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WO2024081663A2 - Systèmes et procédés pour matériaux de couplage optique et acoustique, systèmes et procédés d'utilisation - Google Patents

Systèmes et procédés pour matériaux de couplage optique et acoustique, systèmes et procédés d'utilisation Download PDF

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Publication number
WO2024081663A2
WO2024081663A2 PCT/US2023/076492 US2023076492W WO2024081663A2 WO 2024081663 A2 WO2024081663 A2 WO 2024081663A2 US 2023076492 W US2023076492 W US 2023076492W WO 2024081663 A2 WO2024081663 A2 WO 2024081663A2
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Prior art keywords
coupling medium
gellan gum
adapter
optical
coupling
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WO2024081663A3 (fr
Inventor
Russell WITTE
Christopher SALINAS
Eric REICHEL
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University of Arizona
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University of Arizona
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Publication of WO2024081663A3 publication Critical patent/WO2024081663A3/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/42—Details of probe positioning or probe attachment to the patient
    • A61B8/4272—Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue
    • A61B8/4281—Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue characterised by sound-transmitting media or devices for coupling the transducer to the tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0093—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy
    • A61B5/0095—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy by applying light and detecting acoustic waves, i.e. photoacoustic measurements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy

Definitions

  • the present disclosure generally relates to materials, compositions, and devices for use with systems and methods of photoacoustic imaging as well as monitoring therapy.
  • Biomedical photoacoustic imaging is a high-resolution imaging modality that uses the optical properties of a material to gain image contrast. Exposure of tissue to short-pulsed light generates ultrasound (US) through optical absorption, where these acoustic waves can be imaged by traditional US means.
  • US ultrasound
  • the present disclosure relates to a coupling device for imaging configured to efficiently propagate light and sound.
  • the coupling device is configured for optical imaging with ultrasound modulation, such as wherein the optical imaging is laser speckle doppler imaging combined with ultrasound neuromodulation.
  • the present disclosure relates to photoacoustic adapter for use with an ultrasonic probe.
  • the adapter can include a proximal portion configured to engage the ultrasonic probe, a distal portion configured to contact a sample surface, and a coupling medium chamber disposed between the proximal portion and the distal portion.
  • the coupling medium chamber includes a coupling medium.
  • the adapter is an inline adapter configured to co-align optical transmissions from the ultrasonic probe and acoustic emissions received at the ultrasonic probe.
  • the coupling medium includes a water-based gelling agent.
  • the water-based gelling agent can include low-acyl Gellan gum.
  • the coupling medium includes deuterium oxide (“heavy water”) and a gelling agent.
  • the gelling agent can include low-acyl Gellan gum.
  • the present disclosure also relates to a photoacoustic reflection apparatus for real-time optical monitoring using ultrasound.
  • the apparatus includes a housing that defines a photoacoustic reflection chamber.
  • the housing can also include a first optical aperture defined in a first surface, a second optical aperture defined in a second surface, where the second surface is disposed opposite the first surface, and the first and second optical apertures are coaligned along a first axis.
  • the housing also defines an ultrasound transducer port in a third surface that is substantially parallel to the first axis such that acoustic emissions from an ultrasound transducer are perpendicular to the first axis.
  • the apparatus also includes a coupling medium disposed within the housing and a prism reflector affixed within the housing, where the acoustic emissions contact the prism reflector and are reflected along the first axis towards a sample aligned with the second optical aperture. A response of the sample is observable by an optical sensor aligned with the first optical aperture.
  • the coupling medium includes water. In another aspect, the coupling medium includes deuterium oxide. In yet another aspect, the coupling medium includes a mixture of a transparent gelling agent and water or a mixture of Gellan gum and deuterium oxide.
  • the present disclosure also relates to an ultrasonic coupling medium for use with an ultrasonic probe.
  • the coupling medium includes a mixture of Gellan gum and deuterium oxide.
  • the mixture contains Gellan gum in a range between 1.5% w/w and 3% w/w.
