A facile synthesis of novel self-assembled gold nanorods designed for near-infrared imaging

Molecular imaging techniques now allow recognition of early biochemical, physiological, and anatomical changes before manifestation of gross pathological changes. Photoacoustic imaging represents a novel non-ionizing detection technique that combines the advantages of optical and ultrasound imaging. Noninvasive photoacoustic tomography (PAT) imaging in combination with nanoparticle-based contrast agents show promise in improved detection and diagnosis of cardiovascular and cancer related diseases. In this report, a novel strategy is introduced to achieve self-assembled colloidal gold nanorods, which are constrained to the vasculature. Gold nanorods (2-4 nm) were incorporated into the core of self-assembled lipid-encapsulated nanoparticles (sGNR) (approximately 130 nm), providing more than hundreds of gold atoms per nanoparticle of 20% colloid suspension. The physico-chemical characterization in solution and anhydrous state with analytical techniques demonstrated that the particles were spherical and highly mono dispersed. In addition to the synthesis and characterization, sensitive near-infrared photoacoustic detection was impressively demonstrated in vitro.     

Ratiometric Photoacoustic Molecular Imaging for Methylmercury Detection in Living Subjects

Photoacoustic molecular imaging is an emerging and promising diagnostic tool for heavy metal ions detection. Methylmercury (MeHg⁺) is one of the most potent neurotoxins, which damages the brain and nervous system of human beings through fish consumption. The development of a selective and sensitive method for MeHg⁺ detection is highly desirable. In this Communication, we develope a chemoselective photoacoustic sensor (LP‐hCy7) composed of the liposome (LP) and MeHg⁺‐responsive near‐infrared (NIR) cyanine dye (hCy7) for MeHg⁺ detection within living subjects, such as zebrafish and mouse. The as‐prepared LP‐hCy7 nanoprobe displays unique dual‐shift NIR absorbance peaks and produces a normalized turn‐on response after the reaction of MeHg⁺ and hCy7 through a mercury‐promoted cyclization reaction. The absorbance intensities of LP‐hCy7 nanoprobe at 690 and 860 nm are decreased and increased, respectively. The ratiometric photoacoustic signal (PA860/PA690) is noticeably increased in the presence of MeHg⁺. These findings not only provide a ratiometric photoacoustic molecular imaging probe for the detection of metal ions in vivo, but also provides a tool for spectroscopic photoacoustic molecular imaging.     

Photoacoustic Probes for Molecular Detection: Recent Advances and Perspectives

Photoacoustic (PA) imaging (PAI) is a noninvasive and nonionizing biomedical imaging modality that combines the advantages of optical imaging and ultrasound imaging. Based on PAI, photoacoustic detection (PAD) is an emerging approach that is involved with the interaction between PA probes and analytes resulting in the changes of photoacoustic signals for molecular detection with rich contrast, high resolution, and deep tissue penetration. This Review focuses on the recent development of PA probes in PAD. The following contents will be discussed in detail: 1) the construction of PA probes; 2) the applications and mechanisms of PAD to different types of analytes, including microenvironments, small biomolecules, or metal ions; 3) the challenges and perspectives of PA probes in PAD.     

Polymer microring resonators for high-sensitivity and wideband photoacoustic imaging

Polymer microring resonators have been exploited for high-sensitivity and wideband photoacoustic imaging. To demonstrate high-sensitivity ultrasound detection, highfrequency photoacoustic imaging of a 49-μm-diameter black bead at an imaging depth of 5 mm was imaged photoacoustically using a synthetic 2-D array with 249 elements and a low laser fluence of 0.35 mJ/cm². A bandpass filter with a center frequency of 28 MHz and a bandwidth of 16 MHz was applied to all element data but without signal averaging, and a signalto- noise ratio of 16.4 dB was obtained. A wideband detector response is essential for imaging reconstruction of multiscale objects, e.g., various sizes of tissues, by using a range of characteristic acoustic wavelengths. A simulation of photoacoustic tomography of beads shows that objects with their boundaries characteristic of high spatial frequencies and the inner structure primarily of low spatial frequency components can be faithfully reconstructed using such a detector. Photoacoustic tomography experiments of 49- and 301-μm-diameter beads were presented. A high resolution of 12.5 μm was obtained. The boundary of a 301-μm bead was imaged clearly. The results demonstrated that the high sensitivity and broadband response of polymer microring resonators have potential for high resolution and high-fidelity photoacoustic imaging.     

