Methods and systems for melanin absorption-compensated blood oxygen

Abstract

Provided herein is a system and method for measurement of analyte concentration of a subject or a blood vessel of a subject comprising emitting a first optical pulse at a first wavelength and a second optical pulse at a second wavelength towards a portion of skin of the subject having a skin pigmentation, detecting a first acoustic signal resulting from the first optical pulse and a second acoustic signal from the second optical pulse, wherein the first acoustic signal and the second acoustic signal have a differential acoustic response based on the skin pigmentation, normalizing a portion of the first acoustic signal based on the second acoustic signal, and determining a concentration of an analyte based on the normalized portion of the first acoustic signal to compensate for skin pigmentation.

Description

AttyDktNo.: 48357-715601METHODS AND SYSTEMS FOR MELANIN ABSORPTION-COMPENSATED BLOOD OXYGENCROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 721,391, filed November 15, 2024, which application is incorporated herein by reference.BACKGROUND

[0002] Variable melanin content and skin tone may adversely affect the performance of optical medical devices and has been a significant clinical risk in need of mitigation. Conventional pulse oximeter devices do not account for the melanin content of a subject in measurements of physiological information. The present disclosure relates to medical systems, devices, and methods for measuring concentrations of analytes in tissue, such as for determining blood oxygenation and hemoglobin concentration.SUMMARY

[0003] In an aspect, the present disclosure provides a method for measurement of an analyte level of a subject or a blood vessel of a subject. In some embodiments, the method comprises emitting a first optical pulse at a first wavelength and a second optical pulse at a second wavelength towards a portion of skin of the subject having a skin pigmentation. In some embodiments, the method comprises detecting a first acoustic signal resulting from the first optical pulse and a second acoustic signal resulting from the second optical pulse. In some cases, the first acoustic signal and the second acoustic signal have a differential acoustic response based on the skin pigmentation. In some embodiments, the method comprises normalizing a portion of the first acoustic signal based on the second acoustic signal. In some embodiments, the method comprises determining an analyte level based on the normalized portion of the first acoustic signal to compensate for skin pigmentation. In some embodiments, determining the analyte level comprises determining the concentration of an analyte. In some embodiments, the first wavelength is from 600 nanometers (nm) to 793 nm. In some embodiments, the first wavelength is 760 nm. In some embodiments, the first wavelength is 660 nm. In some embodiments, the second wavelength is from 794 nm to 1300 nm. In some embodiments, the second wavelength is 800 nm. In some embodiments, the second wavelength is 900 nm. In some embodiments, the method further comprises emitting a third optical pulse at a third wavelength and detecting a third acoustic signal resulting from the third optical pulse. In some embodiments, the third wavelength is from 600 nm to 1,300 nm. In some embodiments, the third wavelength is 1064 nm. In some embodiments, normalizing the portion of the first acoustic signal by the secondAttyDktNo.: 48357-715601acoustic signal includes subtracting a portion of the third acoustic signal from at least one of the first acoustic signal and the second acoustic signal. In some embodiments, determining the analyte level comprises determining an oxygen saturation of the subject. In some embodiments, determining the oxygen saturation of the subject includes normalizing blood and vessel peak ratio by the normalized skin portion of the first acoustic signal. In some embodiments, determining the oxygen saturation of the subject based on the normalized portion of the first acoustic signal comprises using EQUATION 15. In some embodiments, the method further comprises determining the light intensity of the first optical pulse, and normalizing the first acoustic signal based on the light intensity of the first optical pulse. In some embodiments, the method further comprises determining the light intensity of the second optical pulse, and normalizing the second acoustic signal based on the light intensity of the second optical pulse. In some embodiments, emitting the first optical pulse at the first wavelength and the second optical pulse at the second wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array. In some embodiments, detecting the first acoustic signal resulting from the first optical pulse and the second acoustic signal from the second optical pulse comprises using a piezoelectric sensor. In some embodiments, the first acoustic signal is generated at a skin layer of the subject. In some embodiments, the first acoustic signal is generated at a vessel layer of the subject. In some embodiments, the second acoustic signal is generated at a skin layer of the subject. In some embodiments, the second acoustic signal is generated at a vessel layer of the subject. In some embodiments, the portion of skin covers a blood vessel of the subject. In some embodiments, the blood vessel is a radial artery, a super sagittal sinus (SSS), or an internal jugular vein.

[0004] In an aspect, the present disclosure provides a method for measurement of blood oxygenation of a subject or a blood vessel of the subject. In some embodiments, the method comprises emitting a plurality of first optical pulses at a first wavelength towards a portion of skin of the subject having a skin pigmentation. In some embodiments, the method comprises detecting a first acoustic signal generated in response to the plurality of first optical pulses, the first acoustic signal being generated at a vessel layer of the subject. In some embodiments, the method comprises detecting a second acoustic signal generated in response to the plurality of first optical pulses, the second acoustic signal being generated at a skin layer of the subject. In some cases, the second acoustic signal has a differential acoustic response to the plurality of first optical pulses at the first wavelength based on one or more of the skin pigmentation or oxygen saturation of the subject. In some embodiments, the method comprises normalizing a portion of the first acoustic signal based on the second acoustic signal. In some embodiments, the methodAttyDktNo.: 48357-715601comprises determining an oxygen saturation of the subject based on the normalized portion of the first acoustic r signal. In some embodiments, normalizing the portion of the first acoustic signal based on the second acoustic signal comprises normalizing a first ratio of the first acoustic signal and the third acoustic signal based on a second ratio of the second acoustic signal and the fourth acoustic signal. In some embodiments, one or more of the first ratio or second ratio is dynamic based on one or more of skin pigmentation or oxygen saturation of the subject. In some embodiments, the first wavelength is from 600 nm to 793 nm. In some embodiments, the first wavelength is 760 nm. In some embodiments, the first wavelength is 660 nm. In some embodiments, the second wavelength is from 794 nm to 1300 nm. In some embodiments, the second wavelength is 800 nm. In some embodiments, the second wavelength is 900 nm. In some embodiments, emitting the plurality of first optical pulses at the first wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array. In some embodiments, emitting the plurality of second optical pulses at the second wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array. In some embodiments, detecting the first acoustic signal and detecting the second acoustic signal comprises using a piezoelectric sensor. In some embodiments, the portion of skin covers a blood vessel of the subject. In some embodiments, the blood vessel is a radial artery, a super sagittal sinus (SSS), or an internal jugular vein.

[0005] In an aspect, the present disclosure provides a method for measurement of blood oxygenation of a subject or a blood vessel of the subject. In some embodiments, the method comprises emitting a first optical pulse wavelength configured to evoke a first acoustic signal from a portion of skin of the subject and a first acoustic signal from a blood vessel of the subject. In some embodiments, the method comprises emitting a second optical pulse wavelength different from the first optical pulse wavelength, the second optical pulse wavelength configured to evoke a second acoustic signal from the portion of skin and a second acoustic signal from the blood vessel. In some embodiments, the method comprises detecting the first acoustic signal from the portion of skin, the first acoustic signal from the blood vessel, the second acoustic signal from the portion of skin, and the second acoustic signal from the blood vessel. In some embodiments, the method comprises normalizing the first acoustic signal from the blood vessel and the second acoustic signal from the blood vessel by the first acoustic signal from the portion of skin and the second acoustic signal from the portion of skin. In some embodiments, the method comprises determining an oxygen saturation of the subject based on the normalized first acoustic signal from the blood vessel and the normalized second acoustic signal from the blood vessel. In some embodiments, the first acoustic signal from the blood vessel reflectsAttyDktNo.: 48357-715601deoxygenated hemoglobin and the second acoustic signal from the blood vessel reflects oxygenated hemoglobin. In some embodiments, the first optical pulse wavelength is from 600 nm to 793 nm. In some embodiments, the first optical pulse wavelength is 760 nm. In some embodiments, the first optical pulse wavelength is 660 nm. In some embodiments, the second optical pulse wavelength is from 794 nm to 1300 nm. In some embodiments, the second optical pulse wavelength is 800 nm. In some embodiments, the second optical pulse wavelength is 900 nm. In some embodiments, emitting the first optical pulse wavelength and the second optical pulse wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array. In some embodiments, detecting the first acoustic signal from the portion of skin, the first acoustic signal from the blood vessel, the second acoustic signal from the portion of skin, and the second acoustic signal from the blood vessel comprises using a piezoelectric sensor. In some embodiments, the blood vessel is a radial artery, a super sagittal sinus (SSS), or an internal jugular vein.

