System for biological fluid isomer analysis.

Abstract

A sensor device for measuring the level of one or more stereoisomers in a body fluid, for example lactate in sweat. The device includes a body fluid collection means and an optical measurement system. The measurement of the isomer level is based on the measurement of optical properties of incident light that are known to be modified in a reliable and reproducible manner by the intrinsic optical activity of at least one isomer in the sample. By measuring the optical properties, an indication of the concentration of at least one stereoisomer can be derived. For example, D- and L-lactate are mirror images, and the optical activity of each has the effect of modifying the rotation angle of the light polarization. It also has the effect of modifying the central frequency of the spectral composition of the incident light. In either case, a change in the polarization state is applied to the light before or after application to the sample.

Description

[Technical field]

[0001] The present invention relates to a system for body fluid isomer analysis, for example for detecting lactic acid in sweat. [Background technology]

[0002] Stereochemistry, stereoisomerism, or spatial isomerism is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (composition) but differ in the three-dimensional orientation of their atoms in space.

[0003] Enantiomers are a class of stereoisomers. Enantiomers, also known as optical isomers, are two stereoisomers that are related to each other by reflection and are non-superimposable mirror images of each other.

[0004] Many clinically relevant chemical compounds in body fluids are stereoisomers, i.e., they exist in at least two stereoisomers. Examples include nearly all naturally occurring amino acids, such as alanine, lysine, proline, photoisomers of bilirubin (e.g., produced during phototherapy), as well as metabolic products such as lactic acid.

[0005] Regarding lactic acid, it is present in many body fluids, including blood and sweat. Lactic acid exists as two optical stereoisomers: L-lactic acid and D-lactic acid, which are shown in Figure 1.

[0006] Two isomers are called mirror images of each other, have the same chemical and physical properties, and are called enantiomers or optical isomers if they behave differently toward plane polarized light. Molecules with such mirror image geometry are also called chiral. The mirror image of a chiral compound is not superimposable on the original compound. The mirror images are called left-handed and right-handed enantiomers. Chiral molecules are also characterized by their propensity to rotate the plane of polarized light.

[0007] Enantiomers are of great importance, especially in biochemistry and medicinal chemistry. For example, the painkiller ibuprofen exists as two enantiomers, only one of which (the S-isomer) is effective in treating pain. Also, L-DOPA (L-dopamine), a drug used to treat Parkinson's disease, is only effective as the L- or R-enantiomer in therapy.

[0008] Specifically for lactate, this is a risk-generating biomarker, for example for risk stratification of sepsis. In the United States, more than 1.5 million people suffer from sepsis every year, of which at least 250,000 are fatal. Lactate levels are measured for risk stratification of patients suspected of having sepsis.

[0009] The predominant form of lactate in humans is L-lactate. Blood contains 50-100 times more L-lactate than D-lactate. Therefore, spot-check analyses usually measure only L-lactate, while D-lactate (which also has clinical information) is either not targeted or is obscured by the predominant L-lactate concentration. The smaller amount of D-lactate normally present in human blood (concentrations of 5-20 μmol / L compared to 1000 μmol / L for L-lactate in healthy adults) comes exclusively from exogenous sources (daily diet and carbohydrate-fermenting bacteria normally present in the gastrointestinal tract).

[0010] Traditionally, serum lactate levels are low in healthy individuals at rest. The reference range is approximately 1 ± 0.5 mmol / L, and in critically ill patients it is less than 2 mmol / L, but studies done on human lactate levels showed that an increase in lactate levels from 2.1 to 8 mmol / L at rest reduced survival from 90% to 10%. Normal lactate levels vary, but elevated blood lactate levels are an early sign of sepsis.

[0011] If a patient's serum lactate level is >2mmol / L at rest, either blood pressure and / or serum lactate levels should be monitored. Current guidelines for the management of severe sepsis or septic shock state that a blood lactate level greater than 4mmol / L at rest mandates immediate resuscitation of severe sepsis or septic shock.

[0012] Guidelines for the management of severe sepsis and septic shock require blood lactate to be measured at least twice within 6 hours. Usually, a so-called racemic mixture of lactated Ringer's solution (14 mmol / L D-lactate, 14 mmol / L L-lactate, 3.1 g / L) is given via an intravenous (IV) line at a rate of 30 mL / kg body weight per hour to patients after septic shock or with high fluid loss.

[0013] Healthy individuals can also develop high serum lactate levels, i.e., during intense exercise, due to too little oxygen in the muscles to meet the energy demands, but this application focuses on individuals at rest.

[0014] Typically, there is a variable time lag between blood lactate and sweat lactate due to clearance and active / passive transport mechanisms. Therefore, a means to improve the clinical quality of sweat lactate measurements and differentiate between D- and L-lactate is highly desirable.

[0015] The implementation of bedside lactate monitoring in the emergency department has also been associated with shorter time to intravenous transfusion in patients with suspected sepsis and reduced intensive care unit admission and mortality. Measurement of lactate levels helps identify appropriate treatment for cardiac surgical patients, acute kidney injury, and patients with community-acquired pneumonia.

[0016] Various methods and devices with different device characteristics and accuracy, such as high performance liquid chromatography (HPLC), colorimetry, fluorescence, spectrophotometry, and amperometric sensors, have been used for D-lactate and L-lactate detection. Each method has advantages and limitations. Colorimetry can achieve stable results, but its sensitivity is relatively low. For fluorescence, the device is relatively complicated. For spectrophotometry, the process is relatively time-consuming.

[0017] Depending on activity level, sweat lactate concentrations may be higher or lower than the corresponding blood lactate levels. Summary of the Invention [Problem to be solved by the invention]

[0018] Therefore, there is a need to improve the quality of sweat lactate measurements to provide a more clinically meaningful measurement of sweat lactate in relation to blood. Lactate measurements are also of interest for other conditions, such as providing an early indicator of ischemic pressure ulcers.

[0019] As mentioned above, spot-check analyses performed in clinical laboratories usually measure only L-lactate using ELISA assays or blood gas analyzers, while D-lactate (which also has clinical information) is not targeted or is obscured by the high content of L-lactate. Furthermore, as with any circulating biomarker, there is usually a (variable) time lag between blood lactate and sweat lactate due to clearance processes and active / passive transport mechanisms (diffusion time from plasma to sweat glands and lactate transport kinetics on the red blood cell membrane).

[0020] Therefore, a means to improve the quality of sweat lactate measurements and differentiate between D- and L-lactate (or provide a measure of the relative ratio of D / L-lactate concentrations) would be highly desirable as it could provide additional clinical value and diagnostic information. For example, such a distinction could enable the following use cases, addressing unmet clinical needs and increasing the accuracy and meaningfulness of sweat lactate measurements: (i) A well-defined reference time point calibration (sensor calibration) for sweat lactate and the possibility to determine the time lag between the concentration change in sweat and the corresponding change in blood, (ii) Establish a conversion factor / transfer function between blood (lactate) and sweat (lactate) concentrations; (iii) Direct measurement of D-lactate as an indicator of onset of infection (such as sepsis, infection, ischemia, traumatic shock, or liver dysfunction). [Means for solving the problem]

[0021] The invention is defined by the independent claims. The dependent claims define advantageous embodiments.

[0022] According to an embodiment of an aspect of the present invention, there is provided a body fluid sensor comprising a body fluid collection system, a polarized light source for directing analytical light towards a collected body fluid sample, at least one polarization state modifier, a light detector, and a processor for processing the detected light.

[0023] In operation, the polarization state changer and the collected bodily fluid sample are along a common optical path between the light source and the light detector, and the processor derives optical properties of the detected light altered by the polarization change induced by the bodily fluid sample to determine a concentration of at least a first stereoisomer of a predefined molecule in the bodily fluid sample, or a ratio of the concentrations of at least a first stereoisomer and a second stereoisomer of a molecule present in the bodily fluid sample.

[0024] The polarization state modifier is positioned between the polarized light source and the sample, optically upstream from the sample.

[0025] The optical property determined by the processor is the polarization change caused by the optical activity of the bodily fluid sample.

[0026] For example, an optical property of the detected light determined or derived by the processor is the polarization of the detected light (i.e., the polarization state of the detected light), thereby determining the polarization change caused by the optical activity of the bodily fluid sample.

[0027] That is, the processor measures the polarization (ie, polarization state) of the detected light and determines the change in polarization caused by the optical activity of the bodily fluid sample.

[0028] As will be further explained below, embodiments of the present invention provide an optical approach to measure the concentration of stereoisomeric molecules in body fluids. This optical approach allows the method to be fast, effective, applied in real time, and can be applied to different body fluids and for the detection of any stereoisomeric molecule. Although the present invention is initially motivated with the aim of measuring lactate concentration, e.g. in sweat, as will become clear, the solution created by the inventors can in fact be applied to measure the concentration of any stereoisomeric molecule and in any body fluid.

[0029] The bodily fluid is sweat, however, other suitable bodily fluids include urine, saliva, vaginal fluid, and / or semen.

[0030] At least the first and second stereoisomers are first and second mirror images.

[0031] As described above, the at least first and second stereoisomers are stereoisomers of lactic acid. In this case, the at least first stereoisomer is D-lactic acid. The at least second stereoisomer is L-lactic acid. The measurement of D-lactic acid can be used to provide an indication of infection, ischemia, or traumatic shock.

[0032] The polarization change caused by the optical activity of the sample can be a polarization rotation (i.e. a change in the polarization angle). The polarization change can be a change in the polarization linearity (e.g. from linear to elliptical or from circular to elliptical (or vice versa)). It can also be a change in ellipticity or circularity. In the particular embodiment described herein below, linear polarization is used, but it should be recognized that any other form of polarization can also be advantageously applied.

[0033] D- and L-lactic acid are enantiomers (a class of stereoisomers), each causing a rotation of the plane of polarized light passing through them in an opposite respective direction. The rotation is additive, so when two enantiomers are present in the same solution, their optical activity results in a net effective optical rotation. Thus, by measuring the net polarization rotation angle (the angle of rotation of the plane of polarization of linearly polarized light caused by the solution), the ratio of D- and L-lactic acid in a solution can be determined. The same approach can be applied to any stereoisomeric molecule present in the fluid being probed.

[0034] The net polarization rotation of a sample can be probed in a variety of ways. One approach is to directly measure the change in polarization angle induced by the sample. This approach uses polarimetry; this is the method outlined above. The second approach is to use optical quantum weak measurements; here, the change in the center frequency of the spectrum of light is directly measured. This is induced by the optical activity of the sample when it is illuminated with two perpendicularly polarized beams with a 180 degree phase shift. This approach is outlined below. Both of these approaches probe the same intrinsic physical property of the sample, namely its optical activity (polarization rotation), but the two approaches each directly measure a different optical property of the detected light.

