Publication date: 2014-09-25

Abstract

Systems and methods for non-invasive measurement of a concentration of a target analyte in a sample are disclosed. An exemplary method may comprise directing a non-time- multiplexed probe beam at the sample including a first radiation and a second radiation. The method may include obtaining an analytic beam that has interacted with the sample. The method may also include variably filtering the analytic beam to generate a time-multiplexed analytic beam. The method may further include generating a time-multiplexed electrical signal by a detector detecting the time-multiplexed analytic beam. The time-multiplexed analytic beam may include sequential time intervals, each time interval including a sequence of the first and second radiation. The method may include demultiplexing the time- multiplexed electrical signals into different data streams. The method may also include determining the concentration of the target analyte based on a difference between a data- stream corresponding to the first radiation and the second radiation.

Description

MULTIPLEXING AND NON-MULTIPLEXING NONINVASIVE ANALYTE CONCENTRATION MEASUREMENT SYSTEM AND METHODS

Priority Claim

[0001] This application is a non-provisional application claiming priority to U.S.

Provisional Patent Application No. 61/788,261, filed March 15, 2013 and titled

"Multiplexing and Non-Multiplexing Noninvasive Analyte Concentration Measurement System and Methods," all of which is incorporated herein by reference.

Field of the Invention

[0002] The present disclosure generally relates to the field of biomedical testing and, more particularly, to methods and devices for noninvasive measurement of concentration of analytes in body tissues.

Background

[0003] Glucose in the blood of people with diabetes must be measured and monitored frequently. Monitoring the blood glucose is traditionally accomplished by pricking the skin, for example, at the fingertip, to draw blood that is then directly measured for its glucose content. Some people must measure their blood glucose level several times a day, In an effort, to increase the convenience and comibrt of this process, non-invasive methods of measuring glucose are desired.

[0004] Present methods of non-invasive measurement of analytes, such as glucose, in samples, such as human tissue, include directing a probe beam of electromagnetic radiation at the sample. The probe beam includes a wavelength absorbed by the analyte and a

wavelength that is less absorbed by the analyte. The intensity of the different wavelengths after interacting with the sample are compared to estimate the amount of analyte present in the sample. [0005] The present invention is an improvement over U.S. Pat. No. 7,003,337 issued to Harjunmaa et al. (hereafter, the '"337 patent"), which is incorporated herein in its entirety by reference. The method of the '337 patent includes directing at a sample a time-multiplexed electromagnetic radiation probe beam that contains alternating components of desired narrow line-width wavelengths. At least two of the alternating wavelengths have different absorption coefficients with respect to the analyte, The method of the '337 patent includes balancing the two wavelengths by optical bridge balancing, such that the radiations of the two wavelengths directed at the sample emerge from the sample with the same intensity, for example. The method further includes taking measurements of the concentration of the analyte by directing the time-multiplexed balanced probe beam at the sample which, during the measurement, is manipulated to varying thicknesses. The different wavelength components of the probe beam, after it. has interacted with the sample, have intensities that change by different amounts. This difference is a based on the concentration of the analyte in the sample. The post-sample probe beam is then detected and converted into electrical signals to be processed with algorithms that quantify the differences. The quantified differences are utilized to estimate the concentration of the analyte

[§006] The methods of the '337 patent improves upon previous methods in providing a simple, accurate, and reliable non-invasive measurement of analyte concentrations.

However, the methods potentially introduce instability and noise into the measurement due to the characteristics of the time-multiplexed signal.

[0007] Other related patent include U.S. Patent Nos. 5,1 12,124; 5,137,023; 5,183,042; 5,277,181 ; 5,372,135; 5,099,123; 5,178,142; and 8,175,666; each of which is incorporated by reference herein in its entirety.

7 Summary

[0008] in one aspect of this disclosure, a method of non-invasive measurement of a concentration of a target analyte in a fluid in a sample includes directing a non-time- multiplexed probe beam at the sample, wherein the probe beam comprises a plurality of radiations including a first radiation and a second radiation having different wavelengths. The method also includes obtaining an analytic beam, wherein the analytic beam is a portion of the probe beam that has interacted with the sample. The method further includes variably filtering the analytic beam by a variable filter to generate a time-multiplexed analytic beam, wherein the time multiplexed analytic beam includes sequential time intervals, and each time interval includes a sequence of the first radiation and the second radiation. The method also includes generating a time-multiplexed electrical signal by a detector detecting the time- multiplexed analytic beam. The method further includes demultiplexing the time- multiplexed electrical signals into different data streams, wherein a data stream corresponds to one of the plurality of radiations. The method also includes determining the concentration of the target analyte based on a difference between a data stream corresponding to the first radiation and a data stream corresponding to the second radiation,

[0009J In another aspect of this disclosure, a method of non-invasive measurement of a concentration of a target analyte in a fluid in a sample includes directing a non-time multiplexed probe beam at the sample, wherein the probe beam comprises a plurality of radiations including a first radiation and a second radiation having different wavelengths. The method also includes obtaining an analytic beam, wherein the analytic beam is a portion of the probe beam thai has interacted with the sample. The method further includes receiving the analytic beam by a plurality of detectors. The method also includes generating a plurality of data streams, one from each of the plurality of detectors, wherein a data stream

corresponds to one of the plurality of radiations. The method further includes determining the concentration of the target analyte based on a difference between a data stream corresponding to the first radiation and a data stream corresponding to the second radiation, [0010] In yet another aspect of this disclosure, an apparatus for non-invasive measurement of a concentration of a target analyte in a fluid in a sample includes a source for generating a non-time-multiplexed probe beam, wherein the probe beam includes a. plurality of radiations including a first radiation and a second radiation having different wavelengths. The apparatus further includes a variable filter comprising a plurality of filter elements for filtering an analytic beam to generate a time-multiplexed analytic beam. The analytic beam includes a portion of the probe beam that has interacted with the sample. The time- multiplexed analytic beam includes sequential time intervals, and each time interval includes a sequence of the first radiation and the second radiation. The apparatus also includes a detector, for detecting the time-multiplexed analytic beam and generating a time-multiplexed electrical signal. The apparatus further includes a demultiplexer for demultiplexing the time- multiplexed electrical signal into different data streams, wherein a data stream corresponds to one of the plurality of radia tions, The apparatus also includes a processor for controlling a measurement sequence, estimating an amount of fluid in the sample, arid determining the concentration of the target analyte.

