Point-of-care transesophageal echo oximetry with a miniature nasal probe for central hemodynamic assessment

Abstract

An apparatus for transesophageal echo oximetry includes: an insertion tube having an optical fiber disposed therein; a probe disposed at an end of the insertion tube, the probe including an acoustic transducer and a reflector that aligns the acoustic transducer and the optical fiber; and a controller in communication with the acoustic transducer, the controller configured to: generate an ultrasound image of a sample using the acoustic transducer and the reflector; direct light from the optical fiber towards the reflector and into the sample; collect an optoacoustic signal from the sample based on the directed light using the acoustic transducer and the reflector; and determine a blood oxygen level of the sample based on the optoacoustic signal.

Description

[Technical field]

[0001] This application claims priority to U.S. patent application Ser. No. 63 / 231,607, filed Aug. 10, 2021, the disclosure of which is incorporated by reference in its entirety.

[0002] This invention was made with Government support under Grant No. HU0001-17-2-0009 awarded by the Uniform Services University of the Health Sciences. The Government has certain rights in this invention. [Background technology]

[0003] Real-time assessment of central hemodynamics at the point of care may improve the treatment of cardiovascular, trauma, and intensive care patients. The standard approach using highly invasive pulmonary catheters provides a comprehensive assessment of hemodynamic function but is impractical at the point of care. Echocardiography is gaining popularity as a non-invasive alternative but is inadequate to answer important questions regarding parameters such as oxygen sufficiency in the body. Summary of the Invention

[0004] Therefore, new systems, methods, and devices for transesophageal echo oximetry are desirable.

[0005] Hemorrhagic shock is a preventable, but sometimes fatal, condition. Mixed venous oxygenation (SvO2) measured from the pulmonary artery is a sensitive, immediate, and reliable indicator of blood loss and circulatory shock. In current clinical practice, SvO2 measurement requires placement of a pulmonary artery catheter through a highly invasive procedure that carries a significant risk of severe complications. This procedure requires a sterile environment and general anesthesia, making it impractical to perform at the point of care. The TEO embodiments disclosed herein are capable of continuously monitoring SvO2 using photoacoustics. Oxygenated and deoxygenated blood absorb different amounts of light at different wavelengths and emit ultrasound waves of different amplitudes, allowing for assessment of blood oxygenation, while at the same time the TEO device can acquire real-time ultrasound images of cardiac structures. Combining ultrasound structural information with photoacoustic information allows for the derivation of a comprehensive set of hemodynamic information, such as heart rate, blood flow, blood pressure, preload, afterload, cardiac output, arterial oxygenation, venous oxygenation, oxygen delivery, or oxygen consumption. The TEO techniques disclosed herein do not require central line placement and can be used in unsedated patients.

[0006] Thus, in one embodiment, the present disclosure provides an apparatus for transesophageal echo oximetry including an insertion tube having an optical fiber disposed therein and a probe disposed at an end of the insertion tube, the probe including an acoustic transducer and a reflector with which the acoustic transducer and the optical fiber are aligned. The apparatus may also include a controller in communication with the acoustic transducer, and the controller may be configured to generate an ultrasound image of the sample using the acoustic transducer and the reflector, direct light from the optical fiber towards the reflector and into the sample, collect an optoacoustic signal from the sample based on the directed light using the acoustic transducer and the reflector, and determine a blood oxygen level of the sample based on the optoacoustic signal.

[0007] In certain embodiments of the device, the probe may further include a micromotor coupled to the reflector and in communication with a controller, which may be further configured to rotate the reflector using the micromotor, generate an ultrasound image of the sample using the acoustic wave transducer and the rotating reflector, direct light from the optical fiber towards the rotating reflector and into the sample, collect an optoacoustic signal from the sample based on the directed light using the acoustic transducer and the rotating reflector, and determine a blood oxygen level of the sample based on the collected optoacoustic signal using the rotating reflector.

[0008] Some embodiments of the device may further include a pulsed light source coupled to the optical fiber and in communication with the controller. In certain embodiments of the device, the pulsed light source may emit light pulses having a pulse duration of at least 1 ns and no more than 100 ns. In certain embodiments of the device, the pulsed light source may emit light pulses including near infrared light (600 to 2500 nm). In various embodiments of the device, the pulsed light source may be switchable between two different wavelengths of light. In some embodiments of the device, the pulsed light source may emit light pulses including wavelengths in at least one range of 750 nm to 770 nm or 900 nm to 1100 nm. In certain embodiments of the device, the pulsed light source may emit light pulses including at least one wavelength of 760 nm or 1053 nm. In other embodiments of the device, the pulsed light source may emit light pulses including at least one wavelength of 760 nm or 1064 nm.

[0009] In various embodiments of the device, the pulsed light source may emit light pulses having an energy of greater than -10 mJ. In some embodiments of the device, the pulsed light source may be air-cooled. In certain embodiments of the device, the pulsed light source may include a power source including a battery. In various embodiments of the device, the pulsed light source may be coupled to the optical fiber using a microlens array and a spherical lens to project the output of the pulsed light source onto the end of the optical fiber.

[0010] In certain embodiments of the apparatus, the pulsed light source may include a first resonant cavity driven by a pair of laser diodes, a second resonant cavity in optical communication with the first optical cavity, an electro-optic modulator, and an output configured to emit optical pulses. The electro-optic modulator may have a first position to transmit light from the first resonant cavity to the output, and the electro-optic modulator may have a second position to transmit light from the first resonant cavity to the second resonant cavity, and the optical pulses emitted from the output may include a first wavelength from the first resonant cavity when the electro-optic modulator is in the first position, and the optical pulses emitted from the output may include a second wavelength from the second resonant cavity that is different from the first wavelength when the electro-optic modulator is in the second position.

[0011] In some embodiments of the device, the optical fiber may extend through an opening in the acoustic transducer. In certain embodiments of the device, the probe may include a housing having a reflector and an acoustic transducer disposed therein, and the housing may include an acoustic coupling fluid disposed therein.