Carbon nanotubes as photoacoustic molecular imaging agents in living mice

Photoacoustic imaging of living subjects offers higher spatial resolution and allows deeper tissues to be imaged compared with most optical imaging techniques. As many diseases do not exhibit a natural photoacoustic contrast, especially in their early stages, it is necessary to administer a photoacoustic contrast agent. A number of contrast agents for photoacoustic imaging have been suggested previously, but most were not shown to target a diseased site in living subjects. Here we show that single-walled carbon nanotubes conjugated with cyclic Arg-Gly-Asp (RGD) peptides can be used as a contrast agent for photoacoustic imaging of tumours. Intravenous administration of these targeted nanotubes to mice bearing tumours showed eight times greater photoacoustic signal in the tumour than mice injected with non-targeted nanotubes. These results were verified ex vivo using Raman microscopy. Photoacoustic imaging of targeted single-walled carbon nanotubes may contribute to non-invasive cancer imaging and monitoring of nanotherapeutics in living subjects.     

Three-dimensional photoacoustic imaging using a two-dimensional CMUT array

In this paper, we describe using a 2-D array of capacitive micromachined ultrasonic transducers (CMUTs) to perform 3-D photoacoustic and acoustic imaging. A tunable optical parametric oscillator laser system that generates nanosecond laser pulses was used to induce the photoacoustic signals. To demonstrate the feasibility of the system, 2 different phantoms were imaged. The first phantom consisted of alternating black and transparent fishing lines of 180 μm and 150 μm diameter, respectively. The second phantom comprised polyethylene tubes, embedded in chicken breast tissue, filled with liquids such as the dye indocyanine green, pig blood, and a mixture of the 2. The tubes were embedded at a depth of 0.8 cm inside the tissue and were at an overall distance of 1.8 cm from the CMUT array. Two-dimensional cross-sectional slices and 3-D volume rendered images of pulse-echo data as well as photoacoustic data are presented. The profile and beamwidths of the fishing line are analyzed and compared with a numerical simulation carried out using the Field II ultrasound simulation software. We investigated using a large aperture (64 x 64 element array) to perform photoacoustic and acoustic imaging by mechanically scanning a smaller CMUT array (16 x 16 elements). Two-dimensional transducer arrays overcome many of the limitations of a mechanically scanned system and enable volumetric imaging. Advantages of CMUT technology for photoacoustic imaging include the ease of integration with electronics, ability to fabricate large, fully populated 2-D arrays with arbitrary geometries, wide-bandwidth arrays and high-frequency arrays. A CMUT based photoacoustic system is proposed as a viable alternative to a piezoelectric transducer based photoacoustic systems.     

Two-dimensional photoacoustic imaging by use of Fourier-transform image reconstruction and a detector with an anisotropic response

Theoretical and experimental aspects of two-dimensional (2D) biomedical photoacoustic imaging have been investigated. A 2D Fourier-transform-based reconstruction algorithm that is significantly faster and produces fewer artifacts than simple radial backprojection methods is described. The image-reconstruction time for a 208 x 482 pixel image is approximately 1 s. For the practical implementation of 2D photoacoustic imaging, a rectangular detector geometry was used to obtain an anisotropic detection sensitivity in order to reject out-of-plane signals, thereby permitting a tomographic image slice to be reconstructed. This approach was investigated by the numerical modeling of the broadband directional response of a rectangular detector and imaging of various spatially calibrated absorbing targets immersed in a turbid phantom. The experimental setup was based on a Q-switched Nd:YAG excitation laser source and a mechanically line-scanned Fabry-Perot polymer-film ultrasound sensor. For a 800 microm x 200 microm rectangular detector, the reconstructed image slice thickness was 0.8 mm up to a vertical distance of z = 3.5 mm from the detector, increasing thereafter to 2 mm at z = 10 mm. Horizontal and vertical spatial resolutions within the reconstructed slice were approximately 200 and 60 microm, respectively.     