  • the present disclosure relates to a method of fabricating a coupling medium.
  • the method includes steps such as pre-heating deuterium oxide, porting gellan gum into the deuterium oxide, stirring the resultant mixture until the gellan gum dissolves into the deuterium oxide, degassing the mixture to remove bubble artifacts, pouring the mixture into a molding apparatus, and chilling the mixture until the mixture forms a gel in the shape of the molding apparatus.
  • FIGS. 1A and 1B are a pair of laser speckle images of a brain “before” and “after” before and after TBI that shows a significant reduction in blood flow post-TBI;
  • FIG. 2A is an illustration showing a system for real-time photoacoustic imaging that includes a photoacoustic adapter for use with an ultrasonic probe and an optical sensor;
  • FIG. 2B is an illustration showing a system for real-time photoacoustic imaging that includes an “inline” photoacoustic adapter for use with an ultrasonic probe;
  • FIG. 2C is an image showing one embodiment of the photoacoustic adapter of FIG. 2B;
  • FIGS. 3A-3C are a series of images taken by an optical sensor (e.g., the optical sensor of FIG. 2A) during therapeutic ultrasound treatment;
  • an optical sensor e.g., the optical sensor of FIG. 2A
  • FIGS. 4A-4D are a series of graphical representations showing blood perfusion of an object of interest during therapeutic ultrasound treatment
  • FIG. 5 is a graphical representation showing absorption coefficient for water and lipids across different wavelengths of light
  • FIGS. 6A-6C is an illustration of various experimental setups used to determine the speed of sound and acoustic attenuation, according to various embodiments
  • FIG. 7 is an illustration of an expected baseline photoacoustic signal measured with an acoustic microscope and an acoustic microscope setup testing the optical clarity of each coupling material, according to various embodiments;
  • FIG. 7A shows an acoustic microscope setup for testing optical clarity of each coupling material
  • FIG. 7B shows an expected baseline photoacoustic signal measured with an acoustic microscope
  • FIG. 8 is a graphical representation showing acoustic attenuation for various coupling materials including gellan gum
  • FIGS. 9A-9D are a series of photoacoustic images of an 800 pm Gaussian spot through each material;
  • FIG. 9E is a graphical representation showing a “cross-sectional slice” of the relative photoacoustic amplitudes for baseline, gellan gum, Humimic, and agarose, corresponding with FIGS. 9A-9D;
  • FIGS. 10A and 10B are a pair of illustrations respectively showing transmission-mode and reflection-mode setups for quantification of optical loss and acoustic propagation of gellan gum as a coupling media;
  • FIGS. 11 A and 11 B is a graphical representation showing transmission-mode data (absorption plots) for quantification of optical loss for both heavy water gellan gum and distilled water gellan gum;
  • FIG. 12 is a graphical representation showing axial spatial resolution for pulse-echo images obtained from a sample with fine graphite particles using humimic, heavy water gellan gum and distilled water gellan gum as coupling media;
  • FIG. 13 is a sequence of photoacoustic images at various wavelengths for both heavy water gellan gum and distilled water gellan gum;
  • FIG. 14 is a graphical representation showing photoacoustic surface spectra for samples imaged using heavy water gellan gum and distilled water gellan gum, demonstrating signals above noise for heavy water gellan gum across the full range, including distinct peaks of lipid/water;
  • FIGS. 15A-15C display a PA imaging cross-section of a bovine tissue sample along with spectral data captured using heavy water gellan gum as coupling media;
  • FIG. 16 shows a method for fabrication of a coupling medium including heavy water and gellan gum.
  • the present disclosure relates to materials, compositions, and devices with novel/optimal optical and acoustic properties that enable or improve systems and methods of coupling of light and sound for biomedical and defense applications related to imaging (e.g., photoacoustic) and monitoring therapy (e.g., image-guided ultrasound neuromodulation).