[0012] In certain embodiments of the device, the controller may be further configured to determine a blood oxygen level of the sample based on the photoacoustic signal every second when determining the blood oxygen level of the sample based on the photoacoustic signal. In certain embodiments of the device, the controller may be further configured to determine at least one of a heart rate, blood flow, blood pressure, preload, afterload, cardiac output, oxygen supply, or oxygen consumption of the sample based on the photoacoustic signal and an ultrasound image of the sample when determining the blood oxygen level of the sample based on the photoacoustic signal.

[0013] In various embodiments of the device, the diameter of the probe may be 6 mm or less. In certain embodiments of the device, the probe may be configured to be delivered through a nasal tube. In certain embodiments of the device, the probe may be disposed within a balloon, and the balloon may be inflated with a fluid. Some embodiments of the device further include a portable power source, and the device may be configured to be stored within a portable case.

[0014] Some embodiments of the present disclosure provide a method for transesophageal echo oximetry that includes providing an insertion tube with an optical fiber disposed therein and a probe disposed at an end of the insertion tube, the probe including a reflector that aligns the acoustic transducer and the optical fiber. The method may include using a controller in communication with the acoustic transducer to generate an ultrasound image of the sample using the acoustic transducer and the reflector, using the controller to direct light from the optical fiber towards the reflector and into the sample, using the controller to collect an optoacoustic signal from the sample based on the directed light using the acoustic transducer and the reflector, and using the controller to determine a blood oxygen level of the sample based on the optoacoustic signal.

[0015] In certain embodiments of this method, the probe may further include a micromotor coupled to the reflector and in communication with the controller, and the method may further include rotating the reflector using the micromotor, generating an ultrasound image of the sample using the acoustic transducer and the rotating reflector, directing light from the optical fiber towards the rotating reflector and into the sample, collecting an optoacoustic signal from the sample based on the directed light using the acoustic transducer and the rotating reflector, and determining a blood oxygen level of the sample based on the collected optoacoustic signal.

[0016] Some embodiments of the method may further include providing a pulsed light source coupled to the optical fiber and in communication with the controller. Certain embodiments of the method may further include emitting light pulses using the pulsed light source having a pulse duration of at least 1 ns and no more than 100 ns. Certain embodiments of the method may further include emitting light pulses using the pulsed light source including far infrared or near infrared light (600 to 2500 nm). In various embodiments of the method, emitting light pulses may further include switching between two different wavelengths of light using the pulsed light source. In some embodiments of the method, emitting light pulses may further include emitting light pulses using the pulsed light source including wavelengths in at least one range of 750 nm to 770 nm or 900 nm to 1100 nm. In various embodiments of the method, emitting light pulses may further include emitting light pulses using the pulsed light source including at least one wavelength of 760 nm or 1053 nm or at least one wavelength of 760 nm or 1064 nm.

[0017] In some embodiments of the method, emitting a light pulse may further include emitting a light pulse having an energy of more than 10 mJ with a pulsed light source. In certain embodiments of the method, providing a pulsed light source may further include providing a pulsed light source that is air-cooled. In certain embodiments of the method, providing a pulsed light source may further include providing a pulsed light source that includes a power source including a battery.

[0018] Some embodiments of the method may further include coupling the pulsed light source to the optical fiber using a microlens array and a spherical lens, and projecting an output of the pulsed light source onto an end of the optical fiber based on the coupling of the pulsed light source and the optical fiber.

[0019] In various embodiments of the method, providing an insertion tube having an optical fiber disposed therein may further include extending the optical fiber through an opening in the acoustic transducer. In some embodiments of the method, providing an insertion tube having an optical fiber disposed therein and a probe disposed at an end of the insertion tube may further include providing a housing having a reflector and an acoustic transducer disposed therein, and the housing may have an acoustic coupling fluid disposed therein.

[0020] In certain embodiments of the method, determining a blood oxygen level of the sample based on the photoacoustic signal may further include determining a blood oxygen level of the sample based on the photoacoustic signal every second. In some embodiments of the method, determining a blood oxygen level of the sample based on the photoacoustic signal may further include determining at least one of a heart rate, blood flow, blood pressure, preload, afterload, cardiac output, oxygen supply, or oxygen consumption of the sample based on the photoacoustic signal and an ultrasound image of the sample.

[0021] In certain embodiments of the method, providing an insertion tube having an optical fiber disposed therein and a probe disposed at an end of the insertion tube may further include providing a probe having a diameter of 6 mm or less. In some embodiments of the method, providing an insertion tube having an optical fiber disposed therein and a probe disposed at an end of the insertion tube may further include providing a probe configured to be delivered through a nasogastric tube.

[0022] In various embodiments of the method, providing an insertion tube having an optical fiber disposed therein and a probe disposed at an end of the insertion tube further includes providing the probe disposed within a balloon, the balloon being inflated with a fluid. Some embodiments of the method may further include providing a portable power source and storing the insertion tube, the probe, the controller, and the portable power source in a carrying case.

[0023] Various objects, features, and advantages of the disclosed subject matter can be more fully understood by reference to the following detailed description of the disclosed subject matter when considered in conjunction with the following drawings, in which like reference numerals indicate like elements and in which: [Brief description of the drawings]