Gold nanoprisms as a hybrid <Emphasis Type="Italic">in vivo</Emphasis> cancer theranostic platform for <Emphasis Type="Italic">in situ</Emphasis> photoacoustic imaging,angiography, and localized hyperthermia

The development of high-resolution nanosized photoacoustic contrast agents is an exciting yet challenging technological advance. Herein, antibody (breast cancer-associated antigen 1 (Brcaa1) monoclonal antibody)- and peptide (RGD)-functionalized gold nanoprisms (AuNprs) were used as a combinatorial methodology for in situ photoacoustic imaging, angiography, and localized hyperthermia using orthotopic and subcutaneous murine gastric carcinoma models. RGD-conjugated PEGylated AuNprs are available for tumor angiography, and Brcaa1 monoclonal antibody-conjugated PEGylated AuNprs are used for targeting and for in situ imaging of gastric carcinoma in orthotopic tumor models. In situ photoacoustic imaging allowed for anatomical and functional imaging at the tumor site. In vivo tumor angiography imaging showed enhancement of the photoacoustic signal in a time-dependent manner. Furthermore, photoacoustic imaging demonstrated that tumor vessels were clearly damaged after localized hyperthermia. This is the first proof-of-concept using two AuNprs probes as highly sensitive contrasts and therapeutic agents for in situ tumor detection and inhibition. These smart antibody/peptide AuNprs can be used as an efficient nanotheranostic platform for in vivo tumor detection with high sensitivity, as well as for tumor targeting therapy, which, with a single-dose injection, results in tumor size reduction and increases mice survival after localized hyperthermia treatment.

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Performance of near-infrared dyes as effective contrast agents for breast cancer detection through simulation of photoacoustic imaging

ABSTRACT

Targeted photoacoustic imaging using exogenous contrast agents can potentially improve early detection of breast cancer, even at significant depths inside the breast. In this study, computer simulations were performed to compare the photoacoustic performance of 11 different near-infrared (NIR) dyes for detecting tumours deep inside the breast tissue. It was observed that the three high performing NIR dyes produced at least two-fold contrast enhancement of a spherical breast tumour embedded at 4?cm depth inside the breast than those of the corresponding endogenous contrast agents. These three selected dyes were employed to visualize small blood vessels deep inside the breast tissue. Although methylene blue provided the best contrast in visualizing tumour blood vessels at depths beyond 3?cm, considering other factors such as availability of suitable targeting agent, indocyanine green at 800?nm may be preferred over all other dyes for deep breast imaging applications.     

Four-micron period ion-implanted bubble test circuits

Packaged magnetic bubble test circuits made with 4-µm period ion-implanted circuits were operated over -55° to +110°C. The circuits used bidirectional transfer and nondestructive detection and were made on bismuth-containing magnetic garnet films. Passivated circuits that incorporated an improved transfer conductor design were operated on films with higher Gilbert damping parameters. Potential advantages to using films wih lower bubble aspect ratios for ion-implanted circuits are discussed. However nondestructive readout (NDRO) detection was not realized with these "flat" bubbles.     

Fabrication process for ion-implanted and Permalloy hybrid magneticbubble memory devices

A fabrication process for ion-implanted and Permalloy hybrid bubble memory devices has been developed. The mask patterns of polyimide (PIQ) for ion-implanted tracks are fabricated using a tri-level resist process where the top imaging resists are delineated by deep UV contact printing. The minimum feature of the PIQ pattern is 0.75 μm and can be controlled precisely. The sidewalls of PIQ patterns are smooth and vertical. At the junctions between ion-implanted and Permalloy tracks, tapered resist patterns are used as masks for implantation. Novolak-based resist is used and is reflowed thermally to obtain a tapered profile. Fabrication conditions, such as type of resist and baking temperature, were investigated to achieve good reproducibility. Tapered resist patterns are also used as masks for iron milling which reduces the thickness of garnet film in the area of the Permalloy tracks. This is necessary to adjust the operating bias field of Permalloy tracks to that of the ion-implanted tracks. A prototype of a 4-Mb memory device was fabricated, confirming the feasibility of the present process     

Detecting mineral content in turbid medium using nonlinear Raman imaging: feasibility study

Osteoporosis is a bone disease characterized by reduced mineral content with resulting changes in bone architecture, which in turn increases the risk of bone fracture. Raman spectroscopy has an intrinsic sensitivity to the chemical content of the bone, but its application to study bones in vivo is limited due to strong optical scattering in tissue. It has been proposed that Raman excitation with photoacoustic detection can successfully address the problem of chemically specific imaging in deep tissue. In this report, the principal possibility of photoacoustic imaging for detecting mineral content is evaluated.     