[0011] In yet a further aspect of this disclosure, an apparatus for non-invasive measurement of a concentration of a target analyte in a fluid in a sample includes a source for generating a non~time~niultiplexed probe beam, wherein the probe beam comprises a plurality of radiations including a first radiation and a second radiation having different wavelengths. The apparatus also includes a plurality of detectors for detecting an analytic beam. Each detector detects a portion of the analytic beam and generates an analytic electrical signal, wherein the analytic beam is a portion of the probe beam that has interacted with the sample. The apparatus further includes a processor for controller a measurement sequence, estimating an amount of fluid in the sample, and determining the concentration of the target analyte. [0012] In another aspect of this disclosure, a system for non-invasive measurement of a concentration of a target analyte i a fluid in a sample includes a probe beam generator comprising one or more sources for generating a non-time-multiplexed probe beam having a plurality of radiations, including a first radiation and a second radiation of different wavelengths. The first radiation includes a wavelength for which the target analyte has a corresponding first absorption coefficient. The second radiation includes a wavelength for which the target analyte has a corresponding second absorption coefficient that is lower than the first absorption coefficient. The system also includes an analytic beam receiver comprising one or more detection devices for detecting an analytic beam and converting information contained in the analytic beam into one or more analytic electrical signals. The analytic beam includes a portion of the probe beam that has interacted with the sample. The system further includes an analytic electrical signals processor that generates digital data streams from the one or more analytic electrical signals, and determines the concentration of the target analyte based on the digital data streams. Brief Description of d e D awing

[0013] It is to be understood that the following detailed description is exemplary and explanatory only and is not restrictive of any invention, as claimed, The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the inventions and together with the description, serve to explain the principles of the inventions, in the drawings:

[0014] Fig, .1 is a block diagram of a system for non-invasive measurement of a concentration of target analyte in accordance with various illustrati ve embodiments of this disclosure,

[0015] Fig. 2 is another block diagram of a system for non-invasive measurement of a concentration of target analyte in accordance with some illustrative embodiments of this disclosure. [0016] Fig. 3 is another block diagram of a system for non-invasive measurement of a concentration of target analyte in accordance with some illustrative embodiments of this disclosure.

[0017] Fig. 4 is another block diagram of a system for non-invasive measurement of a concentration of target analyte in accordance with various illustrati ve embodiments of this disclosure.

[0018] Fig. 5 is a flowchart for a method of non-invasive measurement of a concentration of a target analyte in accordance with some embodiments.

[0019] Fig. 6 is another flowchart for a method of non-invasive measurement of a concentration of a target analyte in accordance with some embodiments.

Detailed Description

[0020] For simplicity and clarity of illustration, reference numerals may be repeated among the figures to indicate corresponding or analogous elements. Also, similarly-named elements perform similar functions and are similarly designed, unless specified otherwise. Numerous details are set forth to provide an understanding of the embodiments described herein. The embodiments may be practiced without these details. In other instances, well-known methods, procedures, and components have not been described in detail to avoid obscuring the embodiments described. The description is not to be considered as limited to the scope of the embodiments described herein.

[0021] Fig. 1 is a block diagram of a system 100 for non-invasive measurement of a concentration of a target analyte in accordance with various illustrative embodiments of this disclosure. System 100 comprises a probe beam generator 1 10, a sample-state-adjuster 130, an analytic beam receiver 140, and an analytic electrical signals processor 150. in various embodiments, sample-state-adjuster 130 adjusts a sample 120 containing a target analyte 122. Probe beam generator 110 generates a probe beam 1 1 1 , and directs probe beam 1 1 1 at sample 120. After interacting with sample 120, either by being transmitted through sample 120. reflected off sample 120. or transilected by sample 120, probe beam 1 1 1 transforms into an analytic beam 141. Analytic beam receiver 140 receives analytic beam 141 and generates an analytic electrical signal 151. Analytic electrical signals processor 150 receives and processes analytic electrical signal 151 , and generates an estimate of the concentration of target analyte 122 in sample 120.

[9022] In various embodiments of this disclosure, target analyte 122 resides in sample 120. In some embodiments, target analyte 122 may reside in a sample fluid and/or sample matrix of sample 120. in some embodiments, the sample is a portion of biologic tissues, die sample fluid is blood, and the sample matrix is the portion of biologic tissue excluding the sample fluid, for instance epithelial tissue, extracellular matrix, intracellular matrix, and interstitial fluid. In some embodiments, sample 120 could be a part of an earlobe or a finger, or other body parts. In various embodiments, the sample fluid is displaceable from sample 120, for example, by applying a pressure to sample 120. The applied pressure may cause a change in the fluid volume of sample 120, or a portion of sample 120.

[0023] Probe beam generator 110 may generate probe beam 1 1 1 by one or more sources of narrow line-width radiations of various output radiations. In some embodiments, the source of radiation may comprise at least one of a light-emitting diode (LED) or a diode laser. Probe beam 1 1 1 may be a continuous, blended (spatially multiplexed) beam of a plurality of wavelengths. That is. in contrast to a time-multiplexed probe beam, probe bearn 1 1 1 may provide constant illumination at all of the plurality of wavelengths that probe beam 1 1 1 comprises. Such continuous, steady state illumination may improve the temporal stability of probe beam 1 1 1 and consequently of the signals derived from probe beam 1 1 1 as compared with a time-multiplexed probe beam. In some other embodiments, probe beam 1 1 1 may be a single, blended but time-intermittent illumination. For example, probe beam 1 1 1 may be a pulsed beam, and each pulse may comprise a combination of all wavelengths of probe beam 1 1 1. [0024] In various embodiments, there are several advantages due to probe beam 1 1 1 not being time-multiplexed. For example, probe beam 1 1 1 allows for increased sampling duty cycles of measurement and greater signal integration resulting in lower levels of noise, compared to, for instance, the system of the '337 patent, In some embodiments, the reduction in noise may be due to the illumination period of the sample being longer than the sampling time, allowing multiple signal samples to be taken and averaged together, Further, in the '337 patent, the deep square-wave drive of light sources potentially causes instability and internal interferences, such as cross-talk, that results from the sharp transition states of the square wave. Various embodiments of this disclosure remove this potential instability and interference,

[0025] in various embodiments, at least one of the radiations of probe beam 1 1 1 may be a first radiation of a first wavelength that is absorbed by target analyie 122, characterized by a first absorption coefficient, For example, such a radiatio may be infrared radiation that is absorbed by glucose, with a wavelength between 1550 nm and 1700 mil, or more specifically between 1600 nm to 1650 run, and in various exemplary embodiments, 1620 nm. At least another of the radiations of probe beam 1 11 may be a second radiation having a second wavelength that target analyte 122 does not absorb as much in comparison with the first wavelength, characterized by a second absorption coefficient. In various embodiments, the first radiation of the first wa velength may include, a single wavelength or a plurality of wavelengths. Likewise, the second radiation may include a single wavelength or a plurality of wavelengths. For example, a radiation having "a wavelength" may refer to a radiation of a single wavelength, or may refer to a radiation with a non-zero llnewidth, comprising a plurality of wavelengths within a range around a dominant wavelength, or may refer to a radiation with several distinct wavelengths that are averaged for an effective wavelength. [0026] in various embodiments, before measurements are taken, the first, radiation and second radiation may be adjusted by an optical bridge balancing calibration process, as disclosed in the '337 patent, for example, The optical bridge balancing may include displacing most of a sample fluid from sample 120, directing probe beam 1 1 1 at sample 120, and measuring the intensities of the radiations of probe beam 1 1 1. In various embodiments, the bridge balancing may further include making adjustmenis such that the first radiation and the second radiation emerge from sample 120 with the same intensity. The adjustment may be made by in at least one of the intensity or wavelength of at least one of the first radiation or second radiation. Equivalently, the adjustment may be made in one of at least intensity or wavelength of at least one of the first radiation or second radiation such that the effective absorption coefficient of the sample for the first radiation and the second radiation are the same. In various other embodiments, optical bridge balancing may occur at other points of time relative to taking measurements.