[0024] [Figure 1] Figure 1 shows a portable TEO console for in vivo applications. (Panel A) Photograph of the system. (Panel B) Technical drawing showing the internal configuration of the system. (Panel C) Functional block diagram showing the connections between the system components. [Diagram 2] Figure 2 shows a compact dual-wavelength light source unit. (Panel A) Technical drawing of the customized OPO laser. (Panel B) Fast wavelength tuning by electro-optic modulation. M: mirror (e.g. dichroic mirror), EOM: electro-optic modulator (e.g. Pockels cell), ND: YLF: neodymium-doped lithium yttrium fluoride crystal, OC: output coupler, LD: laser diode, SHG: second harmonic generator, PBS: polarizing beam splitter, BD: beam dumper, BBO: barium borate crystal, W: laser window. (Panel C) Efficient nanosecond light coupling through a single optical fiber using the conventional method (top) and the procedure of this disclosure (bottom), with sub-panels (A) to (E) showing cross-sectional views of the light beam at the indicated point during transmission. [Diagram 3] Figure 3 shows the transnasal TEO probe. (Panel A) Photograph showing transnasal deployment of the probe in an adult nasogastric training manikin. (Panel B) Technical drawing showing the internal configuration of the probe. (Panel C) Photograph showing the balloon in a deflated (top, 6 mm diameter) and inflated (bottom, 20 mm diameter) state. [Figure 4] Figure 4 shows the transnasal TEO probe. (Panel A) Technical drawing of the probe showing the internal configuration of the proximal connector and distal measuring tip (inset). (Panel B) Photograph of the TEO probe aligned with a commercially available nasogastric tube. (Panel C) Transnasal placement of the TEO probe on a nasogastric feeding training manikin. [Diagram 5]Figure 5 shows data on monitoring blood oxygenation changes in vivo by TEO. (Panel A) Frame of real-time ultrasound image showing the position of the aorta (yellow asterisk) and the angular position where acoustic measurements are made (red line). Field of view: 10 cm x 10 cm. (Panel B) Change in fraction of inspired oxygen (FiO2). (Panel C) Change in aortic oxygen saturation (SaO2) in response to FiO2 adjustment. Green line: continuous TEO measurements of blood oxygenation. Red diamonds: blood oxygenation measured from individual blood samples by a commercial blood gas analyzer. (Panel D) Comparison of SaO2 measurements obtained by TEO and blood gas analyzer showing excellent correlation. Solid line: best fit line from linear regression. Dashed line: 95% confidence band for the slope of the linear regression. [Figure 6] Figure 6 shows a laser safety study of esophageal tissue exposed to TEO light. (Panel A) Photograph showing the exposed areas. The central area (black dashed circle and black arrow) receives full power from the OPO laser. Two registration sites (red arrows) were marked with red tissue ink to indicate sites for histological analysis. (Panels B to D) Representative NTBC-stained tissue sections exposed for different exposure times (1 min, 10 min, and 30 min, respectively) show no tissue damage at the laser exposed sites. [Figure 7] FIG. 7 illustrates an example of a system for transesophageal echo oximetry according to some embodiments of the disclosed subject matter. [Figure 8] FIG. 8 illustrates example hardware that may be used to implement computing devices and servers according to some embodiments of the disclosed subject matter. [Figure 9] FIG. 9 illustrates an example of a method for transesophageal echo oximetry according to some embodiments of the disclosed subject matter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] In accordance with some embodiments of the disclosed subject matter, mechanisms (which may include systems, methods, and devices) for transesophageal echo oximetry are provided.

[0026] Thus, disclosed herein are various embodiments of a procedure for performing transesophageal echo oximetry (TEO) in which a small probe is placed in the esophagus to simultaneously generate echographic images and spectrophotoacoustic measurements from the heart. The probe may be introduced into the esophagus through the nose to minimize gag reflex and improve patient tolerance. In various embodiments, the probe may have a relatively small insertion diameter (e.g., 6 mm or less or 18 Fr or less). As a result, placement of a transnasal TEO probe is similar to the method used with commercially available nasogastric tubes and can be performed by minimally trained personnel without administering sedatives to the patient.

[0027] The disclosed TEO system utilizes photoacoustics, whereby ultrasound waves are generated in tissue by light pulses of wavelengths that are absorbed differently by oxygenated and deoxygenated blood, allowing blood oxygenation to be measured in a vessel or chamber of interest. For example, the device can acquire real-time sonographic images of cardiac structures. The device can also shine light through the esophagus into the pulmonary artery and receive ultrasound waves from the pulmonary artery at a location determined by analysis of the sonographic images, providing a much less invasive measurement of mixed venous oxygenation than a pulmonary catheter. By combining ultrasound and photoacoustic measurements, a comprehensive set of hemodynamic information, such as heart rate, blood flow, blood pressure, preload, afterload, cardiac output, oxygen delivery, or oxygen consumption, can be derived. Thus, various embodiments of the TEO device may replace current highly invasive PACs with a low-risk comprehensive hemodynamic monitor, which may help save lives by enabling easy and reliable hemodynamic assessment near the point of care.

[0028] Disclosed herein are various embodiments of devices and methods for transesophageal echo oximetry (TEO) in which a small probe is placed in the esophagus to simultaneously generate echographic images and spectroscopic photoacoustic measurements from the heart. In various embodiments, the technique utilizes photoacoustics, whereby ultrasound waves are generated in tissue by light pulses of wavelengths that are absorbed differently by oxygenated and deoxygenated blood, allowing blood oxygenation to be measured in a vessel or chamber of interest. For example, a device can shine light through the esophagus into the pulmonary artery and receive ultrasound waves from the pulmonary artery, providing a much less invasive measurement of mixed venous oxygenation than a pulmonary catheter. Also, embodiments of the disclosed device can simultaneously obtain real-time echographic images of cardiac structures. Combining ultrasound and photoacoustic measurements, derivation of a comprehensive set of hemodynamic information, such as heart rate, blood flow, blood pressure, preload, afterload, cardiac output, oxygen delivery, or oxygen consumption, is feasible. Therefore, TEO may be a life-saving alternative to highly invasive PAC by providing a low-risk, comprehensive hemodynamic monitor and enabling easy and reliable hemodynamic assessment near the point of care.

[0029] This disclosure describes several embodiments of a portable, battery-powered, handheld TEO system and a miniature transnasal TEO probe that can be used at the point of care. The TEO system embodiments include a battery-powered device with a customized, dual-wavelength light source suitable for in vivo mixed venous oxygenation monitoring (FIGS. 1A and 1B). In various embodiments, the device is 62×49×22 cm 3 As shown in the embodiment of FIG. 1C, the system includes six subunits: a light source unit, a battery power unit, a data acquisition unit, a motor drive unit, a ventilation unit, and a user interface unit.