  • imaging e.g., photoacoustic
  • monitoring therapy e.g., image-guided ultrasound neuromodulation
  • Photoacoustic imaging is a powerful screening tool for cancer detection; capable of mapping vasculature, measuring blood oxygenation, and providing material specificity.
  • PAI laser systems must be highly efficient in light delivery.
  • Several types of media have been proposed for coupling light and sound from a laser to a tissue interface.
  • One approach combines an ultrasound (US) probe with an inline adapter using a photoacoustic prism/reflector filled with water, agarose gel or optically transparent rubber for coupling.
  • adapter efficiencies are hindered by suboptimal material properties (optical/acoustic), all which degrade image quality (e.g., artifacts, lower signal-to-noise ratios, etc.).
  • Biomedical PAI is a high-resolution imaging modality that uses the optical properties of a material to gain image contrast. Exposure of tissue to short-pulsed light generates US through optical absorption, where these acoustic waves can be imaged by traditional US means. By taking advantage of endogenous or exogenous contrast agents, PAI can provide tissue specificity, making it an excellent candidate for non-invasive cancer screening. PAI however does not come without its challenges, as the dependance upon optical and acoustic tissue properties can require complex system designs. For clinical applications such as in vivo skin imaging, it is common to combine light and sound with an inline reflector, which coaxially aligns the optical and acoustic paths within a single coupling media.
  • the coupling media plays a crucial role as it must maximize light transmission to tissue while minimizing ultrasound attenuation. Furthermore, in systems such as photoacoustic microscopes, incident light must remain unaberrated, requiring minimal optical scattering. Finally, an ideal coupling media must have similar mechanical properties (speed of sound, acoustic impedance, etc.) to tissue to prevent reflection losses at interfaces.
  • PA coupling media such as water, oilbased rubbers, or agarose gel (AG) partially meet these requirements, however each lack in their own regard.
  • Water has high optical and acoustic clarity but is prone to leakage and can introduce artifacts due to bubbles in the liquid.
  • Oil-based rubbers can maintain their structure and possess a long shelf life. However, these materials tend to be more acoustically attenuating, particularly towards high frequency ultrasound.
  • AG couples well to tissue with minimal acoustic attenuation but increase overall optical scattering.
  • the present disclosure relates to the use low acyl gellan gum (GG) for PA coupling as it is both optically and acoustically clear and demonstrated high durability as a coupling media.
  • GG low acyl gellan gum
  • the systems outlined herein including a photoacoustic reflection apparatus and coupling media, enable real-time monitoring of organ function during therapeutic ultrasound.
  • An embodiment of the system is presented herein in the context of therapeutic transcranial ultrasound (e.g., low-intensity pulsed ultrasound (LIPIIS)), which has been shown to decrease recovery time from traumatic brain injury (TBI).
  • LIPIIS low-intensity pulsed ultrasound
  • TBI traumatic brain injury
  • transcranial LIPIIS improves functional prognosis after TBI, increases blood perfusion, reduces edema, and is neuroprotective.
  • neuroprotective mechanisms of transcranial ultrasound are not well-understood.
  • Factors of interest during therapeutic ultrasound include hemodynamics, neuronal activity, oxygen saturation, and temperature. For example, FIG.
  • FIG. 1 A shows laser speckle images of a brain before and after TBI that shows a significant reduction in blood flow in the circled region of FIG. 1B.
  • imaging systems can look at snapshots before and after treatment as in FIGS. 1A and 1B but are considerably limited in providing real-time monitoring of hemodynamics and other factors.
  • FIG. 2A is an illustration of one embodiment of a photoacoustic adapter defining an acoustic reflection window that enables monitoring of the realtime physical response to application of ultrasound.
  • the apparatus may be configured for use with existing ultrasound transducers (e.g., ultrasound probe 20) and optical sensors or cameras (e.g., imaging device 30) to provide real-time observation and monitoring therapy among others uses.
  • FIG. 2A shows a first system 100 for real-time photoacoustic imaging that includes a photoacoustic adapter 102 for use with an ultrasonic probe 20 (or “ultrasound transducer”) and an optical sensor 30.
