A Self-Healing Optoacoustic Patch with High Damage Threshold and Conversion Efficiency for Biomedical Applications

Compared with traditional piezoelectric ultrasonic devices,optoacoustic devices have unique advantages such as a simple preparation process,anti-electromagnetic interference,and wireless long-distance power supply.However,current optoacoustic devices remain limited due to a low damage threshold and energy conversion efficiency,which seriously hinder their widespread applications.In this study,using a self-healing polydimethylsiloxane(PDMS,Fe-Hpdca-PDMS)and carbon nanotube composite,a flexible optoacoustic patch is developed,which possesses the self-healing capability at room temperature,and can even recover from damage induced by cutting or laser irradiation.Moreover,this patch can generate high-intensity ultrasound(>25 MPa)without the focusing structure.The laser damage threshold is greater than 183.44 mJ cm^(-2),and the optoacoustic energy conversion efficiency reaches a major achievement at 10.66×10^(-3),compared with other carbon-based nanomaterials and PDMS composites.This patch is also been successfully examined in the application of acoustic flow,thrombolysis,and wireless energy harvesting.All findings in this study provides new insight into designing and fabricating of novel ultrasound devices for biomedical applications.

PERFORMANCE OF BLIND DECONVOLUTION IN OPTOACOUSTIC TOMOGRAPHY

In this paper,we consider the use of blind deconvolution for optoacoustic(photoacoustic)imaging and investigate the performance of the method as means for increasing the resolution of the reconstructed image beyond the physical restrictions of the system.The method is demonstrated with optoacoustic measurement obtained from six-day-old mice,imaged in the near-infrared using a broadband hydrophone in a circular scanning configuration.Wefind that estimates of the unknown point spread function,achieved by blind deconvolution,improve the resolution and contrast in the images and show promise for enhancing optoacoustic images.

BIOMEDICAL OPTOACOUSTICS

Optoacoustics is a promising modality for biomedical imaging,sensing,and monitoring with high resolution and contrast.In this paper,we present an overview of our studies for the last two decades on optoacoustic effects in tissues and imaging capabilities of the optoacoustic technique.In our earlier optoacoustic works we studied laser ablation of tissues and tissue-like media and proposed to use optoacoustics for imaging in tissues.In mid-90s we demonstrated detection of optoacoustic signals from tissues at depths of up to several centimeters,well deeper than the optical diffusion limit.We then obtained optoacoustic images of tissues both in vitro and in vivo.In late 90s we studied optoacoustic monitoring of thermotherapy:hyperthermia,coagulation,and freezing.Then we proposed and studied optoacoustic monitoring of blood oxygenation,hemoglobin concentration,and other physiologic parameters.

A multifunctional nanoaggregate-based system for detection of rheumatoid arthritis via Optoacoustic/NIR-Ⅱ fluorescent imaging and therapy via inhibiting JAK-STAT/NF-κB/NLRP3 pathways

Rheumatoid arthritis(RA)is a debilitating autoimmune disease that causes chronic pain and serious complications,presenting a significant challenge to treat.Promising approaches for treating RA involve signaling pathways modulation and targeted therapy.To this end,a multifunctional nanosystem,TPC-U@HAT,has been designed for RA therapy,featuring multitargeting,dual-stimuli response,and on-demand drug release capabilities.TPC-U@HAT is composed of a probe/prodrug TPC,a JAK1 kinase inhibitor upadacitinib,and the drug carrier HAT.TPC is composed of an aggregation-induced emission(AIE)-active NIR-II chromophore TPY and an NF-κB/NLRP3 inhibitor caffeic acid phenethyl ester(CAPE),connected via boronic ester bond which serves as the reactive-oxygen-species-responsive linker.The carrier,HAT,is created by grafting bone-targeting alendronate and hydrophobic tocopheryl succinate onto hyaluronic acid chains,which can encapsulate TPC and upadacitinib to form TPC-U@HAT.Upon intravenous injection into mice,TPC-U@HAT accumulates at inflamed lesions of RA through both active and passive targeting,and the overexpressed hyaluronidase and H_(2)O_(2) therein cleave the hyaluronic acid polymer chains and boronate bonds,respectively.This generates an AIE-active chromophore for detection and therapeutic evaluation of RA via both optoacoustic imaging and NIR-II fluorescent imaging and concomitantly releases CAPE and upadacitinib to exert efficacious therapy by inhibiting NF-κB/NLRP3 and JAK-STAT pathways.

