Use of optical energy meter in normalizing acoustic signals produced by laser pulses of various wavelengths to allow accurate calculation of blood oxygenation

Abstract

SOLUTION: The systems, devices, and methods herein make optoacoustic measurements and correct or normalize them for variations in optical energy level of the different light pulses used. An optical source directs optical pulses to tissue, an optical energy meter measures the optical energy of the different optical pulses, an acoustic detector measures an acoustic response generated by the tissue in response to the optical pulses, and a processor calculates a concentration of an analyte based on the measured acoustic response and as corrected or normalized for the different energy levels among the optical pulses.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] Cross-reference This application claims priority to U.S. Provisional Patent Application No. 63 / 084,706, filed September 29, 2020, which is hereby incorporated by reference in its entirety.

Background Art

[0002] The present disclosure relates to medical systems, devices, and methods, and more particularly to measuring the concentration of analytes in tissue, such as determining blood oxygenation and / or hemoglobin concentration.

[0003] In many research, medical, and clinical applications, measurement of analyte concentration is required. Pulse oximetry is a commonly used technique, for example, to determine a subject's blood oxygenation in real time. However, pulse oximetry faces many challenges in determining blood oxygenation in deeper blood vessels, which may improve the subject's overall blood oxygen concentration. Therefore, alternative techniques such as photoacoustic or photoacoustic measurements have been developed. Nevertheless, improvements are desired, for example, in photoacoustic or photoacoustic measurement techniques to improve measurement accuracy.

Summary of the Invention

[0004] The present disclosure generally relates to medical systems, devices, and methods for their use, and more particularly to photoacoustic or photoacoustic measurement and diagnostic systems, devices, and methods. Systems, devices, and methods for photoacoustically (i.e., photoacoustically) determining one or more physiological parameters are described. Systems, devices, and methods for correcting such photoacoustic measurements based on the measured light energy levels of a plurality of light pulses used to interrogate a sample are described.

[0005] One or more light sources of an exemplary system may direct a plurality of optical pulses towards tissue, such as skin. An acoustic detector of the system can detect an acoustic response generated by the tissue in response to the optical pulses. Calculation of the analyte concentration may be based on various characteristics and / or ratios between various characteristics, such as the amplitude(s) of the acoustic signal(s) generated in the tissue in response to the optical pulses. For signal averaging, each calculation may depend on the ratio of each group of optical pulses of a plurality of wavelengths. Variations in the amplitude of the optical energy generated by the light source at each wavelength can lead to inaccurate calculation of the analyte concentration. An exemplary system of the present disclosure may further include an optical energy meter for measuring the optical energy level of the optical pulses directed towards the tissue. A processor of the system may calculate the concentration of an analyte, typically hemoglobin, based on the acoustic response normalized or corrected for different energy levels of different optical pulses that cause the acoustic response. Thereafter, more accurate photoacoustic measurements and calculation of the concentration of the analyte can be performed by applying such correction or normalization to the acoustic response. In particular, the optical energy at each wavelength can be measured with an energy meter and the resulting acoustic signal(s) can be normalized to a predetermined energy level(s).

[0006] The energy of each pulse emitted by the light source may be measured in proximity to the output orifice of the light source, for example, by directing a portion of the energy of the pulse towards the aperture of the optical energy meter, such as by using a beam splitter. The remainder of the energy of the pulse can be directed towards the tissue through an optical delivery system that may include one or more optical fibers or light guides. The processor may be instructed to divide the waveform of the acoustic signal generated in response to the optical pulse by the energy of the optical pulse, thereby normalizing the waveform of the acoustic signal.

[0007] In many embodiments, optical pulses of various wavelengths are used. When multiple wavelengths are used, since the transmittance of the optical delivery system can vary at different wavelengths, the ratio of the energy measured by the energy meter at the light source output to the energy incident on the tissue after passing through the optical delivery system can be established beforehand for each of the wavelengths used in the system calibration step(s). The processor may be instructed to use the calibration factor when normalizing the acoustic signal with respect to its energy and, optionally, apply additional multiplier(s) and / or divider(s) depending on the selected ratio type.