[0030] Reliable photoacoustic assessment of blood oxygenation requires a light source capable of generating light pulses with short pulse duration (1-100 ns) and sufficient energy (more than 10 mJ) and switchable between two selected far-infrared or near-infrared wavelengths (e.g., 600-2500 nm), preferably around 760 nm (e.g., 750 nm-770 nm) and around 1000 nm (e.g., 900 nm-1100 nm), respectively. In various embodiments, each laser pulse group includes at least one pulse at each wavelength. The time interval between laser pulses in the same group may be 25 ms (range: 100 ns-100 ms, shorter time intervals are preferred to reduce or avoid measurement errors caused by tissue motion). The repetition rate of the pulse groups may be 1 Hz (range: 0.1-100 Hz). To make the finished device portable, the light source in certain embodiments needs to be small in size, battery-powered, and air-cooled. In some embodiments, the optical pulses are generated by an optical parametric oscillator (OPO) laser, and all optical and electronic components are housed in a 41×13×15 cm 3The laser is integrated into a small housing with a size of 1000 nm (Figure 2A). As shown in Figure 2B, the laser features two resonant cavities. The first cavity (between M1 and OC1) was designed to generate 1053 nm light pulses with short duration of 3 to 4 ns and high energy of over 90 mJ by efficient energy extraction by a neodymium-doped yttrium lithium fluoride crystal (ND:YLF) from seed light provided by two high-power laser diodes (LD1 and LD2), as well as by active Q-switching provided by a polarizer (P1) and an electro-optical modulator (EOM1) such as a Pockels cell. The second electro-optical modulator (EOM2) is used to shift the polarization of the 1053 nm light between vertical and horizontal orientations. In the vertical case, a second harmonic generator (SHG) converts these 1053 nm light pulses into 526.5 nm green light. The second laser cavity (between M6 and OC2) further converts these green pulses to 760 nm light using a nonlinear barium borate crystal (BBO), which is directed by mirrors M9 to M11 to the exit window (W) with an energy of over 20 mJ per pulse. If the polarization of the 1053 nm pulses is horizontal, they are not converted and go directly to the exit window (W) with an energy of over 40 mJ per pulse. The 760 nm and 1053 nm pulse durations were measured to be 2.65 ns and 3.25 ns, respectively. In external trigger mode, the laser emits two light pulses at any combination of two wavelengths per second with an interpulse interval of 25 ms.

[0031] OPO lasers have two unique advantages: 1) OPO lasers are pumped by energy-efficient laser diodes. Compared with flashlamp-pumped lasers used in typical photoacoustic devices, OPO lasers have higher energy conversion efficiency, do not require bulky liquid cooling systems, and generate less noise. Thus, systems can be compact and quieter with air cooling. 2) OPO lasers implement a unique method that provides rapid pulse-to-pulse wavelength switching by electro-optic modulation. Compared with traditional methods that use mechanical switching (e.g., optical shutters), OPO lasers are not only much faster, but also minimize wear over long-term use. Thus, they help to improve the accuracy of oxygenation assessment by minimizing motion artifacts between photoacoustic measurements and extend system lifetime.

[0032] Remote irradiation of mJ-level nanosecond light pulses typically requires the use of bulky fiber bundles containing many optical fibers to distribute the light energy over a large input surface area to avoid damage to the fiber end face. In some embodiments, an optical setup capable of coupling high energy light pulses into a single optical fiber with high efficiency and robustness is shown in FIG. 2C. Conventional fiber coupling setups use one or more lenses to focus the light into a single spot with high energy density on or in front of the fiber surface, which can lead to fiber or air destruction, especially if there is a hot spot in the incoming light beam (typically occurring with OPO lasers). In addition, it is also difficult to consistently achieve high light throughput, since different wavelengths of light result in different size foci.

[0033] An embodiment of the disclosed procedure splits the incoming beam into many sub-beams using a microlens array and then overlaps them in a small rectangular area on the fiber surface using a spherical lens. In this way, laser-induced destruction in the fiber or air due to energy dispersion is avoided. The non-uniform energy pattern of the incoming beam, which is larger than the size of a single microlens element (0.5 mm in our setup), is homogenized to mitigate laser damage caused by hot spots. (Figure 2C, compare subpanels (B) and (C)).

[0034] Finally, the size of the light beam on the fiber surface is determined only by the parameters of the optical elements and remains independent of the light wavelength. Simulations show that this lens array setup helps to avoid laser-induced destruction in the fiber or air by reducing the peak optical energy density in the optical path by more than 20 times and dispersing the energy to multiple optical foci (Fig. 2C, compare subpanels (D) and (E)). Also, the coupling efficiency of this method at 760 nm and 1053 nm is only 11% compared to 87% by the conventional method. Furthermore, experiments show that this setup successfully delivers light from an OPO laser through a single 550 μm core silica fiber with a throughput of over 70% at both 760 nm and 1053 nm. So far, no laser-induced damage to the optical fiber has been observed during use.

[0035] In various embodiments, blood oxygenation may be evaluated once per second (e.g., at a rate of about 1 Hz), while in other embodiments blood oxygenation may be evaluated at more frequent or less frequent time intervals, e.g., in the range of 0.1 Hz to 100 Hz. During each measurement cycle, 38 cardiac ultrasound images are first acquired, followed by two photoacoustic frames at 1053 nm and 760 nm, respectively. For each image / frame, signals are acquired at 250 different angular positions along a circle by rotating the reflector by a micromotor. An optimal position for measuring the photoacoustic signal from the pulmonary artery for mixed venous monitoring may be identified from the ultrasound image. First, an object of interest, e.g., the pulmonary artery, may be identified on the ultrasound image (e.g., at least one of frames 1 to 38) by either user annotation or an automated image analysis algorithm (e.g., using machine learning). Then, light of the two selected wavelengths is emitted at an angular position that crosses approximately the center of the target, e.g., in frames 39 and 40, and after two photoacoustic measurements are obtained, the blood oxygenation of the target is calculated. Based on such a procedure, laser filtering is automatically activated at these positions and photoacoustic emissions from the relevant positions are obtained. In the motor drive unit, the stepper motor controller was programmed to rotate the probe micromotor with high repeatability using 1 / 32 microstepping to ensure that photoacoustic signals in the same cycle are acquired from the same angular positions. In the data acquisition unit, a customized high-repetition radio frequency pulser is used to generate ultrasound waves for ultrasound imaging. A timing signal generation circuit generates TTL pulses to synchronize the firing of the laser and the pulser with the data acquisition of the ultrasound and photoacoustic signals. The signals are then digitized by a high-speed digitizer and processed by a fanless mini PC. Finally, the control software has been developed in Labview, and the computationally intensive data processing tasks are implemented in C and included as dynamic link libraries. The user can operate the system in real time via a touch screen with a user-friendly graphic interface, adjust the settings, and observe the results.