[0027] Probe beam 111 may also include a third radiation of a third wavelength that is absorbed by a component of the sample fluid. The third radiation may be distinctly different from the first radiation and the second radiation, f or example, the third radiation may be of a wavelength that is absorbed by hemoglobin, a component of blood. In various embodiments, the wavelength of the third radiation may be between 500 iim to 600 ran, and in various exemplary embodiments, might be a wavelength of 525 am. In some embodiments, the third radiation of probe beam 11 1 may be used to estimate a volume of sample fluid, e.g.. blood, in sample 120. The volume of sample fluid may then be used in determining the concentration of target anaiyte 122 and/or timing measurements of the sample, as discussed in further detail below.

[0028] Samp!e-state-adjuster 130 may include an apparatus that interfaces with sample 120 and adjusts sample 120 to hold various volumes of sample fluid. For each different volume, sample 120 may be considered to be in a particular sample state. Thereby, sample-state- adj usted 130 may adjust the sample state of sample 120 by adjusting the volume of sample 120. In some embodiments, this adjustment is achieved by a compressor device, which can incrementally squeeze sample 120, The compressor device may squeeze sample 120 between a range of a first sample state, where most of the sample fluid is displaced from sample 120, and a second sample state, where all of the sample fluid is permitted to return. In some other embodiments, the adjustment may be achieved by a vacuum device, which changes the sample state by vacuum or suction,

|0029] In various embodiments, as sampie-state-adjuster 130 forces out most of the sample fluid , most of target analyte 122 that resides in the sample fluid may be forced out of sample 120. Likewise, when sample-state-adjuster 130 adjusts sample 120 so that sample fluid returns into sample 120, target analyte 122 also returns into sample 120. In various embodiments, with the change of sample states, the amount of target analyte in sample 120 changes, Accordingly, the amount of first radiation of probe beam i l l that is absorbed by sample 120 changes with various sample states. The amount of second radiation of probe beam 11 1 that is absorbed by sample 120 may also change with various sample states, but by a different amount due to the smaller absorption coefficient of target analyte 122 at the second wavelength. Consequently, as sample-state-adjuster 130 varies the sample state of sample 120, the difference in the intensities of the first and second radiations after emerging from sample 120 may also vary. This difference may be proportional to the amount of target analyte in the portion of sample 120 interacting with probe beam 1 1 1.

[0030] in some embodiments, probe beam 1 1 1 may pass through a diffuser plate (not shown) before interacting with sample 120. The diffuser plate may scatter probe beam 1 1 1 before interaction with sample 120 to reduce the sensitivity of system 100 to inhomogeneiiies in sample 120. in some embodiments, in which sample-state-adjuster 130 includes a compressor device, the squeezing portion of the compressor device may include the diffuser plate on one side of sample 120. In some embodiments, the squeezing portion of sample- state-adjuster 130 on the other side of sample 120 may include the piano surface of a planoconvex lens (not shown) that focuses analytic beam 141 onto analytic beam receiver 140.

[0031] Analytic beam receiver 140 may receive the portion of probe beam 1 1 1 that is transmitted through, reflected off, or transileeted by sample 120 as analytic beam 141. In some embodiments, analytic beam 141 may be a combination of the same first, second, and third electromagnetic radiations of the first, second, and third wavelength of probe beam 1 1 1. However, the intensities of each of the first, second, and third radiations in analytic beam 141 may be different than in probe beam 1 1 1, due to the amount of analyte and other components in sample 120. In some embodiments, analytic beam receiver 140 may separate portions of analytic beam 141 according to wavelengths using one or more detection devices. The one or more detection devices may generate corresponding analytic electrical signal 151 , comprising one or a plurality of signals, to he processed by analytic electrical signals processor 150. In some embodiments, analytic beam receiver 140 may separate portions of analytic beam 141 according to wavelength using one or more wavelength-specific filters prior to the one or more detection devices. In some embodiments, analytic beam receiver 140 may time- multiplex portions of analytic beam 141 according to wavelength, post-sample and prior to the one or more detection devices. Various embodiments of analytic beam receiver 140 are described in further detail below.

[0032] Analytic electrical signals processor 150 may receive, analytic electrical signal 151 and perform signal processing, including analog-to-digital conversion of analytic electrical signal 1 51 to generate digital data streams. Analytic electrical signals processor 150 may determine the concentration of target analyte 122 in sample 120 based on the digital data streams, for example, as disclosed in the "377 patent. In some embodiments, analytic electrical signals processor 150 includes a central processor unit (CPU) or a microprocessor, a random access memory (RAM), and secondary memory storage, such as a hard disk.

[0033] Fig. 2 is a block diagram of a system 200 for non-invasive measurement of a concentration of target analyte 222 in accordance with various illustrative embodiments of this disclosure. System 200 comprises a probe beam generator 210, a sample-state-adjuster 230, an analytic beam receiver 240, an analytic electrical signals processor 250, and a selector 260. System 200 is illustrative of various embodiments in which time-multiplexing of signals corresponding to a first radiation, second radiation, or third radiation, occurs after the radiations have interacted with a sample 220, Descriptions of various components of system 200 that are similar to system 100 are omitted.

[0034] In various embodiments, probe beam generator 21 0 may comprise a plurality of sources of electromagnetic radiation 212 to generate a probe beam 21 1. For example, in an exemplary embodiment, probe beam generator 210 includes a diode laser with a 1620-nm wavelength, another two diode lasers of 137Q-nm wavelength and 1385-nm wavelength, and a LED with a 525 -nm wavelength. The 1620-nm wavelength radiation may be a first radiation, or a principal radiation, that is absorbed by exemplary target analyte glucose. The 1370-nm and 1385-nm wavelength radiations may combine to be a second radiation, or reference radiations, that is less absorbed by target anal te glucose. The 525-nm wavelength radiation may be a third radiation drat, is absorbed by hemoglobin, a component of exemplary sample fluid blood. In other embodiments, probe beam generator 210 may comprise an incandescent light source with a continuous thermal spectrum, thereby avoiding the need for multiple light sources. However, in some situations, using such incandescent Light source may sacrifice the possibility of optical bridge balancing.