  • the photoacoustic adapter 102 includes a coupling medium chamber 120 having a coupling medium that engages the ultrasonic probe 20 and contacts a surface of a sample.
  • the coupling medium chamber 120 can include a first optical window 122 and a second optical window 124 defined opposite from the first optical window 122.
  • the first optical window 122 can be associated with the optical sensor 30 and the second optical window 124 can contact an object of interest 2 (e.g., a sample such as in-vivo tissue).
  • the coupling medium chamber 120 can include an ultrasound transducer port 126 that engages the ultrasound transducer 20.
  • the first optical window 122 and the second optical window 124 can be coaligned along a first axis and the ultrasound transducer port 126 can be aligned along a second axis that is perpendicular to the first axis as shown.
  • the coupling medium chamber 120 can include a prism element 128 positioned therein that reflects acoustic emissions from the ultrasound transducer 20 towards the object of interest 2, e.g., altering a path of the acoustic emissions to align with the first axis.
  • the optical sensor 30 can observe a response of the object of interest 2 resultant of the acoustic emissions from the ultrasound transducer 20.
  • FIG. 2B shows an illustration of a second system 200 including a photoacoustic adapter 202 for use with an ultrasonic probe 40.
  • the ultrasonic probe 40 can deliver optical transmissions (e.g., a laser) to the object of interest 2 and can observe acoustic emissions from the object of interest 2 resultant of the light from the ultrasonic probe 40.
  • the photoacoustic adapter 202 can be thus configured to coalign optical transmissions from the ultrasonic probe 40 and acoustic emissions received from the object of interest 2 at the ultrasonic probe 40.
  • the ultrasonic probe 40 can be a standard ultrasound probe that applies acoustic emissions to the object of interest 2 and receives acoustic emissions from the object of interest 2 in response.
  • the photoacoustic adapter 202 can likewise include a coupling medium chamber 220 filled with a coupling medium (e.g., coupling media with gellan gum as outlined in section 3 or section 4 herein) and defining a proximal portion 222 and a distal portion 224 opposite from the proximal portion 222.
  • the proximal portion 222 can be associated with the photoacoustic probe 40 and the distal portion 224 can contact the object of interest 2 (e.g., a sample such as in-vivo tissue).
  • FIG. 2C shows a version of the photoacoustic adapter 202 for reflection-mode SWIR, embodied as a “probe jacket” that covers a distal portion of the ultrasonic probe 40 and positions the coupling media at the distal portion of the ultrasonic probe 40. As shown, the distal portion 224 of the coupling medium chamber 220 contacts the object of interest 2.
  • the coupling medium disposed within the coupling medium chamber 120 (FIG. 2A) or 220 (FIG. 2B) can include a gelling agent, which can include gellan gum.
  • the coupling medium can further include hydrogen oxide (H2O, or “water”) or can alternatively include deuterium oxide (D2O, or “heavy water” which is an isotope of water).
  • H2O hydrogen oxide
  • D2O deuterium oxide
  • a first example implementation validated in section 3 herein includes a coupling medium having gellan gum and deionized hydrogen oxide, and is compared with other coupling media including hydrogen oxide (without gellan gum), agarose and humimic medical gelatin.
  • a second example implementation validated in section 4 herein includes a coupling medium having gellan gum and deuterium oxide, and is compared with other coupling media including gellan gum with hydrogen oxide as in the first example implementation, pure deuterium oxide, pure hydrogen oxide, and humimic medical gelatin.
  • FIGS. 3A-3C show a sequence of images taken by an optical sensor such as the optical sensor 20 of FIG. 2A during therapeutic ultrasound treatment (as opposed to “before” and “after” as discussed above).
  • FIG. 3A shows a “baseline” image for Pre-US intervention (averaged frames before application of therapeutic ultrasound)
  • FIG. 3B shows an image with averaged frames taken during application of therapeutic ultrasound
  • FIG. 3B shows an image with averaged frames taken after application of therapeutic ultrasound.