[0006] In an aspect, the present disclosure provides a method for determining a melanin level of a portion of skin of a subject. In some embodiments, the method comprises emitting a first optical pulse at a first wavelength towards a portion of skin of a subject having a skin pigmentation. In some embodiments, the method comprises emitting a second optical pulse at a second wavelength towards the portion of skin of the subject. In some embodiments, the method comprises detecting a first acoustic signal resulting from the first optical pulse. In some embodiments, the method comprises detecting a second acoustic signal from the second optical pulse, wherein the first acoustic signal and the second acoustic signal have a differential acoustic response based on the skin pigmentation. In some embodiments, the method comprises normalizing a portion of the first acoustic signal based on the second acoustic signal. In some embodiments, the method comprises determining a melanin level or pigmentation of the portion of skin, based on the normalized portion of the first acoustic signal. In some embodiments, the first wavelength is from 600 nm to 793 nm. In some embodiments, the first wavelength is 760 nm. In some embodiments, the first wavelength is 660 nm. In some embodiments, the second wavelength is from 794 nm to 1300 nm. In some embodiments, the second wavelength is 800 nm. In some embodiments, the second wavelength is 900 nm. In some embodiments, emitting the first optical pulse at the first wavelength and the second optical pulse at the second wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array. In some embodiments, detecting the first acoustic signal resulting from the first optical pulse and the second acoustic signal resulting from the second optical pulse comprises using a piezoelectric sensor.AttyDktNo.: 48357-715601

[0007] In an aspect, the present disclosure provides a system for measuring an analyte level of a subject or a blood vessel of a subject. In some embodiments, the system comprises one or more optical transmitters configured to generate one or more optical pulses. In some embodiments, the system comprises one or more acoustic receivers configured to detect one or more acoustic signals resulting from the one or more optical pulses. In some embodiments, the system comprises a processor configured to (i) normalize the one or more acoustic signals and, (ii) output an analyte level of the subject or a blood vessel of the subject based at least in part on the normalized one or more acoustic signals. In some embodiments, the one or more optical pulses comprise a first optical pulse at a first wavelength and a second optical pulse at a second wavelength. In some embodiments, the first wavelength is from 600 nm to 793 nm. In some embodiments, the first wavelength is 760 nm. In some embodiments, the first wavelength is 660 nm. In some embodiments, the second wavelength is from 794 nm to 1300 nm. In some embodiments, the second wavelength is 800 nm. In some embodiments, the second wavelength is 900 nm. In some embodiments, the one or more acoustic signals comprise a first acoustic signal resulting from the first optical pulse and a second acoustic signal resulting from the second optical pulse. In some embodiments, the processor is configured to normalize a portion of the first acoustic signal based on the second acoustic signal. In some embodiments, the analyte level comprises an analyte concentration of the subject. In some embodiments, the analyte is melanin. In some embodiments, the analyte level comprises an oxygen saturation of the subject. In some embodiments, the optical transmitter comprises an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array. In some embodiments, the acoustic receiver is a piezoelectric sensor.

[0008] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure.Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrativeAttyDktNo.: 48357-715601embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0010] FIG. 1 A illustrates a method of detecting an acoustic signal including a skin layer marker and a vessel layer marker, according to some implementations.

[0011] FIG. IB shows a schematic diagram of a system for optoacoustic diagnosis of one or more physiological parameters, according to some implementations.

[0012] FIG. 1C shows a schematic diagram of a handheld probe, according to some implementations.

[0013] FIG. ID shows an image of a handheld probe, according to some implementations.

[0014] FIGs. 2A-2C illustrate relative volumes of non-pulsatile or DC and pulsatile or AC tissue compartments, according to some implementations.

[0015] FIGs. 3 A-3B illustrate an acoustic signal as function of depth through the skin, according to some implementations.

[0016] FIG. 4A illustrates a timing diagram for the illumination of a pulse at single wavelength from a light source, according to some implementations.

[0017] FIG. 4B illustrates a timing diagram for the illumination of multiple pulses at multiple wavelengths, according to some implementations.

[0018] FIG. 5A shows a method for determining an acoustic peak of skin, according to some implementations.

[0019] FIGs. 5B-5E show methods for determining an oxygen saturation based on the acoustic peaks of skin, according to some implementations.

[0020] FIG. 6A shows a standard calibration curve for determining oxygen saturation based on an absorbance ratio, according to some implementations.

[0021] FIG. 6B shows compensated calibration curves for determining oxygen saturation based on various compensated absorbance ratios for melanin absorption, according to some implementations.

[0022] FIG. 7 illustrates a graph of a median skin peak ratio for each of a study population measured according to some implementations with respect to skin tone independently measured by colorimeter reference.

[0023] FIGs. 8A-8B illustrate absorbance ratios of acoustic peaks for two subject’s skins and vessels as a function of time according to some implementations.

[0024] FIGs. 8C-8D illustrate an oxygen saturation level and a series of measured oxygen saturation measurements of the subjects of FIGs. 8A-8B, respectively, as a function of time and as measured by an optoacoustic measurement system, according to some implementations.AttyDktNo.: 48357-715601

[0025] FIG. 9A illustrates a scatterplot of an un-normalized determined oxygen saturation as a function of oxygen saturation as measured by an optoacoustic measurement system, according to some implementations.

[0026] FIG. 9B illustrates a modified Bland-Altman plot of the un-normalized SvO2 as a function of oxygen saturation as measured by an optoacoustic measurement system, according to some implementations.

[0027] FIG. 9C illustrates a scatterplot of a normalized determined oxygen saturation as a function of oxygen saturation as measured by an optoacoustic measurement system, according to some implementations.

[0028] FIG. 9D illustrates a modified Bland-Altman plot of the normalized SvO2 as a function of oxygen saturation as measured by an optoacoustic measurement system, according to some implementations.

[0029] FIG. 10 shows a computer system that is programmed or otherwise configured to implement methods provided herein.

[0030] FIG. 11 shows a plot of saturation measured with the system described herein versus saturation obtained directly by blood gas measurement, according to some implementations.DETAILED DESCRIPTION

[0031] While various embodiments of the disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed.

[0032] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0033] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure.Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example,AttyDktNo.: 48357-715601description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0034] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0035] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0036] The terms “subject,” “individual,” or “patient” are often used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.

[0037] The term “zzz vivo" is used to describe an event that takes place in a subject’s body.

[0038] The term “ex vivo" is used to describe an event that takes place outside of a subject’s body. An ex vivo assay is not performed on a subject. Rather, it is performed upon a sample separate from a subject. An example of an ex vivo assay performed on a sample is an “zzz vitro" assay.

[0039] The term “zzz vitro" is used to describe an event that takes places contained in a container for holding laboratory reagent such that it is separated from the biological source from which the material is obtained. In vitro assays can encompass cell-based assays in which living or dead cells are employed. In vitro assays can also encompass a cell-free assay in which no intact cells are employed.

[0040] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical, clinical, or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefitAttyDktNo.: 48357-715601and / or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[0041] Whenever the term “at least,” “greater than,” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “at least,” “greater than” or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0042] Whenever the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0043] Certain inventive embodiments herein contemplate numerical ranges. When ranges are present, the ranges include the range endpoints. Additionally, every sub range and value within the range is present as if explicitly written out. The term “about” or “approximately” may mean within an acceptable error range for the particular value, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” may mean within 1 or more than 1 standard deviation, per the practice in the art.Alternatively, “about” may mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value may be assumed.

[0044] In an aspect, the present disclosure provides a method for measurement of an analyte level of a subject or a blood vessel of a subject. In some embodiments, the method comprises emitting a first optical pulse at a first wavelength and a second optical pulse at a secondAttyDktNo.: 48357-715601wavelength towards a portion of skin of the subject having a skin pigmentation. In some embodiments, the method comprises detecting a first acoustic signal resulting from the first optical pulse and a second acoustic signal resulting from the second optical pulse. In some cases, the first acoustic signal and the second acoustic signal have a differential acoustic response based on the skin pigmentation. In some embodiments, the method comprises normalizing a portion of the first acoustic signal based on the second acoustic signal. In some embodiments, the method comprises determining an analyte level based on the normalized portion of the first acoustic signal to compensate for skin pigmentation. In some embodiments, determining the analyte level comprises determining the concentration of an analyte. In some embodiments, determining the analyte level comprises determining an oxygen saturation of the subject. In some embodiments, determining the oxygen saturation of the subject includes normalizing blood and vessel peak ratio by the normalized skin portion of the first acoustic signal.