[0035] in various embodiments, radiations 212 from the plurality of sources of

electromagnetic radiation 212 are blended (spatially multiplexed) to form probe beam 21 1. In various embodiments, system 200 calibrates probe beam 21 1 , for example, by optical bridge balancing as described in the '337 patent or any calibration method otherwise known in the art. n various embodiments, the calibration may be performed by a general purpose and/or a dedicated processor that may be part of system 200 or a separate unit such as a remote server. After calibration of probe beam 21 1 , probe beam generator 210 may direct, probe beara 21 1 at sample 220 in a plurality of sample states, Sample-state-adjuster 230 may adjust sample 220 into the various sample states, in some embodiments, system 200 may include a diffuser plate and/or plano-convex lens (not shown) on either side of sample 220, as described abo e.

[0036] In various embodiments, analytic beam 241 may emerge from sample 220 by transmission, reflectance, or txansfiectance. Analytic beam 241 may comprise the plurality of radiations of probe beam 21 1, but at differing intensities due to interaction with sample 220. Analytic beara receiver 240 may receive analytic beam 241 and generate analytic electrical signal 251 in the form of a time-multiplexed electrical signal. In some embodiments, analytic beam receiver 240 may include a variable filter 280, such as a filter wheel, a tunable filter, or any other filter capable of selectively filtering radiation at a plurality of wavelengths.

Selector 260 may determine which wavelength-specific filter of variable filter 280 is successively activated. For example, variable filter 280 may be a filter wheel comprising three distinct filters. In some embodiments, one of the filters may transmit radiations with wavelengths above 1550 nm, such as a first radiation. The second filter may transmit radiations with wavelengths between 1000 nm and 1450 nm, such as a second radiation, and block wavelengths above 1550 nm and below 1000 nm. The third filter may transmit radiations with wavelengths around 525 nm, such as a third radiation, and block wavelengths longer than 525 nm. Selector 260 may control the filter wheel such that analytic beam 241 is filtered by one of the three filters, for various periods of time. A time -multiplexed analytic beam 271 may emerge from variable filter 280, which includes sequences of radiation- specific portions of analytic beam 241 . For example, selector 260 may control variable filter 280 such that only the first radiation is transmitted, then the second radiation, and then the third radiation, in a cyclic, periodic fashion, in the example of the filter wheel, selector 260 may control variable filter 280 such that it rotates at a constant RPM. In various

embodiments, selector 260 may include a filter position sensor, The filter position sensor may provide information as to which filter selector 260 is selecting, and as a result, which wavelength-specific radiation is being transmitted.

[0037] Analytic beam receiver 240 may also include a detector 270. Detector 270 may receive time-multiplexed analytic beam 271 and generate a corresponding time-multiplexed electrical signal 251, which is processed and analyzed by analytic electrical signals processor 250. In some embodiments, detector 270 may be an indium-gallium-arsenide (InGaAs) photodiode, in some embodiments, a dark current measurement is performed when the filter wheel structure between two filters obscures time-multiplexed analytic beam 271 from detector 270. The dark current is current signal generated by detector 270 in the absence input signals and may be used to calibrate detector 270.

[0038] Analytic electrical signals processor 250 may receive time-multiplexed electrical signal 251 from detector 270. Analytic electrical signals processor 250 may include module 252. Module 252 may include a demultiplexer for demultiplexing time-multiplexed electrical signal 251 into a plurality of distinct data streams 253. Each data stream may correspond to one of the plurality of electromagnetic radiations in probe beam 21 1 , e.g., the first radiation, the second radiation, or the third radiation, In some embodiments, the demultiplexer may be keyed by a position filter sensor of selector 260, which provides information as to which wavelength-specific radiation is being transmitted to detector 270 and subsequently to analytic electrical signals processor 250. Analytic electrical signals processor 250 may use such information to determine which wavelength-specific radiation corresponds to portions of time-multiplexed electrical signal 251 and to demultiplex time-muiiiplexed electrical signal 250. Module 252 may also include an analog-to-digital converter for producing digital data streams from analytic electrical signal 251. In various embodiments, analytic electrical signal 251 may be demultiplexed before conversion or after conversion from analog to digital signals.

[0039] Analytic electrical signals processor 250 may also include analytic processor module 254, Analytic processor 254 may analyze data streams 253 and determine the concentration of target analyte 222 based on data streams 253. For example, analytic processor 254 may determine the concentration of target analyte 222 based on data corresponding to the difference in intensities of the first and second radiations for various sample states of sample 220.

[0040 J Measurements may be performed as described, for example, in the '337 patent, and U.S. Patent No. 8,175,666 (the '666 patent), incorporated by reference herein in its entirety, except that all light sources are simultaneously on at constant power levels to generate a blended probe beam 21 1. Embodiments of the disclosure according to system 200 provide improvements, such as temporal stability, over the current art.

[0(141] Fig, 3 is a block diagram of a system 300 for non-invasi ve measurement of a concentration of target analyte 322 in accordance with various illustrative embodiments of this disclosure. System 300 comprises a probe beam generator 310, a sample-state-adj uster 330, an analytic beam receiver 340, and an analytic electrical signals processor 350. System 300 is illustrative of various embodiments in which multiple detectors are utilized to detect an analytic beam 341, instead of time-multiplexing the analytic beam after the sample. In other words, system 300 may differ from system 200 by employing spatial wavelength separation without temporal separation. Descriptions of various components of system 300 that are similar to components already described above are omitted,

[0042] Probe beam generator 310 may include a plurality of sources of electromagnetic radiation 312 to generate probe beam 31 1 . Probe beam generator 310 may direct probe beam 31 1 at. sample 320 that includes target analvte 322, Sample-state-adjuster 330 may adjust, sample 320 to be in various sample states. Probe beam 31 1 may interact with sample 320 in the various sample states and emerge from sample 320 as analytic beam 341.

[0043] Analytic beam receiver 340 may receive analytic beam 341 and generate a plurality of non-time-multiplexed analytic electrical signals 351. In some embodiments, a spatial diffuse* (not shown) may be placed in the path of analytic beam 341, between sample 320 and analytic beam receiver 340. The spatial diffuser may provide a fully diffused beam to analytic beam receiver 340. in some other embodiments, analytic beam 341 may be fully diffused simply as a result of passing through sample 320. In various embodiments, analytic beam receiver may include a wavelength-selectable splitter 390. Wavelength-selectable splitter 390 may receive and split analytic beam 341 into a plurality of split beams 371 according to wavelength. For example, wavelength-selectable splitter 390 may split analytic beam 341 into three split beams 371 , corresponding to a first radiation with a first absorption coefficient for target analvte 322, a second radiation with a second absoiption coefficieni for target analvte 322 that is smaller than the first absoiption coefficient, and a third radiation with a third absorption coefficient for a component of the sample fluid. Each wavelength- specific split beam 371 may be received by one of a plurality of detectors 370, each of which generates one of a plurality of wavelength- specific analytic electrical signals 351.