  • FIGS. 4A and 4B are a pair of graphical representations showing real-time blood perfusion taken during application of therapeutic ultrasound over an 11 -minute period with a 5-minute “on” interval followed by a 5-minute “off” interval.
  • FIG. 4A shows real-time blood perfusion for a full area of the object of interest observable by an optical sensor (e.g., optical sensor 20 of FIG. 2A), and FIG. 4B shows real-time blood perfusion for a region of interest (e.g., a region of the brain damaged by TBI).
  • FIGS. 4C and 4D are another pair of graphical representations showing real-time blood perfusion taken during application of therapeutic ultrasound over a 6-minute period with alternating 1 -minute “on” intervals and 1 -minute “off intervals.
  • FIG. 4C shows real-time blood perfusion for a full area of the object of interest observable by an optical sensor (e.g., optical sensor 20 of FIG. 2A), and FIG.
  • FIGS. 4D shows real-time blood perfusion for a region of interest (e.g., a region of the brain damaged by TBI.
  • the photoacoustic adapter arrangements shown in FIGS. 2A-2C enable real-time observation of characteristics such as blood perfusion during therapeutic ultrasound treatment as shown in FIGS. 3A-4D
  • the coupling medium includes gellan gum as a gelling agent and addresses technological limitations of current coupling media with respect to photoacoustic imaging.
  • Some technologies for imaging lipids allow high contrast but only at superficial depths within tissue.
  • FIG. 5 plots absorption coefficient for water and lipids across different wavelengths of light. Greater absorption of light in the SWIR leads to greater lipid contrast, and thus better imaging of lipids within an object of interest.
  • sections 3 and 4 outline coupling media that aim to improve fidelity in photoacoustic imaging, especially within the SWIR range.
  • the disclosure presents quantification of acoustic and optical properties of low acyl gellan gum as a coupling agent and compare to common coupling agents to identify the benefits and tradeoffs of each material for PAI.
  • Properties examined in this section include acoustic attenuation, impedance, density, speed of sound, optical transmittance and optical absorbance of gellan gum at 1.5 - 2.5% (w/w), and compared to agarose at 1 .5% (w/w), Humimic Medical Gelatin #0, and diH20.
  • the goal of the validation study was to quantify the acoustic and optical properties of low acyl gellan gum (GG) and compare to common coupling agents to identify the benefits and tradeoffs of each material for PAI.
  • GG low acyl gellan gum
  • Sample preparations varied for each material. AG and GG start in dry powered form, and therefore must be hydrated. Preparation of these materials included steps of mixing the desired percent by weight (%w/w) powdered GG with diH20. This mixture was then heated and stirred until the GG has fully dissolved ( ⁇ 100°C). This mixture was then degassed ( ⁇ -25 inHg) to remove bubble artifacts. Finally, the resultant gel liquid was poured into the desired mold and chilled until gelling temperature ( ⁇ 70°C for GG). For this study, multiple samples of GG were tested from 1 .5% - 2.5% (w/w) at 0.25% (w/w) increments to determine variations in optical and acoustic properties.
  • preparation of AG for comparison with GG included steps of mixing the desired percent by weight (%w/w) powdered AG with diH20. This mixture was then heated and stirred until the AG has fully dissolved ( ⁇ 100°C). This mixture was then degassed ( ⁇ -25 inHg) to remove bubble artifacts. Finally, the resultant gel liquid was poured into the desired mold and chilled until gelling temperature ( ⁇ 36°C for AG). AG was tested at 1 .5 % (w/w).
  • Humimic is an oil-based rubber and processed by the manufacturer. For preparation, Humimic was melted at - 100°C, where it was then be poured into a mold and cooled to room temperature. To remove bubble artifacts, application of an external heat gun was used.
  • Optical transmittance was measured by sample illumination with a tunable short pulsed laser (Opolette HE 532 LD 680 - 1000 nm, 5 ns, 12 mJ) and an optical power meter (Coherent J-Power 1132205) (FIG. 6B).