[0045] In an aspect, the present disclosure provides a method for measurement of blood oxygenation of a subject or a blood vessel of the subject. In some embodiments, the method comprises emitting a plurality of first optical pulses at a first wavelength towards a portion of skin of the subject having a skin pigmentation. In some embodiments, the method comprises detecting a first acoustic signal generated in response to the plurality of first optical pulses, the first acoustic signal being generated at a vessel layer of the subject. In some embodiments, the method comprises detecting a second acoustic signal generated in response to the plurality of first optical pulses, the second acoustic signal being generated at a skin layer of the subject. In some cases, the second acoustic signal has a differential acoustic response to the plurality of first optical pulses at the first wavelength based on one or more of the skin pigmentation or oxygen saturation of the subject. In some embodiments, the method comprises normalizing a portion of the first acoustic signal based on the second acoustic signal. In some embodiments, the method comprises determining an oxygen saturation of the subject based on the normalized portion of the first acoustic signal. In some embodiments, normalizing the portion of the first acoustic signal based on the second acoustic signal comprises normalizing a first ratio of the first acoustic signal and the third acoustic signal based on a second ratio of the second acoustic signal and the fourth acoustic signal. In some embodiments, one or more of the first ratio or second ratio is dynamic based on one or more of skin pigmentation or oxygen saturation of the subject.

[0046] In an aspect, the present disclosure provides a method for measurement of blood oxygenation of a subject or a blood vessel of the subject. In some embodiments, the method comprises emitting a first optical pulse wavelength configured to evoke a first acoustic signal from a portion of skin of the subject and a first acoustic signal from a blood vessel of the subject.AttyDktNo.: 48357-715601In some embodiments, the method comprises emitting a second optical pulse wavelength different from the first optical pulse wavelength, the second optical pulse wavelength configured to evoke a second acoustic signal from the portion of skin and a second acoustic signal from the blood vessel. In some embodiments, the method comprises detecting the first acoustic signal from the portion of skin, the first acoustic signal from the blood vessel, the second acoustic signal from the portion of skin, and the second acoustic signal from the blood vessel. In some embodiments, the method comprises normalizing the first acoustic signal from the blood vessel and the second acoustic signal from the blood vessel by the first acoustic signal from the portion of skin and the second acoustic signal from the portion of skin. In some embodiments, the method comprises determining an oxygen saturation of the subject based on the normalized first acoustic signal from the blood vessel and the normalized second acoustic signal from the blood vessel. In some embodiments, the first acoustic signal from the blood vessel reflects deoxygenated hemoglobin and the second acoustic signal from the blood vessel reflects oxygenated hemoglobin.

[0047] In an aspect, the present disclosure provides a method for determining a melanin level of a portion of skin of a subject. In some embodiments, the method comprises emitting a first optical pulse at a first wavelength towards a portion of skin of a subject having a skin pigmentation. In some embodiments, the method comprises emitting a second optical pulse at a second wavelength towards the portion of skin of the subject. In some embodiments, the method comprises detecting a first acoustic signal resulting from the first optical pulse. In some embodiments, the method comprises detecting a second acoustic signal from the second optical pulse, wherein the first acoustic signal and the second acoustic signal have a differential acoustic response based on the skin pigmentation. In some embodiments, the method comprises normalizing a portion of the first acoustic signal based on the second acoustic signal. In some embodiments, the method comprises determining a melanin level or pigmentation of the portion of skin, based on the normalized portion of the first acoustic signal.

[0048] In an aspect, the present disclosure provides a system for measuring an analyte level of a subject or a blood vessel of a subject. In some embodiments, the system comprises one or more optical transmitters configured to generate one or more optical pulses. In some embodiments, the system comprises one or more acoustic receivers configured to detect one or more acoustic signals resulting from the one or more optical pulses. In some embodiments, the system comprises a processor configured to (i) normalize the one or more acoustic signals and, (ii) output an analyte level of the subject or a blood vessel of the subject based at least in part on the normalized one or more acoustic signals. In some embodiments, the analyte level comprises anAttyDktNo.: 48357-715601analyte concentration of the subject. In some embodiments, the analyte is melanin. In some embodiments, the analyte level comprises an oxygen saturation of the subject.

[0049] FIG. 1 A illustrates a system 100 and method for detecting oxygenation using an acoustic signal including a skin layer marker and a vessel layer marker according to some implementations. In some implementations, the system is configured to compensate for melanin absorption in the skin while calculating vessel / tissue oxygen saturation beneath it. Methods as described herein may include illuminating a subject’s tissue using monochromatic light and detecting an acoustic response to the illumination. The tissue may comprise a skin layer 165 and a vessel layer 170. In an example, illuminating the subject’s tissue may be performed for a few microseconds. In some embodiments, the first acoustic signal is generated at a skin layer of the subject. In some embodiments, the first acoustic signal is generated at a vessel layer of the subject. In some embodiments, the second acoustic signal is generated at a skin layer of the subject. In some embodiments, the second acoustic signal is generated at a vessel layer of the subject. In some embodiments, the portion of skin covers a blood vessel of the subject. In some embodiments, the blood vessel is a radial artery, a super sagittal sinus (SSS), or an internal jugular vein. In an example, the acoustic signal may detect absorbers in the tissue which may expand and contract following their optical excitation. Examples of absorbing chromophores in the tissue may include melanin in the skin layer and the oxyhemoglobin and deoxyhemoglobin constituents of blood within the vessel layer. Before, after, and / or in between the skin layer and the vessel layer, the light may scatter into zones 185 with low absorption. In some implementations, the method includes illuminating the tissue using at least two wavelengths and detecting at least two acoustic signals indicative of an amount of light absorbed at a given depth or location for each wavelength. FIG 1 A illustrates that a first peak of a first acoustic signal 175 may be associated with the skin layer 165 and a second peak of a second acoustic signal 180 may be associated with the vessel layer 170. In some implementations, the system is configured as a central venous oxygenation monitor.

[0050] The present disclosure provides a system for optoacoustic diagnosis of one or more physiological parameters. In some implementations, a system may comprise a console unit and a handheld probe. The handheld probe may include a laser light source for illumination and an ultrasound transducer for detecting an acoustic signal. In an aspect, an acoustic sensor may be used to identify a depth of the melanin layer. Examples of the console unit and the handheld probe may include those disclosed in PCT / US2016 / 022045, PCT / US2015 / 039620, PCT / US2017 / 051217, PCT / US2021 / 051608, US Patents 9,380,967; 10,231,656; 10,307,088; 10,226,206; 11,109,782; 11,045,121; 12,076,138, and US Patent Publications ofAttyDktNo.: 48357-715601US20190216376A1, US20190231239A1, US20190142316A1, and US20230233088A1, herein incorporated in their entirety. In an example, the handheld probe includes a laser waveguide configured to illuminate a tissue site with an integrated piezoelectric sensor like those used for ultrasound imaging to record the tissue’s acoustic signal. One or more optical sources of an exemplary system may direct a plurality of optical pulses to tissue such as skin. An acoustic detector of the system may detect the acoustic signal generated by the tissue in response to the optical pulses. In many embodiments, light pulses at different wavelengths are used. In some embodiments, the plurality of optical pulses is at one or more wavelengths from 600 nm to 1,300 nm. In some embodiments, the plurality of optical pulses is at about 760 nm. In some embodiments, the plurality of optical pulses is at about 800 nm. In some embodiments, the plurality of optical pulses is at about 1064 nm. In some embodiments, the one or more optical pulses comprise a first optical pulse at a first wavelength and a second optical pulse at a second wavelength. In some embodiments, the first wavelength is from 600 nanometers (nm) to 793 nm. In some embodiments, the first wavelength is 760 nm. In some embodiments, the first wavelength is 660 nm. In some embodiments, the second wavelength is from 794 nm to 1300 nm. In some embodiments, the second wavelength is 800 nm. In some embodiments, the second wavelength is 900 nm. In some embodiments, the method further comprises emitting a third optical pulse at a third wavelength and detecting a third acoustic signal resulting from the third optical pulse. In some embodiments, the third wavelength is from 600 nm to 1,300 nm. In some embodiments, the third wavelength is 1064 nm. In some embodiments, the first optical pulse wavelength is from 600 nm to 793 nm. In some embodiments, the first optical pulse wavelength is 760 nm. In some embodiments, the first optical pulse wavelength is 660 nm. In some embodiments, the second optical pulse wavelength is from 794 nm to 1300 nm. In some embodiments, the second optical pulse wavelength is 800 nm. In some embodiments, the second optical pulse wavelength is 900 nm.

[0051] In some embodiments, normalizing the portion of the first acoustic signal by the second acoustic signal includes subtracting a portion of the third acoustic signal from at least one of the first acoustic signal and the second acoustic signal. In some embodiments, the method further comprises determining the light intensity of the first optical pulse, and normalizing the first acoustic signal based on the light intensity of the first optical pulse. In some embodiments, the method further comprises determining the light intensity of the second optical pulse, and normalizing the second acoustic signal based on the light intensity of the second optical pulse.

