Numerical study of tunable enhanced chirality in multilayer stack achiral phase-change metamaterials.

We numerically demonstrate a multiband circular dichroism (CD) by tilting achiral metamaterials (MMs) composed of an elliptical nanoholes array (ENA) penetrating through metal/ phase-change material (PCM) /metal multilayer stack, with respect to the incident light. The CD spectrum can be actively tuned across a wide range from the near-infrared (NIR) to mid-infrared (MIR) regime by transiting the state of the PCM (Ge2Sb2Te5) from amorphous to crystalline. Thus, it can switch on/off a multiband chiroptical response in the infrared region. Our simulation also elucidates that the achiral multilayer stack MMs, which have strong magnetic resonances, can enhance the optical chirality inside the elliptical apertures for both amorphous and crystalline states. The switching of the enhanced chirality may pave the way to manipulate electromagnetic waves, such as tunable circular polarizers, chiroptical spectroscopy, and chiral biosensors.

Tuning of giant 2D-chiroptical response using achiral metasurface integrated with graphene.

Tuning the chiroptical response of a molecule is crucial for detecting the material's chirality. Here, we demonstrate a pronounced circular conversion dichroism (CCD) by using an achiral metasurface (AMS) which is composed of a rectangular reflectarray of Au squares separated from a continuous Au film by a dielectric interlayer. This extrinsically 2D chirality originates from the mutual orientation between the AMS and oblique incident wave. The AMS is further incorporated with graphene to tune the CCD spectra in the mid-infrared (MIR) region by electrically modulating the graphene's Fermi level. This approach offers a high fabrication tolerance and will be a promising candidate for controlling electromagnetic (EM) waves in the MIR region from 1500 to 3000 nm.

Laser-induced cavitation in nanoemulsion with gold nanospheres for blood clot disruption: in vitro results.

Optically activated cavitation in a nanoemulsion contrast agent is proposed for therapeutic applications. With a 56°C boiling point perfluorohexane core and highly absorptive gold nanospheres at the oil-water interface, cavitation nuclei in the core can be efficiently induced with a laser fluence below medical safety limits (70 mJ/cm2 at 1064 nm). This agent is also sensitive to ultrasound (US) exposure and can induce inertial cavitation at a pressure within the medical diagnostic range. Images from a high-speed camera demonstrate bubble formation in these nanoemulsions. The potential of using this contrast agent for blood clot disruption is demonstrated in an in vitro study. The possibility of simultaneous laser and US excitation to reduce the cavitation threshold for therapeutic applications is also discussed.

Emerging applications of conjugated polymers in molecular imaging.

In recent years, conjugated polymers have attracted considerable attention from the imaging community as a new class of contrast agent due to their intriguing structural, chemical, and optical properties. Their size and emission wavelength tunability, brightness, photostability, and low toxicity have been demonstrated in a wide range of in vitro sensing and cellular imaging applications, and have just begun to show impact in in vivo settings. In this Perspective, we summarize recent advances in engineering conjugated polymers as imaging contrast agents, their emerging applications in molecular imaging (referred to as in vivo uses in this paper), as well as our perspectives on future research.

Subband photoacoustic imaging for contrast improvement.

Contrast in photoacoustic imaging is primarily determined by optical absorption. This paper proposes a subband imaging method to further enhance the image contrast. The method is based on media with different absorptions generating acoustic waves with different frequency contents. Generally, assuming all other conditions remain the same, a high-absorption medium generates acoustic waves with higher frequency components, and hence the imaging contrast can be enhanced by appropriate selection of the spectral subbands. This study employed both finite-difference, time-domain-based simulations and phantom imaging. The numerical results show that the peak frequencies of the signals for objects with absorption coefficients of 1 and 100 cmM(-1) were 2.4 and 7.8 MHz, respectively. Imaging an agar-based phantom further demonstrated that the contrast between two objects with absorption coefficients of 5.01 and 41.75 cm(-1) can be improved by 4-10 dB when the frequency band was changed from 0-7 to 7-14 MHz. Finally, a method to further enhance the contrast based on optimal weighting is also presented. The proposed method is of particular interest in photoacoustic molecular imaging.