Functional optoacoustic neuro-tomography for scalable whole-brain monitoring of calcium indicators

Non-invasive observation of spatiotemporal activity of large neural populations distributed over entire brains is a longstanding goal of neuroscience.We developed a volumetric multispectral optoacoustic tomography platform for imaging neural activation deep in scattering brains.It can record 100 volumetric frames per second across scalable fields of view ranging between 50 and 1000 mm^(3) with respective spatial resolution of 35–200μm.Experiments performed in immobilized and freely swimming larvae and in adult zebrafish brains expressing the genetically encoded calcium indicator GCaMP5G demonstrate,for the first time,the fundamental ability to directly track neural dynamics using optoacoustics while overcoming the longstanding penetration barrier of optical imaging in scattering brains.The newly developed platform thus offers unprecedented capabilities for functional whole-brain observations of fast calcium dynamics;in combination with optoacoustics'well-established capacity for resolving vascular hemodynamics,it could open new vistas in the study of neural activity and neurovascular coupling in health and disease.

Adding fifth dimension to optoacoustic imaging: volumetric time-resolved spectrally enriched tomography

Optoacoustics provides a unique set of capabilities for bioimaging,associated with the intrinsic combination of ultrasound-and light-related advantages,such as high spatial and temporal resolution as well as powerful spectrally enriched imaging contrast in biological tissues.We demonstrate here,for the first time,the acquisition,processing and visualization of five-dimensional optoacoustic data,thus offering unparallel imaging capacities among the current bioimaging modalities.The newly discovered performance is enabled by simultaneous volumetric detection and processing of multispectral data and is further showcased here by attaining time-resolved volumetric blood oxygenation maps in deep human vessels and real-time tracking of contrast agent distribution in a murine model in vivo.

Time-domain terahertz optoacoustics: manipulable water sensing and dampening

Radiation at terahertz frequencies can be used to analyze the structural dynamics of water and biomolecules,but applying the technique to aqueous solutions and tissues remains challenging since terahertz radiation is strongly absorbed by water.While this absorption enables certain analyses,such as the structure of water and its interactions with biological solutes,it limits the thickness of samples that can be analyzed,and it drowns out weaker signals from biomolecules of interest.We present a method for analyzing water-rich samples via time-domain terahertz optoacoustics over a 104-fold thickness ranging from microns to centimeters.We demonstrate that adjusting the temperature to alter the terahertz optoacoustic(THz-OA)signal of water improves the sensitivity with which it can be analyzed and,conversely,can reduce or even“silence”its signal.Temperature-manipulated THz-OA signals of aqueous solutions allow detection of solutes such as ions with an order of magnitude greater sensitivity than terahertz time-domain spectroscopy,and potentially provide more characteristic parameters related to both terahertz absorption and ultrasonic propagation.Terahertz optoacoustics may be a powerful tool for spectroscopy and potential imaging of aqueous solutions and tissues to explore molecular interactions and biochemical processes.

Comparison of optical detection system,PVDF detection system,and PVDF needle hydrophone for optoacoustic tomography

Optoacoustic tomography （PAT） is a two-dimensional medical imaging method that has the advantage of optical contrast and resolution of ultrasonic waves. The detection systems with a high sensitivity can be used for detecting small tumors, located deeply in human tissues, such as the breast. In this study, the sensitivity of existing ultrasonic detection systems has been compared experimentally with that by using thermoelastic waves as a broadband ultrasonic source. For the comparison, an optical stress transducer （OST）, a polyvinylidene difluoride （PVDF） sheet and a calibrated PVDF needle hydrophone were used. To ensure all of the detection systems interrogated by the same ultrasonic field, a small optical instrument that fixed the generating laser head was constructed. The sensitivity was evaluated by measuring signalto-noise ratios （SNRs） and noise equivalent pressures （NEPs）. The PVDF system, with a 4-kPa NEP has a 22 dB better performance than the OST. The OST showed nearly the same sensitivity as the hydrophone for detecting ultrasound waves at a 1-cm distance in water. PVDF detection system provides a useful tool for imaging of soft tissues because of its high sensitivity and broad detection range.