[0052] FIG. IB shows a schematic diagram of a system 100 for optoacoustically measuring physiological parameters such as blood oxygenation according to some implementations. TheAttyDktNo.: 48357-715601system 100 may comprise a console 110 and a handheld probe 150 operatively coupled with a wire or cable connection 145. The console 110 may comprise a console comprising one or more subsystems or components configured to provide measurement of oxygenation in a patient PA via the handheld probe 150. The console 110 may comprise a computer board or processor 115, a user interface 120, a power supply subsystem 130, a laser emitter or diode subsystem 135, and / or an acoustic sensor subsystem 140. The processor 115 may be in communication with the one or more subsystems or components of the console 110, so as to control and monitor the operation of the subsystems. For example, the processor may comprise one or more universal serial bus (USB) ports or other types of data transfer ports configured to connect to the one or more subsystems. The processor 115 may further comprise an audio port to output alarms and message(s) through a speaker. The power supply subsystem 130 may be configured to provide power to one or more components of the system 110, such as the processor, user interface, laser diode subsystem, and acoustic sensor subsystem. The power supply subsystem 130 may be configured to connect to an external AC or DC power source. The power supply subsystem 130 may comprise a battery to provide back-up power in case of loss of external power.

[0053] In some implementations, the handheld probe 150 may comprise a light or optical source 152 for generating one or more light or optical pulses, an acoustic sensor 154, an optical energy sensor 156 operatively coupled to the light or optical source 152, a light-delivery system 160 coupled to the light or optical source 152, and / or a processor 158 operatively coupled to the light or optical source 152, the acoustic sensor 154, and the optical energy sensor 156. (See FIG. 1C). The optical energy sensor 156 may be, for example, a DET 100A detector from Thorlabs of Newton, N. J., a PE25-C or PE50BB-DIF-C detector from Ophir Optics of Jerusalem, Israel, or an EnergyMax sensor from Coherent Inc. of Santa Clara, Calif. The light or optical source 152 may be, for example, an optical parametric oscillator (OPO), a light-emitting diode (LED), laser diode, laser diode array, another pulsed light source with pulses of nanosecond duration, or the like. In some embodiments, emitting the first optical pulse at the first wavelength and the second optical pulse at the second wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array. In some embodiments, detecting the first acoustic signal resulting from the first optical pulse and the second acoustic signal from the second optical pulse comprises using a piezoelectric sensor. In some embodiments, emitting the plurality of first optical pulses at the first wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array. In some embodiments, emitting the plurality of second optical pulses at the second wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or aAttyDktNo.: 48357-715601laser diode array. In some embodiments, detecting the first acoustic signal and detecting the second acoustic signal comprises using a piezoelectric sensor. In some embodiments, emitting the first optical pulse wavelength and the second optical pulse wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array. In some embodiments, detecting the first acoustic signal from the portion of skin, the first acoustic signal from the blood vessel, the second acoustic signal from the portion of skin, and the second acoustic signal from the blood vessel comprises using a piezoelectric sensor. In some embodiments, the acoustic receiver is a piezoelectric sensor. The light or optical source 152 may be coupled to the light delivery system 160, which may be oriented to direct one or more light pulses to the tissue TI. The one or more light pulses may interact with the skin or other superficial tissue of a subject Examples of suitable tissue TI to be interrogated include superficial veins on a hand or finger, radial artery, superior sagittal sinus (SSS), internal jugular vein, and other blood vessels. In some embodiments, the blood vessel is a radial artery, an SSS, or an internal jugular vein. The one or more light pulses may be short (typically shorter than one hundred nanoseconds) pulses of near-infrared (NIR) light at a wavelength to be absorbed by a chromophore, e.g., hemoglobin. The one or more light pulses may be at wavelengths in the visible, infrared, and / or ultraviolet ranges. For example, the one or more light pulses may be in a wavelength range of about 600 nm to about 1,300 nm. In one example, the one or more light pulses may have a wavelength of about 805 nm, the isosbestic point of hemoglobin. The light pulse(s) may have a wide range of energy levels, as limited by light source or laser, tissue safety, patient safety, and other considerations. For example, an energy level of between about 1 pj and about 1 mJ may be used. The light pulse(s) may have a wide range of repetition rates. For example, the light pulse(s) may have a repetition rate between about 1 to about 10,000 Hz.

[0054] FIG. ID illustrates a view of an optoacoustic sensor as described herein. The optoacoustic sensor may comprise a probe 150.

[0055] In some implementations, a method for measurement of blood oxygenation of a subject or a blood vessel of the subject may include emitting a first optical pulse at a first wavelength and a second optical pulse at a second wavelength towards a portion of skin of the subject having a skin pigmentation, detecting a first acoustic signal resulting from the first optical pulse and a second acoustic signal from the second optical pulse, where the first acoustic signal and the second acoustic signal have a differential acoustic response based on the skin pigmentation, normalizing a portion of the first acoustic signal by the second acoustic signal, and determining a concentration of an analyte based on the normalized portion of the first acoustic signal.AttyDktNo.: 48357-715601

[0056] In an example, the first optical pulse may be at a wavelength of about 760 nm (about 600 to about 793 nm) and the second optical pulse may be at a wavelength of about 800 nm (about 794 to about 1300 nm). These ranges may be chosen to differentiate the absorption of different analytes of tissue. In another example, the first optical pulse may be at a wavelength of about 660 nm and the second optical pulse may be at a wavelength of about 900 nm. In a third example, the first optical pulse may be at a wavelength of about 724 nm and the second optical pulse may be at a wavelength of about 815 nm. In another embodiment, three wavelengths may be used to improve performance by detecting the presence of a second analyte (e.g., water). In an example, a first optical wavelength may be about 760 nm, a second optical wavelength may be about 800 nm, and a third optical wavelength may be about 1064 nm.

[0057] FIG. 2A illustrates relative volumes of non-pulsatile (e.g., DC) and pulsatile (e.g., AC) tissues. Non-pulsatile tissues 200 may comprise venous blood, capillary blood, and / or stationary tissues 210. Pulsatile tissues 205 may comprise arterial blood 215. The pulsatile tissue 205 may undergo periodic changes in red light absorbance 220 and infrared light absorbance 225 over the cardiac cycle 230.

[0058] FIG. 2B illustrates the non-pulsatile tissue 200 and pulsatile tissue 205 in arteries and veins. In an artery 235, the blood in the inner portion of the artery (which may correspond to the diastole measurement in a blood pressure reading) may comprise non-pulsatile tissue 200, while the blood in the outer portion of the artery may comprise pulsatile tissue 205. The entirety of the artery may correspond to the systole measurement in a blood pressure reading. In a capillary or vein 240, all the blood may comprise non-pulsatile tissue 200. The entirety of the capillary or vein may correspond to both systole and diastole measurements.

[0059] FIG. 2C illustrates the red-infrared modulation ratio. The ratio of red to infrared light may comprise the following equation:Ared-AC / Ared-DCAIR-AC / A-IR-DC

[0060] Methods as described herein may quantify and compensate for light absorption in a subject’s skin when calculating blood oxygenation. FIG. 3 A illustrates an acoustic signal passing through a subject’s tissue. An acoustic return peak 175 may be seen at the skin layer 165 due to melanin. Another peak 180 may be seen at the vessel layer 170. Fluid flow rates could be High (H), Medium (M), Low (L) or static (e.g., no fluid flow). Fluid flow rates may be adjusted and their effects determined. Conventional oximetry approaches may not possess the capability to perform such measurements.AttyDktNo.: 48357-715601

[0061] In an aspect, the acoustic signal trace may be an electrical signal on a system in accordance with implementations described herein, In some implementations, an acoustic signal for each wavelength employed may be processed separately. In some implementations, an acoustic signal may be low-pass filtered and averaged using one or more adaptive filters. In an example, the averaging may be weighted by a calculated signal to noise ratio of an acoustic signal trace. In some implementations, the method allows for an absorbance at a particular depth of a particular wavelength to be isolated and recorded. In an aspect, acoustic signal trace peaks for strong chromophores are identifiable in the acoustic signal trace which may be interrogated to infer blood saturation within an in-situ vessel (e.g., LIV or the left innominate vein).

[0062] In an aspect, a subject’s tissue may include a blood vessel and a melanin layer. Each acoustic signal from the tissue may include an acoustic signal associated with the blood vessel and the melanin layer. In some implementations, a method for compensating for light absorption in a subject’s skin may include steps of emitting a first pulse at a first wavelength towards a skin and detecting a first acoustic signal from the skin, emitting a second pulse at a second wavelength towards a skin and detecting a second acoustic signal from the skin, and determining a differential acoustic response from the skin based on the first acoustic signal from the skin and the second acoustic signal from the skin.

[0063] Turning to FIG. 3B, three acoustic signal traces are shown from three wavelengths (760, 800, and 1064 nm). In an aspect, the acoustic signal traces reveal a skin peak 175, which is proportional to the melanin content of the epidermis. Concentration of melanin may be estimated by considering a ratio of absorbance of different wavelengths at the skin peak. Acoustic signal traces at two different wavelengths may be used to estimate the concentration of melanin. The acoustic signal traces may reveal a vessel peak or acoustic peak from the vessel 320. The vessel peak may include a proximal marker or start depth 315 and distal marker or acoustic trough 325. The vessel peak may be used in measurements of analyte concentration as described herein. A device ringdown peak (310) may also be observed.