[0008] Aspects of the present disclosure provide a method for measuring the concentration of an analyte. An exemplary method may include directing a plurality of optical pulses toward a tissue, measuring the optical energy levels of the plurality of optical pulses directed toward the tissue, measuring a plurality of acoustic responses of the tissue in response to the plurality of optical pulses directed toward the tissue, normalizing the plurality of measured acoustic responses based on the measured optical energy levels, and determining the concentration of the analyte based on the normalized plurality of acoustic responses.

[0009] In some embodiments, the step of directing a plurality of optical pulses toward a tissue includes directing a first optical pulse toward the tissue at a first wavelength and directing a second optical pulse toward the tissue at a second wavelength, where the first wavelength and the second wavelength are different.

[0010] In some embodiments, the plurality of optical pulses are at one or more wavelengths between 600 nm and 1,300 nm.

[0011] In some embodiments, the plurality of acoustic responses of the tissue are measured from the same side of the tissue toward which the plurality of optical pulses are directed.

[0012] In some embodiments, the plurality of acoustic responses of the tissue are measured from different sides of the tissue toward which the plurality of optical pulses are directed.

[0013] In some embodiments, the analyte is one or more of hemoglobin, oxyhemoglobin, and deoxyhemoglobin.

[0014] In some embodiments, the method may further include determining blood oxygenation based on the determined concentrations of one or more analytes and the characterized properties of the tissue.

[0015] In some embodiments, the tissue includes one or more blood vessels and the tissue surrounding the one or more blood vessels.

[0016] Aspects of the present disclosure provide a system for measuring the concentration of an analyte. An exemplary system includes at least one light source for directing a plurality of light pulses into a tissue, a light energy meter for measuring the light energy levels of the plurality of light pulses directed into the tissue, an acoustic detector for measuring a plurality of acoustic responses of the tissue to the plurality of light pulses, and a processor for normalizing the plurality of measured acoustic responses based on the measured light energy levels and determining the concentration of the analyte based on the normalized plurality of acoustic responses.

[0017] In some embodiments, the plurality of light sources includes a first light source configured to generate a first light pulse at a first wavelength and a second light source configured to generate a second light pulse at a second wavelength, where the first wavelength and the second wavelength are different.

[0018] In some embodiments, the plurality of light pulses are at one or more wavelengths between 600 nm and 1,300 nm.

[0019] In some embodiments, the at least one light source includes a plurality of light sources, each configured to generate a light pulse at a different wavelength.

[0020] In some embodiments, the at least one light source and the acoustic detector are oriented on the same side of the tissue relative to each other.

[0021] In some embodiments, at least one light source and the acoustic detector are oriented on different sides of the tissue relative to each other.

[0022] Incorporation by reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Brief Description of the Drawings

[0023] The novel features of the present disclosure are set forth particularly in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained from the following detailed description, which illustrates exemplary embodiments in which the principles of the invention are utilized, and from the accompanying drawings. Corresponding reference numerals designate corresponding parts throughout the drawings. The drawings are not necessarily drawn to scale.

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Modes for Carrying Out the Invention

[0024] Detailed references are made here to various embodiments, examples of which are shown in the accompanying drawings. In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention(s) of the present disclosure and the described embodiments. However, the invention may be practiced optionally without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail so as not to unnecessarily obscure aspects of the embodiments.

[0025] The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the claims. As used in the description of embodiments and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, as used herein, the term "and / or" refers to any and all possible combinations of one or more of the associated listed items and is understood to be inclusive. It is further understood that the terms "comprising" and / or "comprises" when used herein specify the presence of the stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0026] As used herein, the term "if" is optionally construed to mean "when" or "at times" or "in response to determining" or "in accordance with a determination" or "in response to detecting" as the case may be, as the context may require. Similarly, the expressions "if determined that [the stated antecedent condition is true]" or "if [the stated antecedent condition is true]" or "when [the stated antecedent condition is true]" are optionally construed to mean "at the time of determination" or "in response to determining" or "in accordance with a determination" or "at the time of detection" or "in response to detecting" that the stated antecedent condition is true, as the context may require.