Localization optoacoustic tomography

Localization-based imaging has revolutionized fluorescence optical microscopy and has also enabled unprecedented ultrasound images of microvascular structures in deep tissues.Herein,we introduce a new concept of localization optoacoustic tomography(LOT)that employs rapid sequential acquisition of three-dimensional optoacoustic images from flowing absorbing particles.We show that the new method enables breaking through the spatial resolution barrier of acoustic diffraction while further enhancing the visibility of structures under limited-view tomographic conditions.Given the intrinsic sensitivity of optoacoustics to multiple hemodynamic and oxygenation parameters,LOT may enable a new level of performance in studying functional and anatomical alterations of microcirculation.

Spiral volumetric optoacoustic tomography visualizes multi-scale dynamics in mice

Imaging dynamics at different temporal and spatial scales is essential for understanding the biological complexity of living organisms,disease state and progression.Optoacoustic imaging has been shown to offer exclusive applicability across multiple scales with excellent optical contrast and high resolution in deep-tissue observations.Yet,efficient visualization of multi-scale dynamics remained difficult with state-of-the-art systems due to inefficient trade-offs between image acquisition time and effective field of view.Herein,we introduce the spiral volumetric optoacoustic tomography technique that provides spectrally enriched highresolution contrast across multiple spatiotemporal scales.In vivo experiments in mice demonstrate a wide range of dynamic imaging capabilities,from three-dimensional high-frame-rate visualization of moving organs and contrast agent kinetics in selected areas to whole-body longitudinal studies with unprecedented image quality.The newly introduced paradigm shift in imaging of multi-scale dynamics adds to the multifarious advantages provided by the optoacoustic technology for structural,functional and molecular imaging.

Optical imaging of post-embryonic zebrafish using multi orientation raster scan optoacoustic mesoscopy

Whole-body optical imaging of post-embryonic stage model organisms is a challenging and long sought-after goal.It requires a combination of high-resolution performance and high-penetration depth.Optoacoustic(photoacoustic)mesoscopy holds great promise,as it penetrates deeper than optical and optoacoustic microscopy while providing high-spatial resolution.However,optoacoustic mesoscopic techniques only offer partial visibility of oriented structures,such as blood vessels,due to a limited angular detection aperture or the use of ultrasound frequencies that yield insufficient resolution.We introduce 3601 multi orientation(multi-projection)raster scan optoacoustic mesoscopy(MORSOM)based on detecting an ultra-wide frequency bandwidth(up to 160 MHz)and weighted deconvolution to synthetically enlarge the angular aperture.We report unprecedented isotropic inplane resolution at the 9–17μm range and improved signal to noise ratio in phantoms and opaque 21-day-old Zebrafish.We find that MORSOM performance defines a new operational specification for optoacoustic mesoscopy of adult organisms,with possible applications in the developmental biology of adulthood and aging.

Photoacoustic imaging of prostate cancer

Photoacoustic imaging(PAI),also known as optoacoustic imaging,is a rapidly growing imaging modality with potential in medical diagnosis and therapy monitoring.This paper focuses on the techniques of prostate PAI and its potential applications in prostate cancer detection.Transurethral light delivery combined with transrectal ultrasound detection overcomes light scattering in the surrounding tissue and provides optimal photoacoustic signals while minimizing invasiveness.While label-free PAI based on endogenous contrast has promising potential for prostate cancer detection,exogenous contrast agents can further enhance the sensitivity and speci¯city of prostate cancer PAI.Further in vivo studies are required in order to achieve the translation of prostate PAI to clinical implementation.The minimal invasiveness,relatively low cost,high speci¯city and sensitivity,and real-time imaging capability are valuable advantages of PAI that may improve the current prostate cancer management in clinic.

PHOTOACOUSTIC GENERATION OF FOCUSED QUASI-UNIPOLAR PRESSURE PULSES

The photoacoustic effect was employed to generate short-duration quasi-unipolar acoustic pressure pulses in both planar and spherically focused geometries.In the focal region,the temporal profile of a pressure pulse can be approximated by the first derivative of the temporal profile near the front transducer surface,with a time-averaged value equal to zero.This approximation agreed with experimental results acquired from photoacoustic transducers with both rigid and free boundaries.For a free boundary,the acoustic pressure in the focal region is equal to the sum of a positive pressure that follows the spatial profile of the optical energy deposition in the medium and a negative pressure that follows the temporal profile of the laser pulse.