[0035] The methods described herein allow for semi-continuous real-time measurement of two stereoisomers of molecules such as D- and L-lactate. The described sensors optionally include an integrated microfluidic sample collection system. The optical measurement embodiments described herein have the advantage that they do not require physical rotation of polarizer elements to detect isomers, nor the use of reagents or capture surface regeneration. In some embodiments, the described sensors are integrated into a device attached to the body (such as an on-body or internal sensor). For example, in one embodiment, a wearable sweat lactate measurement device is proposed.

[0036] Various embodiments described herein potentially enable more accurate and reliable stereoisomer measurements in wearable devices.

[0037] Some embodiments described herein allow for the conversion or transformation of measured sweat stereoisomer concentrations to corresponding blood stereoisomer concentrations.

[0038] In some embodiments, the polarization state changer applies a set of different polarization rotation angles, such that the net change in polarization angle caused by the optical activity of the sample can be derived by sensing the intensity of light received at the detector after being subjected to the different polarization rotation angles. The polarization state changer may include multiple sections, each section incorporating a polarization changer that applies a different one of the multiple different polarization rotation angles, such that multiple polarization rotations can be applied without the need for moving parts.

[0039] In some embodiments, the sensor comprises a controller that controls the polarized light source to generate analytical light of at least two different wavelengths. The different wavelengths may occur at different times, or analytical light may be generated having a spectral composition that includes a mixture of two or more wavelengths (i.e., the wavelengths occur simultaneously).

[0040] In some embodiments, the processor derives individual concentrations of two stereoisomers of the molecule from measurements of optical properties (e.g., from measurements of induced polarization rotation angles) for each of at least two different wavelengths.

[0041] In some embodiments, the bodily fluid collection system includes a fluid conduit subsystem (including one or more fluid conduits) into which a sample is placed during analysis. The fluid conduit subsystem is configured such that the sample placed therein is optically accessible to analytical light. The light passes through the conduit system in which the sample is placed on its way to a detector.

[0042] In some embodiments, the at least one polarization state modifier is included in one or more walls of at least one fluid conduit of the fluid conduit subsystem.

[0043] The wall or walls of the fluid conduit subsystem are configured such that, during operation, there is an optical path to the sample through at least a portion of the wall that includes a polarization state modifier.

[0044] The polarization state changer may be a separate unit coupled to or integrated into the wall of the conduit, or the polarization state changer may form the wall of the conduit. For example, in at least one set of embodiments, at least one polarizer sheet is provided that is rolled into a tubular configuration to form the fluid conduit. As another example, a fluid conduit may be provided that is formed from a material that is pre-strained during manufacture to provide a unique polarization changing behavior.

[0045] In some embodiments, the polarization state modifier is imprinted on a wall of said at least one fluid conduit.

[0046] In some embodiments, the polarization state changer comprises multiple segments along the fluid conduit subsystem having different polarization angles, and the detector separately detects light passing through the different segments.

[0047] If the polarization state changer performs a different modification other than a change in polarization angle, each of the multiple segments applies a different degree of associated modification, such as a different degree of change in polarization ellipticity or circularity, for example, each of the multiple segments comprises a different respective waveplate (e.g., made of the same material but with different thicknesses to provide greater or lesser rotation) having a different degree of rotation.

[0048] All of the segments are positioned, for example, so that during operation they are simultaneously in at least one optical path that extends from the light source, through the sample in the fluid conduit subsystem, to the detector.

[0049] In this way, the detector can obtain measurements for multiple different polarization rotations without having to physically move the polarization state changer. Existing systems rely on actively rotating a single polarizer to obtain measurements at different polarization angles. By providing an array of polarizers at different angles in the beam path, this active rotation can be avoided, allowing for a simpler and more compact sensor.

[0050] In some embodiments, the fluid flow path defined by at least one conduit of the conduit system is arc-shaped, the arc of the conduit lies in a plane, and said common optical path has a directional component perpendicular to said plane.

[0051] For example, the segments are disposed at successive locations along the arcuate fluid flow path.

[0052] This provides an efficient geometry for obtaining multiple polarization angle measurements. Arc-shaped conduits are space efficient, reducing the overall width the light must travel across compared to straight conduits. In some embodiments, it also allows for an efficient construction, where the polarization state changer is a continuous linear polarizer sheet that is folded or rolled to conform to the curved geometry. In this case, the sheet essentially provides a series of different polarization angles for a light source with an optical path perpendicular to the plane of the arc.

[0053] The optical detector and light source may be on opposite sides of the sample or on the same side. For example, in one embodiment, the optical detector and light source are located on the same side of the fluid conduit subsystem, and a reflector is provided at an opposite location of the fluid conduit subsystem, the reflector being along at least one of the optical paths.

[0054] In some embodiments, the sensor further comprises one or more electromagnetic coils for generating an electromagnetic field in a region, the common optical path passing through the electromagnetic field for use in enhancing the angular resolution of the analytical light.

[0055] Having outlined above certain advantageous features of the first main approach to probing the optical activity of a sample using polarimetry, we now outline below advantageous features of the second main approach to probing optical activity, which is based on the use of optical quantum weak measurements, in which the shift in the central frequency of the spectrum of light is measured.

[0056] As mentioned above, this approach has in common with the first approach that the physical property on which the measurements are based is the same, namely the optical activity of the sample.

[0057] According to one set of embodiments, a body fluid sensor is provided, the body fluid sensor comprising: A body fluid collection system; a polarized light source for directing analytical light onto the collected bodily fluid sample; A polarization state changer; A photodetector; a processor for processing the detected light; Equipped with In operation, the polarization state changer and the collected body fluid sample are along a common optical path between the light source and the light detector; The processor derives optical properties of the detected light altered by a polarization change induced by the bodily fluid sample, thereby determining a concentration of at least a first stereoisomer of the predefined molecule in the bodily fluid sample, or a ratio of the concentration of at least a first stereoisomer to a second stereoisomer of the molecule present in the bodily fluid sample; The polarization state changer includes a birefringent element optically upstream from the sample and a linear polarizer optically downstream from the sample, and the optical property determined by the processor is a change or shift in the central wavelength δλ of the optical spectrum of the detected light compared to the optical spectrum of the light generated by the light source.

[0058] The at least first and second stereoisomers are first and second mirror images of the molecule.

[0059] In some embodiments, at least the first and second stereoisomers are isomers of lactic acid. At least the first stereoisomer is D-lactic acid. At least the second stereoisomer is L-lactic acid.

[0060] The bodily fluid is sweat. Other suitable bodily fluids include urine, saliva, vaginal fluid, and / or semen.

[0061] In some embodiments, the birefringent element is a half wave plate.

[0062] In some embodiments, the polarization modification induced by the sample is a polarization rotation, which is caused by the optical activity of the sample.

[0063] In some embodiments, the polarized light source is linearly polarized in a first direction.

[0064] The birefringent element receives a light source and outputs two linearly polarized light beams, each having a perpendicular polarization direction.

[0065] The linear polarizer has a polarization direction perpendicular to the first direction.

[0066] For example, a polarization state changer may be understood to include first and second portions, one portion positioned optically upstream from the sample and the other portion positioned optically downstream from the sample, both disposed along a common optical path through the sample, the first portion comprising a birefringent element and the second portion comprising a linear polarizer.

[0067] A birefringent element includes a birefringent material (ie, a material that exhibits birefringent properties).

[0068] Birefringent elements include electrically addressable liquid crystal polarizer devices, for example, where the birefringent elements are implemented by active electronic control of liquid crystal units to induce desired birefringent behavior from the units.

[0069] In some embodiments, the bodily fluid collection system includes a fluid conduit subsystem into which the bodily fluid sample is placed during analysis.

[0070] In some embodiments, the polarization state modifier is included in one or more walls of at least one fluid conduit of the fluid conduit subsystem.

[0071] In some embodiments, the polarization state modifier is imprinted on a wall of said at least one fluid conduit.

[0072] In some embodiments, the fluid flow path defined by at least one fluid conduit of the fluid conduit subsystem is arc-shaped, the arc of the conduit lies in a plane, and the common optical path between the light source and the detector has a directional component perpendicular to the plane.

[0073] According to either the first main approach (polarimetry) or the second main approach (measurement of central wavelength shift) outlined above, the sensor is provided integrated into a unit that can be attached to the body, for example a wearable unit, such that, when worn, the fluid entry region of the body fluid collection system is held in fluid communication with the skin surface.

[0074] As noted above, certain embodiments according to either the first or second main approach include a fluid conduit subsystem into which a bodily fluid sample is placed during analysis. The fluid conduit subsystem may include at least one fluid conduit for receiving the bodily fluid sample from an inlet and flow control means (such as a valve) for controlling the flow of the sample through the conduit. The conduit system may include an outlet area through which the placed sample may be discharged from the at least one conduit after analysis is completed.

[0075] In the area of ​​in vivo lactate measurement, useful clinical information regarding lactate absorption can be derived by measuring the time lag between injecting a known amount of lactate into the bloodstream and detecting the corresponding response features in the lactate measurement signal of sweat lactate or other body fluid infusion. Next, a proposed advantageous method for obtaining such information is outlined. This can be performed using a sensor device according to any of the embodiments or examples outlined above, or a different source of sweat lactate measurements may be used. The embodiments outlined above have the advantage of allowing rapid, real-time, non-invasive measurements, which is useful for measuring repeated measurements on a regular basis. Alternatively, the following method can be implemented using any other lactate measurement method, such as using another D- and L-lactate sensitive electrochemical sensor or biochemical capture surface (e.g., using Ab-Ag binding and ELISA binding kinetics to determine D- and L-lactate). Furthermore, the same principles are applicable to other stereoisomers found in the human body, such as amino acids.

[0076] Thus, one or more embodiments include: a body fluid sensor for measuring a concentration of at least one stereoisomer of a predefined molecule in a body fluid sample; A controller, obtaining a series of concentration measurements of the subject's body fluid stereoisomers from the sensor over successive measurement sessions; Detecting, in the measurement sequence, the timing of either a positive or negative inflection point in the data sequence; receiving a data input indicating the timing of one or more stereoisomer injection events to be administered to the subject; determining a lag time between at least one stereoisomer injection event and a nearest inflection point in time following the stereoisomer injection event; The present invention provides a system comprising:

[0077] A stereoisomer concentration measurement is a measurement of the concentration of at least one stereoisomer of a predefined molecule in a subject's bodily fluid. A stereoisomer injection event is an injection in which a quantity of the same molecular stereoisomer being measured (e.g., contained within an injectable fluid) is administered to a patient.

[0078] The at least first and second stereoisomers are first and second mirror images of the molecule.

[0079] At least the first and second stereoisomers are isomers of lactic acid.

[0080] At least the first stereoisomer is D-lactic acid. At least the second stereoisomer is L-lactic acid.

[0081] The bodily fluid is sweat. Other suitable bodily fluids include urine, saliva, vaginal fluid, and / or semen.

