Jinjun Xia

Nonlinear contrast enhancement in photoacoustic molecular imaging with gold nanosphere encapsulated nanoemulsions

A composite contrast agent, a nanoemulsion bead with assembled gold nanospheres at the interface, is proposed to improve the specific contrast of photoacoustic molecular imaging. A phase transition in the beads core is induced by absorption of a nanosecond laser pulse with a fairly low laser fluence (∼3.5 mJ/cm2), creating a transient microbubble through dramatically enhanced thermal expansion. This generates nonlinear photoacoustic signals with more than 10 times larger amplitude compared to that of a linear agent with the same optical absorption. By applying a differential scheme similar to ultrasound pulse inversion, more than 40 dB contrast enhancement is demonstrated with suppression of background signals.

Trapping and Photoacoustic Detection of CTCs at the Single Cell per Milliliter Level with Magneto‐Optical Coupled Nanoparticles

Circulating tumor cells (CTCs) have been reported to correlate most closely with cancer development, and can serve as an important marker for metastatic malignancy, tumor recurrence, and prediction of prognosis and therapeutic effi cacy. Detecting and quantifying CTCs, however, have proven to be challenging due to their low abundance in blood. Based on magneto-optical coupled nanoprobes (made of gold nanorod and iron oxide nanoparticles) and photoacoustic (PA) imaging, we report the development of an enabling technology that can detect CTCs at single cell/mL level. Remarkably, at this low cell concentration, approximately 67% of circulating tumor cells can be captured and imaged with just one pass through the magnetic trapping zone. Compared to the conventional in vitro assays, this technology offers signifi cantly improved sensitivity, because it is inherently compatible with large sample volumes. Compared to more advanced in vivo CTC detection methods, this technology can solve the low throughput problem of optical imaging, and streamline the photoacoustic imaging process by combining magnetic enrichment and digital readout into a single step. Most cancer deaths are caused by metastasis, a process

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 GNSs) 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.

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.

NDT of fiber-reinforced composites with a new fiber-optic pump-probe laser-ultrasound system.

Laser-ultrasonics is an attractive and powerful tool for the non-destructive testing and evaluation (NDT&E) of composite materials. Current systems for non-contact detection of ultrasound have relatively low sensitivity compared to contact peizotransducers. They are also expensive, difficult to adjust, and strongly influenced by environmental noise. Moreover, laser-ultrasound (LU) systems typically launch only about 50 firings per second, much slower than the kHz level pulse repetition rate of conventional systems. As demonstrated here, most of these drawbacks can be eliminated by combining a new generation of compact, inexpensive, high repetition rate nanosecond fiber lasers with new developments in fiber telecommunication optics and an optimally designed balanced probe beam detector. In particular, a modified fiber-optic balanced Sagnac interferometer is presented as part of a LU pump–probe system for NDT&E of aircraft composites. The performance of the all-optical system is demonstrated for a number of composite samples with different types and locations of inclusions.

A new fiber-optic non-contact compact laser-ultrasound scanner for fast non-destructive testing and evaluation of aircraft composites

Laser ultrasonic (LU) inspection represents an attractive, non-contact method to evaluate composite materials. Current non-contact systems, however, have relatively low sensitivity compared to contact piezoelectric detection. They are also difficult to adjust, very expensive, and strongly influenced by environmental noise. Here, we demonstrate that most of these drawbacks can be eliminated by combining a new generation of compact, inexpensive fiber lasers with new developments in fiber telecommunication optics and an optimally designed balanced probe scheme. In particular, a new type of a balanced fiber-optic Sagnac interferometer is presented as part of an all-optical LU pump-probe system for non-destructive testing and evaluation of aircraft composites. The performance of the LU system is demonstrated on a composite sample with known defects. Wide-band ultrasound probe signals are generated directly at the sample surface with a pulsed fiber laser delivering nanosecond laser pulses at a repetition rate up to 76 kHz rate with a pulse energy of 0.6 mJ. A balanced fiber-optic Sagnac interferometer is employed to detect pressure signals at the same point on the composite surface. A- and B-scans obtained with the Sagnac interferometer are compared to those made with a contact wide-band polyvinylidene fluoride transducer.

Magnetomotive photoacoustic imaging: in vitro studies of magnetic trapping with simultaneous photoacoustic detection of rare circulating tumor cells.

Photoacoustic (PA) imaging has been demonstrated to be a promising modality in molecular imaging for detection of nanoparticle-targeted diseased cells or tissues. However, intrinsic absorbers, such as blood, produce strong PA background signals that severely degrade the detection sensitivity and specificity of targeted objects. Magnetomotive photoacoustic (mmPA) imaging, a newly developed molecular imaging modality, introduced dynamic manipulation into traditional PA imaging. Unlike conventional PA imaging, magnetomotive manipulation with simultaneous ultrasound/PA imaging of agents incorporating magnetic nanoparticles enables direct visualization of the signal generating object and can dramatically reduce background signals from strong optical absorbers. This paper briefly reviews recent developments in mmPA imaging, including uses of composite contrast agent, design of magnet system, and data processing for motion filtering. The use of mmPA imaging in detecting rare circulating tumor cells in blood vessels, which remains a big challenge for real-time in vivo examination using current methodologies, was also addressed.

Trapping and dynamic manipulation of polystyrene beads mimicking circulating tumor cells using targeted magnetic/photoacoustic contrast agents

Abstract. Results on magnetically trapping and manipulating micro-scale beads circulating in a flow field mimicking metastatic cancer cells in human peripheral vessels are presented. Composite contrast agents combining magneto-sensitive nanospheres and highly optical absorptive gold nanorods were conjugated to micro-scale polystyrene beads. To efficiently trap the targeted objects in a fast stream, a dual magnet system consisting of two flat magnets to magnetize (polarize) the contrast agent and an array of cone magnets producing a sharp gradient field to trap the magnetized contrast agent was designed and constructed. A water-ink solution with an optical absorption coefficient of 10  cm−1 was used to mimic the optical absorption of blood. Magnetomotive photoacoustic imaging helped visualize bead trapping, dynamic manipulation of trapped beads in a flow field, and the subtraction of stationary background signals insensitive to the magnetic field. The results show that trafficking micro-scale objects can be effectively trapped in a stream with a flow rate up to 12  ml/min and the background can be significantly (greater than 15 dB) suppressed. It makes the proposed method very promising for sensitive detection of rare circulating tumor cells within high flow vessels with a highly absorptive optical background.

Suppression of background signal in magnetomotive photoacoustic imaging of magnetic microspheres mimicking targeted cells

Contrast-enhanced photoacoustic (PA) imaging has been proposed to identify circulating metastatic cancer cells magnetically trapped in the vasculature. However, its sensitivity is limited by the presence of a strong blood-background signal. This technique can be further improved by the significant suppression of blood background. In the phantom study presented here, significant background suppression is demonstrated with magnetomotive photoacoustic imaging. Magnetic particles with a mean diameter of 10 μm were integrated (concentration of 0.05 mg/ml) into an ink-water solution with an optical absorption coefficient of 5 cm(-1) to mimic cells targeted with magnetic nanoparticles and magnetically trapped in the human vasculature. Two mechanically moveable permanent magnets were used to accumulate microparticles in the investigated solution and manipulate them within a thin, 1.6-mm-diameter Teflon tube mimicking a blood vessel. Our results clearly indicate that the undesirable background can be effectively suppressed using the difference of PA images corresponding to different locations of accumulated particles.