[0044] Analytic electrical signals processor 350 may receive the plurality of wavelength- specific analytic electrical signals 351. Each analytic electrical signal 350 may be converted to a digital signal by an analog-to-digital converter 352, producing a distinct, wavelength- specific data stream 353. Analytic processor 354 may then process the digital data streams 353. Analytic processor 354 may determine the concentration of target anaiyte 322 based on digital data streams 353, for example, according to methods described in the '337 patent and the '667 patent.

[0045] Various other embodiments accomplish spatial post-sample wavelength separation in different ways. In an exemplary embodiment depicted in Fig. 4A, analytic beam receiver

440 includes a wavelength-agnostic splitter 490, Wavelength-agnostic splitter 490 may- receive and split analytic beam 441 into split beams 481. Each split beam 418 may include a combination of all the radiations of analytic beam 441. Some of the split beams 481 may then be subjected to different wavelength-specific filters 480A and then received by separate detectors 470. In such a manner, separate detectors may receive portions of analytic beam

441 that correspond to wavelength-specific first radiation, second radiation, or third radiation, for example. Each of detectors 470 may generate a wavelength-specific analytic electrical signal 451 , to be processed by an analytic electrical signals processor.

[0046] Fig. 4B depicts another exemplary embodiment, in which a thoroughly diffused, blended post-sample analytic beam 441 is subjected to a smgie segmented filter/detector combination 470B, similar to an RGB filter/CCD array, which samples beam 441 by wavelength spatially in two dimensions. Fig. 4C depicts yet another exemplary embodiment, in which analytic beam 441 is received by a set of stacked detectors 470C. Detectors 470C are arranged such that each preceding detector is transparent to wavelengths intended for detection by subsequent detectors that layer, illustrated in further detail in Fig. 4D. These embodiments are described for illustrative purposes and are not limiting of the disclosure. For example, in some embodiments, an analytic beam receiver 440 may include filters in front of some of detectors 470 in Fig. 4A, but not in front of some others of detectors 470, depending on the bandwidth of the detectors and desired selection of wavelengths. [0047] A specific exemplary embodiment is now described, which has four light sources: one diode laser with a 1 20 nm wavelength, another two with wavelengths 1370 nm and 1385 nm, and a LED with a 525 nm wavelength. The output of the light sources is directed at a sample, such as an earlobe, through a diffuser plate that scatters the input light so as to make the system less sensitive to inhomogeneities in the sample. The sample is lightly squeezed between the diffuser plate and the piano-surface of a plano-convex lens. Right behind the convex surface of said lens, there are four detectors: two indium-gallium arsenide (InGaAs) photodiodes and two silicon (Si) photodiodes, in other embodiments, the number, type, and arrangement of the detectors may be different as known in the art. In some embodiments, there may be only one silicon photodiode and instead of two. All four are laid out symmetrically around the central axis, facing the lens and the sampling area through the lens. Between the lens and one of the InGaAs detectors, there is a filter that transmits wavelengths below 1500 nm and blocks wavelengths above 1500 nm. The InGaAs detector receives the second, or reference, radiation that is less absorbed by glucose. Between the lens and the other InGaAs detector, there is a filter that transmits wavelengths above 1500 nm and blocks wavelengths below 1500 nm. The other InGaAs detector receives the first, or principal, radiation that is absorbed by glucose. Between the lens and the two silicon detectors, there are no filters, because they are not needed, as silicon detectors are not sensitive to wavelengths above 1200 nm. Two silicon detectors are used for symmetry; their outputs are combined. The silicon detectors detect the third radiation that is absorbed by hemoglobin. The measurement is performed as described in the '337 patent and the '666 patent, except that, after the balancing of the optical bridge, all light sources are kept constantly on.

[O048J The embodiment discussed above has several advantages over those in the '337 patent. Tor example, because of the lack of deep square- wave drive of the light sources, the system may be more stable and free of internal interferences. Also, since all detectors receive an undiminished amount of light during measurement, compared to in the '337 patent, d e system may be more efficient. Furthermore, repeated sampling of all input channels can be made truly simultaneous. Also, since the output of the light sources remains constant during the measurement, there is no need for gating to remove transient parts of the signal.

0Θ49] Fig. 5 illustrates a flowchart 500 for non-invasive measurement of a concentration of a target analyte in a sample according to various embodiments, in some exemplary embodiments, the method of flowchart 500 may be performed by a system for non-invasive measuremen t of a concentration of target analyte, such as system 100 or 200. In some embodiments, the target analyte may reside in a sample fluid of the sample, and have a different absorption coefficient at different wavelengths of electromagnetic radiation. The sample may be probed utilizing a blended (spatially multiplexed), non-time-multiplexed beam. The beam may be spatially demultiplexed and time-multiplexed after leaving the sample.

[0050] At Step 510, the sample is adjusted into a sample state, in which the sample has a corresponding fluid volume. Accordingly, the sample may contain a corresponding amount of target analyte based on the concentration of the target analyte i the sample fluid and the volume of the sample. In some embodiments, the sample may be adjusted into a sample state by utilizing sample-state-adjuster 130 or 230, for example. In some other embodimenis, the sample state may be adjusted due to natural pulsation of a heartbeat. That is, with each heartbeat, the volume of sample fluid, such as blood, in the sample may increase or decrease. Measurements according to various embodiments may be timed with natural pulsation, for example, by utilizing a pulse oximeter or based on measurements of the third radiation, Because the third radiation may be absorbed by a component of the sample fluid, e.g., hemoglobin, the intensity of the third radiation after interaction with the sample may be indicative of the volume of sample fluid in the sample at a particular time. Such volume information may be used to identify pulsation.

[0051] At. Step 520, a probe beam is directed at the sample in the sample state. The probe beam may be a blended, non-time-multiplexed electromagnetic beam having a plurality of electromagnetic radiations of different wavelengths. For example, the probe beam may include a first radiation, second radiation, and third radiation. The first radiation may be of a wavelength such that it is absorbed by the target analyte. The second radiation may be of a wa velength such that it is less absorbed by the target analyte. The third radia tion may be of a wavelength such that it is absorbed by a component of the sample fluid. The probe beam may be previously calibrated and balanced, for example by optical bridge balancing. In some embodiments, the optical bridge balancing may be performed according to methods disclosed in the '337 patent and the '666 patent, for example. In some other embodiments, the probe may be calibrated via other known methods.