[0082] For example, at least one set of embodiments may include: A lactate concentration sensor; A controller, obtaining a series of lactate measurements from the sensor for the subject over successive measurement sessions; Detecting, in the measurement sequence, the timing of either a positive or negative inflection point in the data sequence; receiving a data input indicating the timing of one or more lactate injection events to be administered to the subject; a controller that determines a lag time between at least one lactate injection event and a nearest inflection point in time after the lactate injection event; The present invention provides a system comprising:

[0083] In some embodiments, the sensor is a sensor for detecting lactate concentration in sweat.

[0084] The lag time between lactate administration and either the lactate peak or the upward inflection of lactate provides useful clinical information regarding the diffusion of lactate into sweat and excretory processes.

[0085] The timing of the corresponding inflection point (positive or negative) in blood lactate can also be measured, allowing the controller to determine the lag time between blood and sweat.

[0086] The above method may be provided as a separate aspect of the invention, separate from any particular system or apparatus for implementing it, that is, a method is provided that includes obtaining a series of measurements of lactate or other molecular stereoisomers of a subject over successive measurement sessions, detecting in the measurement series the timing of either a positive or negative inflection point in the data series, receiving a data input indicating the timing of one or more lactate (or other molecular stereoisomer) injection events administered to the subject, and determining a lag time between at least one injection event and the closest inflection point in time after the injection event.

[0087] In the area of ​​in vivo lactate measurement, it would be useful to be able to use (non-invasive and relatively rapid) sweat-derived lactate measurements to provide an estimated index of the corresponding blood lactate level. Blood lactate level is a more standard clinical parameter and is well understood by clinicians. It would therefore be very useful to convert sweat lactate measurements to the corresponding expected blood lactate concentration.

[0088] Next, we outline a proposed advantageous method for carrying out such a conversion. This can be carried out using a sensor device according to any of the embodiments or examples outlined above. Alternatively, the following method can be carried out using any other molecular stereoisomer measurement method, such as (for lactate) using another D- and L-lactate sensitive electrochemical sensor or biochemical capture surface (e.g., using Ab-Ag binding and ELISA binding kinetics to determine D- and L-lactate). Moreover, the same principle is applicable to other stereoisomeric molecules found in the human body, such as amino acids.

[0089] According to one or more embodiments, a sweat sensor (such as the sensor described in the earlier embodiments of the present disclosure) for measuring the concentration of at least one stereoisomer of a predefined molecule in a sweat sample; A controller, obtaining a first measurement of a concentration of a molecular stereoisomer of interest from a sensor; obtaining a second measurement of the concentration of the molecular stereoisomer of interest from the sensor, the second measurement following administration of a stereoisomer injection of the stereoisomer of interest to the subject; The following formula: c=(S after -S before ) / (I V i / V b ) to determine a conversion factor c between the sweat concentration of the molecular cube isomer and the blood concentration of the molecular cube isomer; where c is the conversion factor from sweat stereoisomer concentration to blood stereoisomer concentration, and S beforeis the concentration of the stereoisomer of interest in the sweat before the stereoisomer injection, and S after is the stereoisomer concentration of the stereoisomer of interest in the sweat after stereoisomer injection, I is the concentration of the stereoisomer of interest in the stereoisomer injection solution, and V i is the volume of stereoisomer solution injected, and V b is a blood volume of the subject; and a controller.

[0090] In the particular embodiment described above where lactate is the molecule being measured, the stereoisomer of interest is D-lactate or L-lactate. The sweat concentration sensor is, in this case, a sensor for measuring the concentration of lactate (either or both D-lactate and L-lactate) in sweat. The injection is an injection of a D-lactate or L-lactate solution (such as Ringer's solution).

[0091] Thus, more specifically, according to one or more embodiments: A sweat lactate sensor; A controller, obtaining a first sweat lactate measurement from a sensor of a lactate of interest, the lactate of interest including one or both of L-lactate and D-lactate; obtaining a second sweat lactate measurement from the sensor of a concentration of the lactate of interest, the second measurement following administration of a lactate injection of the lactate of interest to the subject; The following formula: c=(S after -S before ) / (I V i / V b ) determining a conversion factor c between L- or D-lactate in sweat and L- or D-lactate in blood; Do the following: where c is the conversion factor from L- or D-lactate concentration in sweat to L- or D-lactate concentration in blood, and S before is the lactate concentration of the lactate of interest in the sweat before lactate injection, and S after is the lactate concentration of the lactate of interest in the sweat after lactate injection, I is the concentration of the lactate of interest in the lactate injection solution, and Vi is the volume of lactate solution injected, and V b is a blood volume of the subject; and a controller.

[0092] By deriving a conversion factor, sweat concentrations can be converted to blood concentrations, eliminating the need for clinicians to wait for blood test analysis.

[0093] These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.

[0094] For a better understanding of the present invention and to show more clearly how it may be carried into effect, reference will now be made, by way of example only, to the accompanying drawings in which: [Brief description of the drawings]

[0095] [Figure 1] FIG. 1 shows the chemical structures of D- and L-lactic acid. [Diagram 2] FIG. 1 is a schematic diagram illustrating Malus' law. [Diagram 3] FIG. 1 illustrates a schematic diagram of an exemplary body fluid measurement sensor according to one or more embodiments. [Figure 4] FIG. 2 illustrates an exemplary body fluid sensor in greater detail in accordance with one or more embodiments. [Diagram 5] FIG. 1 further illustrates an exemplary body fluid sensor according to one or more embodiments. [Figure 6] FIG. 1 shows light intensity as a function of polarization angle applied to two different optically active samples. [Figure 7] 1A-1C illustrate further exemplary configurations of a sensor according to one or more embodiments. [Figure 8] FIG. 2 is a schematic diagram illustrating the effect of a half-wave plate on the polarization state of light. [Figure 9] FIG. 2 illustrates a schematic diagram in an exploded view of the optical configuration of a body fluid sensor system according to one or more embodiments utilizing an optical weak measurement approach. [Figure 10]FIG. 1 illustrates detection of a center frequency shift in the optical spectrum of light used to determine the relative or absolute concentration of molecular stereoisomers. [Figure 11] FIG. 1 shows a schematic diagram of blood lactate concentrations after injection of L- and D-lactate. [Figure 12] FIG. 1 shows the effect of multiple lactate injections on sweat D- / L lactate ratio. [Figure 13] FIG. 1 shows the effect of multiple lactate injections on sweat D- / L lactate ratio. [Figure 14] FIG. 1 shows the determination of the time lag between blood and sweat lactate levels. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0096] The present invention will now be described with reference to the drawings.

[0097] It should be understood that the detailed description and specific examples, while indicating exemplary embodiments of the devices, systems, and methods, are for purposes of illustration only and are not intended to limit the scope of the invention. These and other features, aspects, and advantages of the devices, systems, and methods of the present invention will become better understood from the following description, the appended claims, and the accompanying drawings. It should be understood that the figures are schematic representations only and are not drawn to scale. It should also be understood that the same reference numerals are used throughout the figures to indicate the same or similar parts.

[0098] The present invention provides a sensor device for measuring the level of one or more molecular stereoisomers in a body fluid, for example, the lactate stereoisomer in sweat. The device includes a body fluid collection means and an optical measurement system. The measurement of the isomer level is based on the measurement of optical properties of incident light that are known to be modified in a reliable and reproducible manner by the intrinsic optical activity of at least one isomer in the sample. By measuring the optical properties, an indication of the concentration of at least one stereoisomer of the molecule can be derived. For example, D- and L-lactate are mirror images of lactate, and the optical activity of each has the effect of modifying the rotation angle of the light polarization. It also has the effect of modifying the central frequency of the spectral composition of the incident light. In either case, a change in the polarization state is applied to the light before or after application to the sample.

[0099] According to any of the embodiments described herein, the system can be adapted to measure the concentration of at least one known pair of enantiomers present in a given molecule in a sample.

[0100] In accordance with the present invention, at least two main measurement approaches are possible, referred to as a first main approach and a second main approach, each of which is described in detail below.

[0101] The concepts of the present invention are applicable to the measurement of any stereoisomeric molecule in any biological fluid.

[0102] The following discussion describes embodiments specifically related to the measurement of D- and L-isomers of lactic acid in sweat, however, it should be understood that the same principles can be applied to the measurement of D- and L-lactic acid in any other bodily fluid, and further, as will become apparent, it should be understood that the same principles can be applied to the measurement of any other molecular stereoisomers in sweat or other bodily fluids.

[0103] According to each of the first and second main measurement approaches above, in an embodiment, a sensing device is proposed with an integrated optical sweat isomer analyzer system, which comprises a fluid conduit assembly subsystem, at least one electromagnetic radiation (preferably light) polarization state modifier (polarizer, wire grid polarizer, optical filter, retarder, waveplate, birefringent element, etc.), a polarized light source (one or more LEDs, superluminescent diodes, laser, optical fiber-based illumination source), which may be monochromatic or polychromatic, and an optical detector, such as, for example, a light intensity spectrum analyzer (photomicrospectrometer, spectrometer, polarimeter, Michelson interferometer, etc.).

[0104] The fluid conduit subsystem and the polarization modifier are spatially positioned between the photodetector and the light source such that they all share at least one common optical axis in at least one dimension.

[0105] The device includes a microcontroller adapted to convert the optical detector readings into stereoisomer measurements, in some embodiments the microcontroller may be equipped with a wireless communication module, such as Bluetooth, to enable output of the measurements.

[0106] Preferably, the device further includes an integrated power source or energy source (such as a battery or supercapacitor).

[0107] In some embodiments, an actuator may be included to actuate the polarization state changer to effect a change in the polarization state change, hi some embodiments, the actuator may be a responsive material based actuator.

[0108] The sensor system is constructed and calibrated to measure low concentrations of molecular stereoisomers in a mixture and can distinguish between optically polarizable mirror molecules (such as D- and L-lactic acid).

[0109] The first main measurement approach is described in detail below.

[0110] In this approach, the measurement principle of polarimetry is used to measure the concentration of stereoisomeric molecules in body fluids. To illustrate the principle of this concept, a set of embodiments for detecting D- and / or L-lactic acid concentration in sweat is provided below. The same principle can be applied to other stereoisomeric chemicals in other body fluids.

[0111] In the context of the present invention, D- and L-lactic acid are characterized by their property of rotating the plane of polarized light. This property is called optical activity. The angle by which the plane of polarized light is rotated is called optical rotation, α, and is measured in degrees of optical rotation (° OR). Depending on the direction in which light rotates, the enantiomers are called dextrorotatory (d or +, Latin: right, clockwise) or levorotatory (l or -, Latin: left, counterclockwise). The optical activity of the enantiomers is additive. When different enantiomers coexist in one solution, their optical activities sum to a net effective optical rotation.