  • Optical absorbance was determined by placing each material in identical cuvettes and sampled from 680 nm - 1000 nm with a spectrometer (Ocean Optics USB 4000 VIS/NIR) (FIG. 6C). 3.1-D. Photoacoustic Signal Loss
  • FIGS. 7A and 7B show an acoustic microscope setup for testing optical clarity of each coupling material.
  • Short pulsed laser light was focused with a microscope object (Nikon 4/0.1 ) to an 800 pm Gaussian spot through 15 mm of each material onto a black target.
  • the generated PA signal was then measured with the use of a custom acoustic microscope (Panametrics v324-sm 25MHz) with a resolution of 200 pm (FIG. 7A).
  • FIG. 7B shows an expected baseline photoacoustic signal measured with an acoustic microscope that the results of each coupling material are to be compared against.
  • GG showed substantially higher optical transmittance and lower absorbance compared to AG and Humimic.
  • GG had an average transmittance of 99.3% compared to 95.6% for AG and 97.2% for Humimic.
  • FIGS. 9A-9D PA images of an 800 pm Gaussian spot through each material were captured and are shown in FIGS. 9A-9D.
  • FIG. 9A corresponds with the baseline signal shown in FIG. 7B.
  • FIG. 9B shows a photoacoustic signal where the coupling material is Humimic
  • FIG. 9C shows a photoacoustic signal where the coupling material is GG
  • FIG. 9D shows a photoacoustic signal where the coupling material is AG.
  • FIG. 9E shows a “cross-sectional slice” of the relative photoacoustic amplitudes for baseline, GG, Humimic, and AG, corresponding with FIGS. 9A-9D. Comparing peak PA amplitudes, GG demonstrated significantly less PA signal loss compared to baseline at 16% loss, compared to 43% and 60% signal loss for Humimic and AG respectively.
  • This section compares common PA coupling media with GG and quantify each material’s optical and acoustic characteristics to determine coupling performance. From the data collected, GG demonstrated an improvement on optical clarity (minimal absorption and scattering) and reduction of acoustic attenuation. To determine the overall performance improvement of GG when compared to these other materials, estimations of the signal increase can be made by determining each materials total signal loss in comparison to GG.
  • I I o e ⁇ (1 )
  • I the measured Intensity, /othe initial energy, the absorption coefficient, and z the material thickness.
  • estimated signal improvement due to GG’s optical properties can then be calculated to be: where l g is the light intensity measured through GG, l m the compared coupling media light intensity, and A the change in optical absorption coefficients. Combining Eqn.
  • GG also demonstrated beneficial mechanical variability that is dependent on the GG concentration. At lower %w/w, GG was mechanically similar to soft tissue and deformable. However, at higher %w/w, GG became rigid and held whatever form it was molded into. This variety can allow GG to be used in a variety of experimental conditions depending on the type of coupling required.
  • D2O Deuterium oxide
  • H2O Hydrogen species
  • D2O -based gelatin to facilitate reflection-mode PAI in the SWIR.
  • This section outlines development and assessment of the performance of a gel form of D2O for optimal delivery of light and ultrasound to enable reflection-mode PAI in the SWIR with a penetration of several millimeters into tissue.
  • a gelatin interface simplifies coupling to the sample for reflection-mode imaging and eliminates the potential of leakage or formation of air bubbles.
  • a gelatin coupling medium can also be re-used and re-shaped to conform to different imaging configurations.
  • the advantage of tunability of gelatin stiffness further provides potential for construction of impedance matching layers, which can drastically improve ultrasound propagation to and from an imaging sample.
  • HWG gelatin-based heavy water opto-acoustic coupling medium
  • PE reflectionmode pulse-echo
  • FIGS. 10A-15C show validation results for HWG as a coupling medium.
  • FIG. 16 shows a method 300 for fabrication of HWG.
  • D2O can be pre-heated (step 302 of method 300) to ⁇ 80 °C.