In vivo photoacoustic molecular imaging with simultaneous multiple selective targeting using antibody-conjugated gold nanorods.

The use of gold nanorods for photoacoustic molecular imaging with simultaneous multiple targeting is reported. Multiple targeting is done by utilizing the tunable optical absorption property of gold nanorods. This technique allows multiple molecular signatures to be obtained by simply switching laser wavelength. HER2 and EGFR were chosen as the primary target molecules for examining two cancer cells, OECM1 and Cal27. Both in vitro and in vivo mouse model imaging experiments were performed, with contrast enhancement of up to 10 dB and 3.5 dB, respectively. The potential in improving cancer diagnosis is demonstrated.

A reprogrammable multifunctional chalcogenide guided-wave lens.

The transformation optics (TO) technique, which establishes an equivalence between a curved space and a spatial distribution of inhomogeneous constitutive parameters, has enabled an extraordinary paradigm for manipulating wave propagation. However, extreme constitutive parameters, as well as a static nature, inherently limit the simultaneous achievement of broadband performance, ultrafast reconfigurability and versatile reprogrammable functions. Here, we integrate the TO technique with an active phase-change chalcogenide to achieve a reconfigurable multi-mode guided-wave lens. The lens is made of a Rinehart-shaped curved waveguide with an effective refractive index gradient profile through partially crystallizing Ge2Sb2Te5. Upon changing the bias time of the external voltage imparted to the Ge2Sb2Te5 segments, the refractive index gradient profile can be tuned with a transformative platform for various functions for visible light. The electrically reprogrammable multi-mode guided-wave lens is capable of dynamically acquiring various functionalities with an ultrafast response time. Our findings may offer a significant step forward by providing a universal method to obtain ultrafast and highly versatile guided-wave manipulation, such as in Einstein rings, cloaking, Maxwell fish-eye lenses and Luneburg lenses.

Nanorod-based flow estimation using a high-frame-rate photoacoustic imaging system.

A quantitative flow measurement method that utilizes a sequence of photoacoustic images is described. The method is based on the use of gold nanorods as a contrast agent for photoacoustic imaging. The peak optical absorption wavelength of a gold nanorod depends on its aspect ratio, which can be altered by laser irradiation (we establish a wash-in flow estimation method of this process). The concentration of nanorods with a particular aspect ratio inside a region of interest is affected by both laser-induced shape changes and replenishment of nanorods at a rate determined by the flow velocity. In this study, the concentration is monitored using a custom-designed, high-frame-rate photoacoustic imaging system. This imaging system consists of fiber bundles for wide area laser irradiation, a laser ultrasonic transducer array, and an ultrasound front-end subsystem that allows acoustic data to be acquired simultaneously from 64 transducer elements. Currently, the frame rate of this system is limited by the pulse-repetition frequency of the laser (i.e., 15 Hz). With this system, experimental results from a chicken breast tissue show that flow velocities from 0.125 to 2 mms can be measured with an average error of 31.3%.

Photoacoustic flow measurements based on wash-in analysis of gold nanorods.