[0112] From optical rotation α, specific rotation

number

number

[0113] Specific rotation of a substance

number

[0114] As shown diagrammatically in Figure 2, Malus' law states that the intensity of a beam of plane polarized light after passing through a rotatable polarizer (I final ) varies as the square of the cosine of the angle (θ) that the polarizer is rotated from the position giving the maximum intensity (I0). I final =I0cos 2 θ

[0115] In a standard polarimeter, the polarimetry principle is achieved when a dissolved optically active substance is introduced between two polarizing filters crossed at 90°. The intensity of light at a detector optically downstream from the second polarizing filter varies as a function of the angular position of these two filters. At the zero point, the polarizer and analyzer are placed at an angle of 90° towards each other, which means that no light reaches the detector (0% transmission). As soon as an optically active substance is introduced into the sample, the transmission increases, depending on the polarization plane. To measure the angle of rotation caused by the sample, the analyzer is rotated until the point where the transmission of the detector is again minimal.

[0116] A solution or mixture containing equal amounts (concentrations) of the enantiomers is called a racemic mixture. Racemic mixtures are therefore optically inactive because the clockwise and counterclockwise optical rotations cancel each other out. Conversely, when one enantiomer is present in excess, a net rotation of the plane of polarized light is observed.

[0117] In the limit where all molecules have the same handedness, a substance can be said to be optically pure. Optical purity, or enantiomeric excess (ee), is defined as: the proportion of the more abundant enantiomer minus the proportion of the less abundant enantiomer. A material that is 50% optically pure contains 75% of one enantiomer and 25% of the other. Specific rotation of pure chiral compounds

number

number

[0118] Another definition of enantiomeric excess is given by the formula:

number

[0119] An exemplary device according to at least the first set of embodiments is shown in FIG.

[0120] The device comprises a sweat sensor 12 comprising a sweat collection system 16, a polarized light source 20 for directing analytical light to the collected sweat sample, and a photodetector 24. The device further comprises a polarization state changer (apparatus) 22. At least during operation of the sensor, the polarization state changer and the collected sweat sample are along a common optical path 32 between the light source 20 and the photodetector 24. The polarization state changer may be adapted to affect a change in the angle of light polarization if the source light is linearly polarized. If the source light is not linearly polarized, it can affect a change in different properties of the polarization state, such as polarization ellipticity (in the case of elliptically polarized light) or polarization circularity in the case of circularly polarized light. More generally, the polarization state changer should affect a property or characteristic of the polarization state that is known to be modified by the optical activity of the sample.

[0121] In this embodiment, the sweat collection system includes a fluid conduit subsystem 18, and the sample is drawn into a fluid conduit of the conduit subsystem. Additionally, in this particular embodiment, a polarization state changer 22 is incorporated and positioned within or on one or more walls of a conduit of the conduit subsystem, such that light from the light source 20 passes through the polarization state changer before passing through the sample within the conduit.

[0122] In some embodiments, for example, the polarization state changer 22 may be formed by at least one polarizer sheet that is rolled to define at least one of the fluid conduits. In some embodiments, at least one of the fluid conduits may have walls formed from a layer of dichroic material, such as polyvinyl alcohol, that is prestrained to provide an intrinsic polarization function due to directional mechanical stress (material anisotropy) induced by fabrication.

[0123] However, these particular arrangements are not required. The sweat collection system may have different arrangements for receiving and holding the sample, and the polarization state modifier may be a physically separate element. In general, the polarization state modifier 22 should be located between the polarized light source and the sample, and optically upstream from the sample.

[0124] The sensor further comprises a processor 26 for processing the detected light.

[0125] During operation, the processor 26 is adapted to derive optical properties of the detected light modified by the optical activity of the sample (e.g., polarization rotation induced by the sample) and thereby measure the concentration of D-lactate in the sweat sample, or the ratio of D-lactate to L-lactate concentrations in the sample.

[0126] As mentioned above, the optical property measured by the processor may be the angle of polarization rotation caused by the optical activity of the sample.

[0127] The sensor device 12 may further include a local power source or energy source 30 (battery, supercapacitor, etc.) for powering the light source 20, the light detector 24, and the processor 26.

[0128] The illustrated embodiment is shown in the form of an on-body sensor device that is directly attachable to the skin surface 34, with the sweat collection system adapted to draw a sweat sample directly from the skin surface, although this is not required.

[0129] Although this exemplary device is described as being used for sweat samples, the same device can be applied to any other bodily fluid sample (saliva, tear drops, urine, semen, vaginal fluid, etc.) The device can also be used to test both human and animal bodily fluids.

[0130] Additionally, although this exemplary device is described as being for measuring the concentration of D-lactate and L-lactate, the device can also be used to detect the concentration of any other molecular stereoisomer, or to detect the concentration of a first stereoisomer and the ratio of a second stereoisomer of a given molecule. As will become apparent from the following description, the operating principles work when applied to a substance that contains any first and second stereoisomer of a given molecule, such as naturally occurring amino acids that are photoisomers of alanine, lysine, proline, and bilirubin, for example, formed during phototherapy.

[0131] Furthermore, although this exemplary device is described as utilizing an applied polarization modification in the form of polarization rotation, this is not required. The polarization state modifier 22 can apply different types of polarization modification, such as birefringence. For example, a polarization modifier in the form of a birefringent material (crystals such as mica or quartz, liquid crystal polymers) can be used to generate vertically and horizontally polarized phase shifted light beams (i.e., converting the input light into two distinctly polarized light beams).

[0132] An exemplary device according to at least one set of embodiments is shown in Figure 4. Figure 4 (left) shows a plan view (top down view) of the sensor device. Figure 4 (top right) shows a more detailed view of the fluid conduits of the fluid conduit subsystem 18 shown in Figure 4 (left). Figure 4 (bottom right) shows a perspective view of the passage of light through a series of optical components.

[0133] The sensor device 12 in this embodiment has an arc-like shape. The optical axis 32, previously shown in the schematic diagram of Figure 3, extends out of the page from the perspective of Figure 4 (left). The fluid flow path defined by at least one conduit of the conduit system 18 is arc-like (the arc of the conduit lies in a plane), and the common optical path 32 (along which the light source, detector, polarization state changer 22, and sample are all located) has a directional component perpendicular to said plane.

[0134] The polarization state modifier 22 is included in one or more walls of at least one fluid conduit of the fluid conduit subsystem 18. For example, the polarization state modifier is imprinted into the wall of the at least one fluid conduit.

[0135] The polarization state changer 22 in this embodiment is adapted to apply a set of different polarization rotation angles to light passing through it on its way to the sample held in the conduit subsystem 18. In particular, the polarization state changer 22 comprises a plurality of segments 23 having different polarization angles along the fluid conduit subsystem, and the detector is positioned and calibrated to individually detect light passing through the different segments. The device is configured such that, during operation, all of the segments 23 are simultaneously in at least one optical path 32 extending from the light source 20, through the sweat sample in the fluid conduit subsystem 18, to the detector 24.

[0136] By way of further explanation, according to at least one embodiment, the polarization orientation (or optical rotation) of light passing through the sample at each of a series of locations along the fluid conduit is configured by using segments 23 of polarizer filters or grids (such as wire grid polarizers) disposed on or within (e.g., printed on) the walls of the microfluidic flow channel of the conduit subsystem 18 having variable polarization angles. The integration of these polarizer segments is achieved during fabrication using, for example, lithography or any other thin film fabrication or polarizing filter fabrication techniques. For example, other examples include dichroic absorbing layer polarizing filters made from, for example, polyvinyl alcohol (PVA) plastic that is stretched during fabrication. According to further examples, the polarization state modifiers can also be implemented by liquid crystal modifier devices (such as twisted nematic devices, in-plane switching devices, or fringe domain switching devices).

[0137] The fluid conduit subsystem 18 includes at least one fluid flow path 19. Flow along the flow path is controllable via a valve 44. The at least one fluid flow path 19 includes an inlet 42 for the entry of a sample fluid, such as sweat from the surface of a user's skin. The valve may be set to allow the sample fluid to flow continuously through the flow path, or the valve may be controllable to intermittently draw fluid in to make a measurement and then expel the fluid from the flow path after the measurement has been made.

[0138] Figure 5 (left) illustrates the passage of analytical light through one segment 23 of polarization state changer 22 and one corresponding section of fluid flow path 19. Figure 5 (right) illustrates an example of an entire length of polarization state changer 22 that includes multiple segments 23 disposed at each of a series of successive locations along the length of fluid path 19.

[0139] FIG. 5, for example, shows the source light being horizontally polarized by the illustrated segment 23 of the polarization state changer before passing through the sample.

[0140] The set of different polarization rotation angles applied by the series of segments 23 is determined based on an iterative device optimization and calibration process taking into account a clinically relevant mixture of D-lactate and L-lactate (e.g., for 0.1-10 g / mol of lactate) and the specific rotation of the mixture or molecule of interest (or a sweat sample analyzed by other methods such as ELISA or HPLC).

[0141] In operation, the light detector 24 is configured to detect the intensity of light passed from the light source through the sample via each of the multiple segments 23 of the polarization state changer 22. Thus, a data series of light intensity measurements is obtained for different locations along the length of the fluid flow path 19 (i.e., for polarization rotation angles applied by the polarization state changer 22). The measurements can be made in a static state, i.e., without the need to physically move the polarization state changer. For example, the detector has an array of detection elements of sufficient size and a device that allows simultaneous sensing of portions of light that have passed through different segments of the polarization state changer.

[0142] To determine the concentration ratio of D-lactate to L-lactate from the data series of acquired light intensity measurements, the transmitted light intensity (i.e., the lattice resolved light intensity) is plotted as a function of location along the length of the tube, as shown in FIG. 6. Either the transmission minimum or transmission maximum (i.e., the point of minimum or maximum intensity) is identified or extracted from the plot. From this, the specific optical activity of the sample can be identified based on the known initial polarization of the source light. That is, the net change in polarization (in this case, the optical rotation α) caused by the sample (the optical activity of the sample) can be determined based on the knowledge of the initial polarization of the source light and the maximum and / or minimum intensity vs. polarization rotation angle in the intensity plot. From this, the ratio of the two enantiomeric pairs of D-lactate and L-lactate can be determined based on the prior knowledge of their respective optical activities.

[0143] For example, the concentration determination operation performed by processor 26 may be pre-calibrated according to known D-lactic acid and L-lactic acid solution mixtures and known wavelengths of light to determine an appropriate polarizer 22 angle range and an appropriate reference spectrum so that the acquired intensity measurement signals can be converted into relative and absolute lactate concentrations, i.e., DL concentration ratios.

[0144] Please refer to FIG. 6. FIG. 6 shows an exemplary plot of light intensity as a function of location along the length of the fluid path (i.e., as a function of different polarization rotations applied by the polarization state changer 22) for two samples exhibiting two different respective optical rotations. A first plot 52 is for a sample exhibiting an optical rotation of α=0°, and a second plot 54 is for a sample exhibiting an optical rotation of α=−30°. Either the transmission maximum or minimum +90 degrees can be used to determine the net optical rotation of the sample, from which the isomer concentration ratio can be determined based on the calibration data stored in the memory of the processor 26. The calibration data includes, for example, a pre-determined transfer function for mapping the measured net optical rotation of the sample to the ratio of D-lactate to L-lactate.