[0036] Miniaturization of the console is important for the development of a portable device. To the inventors' knowledge, the battery-powered portable clinical grade photoacoustic system disclosed herein is the first of its kind. All system components are powered by a 300Wh rechargeable lithium-ion battery. On average, the system consumes 70 to 90W when actively monitoring oxygenation. It is estimated that a full charge can provide more than 3 hours of operating time. The console can also be plugged into a standard 110V outlet and operated independently of the battery while the battery is recharging. Heat generated by the system components can be channeled into a central ventilation valley and then dissipated to the environment through ventilation fans installed at both ends of the valley. To protect the light source unit from vibration during portable use, a sheet of vibration absorbing material (e.g., Sorbothane) was installed between the light source unit and the case.

[0037] Nasal TEO probe

[0038] Additionally, a small diameter TEO probe has been developed that can be introduced into the esophagus through the nose (Figure 3A). The probe has a suitable insertion diameter of 6 mm (or 18 Fr) or less. Placement of a transnasal TEO probe is similar to the method used with commercially available nasogastric tubes and can therefore be performed by minimally trained personnel without sedating the patient.

[0039] To obtain cross-sectional ultrasound images of the heart, the acoustic detection path and the optical excitation path need to be rotated in a circular fashion. Two possible rotation methods were investigated, one using a distal micromotor and the other using a proximal torque-transmitting coil. The study showed that a better measurement repeatability is possible with the micromotor-based solution.

[0040] FIG. 3B shows an embodiment of a TEO probe featuring a distal micromotor. The probe generates and detects sound by a customized 6.5 MHz piezoceramic ring transducer (OD=5.5 mm, bore size=1.5 mm, active area=5.0 mm). Light from an OPO laser is first directed to the distal end of the probe through the central bore of the transducer by a 550 μm double-clad silica fiber and then deflected by a rod reflector to illuminate the tissue from the side (e.g., the reflector is at an angle of about 40° to 50°, preferably about 45°, to the long axis of the probe so that the tissue adjacent to the probe is illuminated). The reflector also reflects acoustic waves for ultrasound imaging and photoacoustic measurements. The reflector is attached to a microstepping motor. The transducer, reflector, and micromotor can be aligned and assembled in a CNC-machined plastic housing. For proper acoustic coupling, the housing may be made of a material that may have an acoustic impedance close to that of oil, water, or tissue, such as polymethylmethacrylate (PMMA), polymethylpentene (TPX), or cross-linked polystyrene resin. The housing may be filled with an acoustic coupling fluid, such as water, saline, silicon oil, corn oil, or mineral oil. To prevent contamination of the fiber and micromotor by oil, an optical window may be used to seal the central hole of the transducer, and a customized EPDM dynamic seal may be attached around the rotating shaft. The distal end of the probe may further comprise a polyurethane balloon that may be inflated to a diameter of 20 mm to 25 mm with saline or water. In a specific embodiment, a 5-lumen Pellesen® insertion tube is custom extruded to accommodate the optical fiber, the transducer's signal cable, the motor's electrical wiring, and a liquid channel for balloon inflation.

[0041] As shown in Figure 3C, when the balloon is deflated, the fully assembled transnasal TEO probe measures 6 mm in maximum outer diameter at the distal end, which is comparable to the size of commercially available nasogastric tubes (e.g., Salem Sump® #8888265140, Cardinal). The probe has a small, rigid length of 25 mm at the distal end and a flexible shaft with a bending radius of less than 35 mm and a bending angle of less than 110°. It was found to be easily inserted and withdrawn through the nasal cavity into the esophagus through testing on an adult nasogastric feeding training mannequin (Corman, Nasco) (Figure 3A). Once placed in the esophagus, the balloon can be inflated with water or saline up to 20 mm (Figure 3C), making airless contact with the esophagus to minimize acoustic transmission loss. Ultrasound images are acquired to identify the location of the pulmonary artery, and photoacoustic measurements are made to allow for the assessment of mixed venous oxygenation.

[0042] example

[0043] The following are non-limiting examples of embodiments of the present disclosure.

[0044] In one embodiment, a TEO probe featuring a miniature single-element ultrasound transducer and a rotating light / sound reflector was developed and used to conduct the tests (FIGS. 4A-4C). FIG. 4A shows a technical drawing of the probe, showing the proximal connector and the internal configuration of the distal measurement tip (inset). FIG. 4B shows a photograph of the TEO probe aligned with a commercially available nasogastric tube. FIG. 4C shows the transnasal placement of the TEO probe on a nasogastric feeding training mannequin. The inset of FIG. 4A shows a close-up of the probe providing typical dimensions of the TEO probe, showing that in this embodiment the inflated balloon is about 25 mm in diameter, the probe is about 25 mm long, and the insertion tube is about 5 mm in diameter and the probe body is about 6 mm in diameter. The cross-section of the inset of FIG. 4A shows an embodiment of the ultrasound transducer including an opening through which the optical fiber is inserted. Also shown is how light (straight / expanded beam) and sound (dots perpendicular to the light beam) reflect off the reflector to the side of the probe and into the tissue.

[0045] The reflector can be rotated to obtain cross-sectional ultrasound images of the esophagus and the surrounding large vessels / heart. In various embodiments, the reflector can be rotated using a distal micromotor or using a proximal metallic torque transfer coil. In the embodiment of Figures 4A to 4C, a micromotor is used to rotate the reflector because studies have shown that a micromotor-based solution provides good rotational repeatability necessary to enable photoacoustic measurements from the target.

[0046] Before use, the probe is attached to the console by connecting a customized fiber optic connector to transmit light to the tissue, an SMA connector to transmit and receive ultrasound signals, and an XLR connector to transmit signals to drive the rotation of the micromotor. The distal measurement tip includes an ultrasound transducer, an optical fiber, a micromotor, a reflector, a housing, a balloon, and a flexible insertion tube. A 6.5 MHz ring-type piezoceramic transducer generates and detects ultrasound. A 550 μm double-clad silica fiber transmits light from the OPO laser to the tissue. A dielectric glass rod reflector redirects both light and ultrasound at a 90 degree angle. A stepper micromotor rotates the reflector with good repeatability. A precision-machined light- and sound-transparent acrylic housing serves to align the micromotor, reflector, and transducer. The housing may be filled with a fluid, for example silicone or corn oil, to improve sound transparency. The optical fibers, transducer signal cables, motor electrical wiring, and fluid channels for balloon inflation and deflation run through a custom extruded, 5-lumen Pelletzen insertion tube. A polyurethane balloon surrounds the entire distal end.