多光谱光声层析技术在肿瘤学中的应用进展

多光谱光声层析技术是一种新兴的光声成像技术,兼具光声断层扫描和多光谱成像的优点。该成像技术需要利用内源性和外源性光声成像对比剂进行成像。成像时,激光发射器发射多个波长的激光束照射组织,组织发生热弹性膨胀并产生超声波,将超声换能器接收的光声信号进行后处理,分解光谱信息并重建图像。目前,多光谱光声层析技术已广泛用于多种肿瘤的研究。文章着重介绍光声成像对比剂和多光谱光声层析技术的发展近况以及在临床转化中取得的研究进展。     

Targeted blue nanoparticles as photoacoustic contrast agent for brain tumor delineation

Distinguishing a tumor from non-neoplastic tissue is a challenging task during cancer surgery. Several attempts have been made to use visible or fluorescent agents to aid in the visualization of a tumor during surgery. We describe a novel method to delineate brain tumors, using a highly sensitive photoacoustic imaging technique that is enhanced by tumor-targeting blue nanoparticles serving as a contrast agent. Experiments on phantoms and on rat brains, ex vivo, demonstrate the high sensitivity of photoacoustic imaging in delineating tumors containing contrast agent at a concentration much lower than needed for visualization by the naked eye. The limit of detection of the system for the nanoparticles is about 0.77 μg/mL in water (equivalent to 0.84 μmol/L Coomassie Blue dye). The present exploratory study suggests that photoacoustic imaging, when used with strongly optical absorbing contrast agents, could facilitate cancer surgery intraoperatively by revealing the distribution and extent of the tumor.      

Image reconstruction for photoacoustic scanning of tissue structures

Photoacoustic signal generation can be used for a new medical tomographic technique. This makes it possible to image optically different structures, such as the (micro)vascular system in tissues, by use of a transducer array for the detection of laser-generated wide-bandwidth ultrasound. A time-domain delay-and-sum focused beam-forming technique is used to locate the photoacoustic sources in the sample. To characterize the transducer response, simulations have been performed for a wide variety of parameter values and have been verified experimentally. With these data the weight factors for the spectrally and temporally filtered sensor signals are determined in order to optimize the signal-to-noise ratio of the beam former. The imaging algorithm is investigated by simulations and experiments. With this algorithm, for what is to our knowledge the first time, the three-dimensional photoacoustic imaging of complex optically absorbing structures located in a highly diffuse medium is demonstrated. When 200-mum-diameter hydrophone elements are used, the depth resolution is better than 20 mum, and the lateral resolution is better than 200 mum, independent of the depth for our range of imaging (to ~6 mm). Reduction of the transducer diameters and adaptation of the weight factors, at the cost of some increase of the noise level, will further improve the lateral resolution. The synthetic aperture algorithm used has been shown to be suitable for the new technique of photoacoustic tissue scanning.     

Silica-coated gold nanorods as photoacoustic signal nanoamplifiers

Photoacoustic signal generation by metal nanoparticles relies on the efficient conversion of light to heat, its transfer to the environment, and the production of pressure transients. In this study we demonstrate that a dielectric shell has a strong influence on the amplitude of the generated photoacoustic signal and that silica-coated gold nanorods of the same optical density are capable of producing about 3-fold higher photoacoustic signals than nanorods without silica coating. Spectrophotometry measurements and finite difference time domain (FDTD) analysis of gold nanorods before and after silica coating showed only an insignificant change of the extinction and absorption cross sections, hence indicating that the enhancement is not attributable to changes in absorption cross section resulting from the silica coating. Several factors including the silica thickness, the gold/silica interface, and the surrounding solvent were varied to investigate their effect on the photoacoustic signal produced from silica-coated gold nanorods. The results suggest that the enhancement is caused by the reduction of the gold interfacial thermal resistance with the solvent due to the silica coating. The strong contrast enhancement in photoacoustic imaging, demonstrated using phantoms with silica-coated nanorods, shows that these hybrid particles acting as "photoacoustic nanoamplifiers" are high efficiency contrast agents for photoacoustic imaging or photoacoustic image-guided therapy.     