[0145] Different wavelengths of source light, when applied to a given sample, are associated with different observable functions of optical rotation versus DL-lactate concentration ratio. If these wavelength-specific functions are known, then the absolute concentration of D-lactate and / or L-lactate can be determined by identifying the intersection point of a plot of the measured intensities for each of the multiple wavelengths of applied light.

[0146] According to at least one variant of the above embodiment, the polarized source light additionally passes through an electromagnetic coil arrangement comprising one or more electromagnetic coils for generating an electromagnetic field. This arrangement is known as a Faraday modulator. This can further increase the angular resolution before being coupled to the sweat sample. This causes the vibrations to be superimposed on the polarization plane by the Faraday effect. The Faraday modulator is positioned between the sweat sample and the light source (before the light passes through the fluid path 19).

[0147] According to at least one variant, and as shown in FIG. 7, the (polarized) light source 20 and the photodetector 24 are arranged on the same side of the conduit subsystem 18, and the reflector 62 is located at the opposite location of the fluid conductor subsystem. This reflector is placed along at least one optical path from the light source to the photodetector through the sample. The reflector is, for example, a specular reflector. The reflector 62 may be a separate component or may be integrated on or in the wall of the fluid path (for example as a metal coating acting as a reflective mirror). This arrangement has the advantage of being more compact. As shown in the embodiment illustrated in FIG. 7, the polarization state changer 22 is preferably arranged between the polarized light source 20 and the sample, preferably on one side of the fluid conduit subsystem 18.

[0148] Instead of using the static state approach proposed above, in further embodiments an approach can instead be used in which the polarization state changer is operable to vary the polarization change (such as a variable change rotation) applied at any given time. By repeating a sequence of different polarization changes and measuring the light intensity associated with each polarization change, the same measurement data set is obtained as in the static state approach discussed above.

[0149] Next, we outline the second major approach to measuring the concentrations of molecular stereoisomers in biological fluid samples.

[0150] The second main approach is based on the principle of optical quantum weak measurements.

[0151] According to this second main measurement approach, an additional polarization modifier, for example in the form of a birefringent element (a birefringent material such as mica or quartz, or a liquid crystal polymer), is used to generate vertically and horizontally polarized, phase-shifted light beams (i.e., converting the input light into two clearly polarized light beams).

[0152] Birefringence is an optical property of a material that has a refractive index that depends on the polarization and propagation direction of the light. This optical anisotropy is responsible for the phenomenon of double refraction, whereby a ray of light, when incident on a birefringent material, is split into two rays that follow slightly different optical paths, depending on the polarization. When light passes through a birefringent material, one polarization experiences a greater retardation than the other polarization. This causes a change in the relative phase of the fields and therefore in the polarization.

[0153] In a birefringent material, one polarization travels faster than the other polarization, phase shifting the slow axis polarization by a half or quarter wavelength with respect to the other polarization (i.e., a 90° or 180° phase shift), which ultimately splits an originally linearly polarized light wave into two (phase-shifted) components, or converts an originally linearly polarized light wave into a circularly or elliptically polarized component.

[0154] The phenomenon of birefringence is used in so-called retarders (or waveplates), which change the polarization state of light depending on the retardance of the retarder and the angle between the fast axis of the retarder and the input polarization plane. One polarization component travels through the material at a different speed (due to birefringence) and is phase shifted relative to the other polarization component, producing an altered polarization state.

[0155] For example, a half-wave retarder (or half-wave plate) is called a polarization rotator, and an example is shown diagrammatically in FIG.

[0156] A half-wave retarder reverses the polarization direction of the incident light with respect to the retarder's fast axis. When the angle between the retarder's fast axis and the input polarization plane is 45°, horizontally polarized light is converted to vertically polarized light. A half-wave retarder rotates linearly polarized input light by twice the angle between the retarder's fast axis and the input polarization plane, as shown in Figure 8. A retarder (or wave plate) breaks a light wave into two orthogonal linearly polarized components and creates a phase shift between them. The resulting light waves are generally of different polarization forms. Ideally, a retarder does not polarize or cause any change in the intensity change of a light beam. A retarder simply affects its polarization form.

[0157] In general, waveplates are polarization converters through which one polarization direction propagates faster. Half-waveplates (HWPs) can rotate the plane of polarization by 0 to 90 degrees without losing intensity (creating a combination of vertically and horizontally polarized light with a phase delay of 180 degrees). The fast axis of the HWP is at 45° to the input polarization direction.

[0158] The principle of birefringence is exploited according to at least one set of embodiments that operates according to a second main measurement approach. The general structure and operation of a body fluid sensor according to this set of embodiments is as follows. Again, this example is described with respect to measurements made on sweat samples, but the same device can be applied to any other body fluid. Also, although the device is described as being used to measure D-lactate and / or L-lactate concentration, the same optical principles can be used to measure the concentration of the first and / or second stereoisomeric pairs of any other molecule.

[0159] A sweat sensor is provided that includes a sweat collection system, a polarized light source that directs analytical light onto the collected sweat sample, a polarization state changer, a photodetector, and a processor for processing the detected light.

[0160] In operation, the polarization state changer and the collected sweat sample are along a common optical path between the light source and the photodetector.

[0161] The processor is adapted to derive optical properties of the detected light altered by the polarization change induced by the sweat sample, thereby determining the concentration of D-lactate in the sweat sample, or the ratio of D-lactate to L-lactate in the sweat sample.

[0162] For example, referring to FIG. 9 , the polarization state changer 22 includes a birefringent element 72 optically upstream from the sample and a linear polarizer 74 optically downstream from the sample, and the optical property determined by the processor is a shift in the central wavelength δλ of the optical spectrum of the detected light compared to the optical spectrum of the analytical light produced by the light source.

[0163] In particular, in a preferred embodiment, the polarized light source is linearly polarized in a first direction (e.g., using a first deflector element), the half-wave plate is arranged to receive the light source and output two linearly polarized light beams, each having a perpendicular polarization direction, and the linear polarizer has a polarization direction perpendicular to said first direction.

[0164] The general structure and arrangement of the sensor device is substantially similar to that shown in Figure 3, except for the variations in the polarization state modifier and the processing operations performed by the processor to obtain the stereoisomer measurements. For example, the sample collection system, including the fluid conduit subsystem 18, and the light source are the same. The photodetector is a multi-frequency photodetector, although this is not required for the first measurement approach described above.

[0165] The arrangement of optical components according to this set of embodiments is shown diagrammatically in exploded form in FIG. 9. FIG. 9 (top left) shows an exploded view of the optical components along the optical path from the light source 20 to the photodetector 24, via a birefringent element 72 (such as a retarder or half-wave plate) placed optically upstream from the sample contained in the fluid flow path 19 of the fluid conductor subsystem 18. The source light 20 is linearly polarized (horizontally polarized for the purposes of this example). This initial linear polarization can be achieved using a separate linear polarizer placed between the source and the birefringent element 72, or the polarizing means may be integrated into the source. A linear polarizer having an orthogonal direction or polarization to the source light (i.e., vertical polarization in this case) is placed optically downstream from the sample in the fluid path 19 between the sample and the photodetector 24. In this example, the linear polarizer 74 is integrated in or on the wall of the fluid path holding the sample, as shown diagrammatically in FIG. 9 (top right).

[0166] The photodetector, in this embodiment, is a spectrometer.

[0167] More specifically, according to at least one set of embodiments, the birefringent element 72 provides a polarization rotor and is placed between the sample in the conduit subsystem 18 and the light source 20 and is used to generate a pair of vertically and horizontally polarized, phase-shifted light beams (i.e., convert the input polarized light into two polarized light beams).

[0168] Optionally, one or more of the optical components are integrated as part of the wall of one or more fluid paths 19 of the fluid conductor subsystem 18. In some embodiments, only the linear polarizer 74 is integrated as part of the wall of the fluid path. In another embodiment, both the birefringent element 72 and the linear polarizer are integrated into the wall of the fluid conductor subsystem. The latter option is shown diagrammatically in FIG. 9 (bottom right), which shows the birefringent element 72 and the linear polarizer integrated into opposite wall portions of each fluid path 19 of the fluid conductor subsystem. Such a configuration is fabricated, for example, using lithography or any other thin film technique (e-beam, reverse micromachining, lift-off microstructuring, etc.), for example, using mica as a substrate.

[0169] The birefringent element includes a birefringent material. Alternatively, the birefringent element may include an electrically addressable liquid crystal polarizer device (polarization rotator). The birefringence properties of the liquid crystal polarizer can be controlled, for example, by a processor or a different controller component. As an example, the fluid conduit subsystem 18 is disposed between two transparent electrodes, and the liquid crystal is confined between one of the electrodes and one or more conduits 19.

[0170] To further explain the optical principle of operation, according to this embodiment set, linearly polarized input light is decomposed into horizontally and vertically polarized light components and phase shifted / modulated by 180 degrees using a birefringent element such as a half-wave plate (HWP). This optical measurement procedure is similar to the so-called weak measurement configuration, for example, outlined in the following paper: Qiao et al., The real-time determination of D- and L-lactate based on optical weak meaurement. Anal. Methods, 2019, 11, 2223-2230.

[0171] According to the weak measurement theory, where there is a phase modulation between two eigenstates associated with the system, the shift of the central wavelength of the output optical spectrum has a close relationship to the preselected angle of polarization in the frequency domain. Therefore, the concentration ratio of the two enantiomers can be detected by changing the preselected polarization state using the applied optical rotation. This is because optical weak measurement uses the spectrum or frequency analysis of the quantum mechanical state of polarized light.

[0172] More simply, in weak optical / photon mechanical measurements, the analysis of the optical momentum of two polarized light beams can be achieved in the frequency domain by comparing a preselected quantum mechanical polarization state with a postselected state. The preselected state is established through a first polarizer (integrated with the light source 20 or immediately optically downstream from the light source) in combination with a birefringent element (such as a half-wave plate), while the postselected state is generated by a second polarizer (the aforementioned linear polarizer 74). A measurement is called "weak" when the divergence in the wavelength bandwidth (for analyzing the state) is larger than the shift or phase difference of the polarization states (caused by the optical rotation), i.e., when the two polarized light beams cannot be completely separated in space. The phase difference between the two polarizations caused by the optical rotation of the isomers is measured by weak value amplification.

[0173] Weak quantum measurements offer the advantage of increased sensitivity at the expense of a reduced probability of detection. Because the post-selection state is nearly orthogonal to the pre-selection state (e.g., two crossed polarizers), the photons received by the detector 24 are greatly reduced. To maintain a good signal-to-noise ratio, high-power power supplies such as superluminescent diodes and / or longer integration times are used.

[0174] As mentioned above, in a weak measurement system, there is a weak coupling between the measurement device and the system: perturbations of the system caused by changes in the physical parameter under test (such as changes in optical rotation due to the optical activity of the isomer being probed) generate (phase) differences between eigenstates in momentum space (frequency domain) or position space (time domain).