[0047] After the probe is introduced into the esophagus, the balloon can be inflated with water or saline to make airless contact with the esophageal wall to minimize acoustic transmission loss. To identify the target measurement location, the transducer transmits high-frequency sound waves that bounce off the reflector toward the tissue. Partially reflected sound waves from the tissue return to the transducer. The transducer converts the sound waves into electrical signals and transmits them to the console. The console digitizes the signals and reconstructs a cross-sectional sonography image of the tissue from which the vessel of interest (e.g., pulmonary artery or aorta) can be identified. For photoacoustic measurements, the OPO laser generates a light pulse when the rotating reflector reaches the desired angle. The reflector redirects the light from the fiber to illuminate the target vessel. The generated photoacoustic signal is picked up by the transducer and processed by the console to determine blood oxygenation in the target vessel.

[0048] Figure 4B compares the TEO probe with a commercially available nasogastric tube (Salem Sump® #8888265140, Cardinal). When the balloon is deflated, the TEO probe has a maximum outer diameter of 6 mm, which is comparable in size to a commercially available 18 Fr nasogastric tube. The probe also has a small distal stiffness length of 25 mm, a bending radius of less than 20 mm, and a bending angle of less than 110°. The probe was tested on a commercially available adult nasogastric feeding training mannequin (Corman, Nasco). The results showed that it could be easily inserted into and withdrawn from the esophagus through both nasal passages (Figure 4C).

[0049] Validation of the TEO device in a live pig model

[0050] The TEO device was used to test in vivo blood oxygenation monitoring in pigs to measure mixed venous oxygenation (SvO2) from the pulmonary artery in pigs during controlled hemorrhage. In this example, the device was validated by measuring arterial oxygenation (SaO2) from the aorta in adult-sized pigs (Yorkshires, 60 to 100 kg). SaO2 was adjusted by changing the oxygen fraction in the inspired gas (FiO2). The aorta of the pig is in a similar anatomical position to the pulmonary artery of humans, and because anatomical differences mean that the pulmonary artery of the pig is not close enough to the esophagus to perform measurements with a TEO probe, the aorta was chosen instead for blood oxygenation testing. For reference, the TEO measurements were compared with the results of arterial blood gas analysis obtained by a commercially available CO meter (STAT PROFILE Prime+, Nova Biomedical). Arterial blood was sampled simultaneously with the TEO measurements. By adjusting the FiO2, larger SaO2 changes were brought about in a stepwise controlled manner. This made it possible to validate the performance of the device at the low blood oxygen concentrations seen with SvO2 in hemorrhagic shock.

[0051] The results of the pig study showing the adjustment of FiO2 are shown in Figures 5A to 5D. As shown in Figure 5A, it was possible to easily identify the target vessel, i.e., the aorta, using the ultrasound images acquired by the TEO device (Figure 5A, the aorta is the dark space with a yellow asterisk). Photoacoustic measurements were made at the angular positions marked by the red lines (Figure 6A). Figure 5B shows how SaO2 changed when the FiO2 was adjusted by adjusting the ratio of O2 and N2 in the gas inhaled by the animal. As expected, SaO2 dropped from 100% to less than 50% within 7 min after the FiO2 was decreased from 100% to 15%, and recovered when the FiO2 was increased (Figures 5B to 5C). Blood SaO2 measurements by the TEO (Figure 5C, green line) were found to be highly correlated with blood gas SaO2 readings from simultaneously taken blood samples (Figure 5C, red diamonds), with R2 = 0.91 (Figure 5D).

[0052] Verifying that TEO exposure is safe for esophageal tissue

[0053] Laser safety guidelines (ANSI Z136.1-2014) only list maximum permissible exposures (MPE) for skin and eyes. The skin MPE is often used to guide safe exposure limits for other opaque tissue types. Calculations have identified that the exposures used in TEO are below the skin MPE (99% at 760 nm and 51% at 1053 nm on a single-shot basis, and 10% at 760 nm and 5% at 1053 nm on an average power basis).

[0054] TEO exposure was further studied to determine whether it induced esophageal tissue damage through structural changes or loss of cell viability. Fresh porcine esophagi were harvested immediately after slaughter and immersed in CMRL cell culture medium at 37 °C. An area on the luminal surface of the esophagus was then exposed to TEO light for 1, 10, and 30 min. To guide histological sectioning, two registration sites flanking the exposure site were marked with red tissue ink (Figure 6A). Tissue was cut near the registration marks, mounted in optimal cutting temperature medium, and then frozen. Multiple histological levels (n = 14) were cut from the edge of the red ink and sectioned into spots spaced 400 μm apart. Tissue slides were stained with nitrotetrazolium blue chloride (NBTC). Histochemical staining with NBTC is a well-established method for assessing tissue viability with greater sensitivity and specificity than standard histological staining. Viable tissue stains blue, whereas nonviable heat-damaged tissue does not. All slides were read by an experienced pathologist. Tissue injury was assessed by examining the surface epithelium and underlying tissue layers for obvious physical damage. Cellular injury was assessed by noting discontinuities in staining from deep blue to colorless across the exposed area.

[0055] Representative histology of full-thickness esophageal specimens exposed for 1, 10, and 30 min is shown in Figures 6B-6D, respectively. All slides showed good staining in the areas not exposed to the TEO laser (Figures 6B-6D, red arrows), indicating that the tissue was viable and the NBTC staining was functional. No fading of the NBTC stain, indicative of thermal damage, was observed throughout the exposed areas (Figures 6B-6D, black arrows), demonstrating that TEO exposure is safe for esophageal tissue.