[0052] At Step 530, an analytic beam is obtained. The probe beam interacts with the sample and emerges from the sample as the analytic beam, The analytic beam may be obtained as a transmission, reflection, or transfleetion of the probe beam by the sample. The analytic beam may contain the plurality of electromagnetic radiations of diff erent

wavelengths of the probe beam, but the intensities of the radiations may have changed by different amounts due to interaction with the sample. When the probe beam interacts with the sample, the radiations of different wavelengths may be absorbed to different extents, depending on the amount of target analyte and sample fluid in the sample at the particular sample state. The radiations may also be absorbed to different extents based on the absorption coefficients of the various components of the sample. Therefore, the ratio of intensities of the different radiations in the analytic beam may differ from the probe beam. The subsequent steps in flowchart 500 may be related to extracting data based on this change, and utilizing the data to calculate the concentration of the target analyte.

[0053] At Step 540, the analytic beam is variably filtered, for example, by variable filter 280, At any given time, only one of the radiations of the analytic beam may pass through the variable filter, based on which filter is activated by, for example, selector 260. The active filter of the variable filter may be varied sequentially such that a time-multiplexed analytic beam is generated at Step 541. Time-multiplexed analytic beam may include sequences of one or another of the radiations of the analytic beam. For example, time-multiplexed analytic beam may include a periodic repetition, wherein in a given repeated time period, the analytic beam includes a sequence of the first radiation, the second radiation, and/or then the third radiation,

[0054] At Step 542, a time-multiplexed electrical signal is be generated. The time- multiplexed analytic beam may be detected by a detector, which outputs a corresponding electrical signal as the time-multiplexed electrical signal. At Step 543, the time-multiplexed electrical signal is demultiplexed into different data streams. Each data stream may correspond to one of the electromagnetic radiations of different wavelengths in the probe beam. Demultiplexing may be achieved by using a position sensor that is keyed into the variable filter that was used to time-multiplex the analytic beam, to accurately separate various components of the time-multiplexed electrical signal,

[0055] At Step 599, the concentration of the target analyte may be determined based on the separate data streams corresponding to the different radiations of different wavelengths. In some embodiments, Step 599 may include determining the concentration of the target analyte based on data streams obtained for a plurality of sample states of the sample. That is, in some embodiments, various combinations of Steps 520 to 543 may be repeatedly performed with the sample in a plurality of sample states, to obtain data corresponding to each of the plurality of sample states. Information about the change in intensities for the different radiations at different sample states may then be used to determine the concentration of the target analyte according to, for example, methods disclosed in the '337 patent. For example, at Step 510, the sample may be adjusted to be in a first sample state having a first fluid volume, for a predetermined interval of time, e.g.. a hundredth of a second, a tenth of a second, or a second. Steps 520 to 543 may be then be performed, after which, more sample state measurements may be desired (Step 545: YES). Subsequently, at Step 550, the sample may be adjusted to be in a second sample state having a second fluid volume, for an interval of time. Steps 520 to 543 may be performed with the sample in this second sample state. The sample may also be adjusted to be in one of a continuum of transition sample states in between the first sample state and the second sample state, For instance, the first sample state may be one in which most of the sample fluid is displaced from the sample. The second sample state may be one in which most of the full volume of sample fluid is present in the sample. Other sample states may be ones in which a fraction of the full volume of sample fluid is present in the sample. Once enough sample state measurements are obtained, and more sample state measures are not desired (Step 545 :NO), the concentration of the target analyte may be determined based on a plurality of sample state measurements. The timing may vary according to various embodiments. For example, determining the concentration of target anaiyie at Step 599 may occur continuously and simultaneously in parallel with Steps 520 to 550 for various sample states.

[0O56J Fig. 6 illustrates a flowchart 600 for non-invasive measurement of a concentration of a target analyte in a sample according to various embodiments. In some exemplary embodiments, the method of flowchart 600 may be performed by a system for non-invasive measurement of a concentration of target analyte, such as system 100 or 300. The target analyte may reside in a sample fluid of the sample, and have a different absorption coefficient at different wavelengths of electromagnetic radiation. The sample may be probed utilized a blended (spatially multiplexed), non-time-muliipiexed beam. The beam may be spatially separated (wavelength separated) after leaving the sample, but not temporally separated, as in flowchart 500.

[0057] Steps 610 through 630 are similar to Step 510 and 530 of flowchart 500. The sample is adjusted into a sample state having a fluid volume (Step 610). A non-time- multiplexed probe beam, having a plurality of electromagnetic radiations of different wavelengths is directed at the sample in the sample state (Step 620). An analytic beam is obtained (Step 630), wherein the analytic beam is a reflected, transmitted, or transflected portion of the probe beam by the sample in the sample state.

[0058] At Step 650, the analytic beam may be detected using a plurality of detectors to generate, at Step 651 , a plurality of data streams. Each detector may receive a portion of the analytic beam, and detect radiations in the analytic beam according to the wavelengths that the detector is capable of detecting. In various embodiments, the plurality of detectors may be multiple detector chips in one detector device, as described earlier with respect to Figs, 4B and 4C. in some embodiments, a filter may precede a detector in the path of the analytic beam. Each data stream generated by each detector may correspond to a different radiation of different wavelength of the probe beam,

[0Θ59] At Step 699, a concentration of the target analyte in the sample may be calculated based on the plurality of data streams. Specifically the concentration may be determined based on a difference in detected intensity of at least one of the radiations o the analytic beam, for example the first radiation and/or the second radiation, in various embodiments, Step 699 may include determining the concentration of the target analyte based on data streams obtained for a plurality of sample states of the sample. That is, various combinations of Steps 610 to 651 may be repeatedly performed with the sample in a plurality of sample states, to obtain data corresponding to each of the plurality of sample states, information about the change in intensities for the different radiations at different sample states may then be used to determine the concentration of the target analyte according to, for example, methods disclosed in the '337 patent. For example, at Step 630, the sample may be adjusted to be in a first sample state having a first fluid volume, for a predetermined interval of time, e.g., a hundredth of a second, a tenth of a second, or a second. Steps 620 to 651 may be then be performed, after which, more sample state measurements may be desired (Step 653: YES). Subsequently, at Step 660, the sample may be adjusted to be in a second sample state having a second fluid volume, for an interval of time. Steps 620 to 65 ί may be performed with the sample in this second sample state. The sample may also be adjusted to be in one of a continuum of transition sample states in between the first sample state and the second sample state, For instance, the first sample state may be one in which most of the sample fluid is displaced from the sample. The second sample state may be one in which most of the full volume of sample fluid is present in the sample. Other sample states may be ones in which a fraction of the full volume of sample fluid is present in the sample. Once enough sample state measurements are obtained, and more sample state measures are not desired (Step 653 :NO), the concentration of the target analyte may be determined based on a plurality of sample state measurements. The timing may vary according to various embodiments. For example, determining the concentration of target analyte at Step 699 may occur continuously and simultaneously in parallel with Steps 620 to 660 for various sample states,

[0Θ60] Methods corresponding to flowcharts 500 or 600, or various step in each method, may be performed by a device, hardware, or a software module that is implemented as software code that is executed by a device or hardware, For example, in some embodiments, the tasks may be performed by a processor of a local de vice or of one or more remote servers. Moreover, in some embodiments, one or more of the methods of 500 or 600 may be stored in non-transitory computer-readable medium, e.g., a CD-ROM, computer storage, or a flash memory, to be uploaded and performed by the device.