A Single Composition Architecture‐Based Nanoprobe for Ratiometric Photoacoustic Imaging of Glutathione (GSH) in Living Mice

As one of the reduction species, glutathione (GSH) plays a tremendous role in regulating the homeostasis of redox state in living body. Accurate imaging of GSH in vivo is highly desired to provide a real‐time visualization of physiological and pathological conditions while it is still a big challenge. Recently developed photoacoustic imaging (PAI) with high resolution and deep penetration characteristics is more promising for in vivo GSH detection. However, its application is dramatically limited by the difficult designation of photoacoustic probes with changeable near‐infrared (NIR)‐absorption under reductive activation. A cyanine derivative‐based activatable probe is developed for in vivo ratiometric PAI of GSH for the first time. The probe is structurally designed to output ratiometric signals toward GSH in NIR‐absorption region based on the cleavage of disulfide bond followed by a subsequent exchange between the secondary amine and sulfydryl group formed. Such a ratiometric manner provides high signal‐to‐noise imaging of blood vessels and their surrounding areas in tumor. Concomitantly, it also exhibits good specificity toward GSH over other thiols. Furthermore, the single composition architecture of the probe effectively overcomes the leakage issue compared with traditional multicomposition architecture‐based nanoprobe, thus enhancing the imaging accuracy and fidelity in living body.     

Non-destructive Imaging of Standard Cracks of Railway by Photoacoustic Piezoelectric Technology

The photoacoustic piezoelectric (PAPE) technique is an effective non-destructive testing technique for detecting defects in materials. In this paper, Chinese national standard railway cracks have been detected by thermal wave imaging based on the PAPE technique. First, the theory of the PAPE technique has been introduced and the corresponding imaging principle has been analyzed. Second, the corresponding experimental system has been setup, and the imaging tests have been carried out. Third, two kinds of standard cracks have been examined by the imaging system. The results show that thermal wave imaging based on the PAPE technique can effectively image and identify the cracks at different depths, which lays a foundation for practical application to the detection of rail cracks.     

Intravascular photoacoustic imaging using an IVUS imaging catheter

Catheter-based imaging of atherosclerosis with high resolution, albeit invasive, is extremely important for screening and characterization of vulnerable plaques. Currently, there is a need for an imaging technique capable of providing comprehensive morphological and functional information of plaques. In this paper, we present an intravascular photoacoustic imaging technique to characterize vulnerable plaques by using optical absorption contrast between normal tissue and atherosclerotic lesions. Specifically, we investigate the feasibility of obtaining intravascular photoacoustic (IVPA) images using a high-frequency intravascular ultrasound (IVUS) imaging catheter. Indeed, the combination of IVPA imaging with clinically available IVUS imaging may provide desired functional and morphological assessment of the plaque. The imaging studies were performed with tissue-mimicking arterial vessel phantoms and excised samples of rabbit artery. The results of our study suggest that catheter-based intravascular photoacoustic imaging is possible, and the combination of IVPA with IVUS has the potential to detect and differentiate atherosclerosis based on both the structure and composition of the plaque.     

Image reconstruction in intravascular photoacoustic imaging

Intravascular photoacoustic (IVPA) imaging is a technique for visualizing atherosclerotic plaques with differential composition. Unlike conventional photoacoustic tomography scanning, where the scanning device rotates around the subject, the scanning aperture in IVPA imaging is enclosed within the imaged object. The display of the intravascular structure is typically obtained by converting detected photoacoustic waves into Cartesian coordinates, which can produce images with severe artifacts. Because the acquired data are highly limited, there does not exist a stable reconstruction algorithm for such imaging geometry. The purpose of this work was to apply image reconstruction concepts to explore the feasibility and efficacy of image reconstruction algorithms in IVPA imaging using traditional analytical formulas, such as a filtered back-projection (FBP) and the lambda-tomography method. Although the closed-form formulas are not exact for the IVPA system, a general picture of and interface information about objects are provided. To improve the quality of the reconstructed image, the iterative expectation maximization and penalized least-squares methods were adopted to minimize the difference between the measured signals and those generated by a reconstructed image. In this work, we considered both the ideal point detector and the acoustic transducers with finite- size aperture. The transducer effects including the spatial response of aperture and acoustoelectrical impulse responses were incorporated in the system matrix to reduce the aroused distortion in the IVPA reconstruction. Computer simulations and experiments were carried out to validate the methods. The applicability and the limitation of the reconstruction method were also discussed.