In this study, photoacoustic flow measurement methods based on wash-in analysis are presented. These methods use the rod-to-sphere shape transformations of gold nanorods induced by pulsed-laser irradiation. Due to the shape dependence of the optical absorption of the gold nanorods, these shape transitions are associated with a change in the peak optical absorption wavelength. Pulsed-laser irradiation at the wavelength corresponding to the peak optical absorption of the original gold nanorods allows the particles that undergo shape changes to be viewed as "being destructed" by the laser irradiation at that wavelength, hence, flow information can be derived from the change in ultrasound intensity that is directly related to the wash-in rate of the gold nanorods and the laser intensity. Two flow estimation methods based on the wash-in analysis are described. The first method first applies high-energy laser pulses that induce shape changes in all the nanorods. A series of low-energy pulses then are applied to monitor the acoustic signal change as new nanorods flow into the region of interest. The second method uses single-energy laser pulses such that the "destruction" and "detection" are performed simultaneously. The simulation results show that it is valid to fit the time-intensity curves by exponential models. To demonstrate the validity of the proposed methods, an Nd:YAG pulsed laser operating at 1064 nm was used for optical irradiation, and a 1-MHz ultrasonic transducer was used for acoustic detection. Gold nanorods with a peak optical absorption at 1018 nm and a concentration of 0.26 nM were used to estimate flow velocities ranging from 0.35 to 2.83 mm/s. The linear regression results show that the correlation coefficients between the measured velocities and the true values are close to unity (> or = 0.94), thus demonstrating the feasibility of the proposed photoacoustic techniques for relative flow estimation.

Photoacoustic imaging of multiple targets using gold nanorods.

Photoacoustic (PA) imaging has been used mainly for anatomical and functional imaging. Although functionalized nanoparticles also have been developed for PA molecular imaging, only single targeting has been demonstrated. In this study, PA imaging of multiple targets using gold nanorods is demonstrated experimentally using HER2 and CXCR4 as target molecules. The two corresponding monoclonal antibodies were conjugated to two types of gold nanorod with different aspect ratios. Gold nanorods with mean aspect ratios of 5.9 and 3.7 exhibited peak optical absorptions at 1000 and 785 nm, respectively. Appropriate selection of laser irradiation wavelength enhances PA signals by 7-12 dB and allows signals from gold nanorods corresponding to specific bindings to be distinguished. This approach potentially allows the expression levels of different oncogenes of cancer cells to be revealed simultaneously.

Photoacoustic flow measurements with gold nanoparticles.

The hypothesis that quantitative blood flow measurements are feasible with the time-intensity based method in photoacoustic imaging using gold nanoparticles as contrast agent is experimentally tested. The in vitro results show good linearity between the measurements and the theory, thus suggesting the potential of relative photoacoustic flow measurements with gold nanoparticles.

A 1 kHz A-scan rate pump-probe laser-ultrasound system for robust inspection of composites.

We recently built a fiber-optic laser-ultrasound (LU) scanner for nondestructive evaluation (NDE) of aircraft composites and demonstrated its greatly improved sensitivity and stability compared with current noncontact systems. It is also very attractive in terms of cost, stability to environmental noise and surface roughness, simplicity in adjustment, footprint, and flexibility. A new type of a balanced fiber-optic Sagnac interferometer is a key component of this all-optical LU pump-probe system. Very high A-scan rates can be achieved because no reference arm or stabilization feedback are needed. Here, we demonstrate LU system performance at 1000 A-scans/s combined with a fast 2-D translator operating at a scanning speed of 100 mm/s with a peak acceleration of 10 m/s(2) in both lateral directions to produce parallel B-scans at high rates. The fast scanning strategy is described in detail. The sensitivity of this system, in terms of noise equivalent pressure, was further improved to be only 8.3 dB above the Nyquist thermal noise limit. To our knowledge, this is the best reported sensitivity for a noncontact ultrasonic detector of this dimension used to inspect aircraft composites.

Real-time interleaved photoacoustic/ultrasound (PAUS) imaging for interventional procedure guidance.