[0064] Turning to FIG. 4A, an experimental setup is shown for delivering a set of laser pulses 400. In an example, for each wavelength, laser pulses may be fired 1.0 ms apart with 43 pulses for each wavelength in each measurement cycle. The acoustic signal from these 43 laser pulses may be ensemble-averaged to provide a single acoustic time trace. Turning to FIG. 4B, multiple wavelengths may be multiplexed. In an example, 3 wavelengths (400a, 400b, 400c) may be multiplexed with an arming delay of 204ms, and processing delays of about 75-80ms resulting in a time between cycles of about 410ms. An average number of laser pulses per second may beAttyDktNo.: 48357-715601about 315 with an average number of 43 trace ensemble averages per wavelength per second of about 2.4.

[0065] FIG. 5 A shows a method for determining an acoustic peak of skin according to some implementations. A method for determining an acoustic peak of skin may include illuminating a single wavelength light source (step 500). A method for determining an acoustic peak of skin may include collecting and storing an acoustic signal response (step 505). A method for determining an acoustic peak of skin may include normalizing a raw signal by an illumination power factor (step 510). A method for determining an acoustic peak of skin may include subtracting a background signal collected before interfacing with the skin and reflecting the resonant noise of the sensor (step 515). A method for determining an acoustic peak of skin may include identifying and quantifying a skin peak acoustic response (step 520). A method for determining an acoustic peak of skin may include determining if all wavelengths have been collected (step 525). If all wavelengths have not been collected, the method may return to illuminating a single wavelength light source (step 500). If all wavelengths have been collected, the method may include identifying and quantifying a skin peak power for each wavelength (step 530). The method may include characterizing the skin’s melanin content through comparison of skin peak powers (step 535). In some implementations, the melanin content characterization may be further used or evaluated by an operator. In some cases, the melanin content characterization may be transmitted to a device, such as a computer or tablet, for evaluation. In some cases, the melanin content characterization may be used to inform the selection of a suitable sensor, treatment, or prophylactic for the measured skin tone. In some implementations, subtracting the background signal may include subtracting a portion of an acoustic response trace prior to normalizing. In an example, the acoustic response trace near the interface or device ringdown may be removed to minimize distortions of poor transduction between the probe and the skin. In an example, normalizing a portion of the first acoustic signal by a second acoustic signal may include subtracting a portion of a third acoustic signal from at least one of the first acoustic signal and the second acoustic signal.

[0066] Provided herein is a method for estimating a concentration of melanin of a subject’s skin by considering the ratio of absorbance of different wavelengths at their skin peak. In some implementations, the skin peak may be identified at a predetermined depth or timing of signal detection. The skin peak may be identified between a depth of about 0-3 mm. In some implementations, characterizing skin’s melanin content through comparison of skin peak powers may include fitting a skin peak ratio (R) to an objective skin tone measurement such as a colorimeter. FIG. 7 illustrates a median skin peak ratio as a function of skin tone measurementAttyDktNo.: 48357-715601taken from a number of subjects according to some implementations. In an example, a skin peak ratio may include a portion of ratio of two wavelengths (e.g., 760nm: 800nm). Examples of colorimeter may include Individual Typology Angle (ITA) or a colorimetry measurement that classifies skin tone into different categories, from very light to dark. Examples of colorimetry measurement include Very light: Greater than 55°, Light: 41° to less than 55°, Intermediate: 28° to less than 41°, Tan: 10° to less than 28°, Brown -30° to less than 10°, and Dark: Less than -30°. In some cases, when measured, absorption ratios of the skin peaks for 760nm and 800nm wavelengths appear proportional to the ITA colorimeter skin tone values measured for each subject.

[0067] Provided herein is an identification of a spatially localized skin peak measurement, independent of tissue oxygenation and dependent upon melanin absorption in the epidermis. The spatially localized skin peak measurement may provide a means of providing a calibration curve for use in the calculation of blood oxygen saturation and a metric that may allow a change in curve gradient at lower saturations as a function of measured melanin absorption. In an aspect, this spatially localized skin peak measurement may compensate for the inherent bias caused by melanin absorption in a way that is not possible in conventional non-invasive oximetry.

[0068] FIGs. 5B-5E show methods for determining oxygen saturation based on the acoustic peak of skin according to some implementations. In some implementations, a method for determining oxygen saturation may include a step of characterizing skin’s melanin content through comparison of skin peak powers (step 535). A method for determining oxygen saturation may include generating a calibration curve for use in oxygenation derivation (step 540). A method for determining oxygen saturation may include deriving oxygen saturation (step 545). (See FIG. 5B). In some implementations, a method for determining oxygen saturation may include characterizing skin’s melanin content through comparison of skin peak powers (step 535). A method for determining oxygen saturation may include selecting a calibration curve for use in oxygenation derivation (step 550). A method for determining oxygen saturation may include deriving the oxygen saturation (step 545). (See FIG. 5C). In some implementations, a method for determining oxygen saturation may include characterizing skin’s melanin content through comparison of skin peak powers (step 535). A method for determining oxygen saturation may include selecting a saturation correction for use in oxygenation derivation (step 555). This may be a conventionally derived oxygen saturation (step 560). A method for determining oxygen saturation may include producing a corrected oxygen saturation (step 565) (See FIG. 5D). In some implementations, a method for determining oxygen saturation may include characterizing skin’s melanin content through comparison of skin peak powers (step 535). A method forAttyDktNo.: 48357-715601determining oxygen saturation may include correcting the blood peak measurements as a function of skin peak characterization (step 570). A method for determining oxygen saturation may include deriving the oxygen saturation (step 545). (See FIG. 5E).

[0069] Although the above steps in FIGs. 5A-5E show methods of determining oxygen saturation optoacoustically in accordance with many embodiments, a person of ordinary skill in the art will recognize many variations based on the teaching described herein. The steps may be completed in a different order. Steps may be added or deleted. Some of the steps may comprise sub-steps. Many of the steps may be repeated as often as beneficial to the diagnostic measurement(s).

[0070] FIG. 6A shows a standard calibration curve 600 for determining oxygen saturation based on an absorbance ratio according to some implementations. Conventional oximetry may use a single calibration curve based on a whole population regression analysis, irrespective of the subject’s skin pigment. When there is a disproportionate absorption of red wavelength light due to melanin, a positive bias may be introduced on reported oxygen saturation based on subjects with less pigment in their skin. FIG. 6B shows a plurality of compensated calibration curves 602a-602n for determining oxygen saturation based on compensated absorbance ratios for melanin absorption according to some implementations. Melanin-compensated oximetry can measure localized melanin absorption under a sensor. This may allow generation of an appropriate calibration curve for a subject. By determining the localized melanin absorption, the selected calibration curve may compensate for changes in an effective optical path length of red photons and may mitigate effects of melanin absorption. FIGs. 8C-8D illustrate an oxygen saturation level and a series of measured oxygen saturation measurements of the subjects of FIGs. 8A-8B, respectively, as a function of time and as measured by an optoacoustic measurement system according to some implementations.

[0071] In some implementations, altering the blood or vessel peak measurements for use in oxygenation derivation may be done using a skin peak-compensated oxygen saturation calculation. In some implementations, oxygen saturation calculation may utilize the Beer-Lambert model of optical absorbance provided as:lJ = nlJ p oc~(llOHbcOHb+LlHHbcHHb+Llmelcmel+’'’ )Ad

[0072] (1)

[0073] where / z is absorbance coefficient (absorptivity), c is concentration, / is intensity with incident intensity Io, d is the effective photon path length, HHb is Deoxyhemoglobin as a fraction of total hemoglobin, OHb is oxygenated hemoglobin, and mel is melanin.AttyDktNo.: 48357-715601

[0074] In SpO2, the pulsatile or AC tissue volume may be normalized by the non-pulsatile or DC tissue volume. (See FIGs. 2A-2B).

[0075] To compensate for shallow absorbance by the skin in regional oxygen saturation (rS02), a deep signal may be normalized by a shallow signal. To factor out optical and volumetric changes, an isosbestic wavelength may be used.