[0175] The use of completely imaginary weak values ​​in combination with frequency domain analysis allows the determination of the optical activity of the isomer under investigation by quantitatively analyzing the shift in the central wavelength δλ of the output spectrum. This shift (towards a lower or higher central wavelength depending on the concentration relative to the lactic acid-isomer mixture or racemic reference mixture) is used as a proxy for the optical rotation α of the sample, which can be measured in practice using an optical detector, for example equipped with a microspectrophotometer.

[0176] An example of the measurement principle is shown in Figure 10. Figure 10 shows a schematic example of two optically weak measurement spectra of two different samples, each having a different concentration of the same given isomer of interest. The shift in the central wavelength towards a lower or higher central wavelength relative to the (racemic) reference mixture is a characteristic feature for distinguishing D- and L-lactic acid, or any other isomeric compound.

[0177] As shown by Qiao et al. (supra), the two lactic acid enantiomers (D- and L-lactic acid) produce opposite shifts in wavelength (indicative of their opposite optical activity). In particular, increasing the concentration of D-lactic acid produces a negative wavelength shift, and increasing the concentration of L-lactic acid produces a positive phase shift.

[0178] By measuring the net shift in the central wavelength of the measured optical spectrum, the net optical activity and / or the net concentration ratio of D- and L-lactic acid is obtained, for example, using a pre-determined conversion or translation function or look-up table.

[0179] The two main measurement approaches outlined above can be used directly to determine the concentration ratio of D-lactate and L-lactate. The relationship between this ratio and either the measured polarization rotation at which the intensity peak occurs (first measurement approach) or the shift in the central wavelength of the output light spectrum (second measurement approach) can be pre-determined and pre-stored in the memory of processor 26.

[0180] To determine the absolute concentration of D-lactate and / or L-lactate, several options are possible, as outlined below.

[0181] One option is to use the Beer-Lambert law to measure the molar absorption coefficient of the sample, or the total light absorption by the sample as a function of wavelength, and use this to obtain the decomposition of the sample into its individual contributions to the absorption by one or more components of the sample mixture. The properties of the standard Beer-Lambert law are valid even when two or more materials absorb light in the medium. Each absorber contributes to the total absorbance, and the resulting total absorbance A is a superposition of the individual absorption processes. Based on this, for example, multivariate regression analysis can be used to measure the absolute concentrations of individual components of a biofluid mixture containing multiple components.

[0182] Another option is to include an additional conventional L-lactate sensor (such as an electrochemical sensor) in the sensor device 12 that allows for conversion of the L / D lactate concentration ratio to absolute L-lactate and D-lactate concentrations, i.e., the additional sensor provides the absolute concentration of L-lactate (which is easier to detect due to its higher levels in biological fluids), and the ratio can be used to obtain the D-lactate concentration.

[0183] Another option is to include an additional sensing means to measure the refractive index of the sample. The refractive index is used to provide an indication of the absolute total concentration of D- and L-lactate combined (using a pre-determined transfer function). Using the D / L-lactate concentration ratio gives the individual absolute concentrations of D- and L-lactate.

[0184] First and second further methods are described that use body lactate measurements to obtain further clinically relevant information.

[0185] It should be noted that these first and second methods described below are not necessarily limited to the use of any of the exemplary sensor devices previously described in this disclosure. In general, D- and / or L-lactate measurements are obtained from any suitable means, such as, for example, D- and L-lactate sensitive electrochemical sensors or capture surfaces. Capture surfaces provide alternative sensing means using Ab-Ag binding or ELISA binding kinetics. However, the two main optical approaches described above are preferred because they are simpler, faster, and allow for greater measurement frequencies (e.g., semi-continuous). For example, the alternative approaches require replenishment of reagents and regeneration of the capture surface.

[0186] According to one or more embodiments of at least one aspect of the present invention, a method includes the steps of: obtaining a data series of lactate measurements from the subject over successive measurement sessions; detecting, in the measurement sequence, the timing of either a positive or negative inflection point in the data sequence; receiving a data input indicating the timing of one or more lactate injections or infusion events to be administered to the subject; determining a lag time between at least one lactate injection or infusion event and the closest inflection point in time after the lactate injection or infusion event; A method is provided comprising:

[0187] The lag time indicates the diffusion rate of injected lactate into the body, which may be of clinical relevance, for example, for diagnosing sepsis or predicting septic events.

[0188] A processor is provided adapted to perform the above method.A computer program product is provided comprising code means configured, when executed on a processor, to cause the processor to perform the above method.

[0189] For example, there is provided a system comprising a sweat or other biofluid lactate sensor according to any of the examples or embodiments outlined above in this disclosure, and a controller or processor adapted to perform the above method using lactate measurements obtained from the above sensor.

[0190] In this embodiment, the lactate concentration measurements are used as a reference point calibration, for example in connection with post-operative sepsis detection. In this use case, preferably, either one or more racemic Ringer's infusions (14 mmol D-lactate, 14 mmol L-lactate) or one or more D-lactate injections are given and the onset of one or more characteristic transient peaks in sweat lactate concentration are observed. Optionally, these are used to correlate the sweat lactate measurements with corresponding blood lactate values.

[0191] Since D-lactate is produced by the body itself only in negligible amounts (almost 100 times less than L-lactate), it is advantageous to use D-lactate to monitor the uptake and diffusion of an injected lactate sample, since the D-lactate produced by the body does not interfere with the measurement. In some embodiments, it is proposed to measure the D-lactate concentration in sweat, or the D- / L or L- / D lactate ratio. Due to uptake dynamics and transport processes in the body, there is some time lag Δt between the administration of Ringer's solution and the measurement of the D-lactate response in sweat. The baseline concentration of D-lactate in the body is assumed to be zero, due to negligible production in the body, as mentioned above. After the injection or infusion of Ringer's solution, the D-lactate concentration rises until it reaches a peak concentration. It then exponentially decays to zero due to clearance from the body, unless further Ringer's solution or D-lactate is administered. This characteristic peaking pattern is shown diagrammatically in FIG. 11.

[0192] As shown in Figure 12, the inventors have recognized that when multiple successive infusions of Ringer's solution or injections of D-lactate are administered, it is difficult to determine the exact timing of the inflection point or maximum point due to the intermittent (i.e., semi-continuous) nature of sweat measurement. However, the time difference ΔT from the start of the infusion or injection to the change in slope from a decreasing trend to an increasing trend in the D-lactate concentration, D- / L or L- / D lactate ratio can be measured. That is, the inflection point (change in the direction of the slope) is detected. Thus, in summary, the lactate peak, i.e., either a negative or positive inflection point corresponding to either a sharp rise or a sharp fall, respectively, can be measured.

[0193] Please refer to FIG. 12. FIG. 12 shows measurements of the time lag between each of two discrete lactate injections and the corresponding sweat lactate response. Lactate levels are allowed to return to baseline before the second injection is administered. Both the time lag ΔT1 between the first D-lactate injection and the sweat lactate response (in the form of a positive inflection point in the lactate signal) and the lag time ΔT2 between the second D-lactate injection and the corresponding sweat lactate response (in the form of a positive inflection point) are shown in FIG. 12.

[0194] FIG. 13 shows a further example where lactate infusions are administered multiple times. Each infusion lasts for a certain time duration. The time difference ΔT1 and ΔT2 between the end of each lactate infusion and the corresponding lactate response in the sweat lactate signal (in the form of an inflection in the signal) is shown. Due to the uptake of lactate, the D / L lactate ratio should initially continuously decrease after the second infusion, but then start to increase again, leading to an inflection point. Here, it is assumed that the lactate solution is administered before complete clearance occurs, i.e., without returning to the baseline ratio.

[0195] As mentioned above, L-lactate is naturally produced by the body at much higher concentration levels than D-lactate. However, the endogenous production rate of L-lactate is fairly low (e.g., 0.85 mol / (70 kg body weight x 24 hours)). This means that its effect on the measured D- / L or L- / D lactate ratios is negligible. Also, note that the reported clearance of infused L-lactate is 13.1 ml / (body weight * time) compared to 9.3 ml / (body weight x time) for infused D-lactate. The slightly slower clearance time of infused D-lactate means that the D- / L-lactate ratio asymptotes to ∞ as D- and L-lactate are cleared, while in contrast, the L- / D-lactate ratio asymptotes to 0 as D- and L-lactate are cleared. In practice, it is more advantageous to use the D- / L-lactate ratio rather than the L- / D-lactate ratio. This is because the L- / D-lactate ratio yields very low values ​​which makes it more difficult to measure.

[0196] It should be noted that while Ringer's solution is widely used for intravenous infusion, it is also possible to infuse or inject higher or lower concentrations of D-lactate or different ratios of D- / L-lactate (1:2, 1:4, 2:1, 4:1, etc.). In these cases, the metabolism (including clearance and / or production) of D- and L-lactate may change significantly. However, the basic principle of this embodiment remains unchanged.

[0197] Determining the lag time between lactate injection / infusion and sweat lactate response is clinically useful in several ways.

[0198] First, it is useful as a general biomarker. Changes in lactate levels are the sum of its ongoing production and removal from the blood by excretion (e.g., clearance via urine or sweat) and its metabolic effects (uptake by cells as a direct energy source, conversion to glucose by the liver, etc.). Also, the lag time or different lengths of the lag time give indirect information about the renal filtration rate (renal clearance capacity) and allow monitoring of renal function.

[0199] In addition, the dynamic reference point calibration principle described above also provides a means to determine the time lag response between sweat lactate and blood lactate levels, providing a tool for prognostic patient risk assessment. In particular, changes in the time lag over time reflect changes in patient metabolism, indicating deterioration or improvement, especially in critically ill patients with sepsis and liver dysfunction diseases.

[0200] By way of example, Figure 14 shows a schematic of two data series of lactate concentrations in blood and sweat, respectively. Both sweat lactate measurements and blood lactate measurements are collected separately at a series of time points over a common measurement period. As shown in Figure 14, each time series is plotted and time-aligned with respect to each other to identify their trends over time and the time lag between them.

[0201] Additionally, identifying the lactate lag time is useful for later identifying the cause of changes in sweat (D- and / or L-) lactate concentration. For example, if it is detected that a patient's L-lactate levels begin to rise 15 minutes after the start of a physical therapy session, and the L-lactate lag time for this patient is known to be 15 minutes, then it is very likely that physical therapy caused this rise.