Ultrasound-guided photoacoustic imaging has shown great potential for many clinical applications including vascular visualization, detection of nanoprobes sensing molecular profiles, and guidance of interventional procedures. However, bulky and costly lasers are usually required to provide sufficient pulse energies for deep imaging. The low pulse repetition rate also limits potential real-time applications of integrated photoacoustic/ultrasound (PAUS) imaging. With a compact and low-cost laser operating at a kHz repetition rate, we aim to integrate photoacoustics (PA) into a commercial ultrasound (US) machine utilizing an interleaved scanning approach for clinical translation, with imaging depth up to a few centimeters and frame rates > 30 Hz. Multiple PA sub-frames are formed by scanning laser firings covering a large scan region with a rotating galvo mirror, and then combined into a final frame. Ultrasound pulse-echo beams are interleaved between laser firings/PA receives. The approach was implemented with a diode-pumped laser, a commercial US scanner, and a linear array transducer. Insertion of an 18-gauge needle into a piece of chicken tissue, with subsequent injection of an absorptive agent into the tissue, was imaged with an integrated PAUS frame rate of 30 Hz, covering a 2.8 cm × 2.8 cm imaging plane. Given this real-time image rate and high contrast (> 40 dB at more than 1-cm depth in the PA image), we have demonstrated that this approach is potentially attractive for clinical procedure guidance.

Optimization of the laser irradiation pattern in a high frame rate integrated photoacoustic / ultrasound (PAUS) imaging system.

To integrate real-time photoacoustics (PA) into ultrasound (US) scanners and accelerate clinical translation of combined PAUS imaging, we previously developed a system using a portable, low-cost, low pulse energy, high-repetition rate laser (~1kHz) with a 1D galvo-mirror for rapid laser beam scanning over the imaging area. However, the frame rate and pulse energy are limited because of regulations on the radiance (1 W/cm2). Therefore, a laser scan scheme needs to be optimized to provide high frame rate within this safety limit. In addition, the laser light should be evenly distributed to minimize any artifacts caused by the scanning approach. In this paper, we calculated the laser light distribution using 3D Monte Carlo simulation and further developed the system to scan the laser beam in elevation as well as laterally using a 2-dimensional galvo-mirror scanner to achieve higher frame rates within the radiance safety limit. Insertion of a needle into chicken breast tissue was used to demonstrate our optimized scan scheme.

Cyclic Magnetomotive Photoacoustic/Ultrasound Imaging.

Magnetomotive photoacoustic/ultrasound imaging has shown superior specificity in visualizing targeted objects at cellular and molecular levels. By detecting magnet-induced displacements, magnetic-particle-targeted objects can be differentiated from background signals insensitive to the magnetic field. Unfortunately, background physiologic motion interferes during measurement, such as cardiac-induced motion and respiration, greatly reducing the robustness of the technique. In this paper, we propose cyclic magnetomotive imaging with narrowband magnetic excitation. By synchronizing magnetic motion with the excitations, targeted objects moving coherently can be distinguished from background static signals and signals moving incoherently. HeLa cells targeted with magnetic nanoparticle-polymer core-shell particles were used as the targets for an initial test. A linear ultrasound array was interfaced with a commercial scanner to acquire a photoacoustic/ultrasound image sequence (maximum 1000 frames per second) during multi-cycle magnetic excitation (0.5 - 40 Hz frequency range) with an electromagnet. An image mask defined by a threshold on the displacement-coherence map was applied to the original images for background suppression. The results show that contrast was increased by more than 60 dB in an in-vitro experiment with the tagged cells fixed in a polyvinyl-alcohol gel and sandwiched between porcine liver tissues. Using a single sided system, cells injected subcutaneously on the back of a mouse were successfully differentiated from the background, with less than 20 µm coherent magnetic induced displacements isolated from millimetric background breathing motion. These results demonstrate the technique's motion robustness for highly sensitive and specific diagnosis.

Magneto-optical nanoparticles for cyclic magnetomotive photoacoustic imaging.