[0076] In both cases attempts are made to derive the oxygen saturation of the tissue under investigation using equations (2) or (3)

[0077] SO2= —22212— (2)cOHb+cHHb

[0078] (I-SO2 ) =cHHbc c(3)OHb+ HHb

[0079] P^skis the measured acoustic peak from the skin for a wavelength A, given as:

[0080] PA,sk= I0(l - e_(^. OHbCsk, OHb + ^, HHbCsk, HHb+^,melCsk,mel+ ")Ad-)rsk^fc,an(J (4a)

[0081] P; Viis the measured acoustic peak from the vessel for a wavelength A, given as:

[0082] PA vl= Ioe~hlA, OHbcsk, OHb +!-lA, HHbcsk, HHb + l-lA,melcsk,mel + ''' )Ad(''| _e-(0A, OHbcvl, OHb + 0A, HHbcvl, HHb + 0A,melcvl,mel + "’ (4b)

[0083] where Gamma T is the Gruneisen parameter that describes a thermoelastic pressure expansion resulting from optical absorption. In an aspect, the thermoelastic pressure expansion results in the observed acoustic signal and Xi 5, is a fraction describing the attenuation of the acoustic stress wave during its propagation back to the sensor.

[0084] PA,sk= I0(l - TA,sk)Tskfsfc(5)

[0085] PAvt= l0T,sk ~ T vi)rvt;vi(6)

[0086] where T\x= e~^’0HbCx’0Hb+fJ'^HHbCx’HHb+fJ'^melCx’mel+"'^adxis a transmission coefficient at a depth ‘x’ (e.g., skin or vessel) which is subject to all present chromophores. By rearranging (5), it can be shown that:

[0087] 1 - P\.sk= TA,skwhere P\x= (7)

[0088] Substituting (7) into (6):

[0089] = (1 - TvU) or l --^- = TvU(8)i-P'A.sk i-P'A.sfc

[0090] Taking logs of (8), results in:

[0091] P'A.ylIn ln|e-(^AOHbcvl, OHb + l1A, HHbcvl, HHb + "’)Adv](9)P'A.sk

[0092] (9) can be approximated through a Maclaurin expansion:

[0093] > ^'V1= (pA, OHbcvl, OHb + PA, HHbcvl, HHb ■■■ )Advl(10)1 r'A,skAttyDktNo.: 48357-715601

[0094] For two wavelengths, (10) can be used to calculate the saturation ratio-of-ratios, R, as:_ {lJ-2.1, OHbc,n, OHb+lJ-2.1, HHbcn, HHb+lJ-2.1,~cn,~)^dvi1-pAi.sfc

[0095] P'A2,yl (11)(MA2, OHbcn, OHb + MA2, HHb Cn. HHb+t^,~cn,~^dvl1-p,A2,sfc

[0096] Resulting in:P'Ai.ylp'A2,vl _ R _ (0A1, OHbc,n, OHb + 0A1, HHbcn, HHb)

[0097] 1P'Aj.sk (12)(0A2, OHbcn, OHb + 0A2, HHbcn, HHb)1-p'A2,sk

[0098] Which satisfies a boundary requirement that, when there is no absorption in the skin, R is described only by the vessel peak ratio. Further, from (7) and (12), there is:

[0099] R =E RP*2:PVL / I°’*2(13)1 J$skrsk l^sk'l 0,1.1^skrsk~p2-2.sk / 10,2.2

[0100] Which when Xi and Gamma are small can be approximated top2.ifylimni l D _P^2’vl_ (^Ai. OHbC.n. OHb + ^Ai. HHbCn. HHb)IU1U1I tx — p — f >. (14)—A1-Sk(,0A2, OHbcn, OHb + 0A2, HHbcn, HHblp2-2.sk

[0102] From which, with (2), it can be shown that:

[0103] SO2= T - (15)K(MA2, OHb + MA2, HHb J ^lJ-2.-i, OHb + tJ-2.A, HHb

[0104] If Xi and Gamma are not small, then the generalized form of (13) may be used. In some embodiments, determining the oxygen saturation of the subject based on the normalized portion of the first acoustic signal comprises using EQUATION 15.

[0105] R = rrA2:Pvl"u^, - (13) =c_p2;m(16)^skrsk~pX2fikllo^2,c~p2-2.sk

[0106] In (16), the acoustic peaks have been normalized by incident light intensity.

[0107] For subjects (or phantoms) with skin of two different melanin levels, measurements can be considered at the same saturation to estimate ‘C’. Both measurements can resolve to the same R as seen in (2):PX-j.yl-jpA2,vl1PA2, V12

[0108] R = (17) C-PA-pskiC-pA1,sk2C-P^.skiC-pA2,sk2

[0109] In the alternative, conditions can be considered where there are no, or very small, skin peaks. Thus, the denominator of (16) resolves to 1 allowing other calibration coefficients to be calculated in the absence of any corrective terms.

[0110] So, if fitting a linear equation to calibrate, this becomes:AttyDktNo.: 48357-715601pAi,yl

[0111] R = m. c5f^ + b OR R = m. Rvl-C^ + b (18)_Al-sRC-P^.skC-pA2,sk

[0112] And so, when the skin peak is very small, it therefore becomes:

[0113] R = m. Rvl+ b (19)

[0114] Allowing m and b to be estimated by linear regression as m=0.86 and >=0.21.

[0115] Rearranging (18) results in:

[0116] C = - - -2' (20)\R bj m,. Ry^

[0117] When considered in the context of data collected with melanin and associated skin peaks, C can be estimated from (20) to be an average value of -0.0387.

[0118] FIG. 11 shows plotted results of applying the above method wherein Smeasured (blood oxygen saturation measured by the optoacoustic system described herein) is calculated from the acoustic signals and Starget is obtained directly by blood gas measurement. The results shown in the graph have a mean bias of 1.48% and a standard deviation error of 7.84%.

[0119] Some skin peak absorption ratios may change with oxygen saturation. This can fundamentally undermine existing methods that apply a single correction for skin tone at all saturations. Variable skin peak absorption ratios may indicate a necessity to measure the skin absorbance continuously, using the wavelengths used by the oximeter and at the same site at which the saturation is being measured. FIGs. 8A-8B illustrate absorbance ratios of acoustic peaks for two subject’s skins and vessels as a function of time and saturation (during a controlled hypoxia study) according to some implementations.

[0120] Compensating for the measured skin peak absorbance may significantly improve the Average Root Mean Square (Arms) error measurements. FIG. 9A illustrates a scatterplot of an unnormalized determined oxygen saturation as a function of oxygen saturation according to some implementations. FIG. 9B illustrates a modified Bland-Altman plot of the un-normalized error (system - SvO2) as a function of oxygen saturation according to some implementations. In an example, the un-normalized Arms was 24.8 %. FIG. 9C illustrates a scatterplot of a normalized system determined oxygen saturation as a function of oxygen saturation according to some implementations. FIG. 9D illustrates a modified Bland-Altman plot of the normalized error (system - SvO2) as a function of oxygen saturation according to some implementations. In an example, the normalized Arms was 6.7%.

[0121] The present disclosure provides computer systems that are programmed to implement methods of the disclosure. FIG. 10 shows a computer system 1001 that is programmed or otherwise configured to perform the methods described herein. In an aspect, one or moreAttyDktNo.: 48357-715601portions of the computer system may be part of the handheld probe. The computer system 1001 can be an electronic device of a user or a computer system that is remotely located with respect to the electronic device. The electronic device can be a mobile electronic device.

[0122] The computer system 1001 includes a central processing unit (CPU, also “processor” and “computer processor” herein) 1005, which can be a single core or multi core processor, or a plurality of processors for parallel processing. The computer system 1001 also includes memory or memory location 1010 (e.g., random-access memory, read-only memory, flash memory), electronic storage unit 1015 (e.g., hard disk), communication interface 1020 (e.g., network adapter) for communicating with one or more other systems, and peripheral devices 1025, such as cache, other memory, data storage and / or electronic display adapters. The memory 1010, storage unit 1015, interface 1020 and peripheral devices 1025 are in communication with the CPU 1005 through a communication bus (solid lines), such as a motherboard. The storage unit 1015 can be a data storage unit (or data repository) for storing data. The computer system 1001 can be operatively coupled to a computer network (“network”) 1030 with the aid of the communication interface 1020. The network 1030 can be the Internet, an internet and / or extranet, or an intranet and / or extranet that is in communication with the Internet. The network 1030 in some cases is a telecommunication and / or data network. The network 1030 can include one or more computer servers, which can enable distributed computing, such as cloud computing. The network 1030, in some cases with the aid of the computer system 1001, can implement a peer-to-peer network, which may enable devices coupled to the computer system 1001 to behave as a client or a server.

[0123] The CPU 1005 can execute a sequence of machine-readable instructions, which can be embodied in a program or software. The instructions may be stored in a memory location, such as the memory 1010. The instructions can be directed to the CPU 1005, which can subsequently program or otherwise configure the CPU 1005 to implement methods of the present disclosure. Examples of operations performed by the CPU 1005 can include fetch, decode, execute, and writeback.

[0124] The CPU 1005 can be part of a circuit, such as an integrated circuit. One or more other components of the system 1001 can be included in the circuit. In some cases, the circuit is an application specific integrated circuit (ASIC).