[ΘΘ61] The present disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. Those skilled in the art will appreciate from the foregoing description that modifications and variations are possible in light of the above teachings or may be acquired from practicing the invention, For example, the steps described need not be performed in the same sequence discussed or with the same degree of separation. Likewise various steps may be omitted, repeated, or combined, as necessary, to achieve the same or similar objectives. Similarly, the systems described need not necessarily include all parts described in the embodiments, and may also include other parts not describe in the embodiments.

[0062] Accordingly, the invention is not limited to the above-described embodiments, but instead is defined by the appended claims in light of their full scope of equivalents.

Claims

1. A method of non-invasive measurement of a concentration of a target analyte in a fluid in a sample, the method comprising:

directing a non-time-multiplexed probe beam at the sample, wherein the probe beam comprises a plurality of radiations including a first radiation and a second radiation having different wavelengths;

obtaining an analytic beam, wherein the analytic beam is a portion of the probe beam that has interacted with the sample;

variably filtering the analytic beam by a variable fi ter to generate a time-multiplexed analytic beam, wherein the time-multiplexed analytic beam includes sequential time intervals, and each time interval includes a sequence of the first radiation and the second radiation; generating a time-multiplexed electrical signal by a detector detecting the time- multiplexed analytic beam;

demultiplexing the time-multiplexed electrical signals into different data streams, wherein a data stream corresponds to one of the plurality of radiations; and

determining the concentration of the target analyie based on a difference between a data stream corresponding to the first radiation and a data stream corresponding to the second radiation.

2. The method of claim 1 , wherein

the first radiation includes a wavelength for which the target, analyte has a

corresponding first absorption coefficient; and

the second radiation includes a wavelength for which the target analyte has a corresponding second absorption coefficient that is lower than the first absorption coefficient.

3, The method of claim 2, wherein

the probe beam includes a third radiation of a third wavelength that is absorbed by a component of the fluid in the sample; and

each tim interval of the time-multiplexed analytic beam includes a sequence of the first radiation, the second radiation, and the third radiation.

4, The method of claim 3 , further comprising

estimating a volume of fluid in the sample based on a data stream corresponding to the third radiation.

5, The method of claim 1 , further comprising:

adjusting the sample to be in a sample state, including a first sample state having a first fluid volume, a second sample state having a second fluid volume, and a. third sample state that is one of a continuum of sample states between the first sample state and the second sample state;

directing the non-time-multiplexed probe beam at the sample in a plurality of sample states; and

determining the concentration of the target analyte based on data streams

corresponding to the plurality of sample states.

6, The method of claim 5, wherein

in the first sample state, most of the fluid is displaced from the sample, and in the second sample state, most of the fluid is returned to the sample,

7, The method of claim 5, wherein

adjusting the sample to be in the sample state comprises compressing the sample,

8. The method of claim 5, wherein

adjusting the sample to be in the sample state comprises using natural pulsation due to a heartbeat.

9, The method of claim 1, wherein

the variable filter includes a filter wheel or tunable filter.

10, The method of claim 1, wherein the sample comprises biologic tissues and the fluid comprises blood.

11. The method of claim 1 , wherein the target analyte comprises glucose.

] 2. The method of claim 1, further comprising

calibrating the probe beam to form a balanced probe beam, comprising adjusting the intensity of one of the first radiation and the second radiation, such that the intensity of the first radiation or second radiation that is adjusted emerges from the sample equal to the intensity of the other of the first radiation and the second radiation, wherein

calibrating the probe occurs when the sample is compressed, such that, most of the fluid is displaced from the sample.

13. The method of claim 1, further comprising calibrating the probe beam to form a balanced probe beam, comprising adj listing at least one of a wavelength of the first radiation or the second radiation, such that the

absorption coefficient of the sample for the first radiation and the second radiation is equal.

14. A method of non-invasive measurement of a concentration of a target analyte in a fluid in a sample, the method comprising:

directing a non-time multiplexed probe beam at the sample, wherein the probe beam comprises a plurality of radiations including a first radiation and a second radiation having different wavelengths;

receiving the analytic beam by a plurality of detectors;

generating a plurality of data streams, one from each of the plurality of detectors, wherein a data stream corresponds to one of the plurality of radiations; and

determining the concentration of the target analyte based on a difference between a data stream corresponding to die first radiation and a data stream corresponding to the second radiation.

15. The method of claim 14, wherein

the first radiation includes a wavelength for which the target analyte has a

corresponding first absorption coefficient; and

the second radiation includes a wavelength for which the target analyte has a

corresponding second absorption coefficient that is lower than the first absorption coefficient.

16, The method of claim 14. wherein the probe beam includes a third radiation of a third wavelength that is absorbed by a component of the fluid in the sample.

17. The method of claim 16, further comprising

1 8. ^'The method of claim 14, further comprising

adjusting the sample to be in a sample state, including a first sample state having a first fluid volume, a second sample state having a second fluid volume, and a third sample state that is one of a continuum of sample states between the first sample state and the second sample state;

determining the concentration of the target analyte based on data streams

corresponding to the plurality of sample states.

19. The method of claim 18, wherein

in the first sample state, most of the fluid is displaced from the sample, and in the second sample state, most of the fluid is returned to the sample.

20. The method of claim 18, wherein

adjusting the sample to be in the sample state comprises compressing the sample.

21 . The method of claim 18, wherein adjusting the sample to be in the sample stale comprises using natural pulsation due to a heartbeat,

22. The method of claim 14, wherein the sample comprises biologic tissue and the fluid comprises blood ,

23. The method of claim 14, wherein the target ana!yte comprises glucose.

24. The method of claim 14, further comprising

calibrating the probe occurs when the sample is compressed, such that most of the fluid is displaced from the sample.

25. The method of claim 14, further comprising

calibrating the probe beam to form a balanced probe beam, comprising adjusting at least one of a wa velength of the first radiation or the second radiation, such that the absorption coefficient of the sample for the first radiation and the second radiation is equal,

26. The method of claim 14, wherein

the analytic beam is spli t into a plurality of wavelength-specific split beams by a wavelength-selectable splitter, wherein one of the split beams corresponds to the first radiation and another of the split beams corresponds to the second radiation, and

each split beam is received by one of the plurality of detectors.

27. The method of claim 14. wherein

the analytic beam is split into a plurality of split beams by a wavelength-neutral splitter, and

each split beam is received by one of the plurality of detectors.