[0027] Figures 1A and 1B show an exemplary photoacoustic measurement system (100). The photoacoustic measurement system (100) may include a light or light source (110) for generating one or more lights or light pulses, an acoustic sensor (120), an optical energy sensor (130) operably coupled to the light or light source (110), an optical delivery system (115) coupled to the light or light source (110), and a processor (140) operably coupled to the light or light source (110), the acoustic sensor (120), and the optical energy sensor (130). The optical energy sensor (130) may be, for example, a Thorlabs DET 100A detector in Newton, New Jersey, a PE25-C or PE50BB-DIF-C detector from Ophir Optics in Jerusalem, Israel, or an EnergyMax sensor from Coherent Inc. in Santa Clara, California. The light or light source (110) may be, by way of example, an optical parametric oscillator (OPO), a light-emitting diode (LED), a laser diode, a laser diode array, or other pulsed light sources with nanosecond-duration pulses. The light or light source (110) may be coupled to an optical delivery system (115) oriented to direct one or more light pulses to tissue (TI) such as skin or other surface tissue. Examples of suitable tissue (TI) to be investigated include superficial veins, radial arteries, superior sagittal sinuses, internal jugular veins, and other blood vessels in an infant's hand or an adult's finger. The one or more light pulses may be short, typically shorter than 100 nanoseconds, near-infrared (NIR) light pulses of wavelengths absorbed by chromophores such as hemoglobin. The one or more light pulses may be in the visible, infrared, and / or ultraviolet range, for example, in a wavelength range of 600 nm to 1,300 nm, for example, at a wavelength of 805 nm which is the isosbestic point of hemoglobin. The light pulse(s) may have a wide range of energy levels, for example, between 1 μJ and 1 mJ, as limited by the light source or laser, tissue safety, patient safety, and other considerations. The light pulse(s) may have a wide range of repetition rates, for example, between 1 and 10,000 Hz.

[0028] The acoustic sensor (120) can be configured to detect acoustic signal(s) generated by the tissue (TI) in response to one or more light pulses directed at the tissue (TI). As shown in FIG. 1A, the acoustic sensor (120) can be configured to operate in a reflection mode where the acoustic sensor (120) is oriented on the same side of the tissue (TI) as the light source (110) and can detect the acoustic signal(s) at that location. Alternatively or in combination, as shown in FIG. 1B, the acoustic sensor (120) can be configured to operate in a transmission mode where the acoustic sensor (120) is oriented on the opposite side of the tissue (TI) from the light source (110) and can detect the acoustic signal(s) at that location. The acoustic sensor (120) can include, by way of example, a single broadband acoustic detector, an acoustic array, or an acoustic matrix. Systems and one or more components, such as the acoustic sensor (120) operating in the reflection mode, can be used to interrogate any superficial vein or blood vessel, since the thickness of the entire tissue may not be a limiting factor.

[0029] The processor (140) is operably coupled to the acoustic sensor (120) and the light energy sensor (130) such that it can normalize the detected acoustic response based on the various optical intensities detected. For example, a first acoustic response from the tissue (TI) in response to a first light pulse with a first light energy is detected, and a second acoustic response from the tissue (TI) in response to a second light pulse with a different second light energy can be detected, etc., and the different acoustic responses can be normalized with respect to the different light energies. Based on the normalized acoustic response values, the processor (130) can calculate the concentration of analytes such as total hemoglobin (THb), oxyhemoglobin, and deoxyhemoglobin, by way of example. The calculated concentration can be displayed or otherwise provided to the user using a user interface of the system (100), such as a visual display.