[0056] Computer and Optical Systems

[0057] Referring to FIG. 7, an example transesophageal echo oximetry system (e.g., data collection and processing system) 700 is shown, according to some embodiments of the disclosed subject matter. In some embodiments, a computing device 710 can execute at least a portion of a transesophageal echo oximetry system 704 and provide control signals to a data collection device 702, such as, for example, a disclosed TEO probe. Additionally or alternatively, in some embodiments, the computing device 710 can communicate information regarding the control signals that can execute at least a portion of the transesophageal echo oximetry system 704 to or from a server 720 via a communications network 706. In some such embodiments, the server 720 can transmit information related to the control signals for the transesophageal echo oximetry system 704 back to the computing device 710 (and / or any other suitable computing device). This information may be transmitted and / or presented to a user (e.g., a researcher, an operator, a clinician, etc.) and / or stored (e.g., as part of a research database or medical record associated with the subject).

[0058] In some embodiments, the computing device 710 and / or server 720 may be any suitable computing device or combination of devices, for example, a desktop computer, a laptop computer, a smartphone, a tablet computer, a wearable computer, a server computer, a virtual machine executed by a physical computing device, etc. As described herein, the system for transesophageal echo oximetry 704 may present information regarding the control signal to a user (e.g., a researcher and / or a physician).

[0059] In some embodiments, the communication network 706 may be any suitable communication network or combination of communication networks. For example, the communication network 706 may include a Wi-Fi network (which may include one or more wireless routers, one or more switches, etc.), a peer-to-peer network (e.g., a Bluetooth network), a cellular network (e.g., a 4G network, a 5G network, etc., conforming to any suitable standard, such as CDMA, GSM, LTE, LTE Advanced, WiMAX, etc.), a wired network, etc. In some embodiments, the communication network 706 may be a local area network, a wide area network, a public network (e.g., the Internet), a private network (e.g., a corporate or university intranet), any other suitable type of network, or any suitable combination of networks. Each of the communication links illustrated in FIG. 7 may be any suitable communication link or combination of communication links, such as, for example, a wired link, an optical fiber link, a Wi-Fi link, a Bluetooth link, a cellular link, etc.

[0060] FIG. 8 illustrates example hardware 800 that may be used to implement a computing device 710 and a server 720, according to some embodiments of the disclosed subject matter. As illustrated in FIG. 8, in some embodiments, the computing device 710 may include a processor 802, a display 804, one or more input devices 806, one or more communication systems 808, and / or a memory 810. In some embodiments, the processor 802 may be any suitable hardware processor or combination of processors, such as, for example, a central processing unit, a graphics processing unit, etc. In some embodiments, the display 804 may include any suitable display device, such as, for example, a computer monitor, a touch screen, a television, etc. In some embodiments, the input device 806 may include any suitable input device and / or sensor that may be used to receive user input, such as, for example, a keyboard, a mouse, a touch screen, a microphone, etc.

[0061] In some embodiments, communications system 808 may include any suitable hardware, firmware, and / or software for communicating information over communications network 706 and / or any other suitable communications network. For example, communications system 808 may include one or more transceivers, one or more communications chips and / or chipsets, etc. In particular examples, communications system 808 may include hardware, firmware, and / or software that may be used to establish a Wi-Fi connection, a Bluetooth connection, a cellular connection, an Ethernet connection, etc.

[0062] In some embodiments, memory 810 may include any suitable storage device or devices that may be used to store instructions, values, etc. that may be used, for example, by processor 802 to present content using display 804, communicate with server 720 via communication system(s) 808, etc. Memory 810 may include any suitable volatile memory, non-volatile memory, storage, or any suitable combination thereof. For example, memory 810 may include RAM, ROM, EEPROM, one or more flash drives, one or more hard disks, one or more solid state drives, one or more optical drives, etc. In some embodiments, memory 810 may encode computer programs for controlling the operation of computing device 710. In such embodiments, processor 802 may execute at least a portion of a computer program to present content (e.g., images, user interfaces, graphics, tables, etc.), receive content from server 720, transmit information to server 720, etc.

[0063] In some embodiments, server 720 may include a processor 812, a display 814, one or more input devices 816, one or more communication systems 818, and / or memory 820. In some embodiments, processor 812 may be any suitable hardware processor or combination of processors, such as, for example, a central processing unit, a graphics processing unit, etc. In some embodiments, display 814 may include any suitable display device, such as, for example, a computer monitor, a touch screen, a television, etc. In some embodiments, input device 816 may include any suitable input device and / or sensor that may be used to receive user input, such as, for example, a keyboard, a mouse, a touch screen, a microphone, etc.

[0064] In some embodiments, communications system 818 may include any suitable hardware, firmware, and / or software for communicating information over communications network 706 and / or any other suitable communications network. For example, communications system 818 may include one or more transceivers, one or more communications chips and / or chipsets, etc. In more particular examples, communications system 818 may include hardware, firmware, and / or software that may be used to establish a Wi-Fi connection, a Bluetooth connection, a cellular connection, an Ethernet connection, etc.

[0065] In some embodiments, memory 820 may include any suitable storage device or devices that may be used to store instructions, values, etc. that may be used, for example, by processor 812 to present content using display 814, communicate with one or more computing devices 710, etc. Memory 820 may include any suitable volatile memory, non-volatile memory, storage, or any suitable combination thereof. For example, memory 820 may include RAM, ROM, EEPROM, one or more flash drives, one or more hard disks, one or more solid state drives, one or more optical drives, etc. In some embodiments, memory 820 may encode server programs for controlling the operation of server 720. In such embodiments, processor 812 may execute at least a portion of the server programs for transmitting information and / or content (e.g., tissue identification and / or classification results, user interfaces, etc.) to one or more computing devices 710, receiving information and / or content from one or more computing devices 710, receiving instructions from one or more devices (e.g., personal computers, laptop computers, tablet computers, smartphones, etc.), etc.

[0066] In some embodiments, any suitable computer-readable medium may be used to store instructions for performing the functions and / or methods described herein. For example, in some embodiments, the computer-readable medium may be transitory or non-transient. For example, a non-transient computer-readable medium may include media such as, for example, magnetic media (hard disks, floppy disks, etc.), optical media (compact disks, digital video disks, Blu-ray disks, etc.), semiconductor media (RAM, flash memory, Electrically Programmable Read-Only Memory (EPROM), Electrically Erasable Programmable Read-Only Memory (EEPROM), etc.), any suitable media that is not ephemeral or lacks any semblance of permanence in transmission, and / or any suitable tangible media. As another example, a transitory computer-readable medium may include signals, wires, conductors, optical fibers, circuits on a network, or any suitable media that is ephemeral and lacks any semblance of permanence in transmission, and / or any suitable intangible media.