28. The method of claim 27, wherein

at least one of the split beams is .filtered by wavelength before arriving at a detector,

29. An apparatus for non-invasive measurement of a concentration of a target analyte in a fluid in a sample, the apparatus comprising:

a source for generating a no -time-multiplexed probe beam, wherein the probe beam comprises a plurality of radiations including a first radiation and a second radiation having different wavelengths;

a variable filter comprising a plurality of filter elements for filtering an analytic beam to generate a time-multiplexed analytic beam, wherein

the analytic beam is a portion of the probe beam that has interacted with the sample, and

the time-multiplexed analytic beam includes sequential time intervals, and each time interval includes a sequence of the first radiation and the second radiation;

a detector, for detecting the time-multiplexed analytic beam and generating a time- multiplexed electrical signal:

a demultiplexer for demultiplexing the time-multiplexed electrical signal into different data streams, wherein a data stream corresponds to one of the plurality of radiations; and a processor for controlling a measurement sequence, estimating an amount of fluid in the sample, and determining the concentration of the target analyte.

30. The apparatus of claim 29, wherein

the source for generating the non-time-multiplexed probe beam comprises a plurality of light sources, include an LED or a diode laser.

31. The apparatus of claim 29, wherein

the first radiation includes a wavelength for which the target analyte has a

corresponding first absorption coefficient; and

the second radiation includes a wavelength for which the target analyte has a corresponding second absorption coefficient that is lower than the first absorption coefficient,

32. The apparatus of claim 30, wherein

the source for generating the non-time-multiplexed probe beam comprises one diode laser with a wavelength of about 1620 nm, one diode laser with a wavelength of about 1370 nm, one diode laser with a wavelength of about 1385 nm, and an LED a wavelength of about 525 m l.

33,, The apparatus of claim 29, wherein

the variable filter is a filter wheel comprising three filters:

a first filter thai transmits wavelengths between about 1000 nm and about 1450 nm and blocks wavelengths above about 1550 nrn and below about 1000 nm,

a second filter that transmits wavelengths above about 1550 nm, and a third filter that transmits wavelengths around about 525 nm and blocks wavelengths longer than about 525 nm.

34. The apparatus of claim 29, wherein

the detector is an indium gall um arsenide phoiodiode.

35. The apparatus of claim 29, further comprising

a diffuser plate, for scattering the probe beam before the probe beam arrives at the sample.

36. The apparatus of claim 29, further comprises

a sample- state -adjusting device for adjusting the sample to be in a sample state having a fluid volume, including a first, sample state having a first fluid volume, a second sample state having a second fluid volume, and a third sample state that is one of a continuum of sample states between the first sample state and the second sample state

37. The apparatus of claim 36, wherein

the sample-state-adjusting device includes a compressor for compressing the sample.

38. An apparatus for non-invasive measurement, of a concentration of a target analyte in a fluid in a sample, the apparatus comprising:

a source for generating a non-time-multiplexed probe beam, wherein the probe beam comprises a plurality of radiations including a first radiation and a second radiation having different wavelengths ;

a plurality of detectors for detecting an analytic beam, wherein each detector detects a portion of the analytic beam and generates an analytic electrical signal, and

the analytic beam is a portion of the probe beam that has interacted with the sample; and

a processor for controller a measurement sequence, estimating an amount of fluid in the sample, and determining the concentration of the target analyte.

39. The apparatus of claim 38, further comprising at least one dichroic beam splitter to split the analytic beam into a plurality of split beams based on wavelength before the plurality of detectors.

40. The apparatus of claim 39, wherein

a first split beam of the plurality of split beams corresponds with the first radiation, wherein the first radiation includes a wavelength for which the target analyte has a corresponding first absorption coefficient;

a second split beam of the plurality of split beams corresponds with die second radiation, wherein the second radiation includes a wavelength for which the target analyte has a corresponding second absorption coefficient that is lower than the first absorption coefficient: and

a third split beam of the plurality of split beams corresponds with a third radiation that is absorbed by a component of the fluid in the sample .

41. The a pparatus of c I aim 40, wherein

the first split beam includes a wavelength of about 1620 nm;

the second split beam includes wavelengths of about 1370 nm and 1385 nm; and the third split, beam includes a wavelength of about 525 nrn.

42. The apparatus of claim 38, further comprising

at least one wavelength-neutral beam splitter to split the analytic beam into a plurality of split beams: and

a filter between the beam splitter and one of the plurality of detectors.

43. The apparatus of claim 42, further comprising

a filter that transmits wavelength below about 1500 nm and blocks wavelengths above about 1500 nm, wherein the filter is disposed between the sample and a first detector of the plurality of detectors; and

a filter that transmits wavelengths above 1500 nm and blocks wavelengths below about 1500 nm, between the sample and a second detector of the plurality of detectors.

44. The apparatus of claim 38. wherein

the source for generating the non-time-multiplexed probe beam comprises a plurality of light sources, including an LED or a diode laser.

45. The apparatus of claim 44, wherein

the source for generating the non-time-multiplexed probe beam comprises one diode laser for generating the first radiation with a wavelength of about 1620 nm, one diode laser for generating a portion of the second radiation with a wavelength of about 1370 nm, one diode laser for generating another portion of the second radiation with a wavelength of about 1385 nm, and an LED for generating a third radiation with a wavelength of about 525 nm.

46, The apparatus of claim 38, wherein

the plurality of detectors comprises at least on indium gallium arsenide photodiode and at least one silicon photodiode.

47, The apparatus of claim 38, further comprising

a piano-convex lens that focuses the analytic beam on the detectors.

48, The apparatus of claim 38, further comprising

49, The apparatus of claim 38, wherein

the plurality of detectors are stacked, and each preceding detector is transparent to wavelengths that are detected by successive detectors.

50. The apparatus of claim 3 , wherein

the plurality of detectors is effectively achieved by a single segmented filter and detector combination.

51. The apparatus of claim 38, further comprising

a sample-state-adjusting device for adjusting the sample to be in a sample state having a fluid volume, including a first sample state having a first fluid volume, a second sample state having a second fluid volume, and a third sample state that is one of a continuum of sample states between the first sample state and the second sample state

52. A system for non-invasive measurement of a concentration of a target analyte in a fluid in a sample, the system comprising:

a probe beam generator comprising one or more sources for generating a non-time- multiplexed probe beam having a plurality of radiations, including a first radiation and a second radiation of different wavelengths, wherein

the first radiation includes a wavelength for which the target analyte has a corresponding first absorption coefficient; and

the second radiation includes a wavelength for which the target analyte has a corresponding second absorption coefficient that is lower than th first absorption coefficient; an analytic beam receiver comprising one or more detection devices for detecting an analytic beam and converting information contained in the analytic beam into one or more analytic electrical signals, wherein

an analytic electrical signals processor that generates digital data streams from the one or more analytic electrical signals, and detemiines the concentration of the target analyte based on the digital data streams.