[0030] FIG. 2 shows a flowchart of an exemplary method (200) of photoacoustic measurement. In step (210), one or more light pulses are directed at tissue such as skin or other superficial tissue. The one or more light pulses may be in the wavelength range, energy level range, and / or repetition rate range described herein. Typically, multiple light pulses, each at a different wavelength, are directed at the tissue. In embodiments where multiple light pulses are directed at the tissue, each light pulse may be at a different wavelength. In step (220), the optical energy of the light pulse(s) is measured with an optical energy meter. In step (230), an acoustic signal generated in response to the one or more light pulses may be detected. In step (240), the acoustic signal may be normalized based on the measured optical energy. Acoustic signals in response to different light or light pulses may be normalized to correct for the different energies of the light or light pulses. In step (250), an analyte concentration may be calculated based on the detected and normalized acoustic signal. The analyte concentration may be, for example, total hemoglobin (THb), oxyhemoglobin, and / or deoxyhemoglobin. Steps (210), (220), and (250) may be performed as described in U.S. Patent Application No. 14 / 793,969, filed Jul. 8, 2015 (now U.S. Pat. No. 9,380,967), U.S. Patent Application No. 14 / 794,022, filed Jul. 8, 2015 (now U.S. Pat. No. 10,307,088), U.S. Patent Application No. 14 / 794,037, filed Jul. 8, 2015 (now U.S. Pat. No. 10,231,656), and U.S. Patent Application No. 16 / 253,678, filed Jan. 22, 2019, which are incorporated herein by reference.

[0031] Examples of normalizing measured values of light energy are as follows. A first light pulse can be at a specific wavelength and have energy (E1). The first light pulse can enter tissue and generate an acoustic response from the tissue that can be detected as a waveform (S1(t)), where t is time, typically on the microsecond scale. The processor can be instructed to divide (S1(t)) by (E1). A second light pulse at the same wavelength and having energy (E2) can enter tissue and generate an acoustic response that can be detected as a waveform (S2(t)), where t is time, typically on the microsecond scale. The processor can further be instructed to divide (S2(t)) by E2. The processor can further average these two energy-normalized waveforms (e.g., [S1(t) / E1 + S2(t) / E2] / 2) and use that average to calculate the necessary parameters, i.e., be instructed to find the amplitude of a characteristic peak in the averaged waveform. Usually, more than two waveforms are averaged to improve the accuracy of the calculation.

[0032] The above steps illustrate a method (200) of performing photoacoustic measurements according to an embodiment, but those skilled in the art will recognize many variations based on the teachings described herein. The steps may be accomplished in a different order. Steps may be added or deleted. Some of the steps may include sub-steps. Many of the steps may be repeated as many times as beneficial or advantageous.

[0033] One or more of the steps of method (200) may be performed using one or more of various circuits as described herein, such as a processor, a controller, or a circuit board. Such a circuit may be programmed to provide one or more of the steps of method (200), and the program may include program instructions stored in a computer-readable memory or programmed steps of a logic circuit such as a programmable array logic or a field programmable gate array.

[0034] Experimental data

[0035] In an experiment using a blood vessel phantom (for example, sheep blood placed in a 3 mm diameter plastic tube and the tube immersed in an Intralipid solution that mimics the soft tissue surrounding the blood vessel), the following data was obtained. The oxygen concentration of the blood was gradually varied. Blood samples were taken at each oxygenation concentration and the oxygenation concentration was measured using a standard co - oximeter (for example, the "Gold Standard"). Further, photoacoustic measurements were performed at three wavelength pairs: 700 nm and 800 nm, 760 nm and 800 nm, and 1064 nm and 800 nm. For each wavelength pair, the oxygenation concentration of the blood was calculated using the corresponding algorithm derived from the published light absorption spectra of oxyhemoglobin and deoxyhemoglobin (see, for example, https: / / omlc.org / spectra / hemoglobin / ).

[0036] Figure 3A shows the averaging of the acoustic response (i.e., the photoacoustic signal) to a laser pulse at a specific wavelength. The presented waveforms are not normalized with respect to the average pulse energy at the corresponding wavelength.

[0037] Figure 3B shows the same acoustic response after normalizing the waveforms of the average pulse energy at each wavelength.