  • Gellan gum powder (between 2 and 3% w/w) can be poured slowly into D2O (step 304 of method 300) and mixed with a stir bar to ensure homogeneity (step 306 of method 300).
  • the solution can then be degassed to remove air bubbles (step 308 of method 300) before being poured into a molding apparatus designed for PA and PE imaging (step 310 of method 300).
  • the mixture can then be allowed to cool to room temperature until it forms a gel in the shape of the molding apparatus (step 312 of method 300), where the cooled mixture is formed into a shape conducive for insertion within a coupling medium chamber of a photoacoustic adapter.
  • the HWG is then ready for imaging. Because the stiffness and viscosity of the resulting HWG could be altered by adjusting the concentration of gellan gum, it was determined that a concentration of 2.25% w/w gellan gum was suitable for imaging experiments because it provided mechanical stability while remaining somewhat flexible when coupling to the samples.
  • the thickness of the HWG was ⁇ 5.0 mm for reflection-mode imaging.
  • a commercial ultrasound and PA imaging system (Vevo 3100/LAZR-X, VisualSonics) was first used in transmission-mode to quantify the optical loss through sections of HWG in the SWIR.
  • the container was placed within the output path of the fiber bundles, where acoustic coupling was then achieved from below via contact with a water reservoir and a 25MHz US linear array (MX250, VisualSonics).
  • Black electrical tape was used as a broadband optical absorber and inserted between the molding container and water reservoir as a baseline for estimating PA signal loss as a function of wavelength through the coupling medium.
  • the spectrum of the tape was first measured through air in transmission-mode from 1200 to 2000nm.
  • the PA spectrum was then compared differentially to the broadband spectrum of the tape obtained through an optical path length defined by the thickness of HWG. Differences in these spectra result in the transmission loss corresponding to the new optical pathlength (i.e. , HWG samples at 2% and 3% w/w).
  • This method was repeated for samples of H2O gellan gum (WG) (outlined in section 3 above) to compare the optical loss with HWG.
  • the energy exiting the fiber bundle through the coupling media was also measured with a commercial energy meter (Coherent EnergyMax).
  • Axial full-width half-max was chosen for measurement as it most closely depends on the US wavelength and dispersion (i.e., can relate to frequency-dependent attenuation of the US signal), unlike lateral and elevational resolution which can depend on additional factors, including aperture size and focal distance.
  • a lipid/water phantom composed of 20% lipid shortening (Cisco), 75% diH2O, and 5% w/w agarose was prepared to demonstrate the capabilities of HWG in reflection-mode PAI operating in the SWIR compared to a WG system.
  • the solution of lipid, water and agarose is brought to ⁇ 80°C via hotplate, mixed with a stir bar, and left to cool and solidify at room temperature.
  • HWG and WG coupling agents are molded for reflection-mode imaging with the 25MHz probe and fiber bundle as described previously.
  • Spectral PA data was collected at 5nm intervals from 1200 to 2000nm through both HWG and WG to quantify differences in SNR and detection.
  • Transmission mode data is tabulated and graphed in FIGS. 11A and 11B.
  • the relative PA signals across the band are normalized to black tape for comparing each coupling medium. It is observed that the PA transmission spectrum of HWG (2% and 3% w/w) is similar to the Beer-Lambert signal for 99% heavy water with the same optical pathlength.
  • FIGS. 11A and 11B Energy measurements of the LAZR-X fiber bundle through 2% w/w HWG and WG are displayed in FIGS. 11A and 11B. Criterion required that laser illumination reaching the samples with less than 1 mJ energy was insufficient for producing PA images with adequate SNR.
  • the WG coupling agent for example, strongly absorbed light above 1350nm.
  • Light delivery through HWG maintained sufficient light delivery to the sample (>1mJ) across the entire SWIR region up to 1850nm. PA signals were too weak or undetectable outside these cutoff wavelengths.