[0067] It should be noted that the term mechanism, as used herein, may encompass hardware, software, firmware, or any suitable combination thereof.

[0068] FIG. 9 illustrates an example method 900 for transesophageal echo oximetry according to some embodiments of the disclosed subject matter. As shown in FIG. 9, at 902, the method 900 may provide an insertion tube with an optical fiber disposed therein and a probe disposed at the end of the insertion tube, the probe may include an acoustic transducer and a reflector aligned with the acoustic transducer and the optical fiber. At 904, the method 900 may use a controller in communication with the acoustic transducer to generate an ultrasound image of the sample using the acoustic transducer and the reflector. At 906, the method 900 may use a controller to direct light from the optical fiber towards the reflector and into the sample. At 908, the method 900 may use a controller to collect an optoacoustic signal from the sample based on the light directed using the acoustic transducer and the reflector. Finally, at 910, the method 900 may use a controller to determine a blood oxygen level of the sample based on the optoacoustic signal.

[0069] It should be understood that the foregoing steps of the method of Figure 9 may be executed or performed in any order or sequence, including but not limited to the order and sequence shown and described in the figures. Also, some of the steps of the method of Figure 9 may be executed or performed approximately simultaneously, where appropriate, or in parallel to reduce latency and processing times.

[0070] Thus, while the present invention has been described above with reference to particular embodiments and examples, it is not necessarily so limited, and numerous other embodiments, examples, applications, modifications, and departures from the embodiments, examples, and applications are intended to be encompassed by the appended claims.

Claims

1. An apparatus for transesophageal echocardiographic oxygen measurement, comprising: An insertion tube having an optical fiber disposed therein; A probe disposed at an end of the insertion tube, the probe comprising: An acoustic transducer, and A reflector for aligning the acoustic transducer and the optical fiber; A controller in communication with the acoustic transducer, the controller being configured to: Generate an ultrasonic image of a sample using the acoustic transducer and the reflector; Direct light from the optical fiber in the direction of the reflector and into the sample; Collect a photoacoustic signal from the sample based on the directed light using the acoustic transducer and the reflector; and Determine a blood oxygen concentration of the sample based on the photoacoustic signal. An apparatus comprising the above.

2. The probe further comprises a micromotor coupled to the reflector and in communication with the controller, and the controller is further configured to: Rotate the reflector using the micromotor; Generate an ultrasonic image of the sample using the acoustic transducer and the rotating reflector; Direct light from the optical fiber in the direction of the rotating reflector and into the sample; Collect a photoacoustic signal from the sample based on the directed light using the acoustic transducer and the rotating reflector; and Determine a blood oxygen concentration of the sample based on the collected photoacoustic signal using the rotating reflector. The apparatus according to claim 1, further configured as above.

3. The apparatus according to claim 1, further comprising a pulsed light source coupled to the optical fiber and in communication with the controller.

4. The pulsed light source of claim 3 emits an optical pulse having a pulse duration of at least 1 ns and 100 ns or less.

5. The pulsed light source of claim 3 emits an optical pulse containing near-infrared light.

6. The pulsed light source of claim 5 is switchable between optical pulses of two different wavelengths.

7. The pulsed light source of claim 6 emits an optical pulse containing at least one wavelength range from 750 nm to 770 nm or from 900 nm to 1100 nm.

8. The pulsed light source of claim 7 emits an optical pulse containing at least one wavelength of 760 nm or 1053 nm. ​ ​ ​ Claim 9 The apparatus according to claim 3, wherein the pulsed light source emits an optical pulse having an energy exceeding 10 mJ. Claim 10 The apparatus according to claim 3, wherein the pulsed light source is air-cooled. Claim 11 The apparatus according to claim 3, wherein the pulsed light source includes a power source containing a battery. Claim 12 The apparatus according to claim 3, wherein the pulsed light source is coupled to the optical fiber using a microlens array and a spherical lens, and projects the output of the pulsed light source onto an end of the optical fiber. Claim 13 The pulsed light source a first resonant cavity driven by a pair of laser diodes; a second resonant cavity in optical communication with the first resonant cavity; an electro-optic modulator; and an output configured to emit an optical pulse, wherein the electro-optic modulator has a first position for transmitting light from the first resonant cavity to the output, the electro-optic modulator has a second position for transmitting light from the first resonant cavity to the second resonant cavity, the optical pulse emitted from the output includes a first wavelength from the first resonant cavity when the electro-optic modulator is in the first position, the optical pulse emitted from the output includes a second wavelength from the second resonant cavity different from the first wavelength when the electro-optic modulator is in the second position. The apparatus according to claim 3. Claim 14 The apparatus according to claim 1, wherein the optical fiber extends through an opening of the acoustic transducer. Claim 15 The probe includes a housing in which the reflector and the acoustic transducer are disposed therein, and the housing contains an acoustic coupling fluid disposed therein. The apparatus according to claim 1. Claim 16 The apparatus according to claim 1, wherein when the controller determines the blood oxygen concentration in the sample based on the photoacoustic signal, the controller is further configured to determine the blood oxygen concentration of the sample based on the photoacoustic signal every second. Claim 17 The apparatus according to claim 1, wherein when the controller determines the blood oxygen concentration of the sample based on the photoacoustic signal, the controller is further configured to determine at least one of a heart rate, blood flow, blood pressure, preload, afterload, cardiac output, oxygen supply amount, or oxygen consumption amount of the sample based on the photoacoustic signal and an ultrasonic image of the sample. Claim 18 The apparatus according to claim 1, wherein a diameter of the probe is 6 mm or less. Claim 19 The device according to claim 18, wherein the probe is configured to be delivered through a nasal tube. **Claim 20** The device according to claim 1, wherein the probe is disposed within a balloon, and the balloon is inflated using a fluid. **Claim 21** The device according to claim 1, further comprising a portable power source and configured to be stored in a carrying case.

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