[0038] Thereafter, the amplitude of the most prominent peak of each waveform (i.e., the peak arising from the blood in the tube) was used to calculate blood oxygenation (shown in the graph of Figure 3B) according to the following algorithms: · For the 700 / 800 nm pair, SO2=(1.17 - 0.5×R1)×100%, R1 = A(700) / A(800) · For the 760 / 800 nm pair, SO2=(1.54 - 0.76×R2)×100%, R2 = A(760) / A(800) · For the 1064 / 800 nm pair, SO2=(-0.23 + 1.45×R3)×100%, R3 = A(1064) / A(800)

[0039] The oxygenation values obtained for each wavelength pair are shown in the graph area of Figure 3B.

[0040] Figure 3C shows the complete data set from this experiment. Each data point is the average value of several measurements made for each wavelength pair (the error bars represent the standard deviation). The signals in Figures 3A and 3B belong to the corresponding groups at approximately 408 minutes on the time scale of Figure 3C.

[0041] As will be appreciated, the blood oxygenation derived from energy-normalized photoacoustic signals using three different algorithms correlates well with the values provided by co-oximetry.

[0042] Although the preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will occur to those skilled in the art that do not depart from the scope of the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be utilized in practicing the invention of the present disclosure. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be encompassed thereby.

Claims

**Claim 1** A method for measuring the concentration of an analyte, comprising: directing a plurality of light pulses towards a tissue; measuring the light energy levels of the plurality of light pulses directed towards the tissue; measuring a plurality of acoustic responses of the tissue in response to the plurality of light pulses directed towards the tissue; normalizing the measured plurality of acoustic responses based on the measured light energy levels; and determining the concentration of the analyte based on the normalized plurality of acoustic responses. A method comprising the above steps. **Claim 2** The step of directing the plurality of light pulses towards the tissue includes directing a first light pulse at a first wavelength towards the tissue and directing a second light pulse at a second wavelength towards the tissue, wherein the first wavelength and the second wavelength are different. The method according to claim 1. **Claim 3** The plurality of light pulses are at one or more wavelengths in the range of 600 nm to 1,300 nm. The method according to claim 1. **Claim 4** The plurality of acoustic responses of the tissue are measured from the same side of the tissue towards which the plurality of light pulses are directed. The method according to claim 1. **Claim 5** The plurality of acoustic responses of the tissue are measured from different sides of the tissue towards which the plurality of light pulses are directed. The method according to claim 1. **Claim 6** The analyte is one or more of hemoglobin, oxyhemoglobin, and deoxyhemoglobin. The method according to claim 1. **Claim 7** The method according to claim 1, further comprising determining blood oxygenation based on the determined concentration of one or more analytes and the characterized properties of the tissue. **Claim 8** The tissue includes one or more blood vessels and the tissue surrounding the one or more blood vessels. The method according to claim 1. **Claim 9** A system for measuring the concentration of an analyte, comprising: at least one light source for directing a plurality of light pulses towards a tissue; a light energy meter for measuring the light energy levels of the plurality of light pulses directed towards the tissue; an acoustic detector for measuring a plurality of acoustic responses of the tissue to the plurality of light pulses; and a processor for normalizing the measured plurality of acoustic responses based on the measured light energy levels and determining the concentration of the analyte based on the normalized plurality of acoustic responses. A system comprising the above components. **Claim 10** The plurality of light sources includes a first light source configured to generate a first light pulse at a first wavelength and a second light source configured to generate a second light pulse at a second wavelength, wherein the first wavelength and the second wavelength are different, the system according to claim 9.

11. The plurality of light pulses are at one or more wavelengths from 600 nm to 1,300 nm, the system according to claim 9.

12. The at least one light source includes a plurality of light sources, each light source being configured to generate a light pulse at a different wavelength, the system according to claim 9.

13. The at least one light source and the acoustic detector are oriented on the same side of each other with respect to the tissue, the system according to claim 9.

14. The at least one light source and the acoustic detector are oriented on different sides of each other with respect to the tissue, the system according to claim 9.

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