[0125] The storage unit 1015 can store files, such as drivers, libraries and saved programs. The storage unit 1015 can store user data, e.g., user preferences and user programs. The computer system 1001 in some cases can include one or more additional data storage units that are externalAttyDktNo.: 48357-715601to the computer system 1001, such as located on a remote server that is in communication with the computer system 1001 through an intranet or the Internet.

[0126] The computer system 1001 can communicate with one or more remote computer systems through the network 1030. For instance, the computer system 1001 can communicate with a remote computer system of a user. Examples of remote computer systems include personal computers (e.g., portable PC), slate or tablet PC’s (e.g., Apple® iPad, Samsung® Galaxy Tab), telephones, Smart phones (e.g., Apple® iPhone, Android-enabled device, Blackberry®), or personal digital assistants. The user can access the computer system 1001 via the network 1030.

[0127] Methods as described herein can be implemented by way of machine (e.g., computer processor) executable code stored on an electronic storage location of the computer system 1001, such as, for example, on the memory 1010 or electronic storage unit 1015. The machine executable or machine-readable code can be provided in the form of software. During use, the code can be executed by the processor 1005. In some cases, the code can be retrieved from the storage unit 1015 and stored on the memory 1010 for ready access by the processor 1005. In some situations, the electronic storage unit 1015 can be precluded, and machine-executable instructions are stored on memory 1010.

[0128] The code can be pre-compiled and configured for use with a machine having a processer adapted to execute the code, or can be compiled during runtime. The code can be supplied in a programming language that can be selected to enable the code to execute in a pre-compiled or as-compiled fashion.

[0129] Aspects of the systems and methods provided herein, such as the computer system 1001, can be embodied in programming. Various aspects of the technology may be thought of as “products” or “articles of manufacture” typically in the form of machine (or processor) executable code and / or associated data that is carried on or embodied in a type of machine-readable medium. Machine-executable code can be stored on an electronic storage unit, such as memory (e.g., read-only memory, random-access memory, flash memory) or a hard disk.“Storage” type media can include any or all of the tangible memory of the computers, processors or the like, or associated modules thereof, such as various semiconductor memories, tape drives, disk drives and the like, which may provide non-transitory storage at any time for the software programming. All or portions of the software may at times be communicated through the Internet or various other telecommunication networks. Such communications, for example, may enable loading of the software from one computer or processor into another, for example, from a management server or host computer into the computer platform of an application server. Thus, another type of media that may bear the software elements includes optical, electrical andAttyDktNo.: 48357-715601electromagnetic waves, such as used across physical interfaces between local devices, through wired and optical landline networks and over various air-links. The physical elements that carry such waves, such as wired or wireless links, optical links or the like, also may be considered as media bearing the software. As used herein, unless restricted to non-transitory, tangible “storage” media, terms such as computer or machine “readable medium” refer to any medium that participates in providing instructions to a processor for execution.

[0130] Hence, a machine-readable medium, such as computer-executable code, may take many forms, including but not limited to, a tangible storage medium, a carrier wave medium or physical transmission medium. Non-volatile storage media include, for example, optical or magnetic disks, such as any of the storage devices in any computer(s) or the like, such as may be used to implement the databases, etc. shown in the drawings. Volatile storage media include dynamic memory, such as main memory of such a computer platform. Tangible transmission media include coaxial cables; copper wire and fiber optics, including the wires that comprise a bus within a computer system. Carrier-wave transmission media may take the form of electric or electromagnetic signals, or acoustic or light waves such as those generated during radio frequency (RF) and infrared (IR) data communications. Common forms of computer-readable media therefore include for example: a floppy disk, a flexible disk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD or DVD-ROM, any other optical medium, punch cards paper tape, any other physical storage medium with patterns of holes, a RAM, a ROM, a PROM and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave transporting data or instructions, cables or links transporting such a carrier wave, or any other medium from which a computer may read programming code and / or data. Many of these forms of computer readable media may be involved in carrying one or more sequences of one or more instructions to a processor for execution.

[0131] The computer system 1001 can include or be in communication with an electronic display 1035 that comprises a user interface (UI) 1040. Examples of UI’s include, without limitation, a graphical user interface (GUI) and web-based user interface.

[0132] Methods and systems of the present disclosure can be implemented by way of one or more algorithms. An algorithm can be implemented by way of software upon execution by the central processing unit 1005. The algorithm can, for example, perform the methods for determining oxygen saturation based on the acoustic peak of skin according to some implementations.

[0133] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by wayAttyDktNo.: 48357-715601of example only. It is not intended that the disclosure be limited by the specific examples provided within the specification. While the disclosure has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. Furthermore, it shall be understood that all aspects of the disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is therefore contemplated that the disclosure shall also cover any such alternatives, modifications, variations, or equivalents. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

AttyDktNo.: 48357-715601CLAIMS WHAT IS CLAIMED IS:

1. A method for measurement of an analyte level of a subject or a blood vessel of a subject, the method comprising:emitting a first optical pulse at a first wavelength and a second optical pulse at a second wavelength towards a portion of skin of the subject having a skin pigmentation;detecting a first acoustic signal resulting from the first optical pulse and a second acoustic signal resulting from the second optical pulse, wherein the first acoustic signal and the second acoustic signal have a differential acoustic response based on the skin pigmentation;normalizing a portion of the first acoustic signal based on the second acoustic signal; and determining an analyte level based on the normalized portion of the first acoustic signal to compensate for skin pigmentation.

2. The method of claim 1, wherein determining the analyte level comprises determining the concentration of an analyte.

3. The method of claim 1 or 2, wherein the first wavelength is from 600 nanometers (nm) to 793 nm.

4. The method of claim 3, wherein the first wavelength is 760 nm.

5. The method of claim 3, wherein the first wavelength is 660 nm.

6. The method of any one of the previous claims, wherein the second wavelength is from 794 nm to 1300 nm.

7. The method of claim 6, wherein the second wavelength is 800 nm.

8. The method of claim 6, wherein the second wavelength is 900 nm.

9. The method of any one of the previous claims, further comprising emitting a third optical pulse at a third wavelength and detecting a third acoustic signal resulting from the third optical pulse.AttyDktNo.: 48357-71560110. The method of claim 9, wherein the third wavelength is from 600 nm to 1,300 nm.

11. The method of claim 10, wherein the third wavelength is 1064 nm.

12. The method of any one of claims 9-11, wherein normalizing the portion of the first acoustic signal by the second acoustic signal includes subtracting a portion of the third acoustic signal from at least one of the first acoustic signal and the second acoustic signal.

13. The method of claim any one of the previous claims, wherein determining the analyte level comprises determining an oxygen saturation of the subject.

14. The method of claim 13, wherein determining the oxygen saturation of the subject includes normalizing blood and vessel peak ratio by the normalized skin portion of the first acoustic signal.

15. The method of claim 13 or 14, wherein determining the oxygen saturation of the subject based on the normalized portion of the first acoustic signal comprises using EQUATION 15.

16. The method of any one of the previous claims, further comprising determining the light intensity of the first optical pulse, and normalizing the first acoustic signal based on the light intensity of the first optical pulse.

17. The method of any one of the previous claims, further comprising determining the light intensity of the second optical pulse, and normalizing the second acoustic signal based on the light intensity of the second optical pulse.

18. The method of any one of the previous claims, wherein emitting the first optical pulse at the first wavelength and the second optical pulse at the second wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array.

19. The method of any one of the previous claims, wherein detecting the first acoustic signal resulting from the first optical pulse and the second acoustic signal from the second optical pulse comprises using a piezoelectric sensor.AttyDktNo.: 48357-71560120. The method of any one of the previous claims, wherein the first acoustic signal is generated at a skin layer of the subject.

21. The method of any one of claims 1-19, wherein the first acoustic signal is generated at a vessel layer of the subject.

22. The method of any one of the previous claims, wherein the second acoustic signal is generated at a skin layer of the subject.

23. The method of any one of claims 1-21, wherein the second acoustic signal is generated at a vessel layer of the subject.

24. The method of any one of the previous claims, wherein the portion of skin covers a blood vessel of the subject.

25. The method of claim 24, wherein the blood vessel is a radial artery, a super sagittal sinus (SSS), or an internal jugular vein.

26. A method for measurement of blood oxygenation of a subject or a blood vessel of the subject, the method comprising:emitting a plurality of first optical pulses at a first wavelength towards a portion of skin of the subject having a skin pigmentation;detecting a first acoustic signal generated in response to the plurality of first optical pulses, the first acoustic signal being generated at a vessel layer of the subject;detecting a second acoustic signal generated in response to the plurality of first optical pulses, the second acoustic signal being generated at a skin layer of the subject, wherein the second acoustic signal has a differential acoustic response to the plurality of first optical pulses at the first wavelength based on one or more of the skin pigmentation or oxygen saturation of the subject;normalizing a portion of the first acoustic signal based on the second acoustic signal; and determining an oxygen saturation of the subject based on the normalized portion of the first acoustic signal.