Photoacoustic detection of circulating melanoma cells in late stage patients

Melanoma is the deadliest skin cancer and is responsible for over 7000 deaths in the US annually.The spread of cancer,or metastasis,is responsible for these deaths,as secondary tumors interrupt normal organ function.Circulating tumor cells,or those cells that spread throughout the body from the primary tumor,are thought to be responsible for metastasis.We developed an optical method,photoacoustic flow cytometry,in order to detect and enumerate circulating melanoma cells(CMCs)from blood samples of patients.We tested the blood of StageⅣmelanoma patients to show the ability of the photoacoustic flow cytometer to detect these rare cells in blood.We then tested the system on archived blood samples from StageⅢmelanoma patients with known outcomes to determine if detection of CMCs can predict future metastasis.We detected between 0 and 66 CMCs in StageⅣpatients.For the StageⅢstudy,we found that of those samples with CMCs,two remained disease free and five developed metastasis.Of those without CMCs,six remained disease free and one developed metastasis.We believe that photoacoustic detection of CMCs provides valuable information for the prediction of metastasis and we postulate a system for more accurate prognosis.

Photoacoustic imaging principle and analysis of the images by MSOT

Photoacoustic imaging, also called optoacoustic tomography, is a non-destructive biomedical imaging technique which employs acoustic detection to image optical absorption contrast with high-resolution deep into scattering tissue. Photoacoustic imaging overcomes the limit of high light scattering in the tissue and realized in vivo high-resolution and high-contrast imaging in the deep tissue. Photoacoustic imaging technology has been rapid development in recent years and make constantly breakthrough from a technical level to the application level. This paper describes the basic principles of photoacoustic imaging technology and make an example analysis by multispectral optoacoustic tomography （MSOT）.

Through-needle all-optical ultrasound imaging in vivo: a preclinical swine study

High-frequency ultrasound imaging can provide exquisite visualizations of tissue to guide minimally invasive procedures.Here,we demonstrate that an all-optical ultrasound transducer,through which light guided by optical fibers is used to generate and receive ultrasound,is suitable for real-time invasive medical imaging in vivo.Broad-bandwidth ultrasound generation was achieved through the photoacoustic excitation of a multiwalled carbon nanotube-polydimethylsiloxane composite coating on the distal end of a 300-μm multi-mode optical fiber by a pulsed laser.The interrogation of a high-finesse Fabry–Pérot cavity on a single-mode optical fiber by a wavelength-tunable continuous-wave laser was applied for ultrasound reception.This transducer was integrated within a custom inner transseptal needle(diameter 1.08 mm;length 78 cm)that included a metallic septum to acoustically isolate the two optical fibers.The use of this needle within the beating heart of a pig provided unprecedented realtime views(50 Hz scan rate)of cardiac tissue(depth:2.5 cm;axial resolution:64μm)and revealed the critical anatomical structures required to safely perform a transseptal crossing:the right and left atrial walls,the right atrial appendage,and the limbus fossae ovalis.This new paradigm will allow ultrasound imaging to be integrated into a broad range of minimally invasive devices in different clinical contexts.

Enhanced light-matter interactions in dielectric nanostructures via machine-learning approach

A key concept underlying the specific functionalities of metasurfaces is the use of constituent components to shape the wavefront of the light on demand.Metasurfaces are versatile,novel platforms for manipulating the scattering,color,phase,or intensity of light.Currently,one of the typical approaches for designing a metasurface is to optimize one or two variables among a vast number of fixed parameters,such as various materials’properties and coupling effects,as well as the geometrical parameters.Ideally,this would require multidimensional space optimization through direct numerical simulations.Recently,an alternative,popular approach allows for reducing the computational cost significantly based on a deep-learning-assisted method.We utilize a deep-learning approach for obtaining high-quality factor(high-Q)resonances with desired characteristics,such as linewidth,amplitude,and spectral position.We exploit such high-Q resonances for enhancedlight–matter interaction in nonlinearoptical metasurfaces and optomechanical vibrations,simultaneously.We demonstrate that optimized metasurfaces achieve up to 400-fold enhancement of the third-harmonic generation;at the same time,they also contribute to 100-fold enhancement of the amplitude of optomechanical vibrations.This approach can be further used to realize structures with unconventional scattering responses.