Photoacoustic imaging has emerged as a highly promising tool to visualize molecular events with deep tissue penetration. Like most other modalities, however, image contrast under in vivo conditions is far from optimal due to background signals from tissue. Using iron oxide-gold core-shell nanoparticles, we have previously demonstrated the concept of magnetomotive photoacoustic (mmPA) imaging, which is capable of dramatically reducing the influence of background signals and producing high-contrast molecular images. Here, we report two significant advances toward clinical translation of this technology. First, we introduce a new class of compact, uniform, magneto-optically coupled core-shell nanoparticles, prepared through localized copolymerization of polypyrrole (PPy) on an iron oxide nanoparticle surface. The resulting iron oxide-PPy nanoparticles feature high colloidal stability and solve the photoinstability and small-scale synthesis problems previously encountered by the gold coating approach. In parallel, we have developed a new generation of mmPA featuring cyclic magnetic motion and ultrasound speckle tracking (USST), whose imaging capture frame rate is several hundred times faster than the photoacoustic speckle tracking (PAST) method we demonstrated previously. These advances enable robust artifact elimination caused by physiologic motions and demonstrate the application of the mmPA technology for in vivo sensitive tumor imaging.

Real-time integrated photoacoustic and ultrasound (PAUS) imaging system to guide interventional procedures: ex vivo study.

Because of depth-dependent light attenuation, bulky, low-repetition-rate lasers are usually used in most photoacoustic (PA) systems to provide sufficient pulse energies to image at depth within the body. However, integrating these lasers with real-time clinical ultrasound (US) scanners has been problematic because of their size and cost. In this paper, an integrated PA/US (PAUS) imaging system is presented operating at frame rates >30 Hz. By employing a portable, low-cost, low-pulse-energy (~2 mJ/pulse), high-repetition-rate (~1 kHz), 1053-nm laser, and a rotating galvo-mirror system enabling rapid laser beam scanning over the imaging area, the approach is demonstrated for potential applications requiring a few centimeters of penetration. In particular, we demonstrate here real-time (30 Hz frame rate) imaging (by combining multiple single-shot sub-images covering the scan region) of an 18-gauge needle inserted into a piece of chicken breast with subsequent delivery of an absorptive agent at more than 1-cm depth to mimic PAUS guidance of an interventional procedure. A signal-to-noise ratio of more than 35 dB is obtained for the needle in an imaging area 2.8 × 2.8 cm (depth × lateral). Higher frame rate operation is envisioned with an optimized scanning scheme.

Sono-photoacoustic imaging of gold nanoemulsions: Part I. Exposure thresholds.

Integrating high contrast bubbles from ultrasound imaging with plasmonic absorbers from photoacoustic imaging is investigated. Nanoemulsion beads coated with gold nanopsheres (NEB-GNS) are excited with simultaneous light (transient heat at the GNS's) and ultrasound (rarefactional pressure) resulting in a phase transition achievable under different scenarios, enhancing laser-induced acoustic signals and enabling specific detection of nanoprobes at lower concentration. An automated platform allowed dual parameter scans of both pressure and laser fluence while recording broadband acoustic signals. Two types of NEB-GNS and individual GNS were investigated and showed the great potential of this technique to enhance photoacoustic/acoustic signals. The NEB-GNS size distribution influences vaporization thresholds which can be reached at both permissible ultrasound and light exposures at deep penetration and at low concentrations of targets. This technique, called sono-photoacoustics, has great potential for targeted molecular imaging and therapy using compact nanoprobes with potentially high-penetrability into tissue.

Sono-photoacoustic imaging of gold nanoemulsions: Part II. Real time imaging.

Photoacoustic (PA) imaging using exogenous agents can be limited by degraded specificity due to strong background signals. This paper introduces a technique called sono-photoacoustics (SPA) applied to perfluorohexane nanodroplets coated with gold nanospheres. Pulsed laser and ultrasound (US) excitations are applied simultaneously to the contrast agent to induce a phase-transition ultimately creating a transient microbubble. The US field present during the phase transition combined with the large thermal expansion of the bubble leads to 20-30 dB signal enhancement. Aqueous solutions and phantoms with very low concentrations of this agent were probed using pulsed laser radiation at diagnostic exposures and a conventional US array used both for excitation and imaging. Contrast specificity of the agent was demonstrated with a coherent differential scheme to suppress US and linear PA background signals. SPA shows great potential for molecular imaging with ultrasensitive detection of targeted gold coated nanoemulsions and cavitation-assisted theranostic approaches.