  • FIG. 12 describes the axial spatial resolution for PE images obtained from the sample with fine graphite particles. Analysis of the PSPs reveals similar axial spatial resolution through WG (69.0 ⁇ 1.4pm) and HWG (69.7 ⁇ 3.8pm), indicating that HWG preserves the full acoustic bandwidth of the propagating ultrasound waves similar to a water-based coupling agent. This is not the case with humimic rubber, as the acoustic properties are affected by dispersion and the strong attenuation at high ultrasound frequencies, resulting in a degradation in axial resolution using the 25MHz linear array.
  • PA images of the phantoms using the HWG coupling agent were obtained up to 1850nm as predicted from the absorption coefficients and transmission measurements.
  • water-based gels provided PA images of the sample up to only ⁇ 1350nm as depicted in FIG. 13. Signals received past this WG cutoff do not contain any PA information of the sample due to insufficient light reaching the surface. PA signal above the noise floor can be seen using HWG at 1720nm up to depths of ⁇ 5.0mm with most of the contrast at this wavelength generated from lipids. PA surface spectra are plotted for the samples in FIG. 14, demonstrating signals above noise for HWG across this full range, including distinct peaks of lipid/water.
  • FIGS. 15A-15C display a PA imaging cross-section of the bovine tissue sample along with spectral data. Even at 1220nm (obtainable with WG), the ratio of peak PA signal in the green and yellow regions of interest (ROI) between the HWG and WG images is 3.04x and 1 .41 x respectively, indicating a broad increase in SNR when using HWG coupling as opposed to WG.
  • ROI green and yellow regions of interest
  • HWG enables PAI of tissue samples across a broad spectral range in the SWIR (1200-1850nm), whereas WG is limited to wavelengths ⁇ 1350nm with poor SNR (FIGS. 11A and 11B). It was anticipated that the predicted transmission spectrum of HWG would be similar to that of heavy water in liquid form at the equivalent concentration (99% pure). The results align with this prediction, as illustrated in FIGS. 11A and 11B. Slight shifts in the transmission peaks in the WG sample compared to baseline are likely due to the bonding mechanism of the low- acyl gellan gum, which has been reported previously. This effect is also observed with HWG, indicating the bonding effects of gellan and heavy water are similar to that of WG.
  • HWG has minimal loss of high frequency acoustic waves, preserving spatial resolution for PE imaging as shown in FIG. 12.
  • HWG enables the study of tissue constituents in reflection-mode PA setups without sacrificing spatial resolution.
  • Oil-based rubbers like humimic gels have much stronger acoustic attenuation at high ultrasound frequencies (>20MHz) due to dispersion and absorption. In the context of FIG. 12, this implies the PSF produced for humimic gel should be wider in spatial width, which is corroborated with results using the 25MHz linear array.
  • HWG may be used in ultrasound modulation therapy studies; HWG implemented within a proper system design could enable real-time and efficient imaging for changes in function during ultrasound modulation therapy. This could prove useful for treating several medical conditions ranging from traumatic brain injury and stroke to peripheral neuropathy.

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Abstract

Un système comprend un adaptateur pour un système d'imagerie photoacoustique qui comprend un milieu de couplage constitué de gomme gellane, qui présente des propriétés acoustiques et optiques améliorées pour faciliter l'imagerie photoacoustique (PA) et d'écho d'impulsion (PE). Le système est particulièrement destiné à améliorer l'imagerie dans une bande de fréquence infrarouge à ondes courtes (SWIR). Le milieu de couplage peut comprendre de l'oxyde de deutérium mélangé à de la gomme gellane pour une amélioration supplémentaire de l'imagerie PA et PE. Des études de validation sont présentées ici pour la comparaison de milieux de couplage à base de gomme gellane avec des milieux de couplage actuellement disponibles.
PCT/US2023/076492 2022-10-10 2023-10-10 Systèmes et procédés pour matériaux de couplage optique et acoustique, systèmes et procédés d'utilisation Ceased WO2024081663A2 (fr)

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