[0202] When a transient lactate signal (upward inflection of D-lactate or upward inflection of the D- / L-lactate ratio) is detected by the sweat sensor device, the time lag can be determined and is better correlated with blood lactate levels. Studies have shown that when the racemic mixture is included in a solution for intravenous injection, up to a 13-fold increase in plasma D-lactate concentration and a 2-fold increase in plasma L-lactate concentration are expected, which makes the D-to-L-lactate ratio, in particular, a compelling metric to use for reference point calibration. Within hours of cessation of treatment, pre-infusion D- and L-lactate concentrations return. See in particular: Kuze S, Naruse T, Yamazaki et al. Effects of sodium L-lactate and sodium racemic lactate on intraoperative acid base status. Anesth Analg 1992;75:702-07. See also: Delman K, Malek S, Bundz S et al. Resuscitation with lactated Ringer's solution after hemorrhage:lack of cardiac toxicity. Shock 1996;5:298~303.

[0203] The above described technique for measuring lactate time lag can be easily integrated into the clinical workflow at the patient bedside or during a surgical procedure, especially since it is common to provide one or more lactated Ringer's infusions in such clinical situations.

[0204] In some embodiments, the method further includes a time synchronization between the delivery of the lactate injection or infusion and the lactate measurement series collected by the sweat measurement device. For example, the synchronization of the D- / L-lactate injection / infusion with the sweat device is initiated by scanning a patient code attached to the infusion bag (if an infusion is administered) or by pressing a button that initiates wireless transmission. Alternatively, in some embodiments, automatic detection of the injection can be achieved using only the lactate measurements, for example by detecting a sudden rise in D-lactate after a gradual decrease in D-lactate, especially in clinical scenarios where the lactate uptake time is negligible or very short.

[0205] So, in summary, lactic acid exists in the body as a racemic mixture of D- and L-lactic acid. In the above embodiment, it is proposed to use these two chemical forms of lactic acid. Usually, only L-lactic acid is measured clinically because it is 100 times more concentrated than D-lactic acid. However, by administering a controlled racemic Ringer's solution (or D-lactic acid), D-lactic acid can be artificially increased to obtain additional clinical information on uptake and diffusion time.

[0206] It is generally believed in the art that measurements every 1-2 hours are sufficient in most acute cases, providing clinically relevant data on the decline of lactate levels in critically ill patients (informing potential sepsis and cardiac resuscitation). However, when semi-continuous sweat lactate monitoring is performed, dynamic or adaptive recalibration of the sensor system can be achieved if multiple injections or infusions are given and the time lag is determined using either the recurring transient peaks or inflection points, as outlined above.

[0207] The above procedure for determining lactate uptake lag time can be further supplemented or varied in various ways, as outlined below. These adaptations can make lag time measurements more specific and reliable.

[0208] In some embodiments, the time derivative of the D / L lactate ratio or the L / D lactate ratio, or the D-lactate level may be used instead of the raw signal.

[0209] In some embodiments, the method comprises the steps of: + ]. A change in D-lactate level alone would only indicate a change in sweat rate; that is, an increase in sweat fluid volume would lead to an increase in the concentration of D-lactate. By monitoring the ratio of lactate to sodium (sodium being an indicator of sweat level), it is possible to identify changes in D-lactate due to changes in sweat level. This increases the robustness of the measurement of lactate levels. For example, it was found that the concentration of D-lactate in sweat samples tripled after a short period of running, but the concentration relative to the sodium ion concentration did not change.

[0210] Additionally, although the above exemplary methods are described with respect to measuring lactate, the same principles can be applied to measuring the lag time in the uptake of stereoisomers of any other molecule. For example, nearly all (naturally produced) amino acids (alanine, lysine, etc.) have L- / D stereoisomeric structures.

[0211] Furthermore, the stereoisomer concentration (whether lactate or a different molecule) does not have to be measured in sweat, but may be measured in any other biological fluid.

[0212] Thus, more generally, one aspect of the invention is a method for producing a composition comprising: a body fluid molecule stereoisomer concentration sensor (e.g., as described in any of the embodiments above); A controller, obtaining a data series of stereoisomer concentration measurements from the sensor for the subject over successive measurement sessions; Detecting, in the measurement sequence, the timing of either a positive or negative inflection point in the data sequence; receiving a data input indicating the timing of one or more stereoisomer injection events to be administered to the subject; a controller adapted to determine a lag time between at least one stereoisomer injection event and a nearest inflection point in time following the stereoisomer injection event; The system includes:

[0213] Further methods of using body lactate measurements to obtain further clinically relevant information are described.

[0214] It should be noted that the methods described below are not necessarily limited to the use of any of the exemplary sensor devices previously described in this disclosure. In general, D- and / or L-lactate measurements are obtained from any suitable means, such as, for example, D- and L-lactate sensitive electrochemical sensors or capture surfaces. Capture surfaces provide alternative sensing means using Ab-Ag binding or ELISA binding kinetics. However, the two main optical approaches described above are preferred because they are simpler, faster, and allow for greater measurement frequencies (e.g., semi-continuous). For example, the alternative approaches require replenishment of reagents and regeneration of the capture surface.

[0215] The method outlined below provides a means for establishing a conversion factor for converting measured sweat lactate concentration levels into a corresponding estimate of blood lactate levels.

[0216] Blood lactate levels are a well-known and established biomarker, and clinicians are familiar with working with and interpreting blood lactate concentrations. However, as discussed above, blood lactate measurements take a significant amount of time to return results as samples must be sent to a laboratory, and the methods of obtaining blood samples are inherently invasive. Sweat lactate measurements, on the other hand, are non-invasive and fast. However, to clinicians, sweat lactate levels are less familiar as a biomarker. In order for clinicians to more easily interpret these values, it is useful to convert them to the corresponding blood lactate concentrations.

[0217] To achieve this, three factors in particular need to be considered:

[0218] First, like other biomarkers, blood lactate is not directly excreted through sweat: there is a certain conversion factor c that depends on the type of biomarker.

[0219] Secondly, in the specific case of L-lactic acid, there is an additional complication due to the fact that the sweat glands themselves produce L-lactic acid. Higher sweat rates lead to increased sweat lactate levels. Current clinical theory suggests that with higher sweat rates, the sweat glands have to work harder and therefore produce more L-lactic acid.

[0220] Third, for the purposes of deriving the conversion factors, sweat lactate is assumed to scale linearly with blood, i.e., lactate clearance through the kidneys follows the same kinetics as clearance via the sweat glands.

[0221] Regarding the second consideration above, for simplicity, L-lactate originating from the sweat glands themselves is not included in the following calculations, since it can be determined by other well-known methods, for example as described in WO2019 / 051107. That is, it is assumed that this part independent of the sweat rate has already been determined, and the following derivation does not take into account L-lactate produced by the sweat glands. In some examples, a correction may be made for sweat gland-produced lactate, which is done depending on the measured sweat rate. For example, athletes are associated with high sweat rates, while clinical patients at risk of sepsis after surgery are likely to have a low spontaneous sweat rate due to their mainly sedentary state.

[0222] What is needed is a conversion factor c between sweat and blood lactate measurements. If c is known, the L-lactate concentration in blood can be calculated from the measured concentration in sweat.

[0223] The method proposed below uses one or more lactate injections and the collection of sweat and blood lactate measurements before and after the injections.

[0224] In the following calculations, the following abbreviations are used: c: Conversion factor of L-lactate in sweat to L-lactate in blood, BOL: Blood concentration of L-lactate produced by the body; BRL: L-lactate concentration in blood derived from lactate solution (e.g. Ringer's solution), BL: total concentration of L-lactate in blood (body production + lactate solution origin), SOL: L-lactic acid concentration in sweat SRL: L-lactate concentration in sweat derived from lactic acid solution S: Total concentration of L-lactic acid in sweat (body produced + from lactic acid solution) before (as a subscript): immediately before the lactic acid solution is introduced into the body (or at least before it can be detected in sweat); after (as a subscript): Immediately after the lactic acid solution is introduced into the body (and finds its equilibrium in sweat).

[0225] According to the above definition, the total sweat concentration of L-lactic acid can be defined as: S = c BL (1) Immediately before injecting the lactate solution: S before =c·BOL (2) Immediately after injecting the lactate solution: S after =c (BOL+BRL) (3) Subtracting equation (2) from equation (3): S after -S before =c·BRL (4) Therefore, c=(S after -S before ) / BRL (5) S after and S before is the measured sweat concentration (and therefore known), the BRL can be estimated as: BRL=I V i / V b (6) where I is the concentration of L-lactic acid in the lactic acid solution and V i is the volume of Ringer's solution applied (within a given time period) and V b is the patient's blood volume. For adults, Vb The average is 5 liters.

[0226] Including knowledge of sex, height, weight, or body mass index allows for better estimations using, for example, the Nadler equation or the Lemmens-Bernstein-Brodsky equation. See, for example, Regav Sharma and Sandeep Sharma, Physiology, Blood Volume, StatPearls. Treasure Island (FL): StatPearls Publishing; January 2020, April 25, 2020.

[0227] Pregnancy, hypovolemic shock, and edema also affect blood volume and may be taken into account for a better estimate.

[0228] Using the determined conversion factor c, the sweat concentration values ​​can be converted to (estimated) blood concentration values. Blood lactate concentration is a biomarker that is already familiar to clinicians. Using sweat lactate measurements has the advantage that it avoids the time delay for blood lactate test results to be returned from the laboratory and does not require the invasive procedure of blood sampling.

[0229] Thus, in accordance with the above principles, one or more embodiments include the following steps: obtaining a first sweat lactate measurement (D-lactate, L-lactate, or a ratio of the two); obtaining a second sweat lactate measurement, the second measurement being obtained after administration of a lactate injection to the subject; The following formula: c=(S after -S before ) / (I V i / V b ) (7) to determine a conversion factor c between L- or D-lactate in sweat and L- or D-lactate in blood; having where c is the conversion factor from the L-lactate or D-lactate concentration in sweat to the L-lactate or D-lactate concentration in blood, and S before is the lactate concentration of the lactate of interest in the sweat before lactate injection, and S after is the lactate concentration of the lactate of interest in the sweat after lactate injection, I is the concentration of the lactate of interest in the lactate injection solution, i.e., L-lactate or D-lactate, and V i is the total volume of lactate solution injected, and V b is the total blood volume of the subject.

[0230] The lactate sweat measurements are obtained using a lactate sweat sensor according to any of the embodiments or examples outlined above or any claim of this application, or any other source of sweat lactate measurements may be used.

[0231] According to one or more embodiments of at least one aspect of the present invention, there is provided a system comprising a sweat sensor according to any of the embodiments or examples outlined above, and further comprising a controller or processor adapted to perform the method steps outlined immediately above relating to deriving a conversion factor c between sweat lactate and blood lactate.

[0232] As previously mentioned, the above calculations assume a linear mathematical relationship between blood lactate and sweat lactate. However, in other embodiments, the relationship between sweat lactate and blood lactate may be a different mathematical relationship, such as a first order polynomial relationship (y=mx+nx 2 ) The method may be adapted so that the estimation of the conversion factor c is modeled according to . Thus, the estimation of the conversion factor c is not limited to the assumption of a linear mathematical relationship, and in general any kind of mathematical relationship can be used, either based on theoretical modeling or experimental observation. As a result, the assumption of a linear relationship has been found to produce good and reliable results. However, without wishing to be bound by theory, it is possible that a different kind of relationship may produce superior results, and therefore the invention is not limited to this assumption.