27. The method of claim 26, further comprising emitting a plurality of second optical pulses at a second wavelength toward the portion of skin of the subject.AttyDktNo.: 48357-71560128. The method of claim 27, further comprising detecting a third acoustic signal generated in response to the plurality of second optical pulses, the third acoustic signal being generated at the vessel layer of the subject.

29. The method of claim 28, further comprising detecting a fourth acoustic signal generated in response to the plurality of second optical pulses, the fourth acoustic signal being generated at the skin layer of the subject.

30. The method of claim 29, wherein normalizing the portion of the first acoustic signal based on the second acoustic signal comprises normalizing a first ratio of the first acoustic signal and the third acoustic signal based on a second ratio of the second acoustic signal and the fourth acoustic signal.

31. The method of claim 30, wherein one or more of the first ratio or second ratio is dynamic based on one or more of skin pigmentation or oxygen saturation of the subject.

32. The method of any one of claims 26-31, wherein the first wavelength is from 600 nm to 793 nm.

33. The method of claim 32, wherein the first wavelength is 760 nm.

34. The method of claim 32, wherein the first wavelength is 660 nm.

35. The method of any one of claims 27-34, wherein the second wavelength is from 794 nm to 1300 nm.

36. The method of claim 35, wherein the second wavelength is 800 nm.

37. The method of claim 35, wherein the second wavelength is 900 nm.

38. The method of any one of claims 26-37, further comprising determining the light intensity of the plurality of first optical pulses, and normalizing the first acoustic signal based on the light intensity of the plurality of first optical pulses.AttyDktNo.: 48357-71560139. The method of any one of claims 27-31, further comprising determining the light intensity of the plurality of second optical pulses, and normalizing the second acoustic signal based on the light intensity of the plurality of second optical pulses.

40. The method of any one of claims 26-39, wherein emitting the plurality of first optical pulses at the first wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array.

41. The method of any one of claims 27-31 or 39, wherein emitting the plurality of second optical pulses at the second wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array.

42. The method of any one of claims 26-41, wherein detecting the first acoustic signal and detecting the second acoustic signal comprises using a piezoelectric sensor.

43. The method of any one of claims 26-42, wherein the portion of skin covers a blood vessel of the subj ect.

44. The method of claim 43, wherein the blood vessel is a radial artery, a super sagittal sinus (SSS), or an internal jugular vein.

45. A method for measurement of blood oxygenation of a subject or a blood vessel of the subject, the method comprising:emitting a first optical pulse wavelength configured to evoke a first acoustic signal from a portion of skin of the subject and a first acoustic signal from a blood vessel of the subject;emitting a second optical pulse wavelength different from the first optical pulse wavelength, the second optical pulse wavelength configured to evoke a second acoustic signal from the portion of skin and a second acoustic signal from the blood vessel;detecting the first acoustic signal from the portion of skin, the first acoustic signal from the blood vessel, the second acoustic signal from the portion of skin, and the second acoustic signal from the blood vessel;normalizing the first acoustic signal from the blood vessel and the second acoustic signal from the blood vessel by the first acoustic signal from the portion of skin and the second acoustic signal from the portion of skin; andAttyDktNo.: 48357-715601determining an oxygen saturation of the subject based on the normalized first acoustic signal from the blood vessel and the normalized second acoustic signal from the blood vessel.

46. The method of claim 45, wherein the first acoustic signal from the blood vessel reflects deoxygenated hemoglobin and the second acoustic signal from the blood vessel reflects oxygenated hemoglobin.

47. The method of claim 45 or claim 46, wherein the first optical pulse wavelength is from 600 nm to 793 nm.

48. The method of claim 47, wherein the first optical pulse wavelength is 760 nm.

49. The method of claim 47, wherein the first optical pulse wavelength is 660 nm.

50. The method of any one of claims 45-49, wherein the second optical pulse wavelength is from 794 nm to 1300 nm.

51. The method of claim 50, wherein the second optical pulse wavelength is 800 nm.

52. The method of claim 50, wherein the second optical pulse wavelength is 900 nm.

53. The method of any one of claims 45-52, wherein emitting the first optical pulse wavelength and the second optical pulse wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array.

54. The method of any one of claims 45-53, wherein detecting the first acoustic signal from the portion of skin, the first acoustic signal from the blood vessel, the second acoustic signal from the portion of skin, and the second acoustic signal from the blood vessel comprises using a piezoelectric sensor.

55. The method of any one of claims 45-54, wherein the blood vessel is a radial artery, a super sagittal sinus (SSS), or an internal jugular vein.

56. A method for determining a melanin level of a portion of skin of a subject, the method comprising:AttyDktNo.: 48357-715601emitting a first optical pulse at a first wavelength towards a portion of skin of a subject having a skin pigmentation;emitting a second optical pulse at a second wavelength towards the portion of skin of the subject;detecting a first acoustic signal resulting from the first optical pulse;detecting a second acoustic signal from the second optical pulse, wherein the first acoustic signal and the second acoustic signal have a differential acoustic response based on the skin pigmentation;normalizing a portion of the first acoustic signal based on the second acoustic signal; and determining a melanin level or pigmentation of the portion of skin, based on the normalized portion of the first acoustic signal.

57. The method of claim 56, wherein the first wavelength is from 600 nm to 793 nm.

58. The method of claim 57, wherein the first wavelength is 760 nm.

59. The method of claim 57, wherein the first wavelength is 660 nm.

60. The method of any one of claims 56-59, wherein the second wavelength is from 794 nm to 1300 nm.

61. The method of claim 60, wherein the second wavelength is 800 nm.

62. The method of claim 60, wherein the second wavelength is 900 nm.

63. The method of any one of claims 56-62, further comprising emitting a third optical pulse at a third wavelength, and detecting a third acoustic signal resulting from the third optical pulse.

64. The method of claim 63, wherein normalizing the portion of the first acoustic signal based on the second acoustic signal includes subtracting a portion of the third acoustic signal from at least one of the first acoustic signal and the second acoustic signal.

65. The method of any one of claims 63-64, wherein the third wavelength is from 600 nm to 1300 nm.AttyDktNo.: 48357-71560166. The method of claim 65, wherein the third wavelength is 1064 nm.

67. The method of any one of claims 56-66, further comprising determining the light intensity of the first optical pulse, and normalizing the first acoustic signal based on the light intensity of the first optical pulse.

68. The method of any one of claims 56-67, further comprising determining the light intensity of the second optical pulse, and normalizing the second acoustic signal based on the light intensity of the first optical pulse.

69. The method of any one of claims 56-68, wherein emitting the first optical pulse at the first wavelength and the second optical pulse at the second wavelength comprises using an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array.

70. The method of any one of claims 56-69, wherein detecting the first acoustic signal resulting from the first optical pulse and the second acoustic signal resulting from the second optical pulse comprises using a piezoelectric sensor.

71. A system for measuring an analyte level of a subject or a blood vessel of a subject, the system comprising:one or more optical transmitters configured to generate one or more optical pulses; one or more acoustic receivers configured to detect one or more acoustic signals resulting from the one or more optical pulses; anda processor configured to (i) normalize the one or more acoustic signals and, (ii) output an analyte level of the subject or a blood vessel of the subject based at least in part on the normalized one or more acoustic signals.

72. The system of claim 71, wherein the one or more optical pulses comprise a first optical pulse at a first wavelength and a second optical pulse at a second wavelength.

73. The system of claim 72, wherein the first wavelength is from 600 nm to 793 nm.

74. The method of claim 73, wherein the first wavelength is 760 nm.AttyDktNo.: 48357-71560175. The method of claim 73, wherein the first wavelength is 660 nm.

76. The method of any one of claims 72-75, wherein the second wavelength is from 794 nm to 1300 nm.

77. The method of claim 76, wherein the second wavelength is 800 nm.

78. The method of claim 76, wherein the second wavelength is 900 nm.

79. The system of any one of claims 72-78, wherein the one or more acoustic signals comprise a first acoustic signal resulting from the first optical pulse and a second acoustic signal resulting from the second optical pulse.

80. The system of claim 79, wherein the processor is configured to normalize a portion of the first acoustic signal based on the second acoustic signal.

81. The system of any one of claims 71-80, wherein the analyte level comprises an analyte concentration of the subject.

82. The system of any one of claims 71-81, wherein the analyte is melanin.

83. The system of any one of claims 71-81, wherein the analyte level comprises an oxygen saturation of the subject.

84. The system of any one of claims 71-83, wherein the optical transmitter comprises an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, or a laser diode array.

85. The system of any one of claims 71-84, wherein the acoustic receiver is a piezoelectric sensor.

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