[0233] It should be noted that although the above embodiment is specifically directed to detecting the conversion between sweat and blood concentrations of L- or D-lactic acid, the same method can be applied to other molecular stereoisomers present in both sweat and blood. For example, nearly all (naturally occurring) amino acids (alanine, lysine, etc.) have L- / D stereoisomeric structures.

[0234] As an example, it is known that bilirubin is detectable in both blood and sweat. For example, see the following paper: Ebbesen, F., Madsen, P., Vandborg, P. et al. Bilirubin isomer distribution in jaundiced neonates during phototherapy with LED light centered at 497 nm (turquoise) vs. 459 nm (blue). Pediatr Res 80, 511-515 (2016). In this paper, it is explained that when phototherapy is performed with a first wavelength, one isomer of bilirubin is more prominently present, and when therapy is performed with a second wavelength, the other isomer is more prominently present. It can therefore be seen that the relative concentrations of bilirubin stereoisomers change depending on the situation.

[0235] As a further example, molecules not originating from the body can also be detected, such as stereoisomers of molecules present in or produced by certain pharmaceuticals. See, for example, the following article: Int J Appl Basic Med Res. 2013 January June;3(1):16-18.

[0236] Thus, more generally, one aspect of the invention is a method for producing a composition comprising: A sweat sensor (such as the sensor described in the earlier embodiments of the present disclosure) for sensing the concentration of at least one stereoisomer of a predefined molecule in a sweat sample; A controller, obtaining a first measurement of a concentration of a stereoisomer of interest from a sensor; obtaining a second measurement of the concentration of the stereoisomer of interest from the sensor, the second measurement being obtained after a stereoisomer injection of the stereoisomer of interest into the subject; The following formula: c=(S after -S before ) / (I V i / V b ) determining a conversion factor c between the sweat concentration of the cubic isomer and the blood concentration of the cubic isomer; Do the following: where c is the conversion factor from sweat stereoisomer concentration to blood stereoisomer concentration, and S before is the concentration of the stereoisomer of interest in the sweat before the stereoisomer injection, and S after is the stereoisomer concentration of the stereoisomer of interest in the sweat after stereoisomer injection, I is the concentration of the stereoisomer of interest in the stereoisomer injection solution, and V i is the volume of stereoisomer solution injected, and V b is the subject's blood volume, a controller, The present invention provides a system comprising:

[0237] In the particular embodiment described above for use in measuring lactate, the stereoisomer of interest is D-lactate or L-lactate, and the injection is an injection of a D-lactate or L-lactate solution (such as Ringer's solution).

[0238] The embodiments outlined above use a controller, which includes one or more processors.

[0239] References to a processor in this disclosure may refer to a single processor or multiple processors. The processor may be located in a single containing device, structure, or unit, or distributed among multiple different devices, structures, or units. Thus, references to a processor adapted or configured to perform a particular step or task correspond to that step or task being performed by any one or more of multiple processing components, either alone or in combination. Those skilled in the art will understand how such a distributed processing device can be implemented. A processing device may be provided that includes a communication module or input / output for receiving data and outputting data to further components.

[0240] The one or more processors may be implemented in various ways using software and / or hardware to perform the various functions required. Typically, a processor employs one or more microprocessors that are programmed using software (e.g., microcode) to perform the required functions. A processor may also be implemented as a combination of dedicated hardware to perform some functions and one or more programmed microprocessors and associated circuitry to perform other functions.

[0241] Examples of circuitry that may be used in various embodiments of the present disclosure include, but are not limited to, conventional microprocessors, application specific integrated circuits (ASICs), and field programmable gate arrays (FPGAs).

[0242] In various implementations, the processor may be associated with one or more storage media, such as volatile and non-volatile computer memory, such as RAM, PROM, EPROM, and EEPROM. The storage media may be encoded with one or more programs that, when executed on the one or more processors and / or controllers, perform the necessary functions. The various storage media may be fixed within the processor or controller, or may be transportable such that the stored program or programs may be loaded into the processor.

[0243] Variations of the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the word "a" or "an" does not exclude a plurality.

[0244] A single processor or other unit may fulfill the functions of several items recited in the claims.

[0245] The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0246] The computer program may be stored / distributed on any suitable medium, such as an optical storage medium or a solid-state medium, supplied together with or as part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless communication systems.

[0247] It should be noted that when the term "adapted to" is used in the claims or description, it is intended to be equivalent to the term "configured to."

[0248] Any reference signs in the claims should not be construed as limiting the scope.

Claims

1. A body fluid collection system; a polarized light source for directing analytical light onto the collected bodily fluid sample; At least one polarization state changer; A photodetector; a processor for processing the detected light; A body fluid sensor comprising: In operation, the polarization state changer and the collected body fluid sample are along a common optical path between the polarized light source and the photodetector; the processor derives optical properties of the detected light altered by a polarization change induced by the bodily fluid sample, thereby determining a concentration of at least a first stereoisomer of a predefined molecule in the bodily fluid sample, or a ratio of a concentration of the first stereoisomer to a concentration of a second stereoisomer of a molecule present in the bodily fluid sample; the polarization state changer is disposed between the polarized light source and the bodily fluid sample and optically upstream from the bodily fluid sample; The bodily fluid sensor, wherein the optical property determined by the processor is a polarization change caused by optical activity of the bodily fluid sample.

2. 2. The body fluid sensor of claim 1, wherein the first stereoisomer is D-lactic acid and the second stereoisomer is L-lactic acid.

3. The body fluid sensor according to claim 1 , wherein the body fluid is sweat.

4. The body fluid sensor of claim 1 , wherein the polarization state changer applies a set of different polarization rotation angles.

5. 5. The body fluid sensor of claim 1, further comprising a controller for controlling the polarized light source to generate analytical light of at least two different wavelengths, and wherein the processor derives individual concentrations of the first and second stereoisomers of the molecule from measurements of the optical properties at the difference between the two or more wavelengths.

6. The body fluid sensor of claim 1 , wherein the body fluid collection system comprises a fluid conduit subsystem, and wherein the body fluid sample is placed in the fluid conduit subsystem during analysis.

7. The body fluid sensor of claim 6 , wherein the at least one polarization state modifier is included in one or more walls of at least one fluid conduit of the fluid conduit subsystem.

8. The body fluid sensor of claim 7 , wherein the polarization state modifier is imprinted on the wall of the at least one fluid conduit.

9. 9. The body fluid sensor of claim 6, wherein the polarization state changer comprises a plurality of segments having different polarization angles along the fluid conduit subsystem, and the light detector detects light passing through different segments individually.

10. 10. The body fluid sensor of claim 9, wherein all of the segments are positioned such that, during operation, they are simultaneously in at least one optical path extending from the light source through the body fluid sample in the fluid conduit subsystem to the light detector.

11. 11. The body fluid sensor of claim 6, wherein a fluid flow path defined by at least one conduit of the fluid conduit subsystem is arc-shaped, the arc of the conduit lies in a plane, and the common optical path has a directional component perpendicular to the plane.

12. A body fluid collection system; a polarized light source for directing analytical light onto the collected bodily fluid sample; At least one polarization state changer; A photodetector; a processor for processing the detected light; A body fluid sensor comprising: In operation, the at least one polarization state changer and the collected body fluid sample are along a common optical path between the light source and the light detector; the processor derives optical properties of the detected light altered by a polarization change induced by the bodily fluid sample, thereby determining a concentration of at least a first stereoisomer of the predefined molecule in the bodily fluid sample, or a ratio of the concentrations of at least a first stereoisomer and a second stereoisomer of the predefined molecule present in the bodily fluid sample; the at least one polarization state changer includes a birefringent element optically upstream from the bodily fluid sample and a linear polarizer optically downstream from the bodily fluid sample, and the optical characteristic determined by the processor is a shift in a central wavelength δλ of the optical spectrum of the detected light compared to the optical spectrum of light generated by the light source.

13. the polarized light source is linearly polarized in a first direction; the birefringent element receives the light generated by the polarized light source and outputs two linearly polarized light beams having perpendicular polarization directions, The body fluid sensor of claim 12 , wherein the linear polarizer has a polarization direction perpendicular to the first direction.

14. The body fluid sensor of claim 12 or 13, wherein the birefringent element is a half wave plate.

15. the birefringent element comprises a birefringent material, or The body fluid sensor of claim 12 , wherein the birefringent element comprises an electrically addressable liquid crystal polarizer device.

16. the bodily fluid collection system includes a fluid conduit subsystem, the bodily fluid sample being placed in the fluid conduit subsystem during analysis; 16. The body fluid sensor of claim 12, wherein optionally the at least one polarization state modifier is included in one or more walls of at least one fluid conduit of the fluid conduit subsystem, and optionally the at least one polarization state modifier is imprinted on at least one wall of the at least one fluid conduit.

17. 17. The body fluid sensor of claim 16, wherein a fluid flow path defined by at least one fluid conduit of the fluid conduit subsystem is arc-shaped, the arc of the conduit lies in a plane, and the common optical path between the light source and the detector has a directional component perpendicular to the plane.

18. 18. The body fluid sensor of claim 1 , integrated into a wearable unit.

19. A body fluid sensor according to any one of claims 1 to 18; Controller and A system comprising: The controller: obtaining a data series of concentration measurements of at least one stereoisomer from the subject over successive measurement sessions from the bodily fluid sensor; Detecting, in the measurement sequence, the timing of either a positive or negative inflection point in the data sequence; receiving a data input indicating the timing of one or more stereoisomer injection events to be administered to said subject; The system determines a lag time between at least one stereoisomer injection event and the closest inflection point in time after said stereoisomer injection event.

20. 19. The body fluid sensor according to claim 1, comprising: a sweat sensor; Controller and A system comprising: The controller: obtaining a first measurement of a concentration of a stereoisomer of interest from the body fluid sensor; obtaining a second measurement of the concentration of the stereoisomer of interest from the bodily fluid sensor, the second measurement following administration of a stereoisomer injection of the stereoisomer of interest to the subject; The following formula: c=(S ａｆｔｅｒ -S ｂｅｆｏｒｅ ) / (I・V ｉ / V ｂ ) determining a conversion factor c between the sweat concentration of the cubic isomer of interest and the blood concentration of the cubic isomer of interest; Do the following: where c is the conversion factor from sweat stereoisomer concentration to blood stereoisomer concentration, and S ｂｅｆｏｒｅ is the concentration of the stereoisomer of interest in sweat before injection of the stereoisomer, and S ａｆｔｅｒ is the concentration of the stereoisomer of interest in sweat after injection of the stereoisomer, I is the concentration of the stereoisomer of interest in the stereoisomer injection solution, and V ｉ is the amount of the stereoisomer solution injected, and V ｂ is the blood volume of the subject.

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