Edward Z. Zhang

Backward-mode multiwavelength photoacoustic scanner using a planar Fabry-Perot polymer film ultrasound sensor for high-resolution three-dimensional imaging of biological tissues

A multiwavelength backward-mode planar photoacoustic scanner for 3D imaging of soft tissues to depths of several millimeters with a spatial resolution in the tens to hundreds of micrometers range is described. The system comprises a tunable optical parametric oscillator laser system that provides nanosecond laser pulses between 600 and 1200 nm for generating the photoacoustic signals and an optical ultrasound mapping system based upon a Fabry-Perot polymer film sensor for detecting them. The system enables photoacoustic signals to be mapped in 2D over a 50 mm diameter aperture in steps of 10 microm with an optically defined element size of 64 microm. Two sensors were used, one with a 22 microm thick polymer film spacer and the other with a 38 mum thick spacer providing -3 dB acoustic bandwidths of 39 and 22 MHz, respectively. The measured noise equivalent pressure of the 38 microm sensor was 0.21 kPa over a 20 MHz measurement bandwidth. The instrument line-spread function (LSF) was measured as a function of position and the minimum lateral and vertical LSFs found to be 38 and 15 microm, respectively. To demonstrate the ability of the system to provide high-resolution 3D images, a range of absorbing objects were imaged. Among these was a blood vessel phantom that comprised a network of blood filled tubes of diameters ranging from 62 to 300 microm immersed in an optically scattering liquid. In addition, to demonstrate the applicability of the system to spectroscopic imaging, a phantom comprising tubes filled with dyes of different spectral characteristics was imaged at a range of wavelengths. It is considered that this type of instrument may provide a practicable alternative to piezoelectric-based photoacoustic systems for high-resolution structural and functional imaging of the skin microvasculature and other superficial structures.

In vivo high-resolution 3D photoacoustic imaging of superficial vascular anatomy

The application of a photoacoustic imaging instrument based upon a Fabry-Perot polymer film ultrasound sensor to imaging the superficial vasculature is described. This approach provides a backward mode-sensing configuration that has the potential to overcome the limitations of current piezoelectric based detection systems used in superficial photoacoustic imaging. The system has been evaluated by obtaining non-invasive images of the vasculature in human and mouse skin as well as mouse models of human colorectal tumours. These studies showed that the system can provide high-resolution 3D images of vascular structures to depths of up to 5 mm. It is considered that this type of instrument may find a role in the clinical assessment of conditions characterized by changes in the vasculature such as skin tumours and superficial soft tissue damage due to burns, wounds or ulceration. It may also find application in the characterization of small animal cancer models where it is important to follow the tumour vasculature over time in order to study its development and/or response to therapy.

In vivo preclinical photoacoustic imaging of tumor vasculature development and therapy

The use of a novel all-optical photoacoustic scanner for imaging the development of tumor vasculature and its response to a therapeutic vascular disrupting agent is described. The scanner employs a Fabry-Perot polymer film ultrasound sensor for mapping the photoacoustic waves and an image reconstruction algorithm based upon attenuation-compensated acoustic time reversal. The system was used to noninvasively image human colorectal tumor xenografts implanted subcutaneously in mice. Label-free three-dimensional in vivo images of whole tumors to depths of almost 10 mm with sub-100-micron spatial resolution were acquired in a longitudinal manner. This enabled the development of tumor-related vascular features, such as vessel tortuosity, feeding vessel recruitment, and necrosis to be visualized over time. The system was also used to study the temporal evolution of the response of the tumor vasculature following the administration of a therapeutic vascular disrupting agent (OXi4503). This revealed the well-known destruction and recovery phases associated with this agent. These studies illustrate the broader potential of this technology as an imaging tool for the preclinical and clinical study of tumors and other pathologies characterized by changes in the vasculature.

Photoacoustic tomography in absorbing acoustic media using time reversal

The reconstruction of photoacoustic images typically neglects the effect of acoustic absorption on the measured time domain signals. Here, a method to compensate for acoustic absorption in photoacoustic tomography is described. The approach is based on time-reversal image reconstruction and an absorbing equation of state which separately accounts for acoustic absorption and dispersion following a frequency power law. Absorption compensation in the inverse problem is achieved by reversing the absorption proportionality coefficient in sign but leaving the equivalent dispersion parameter unchanged. The reconstruction is regularized by filtering the absorption and dispersion terms in the spatial frequency domain using a Tukey window. This maintains the correct frequency dependence of these parameters within the filter pass band. The method is valid in one, two and three dimensions, and for arbitrary power law absorption parameters. The approach is verified through several numerical experiments. The reconstruction of a carbon fibre phantom and the vasculature in the abdomen of a mouse are also presented. When absorption compensation is included, a general improvement in the image magnitude and resolution is seen, particularly for deeper features.

A Fabry–Pérot fiber-optic ultrasonic hydrophone for the simultaneous measurement of temperature and acoustic pressure

A dual sensing fiber-optic hydrophone that can make simultaneous measurements of acoustic pressure and temperature at the same location has been developed for characterizing ultrasound fields and ultrasound-induced heating. The transduction mechanism is based on the detection of acoustically- and thermally-induced thickness changes in a polymer film Fabry-Perot interferometer deposited at the tip of a single mode optical fiber. The sensor provides a peak noise-equivalent pressure of 15 kPa (at 5 MHz, over a 20 MHz measurement bandwidth), an acoustic bandwidth of 50 MHz, and an optically defined element size of 10 microm. As well as measuring acoustic pressure, temperature changes up to 70 degrees C can be measured, with a resolution of 0.34 degrees C. To evaluate the thermal measurement capability of the sensor, measurements were made at the focus of a high-intensity focused ultrasound (HIFU) field in a tissue mimicking phantom. These showed that the sensor is not susceptible to viscous heating, is able to withstand high intensity fields, and can simultaneously acquire acoustic waveforms while monitoring induced temperature rises. These attributes, along with flexibility, small physical size (OD approximately 150 microm), immunity to Electro-Magnetic Interference (EMI), and low sensor cost, suggest that this type of hydrophone may provide a practical alternative to piezoelectric based hydrophones.

Multimodal photoacoustic and optical coherence tomography scanner using an all optical detection scheme for 3D morphological skin imaging

A noninvasive, multimodal photoacoustic and optical coherence tomography (PAT/OCT) scanner for three-dimensional in vivo (3D) skin imaging is described. The system employs an integrated, all optical detection scheme for both modalities in backward mode utilizing a shared 2D optical scanner with a field-of-view of ~13 × 13 mm2. The photoacoustic waves were detected using a Fabry Perot polymer film ultrasound sensor placed on the surface of the skin. The sensor is transparent in the spectral range 590-1200 nm. This permits the photoacoustic excitation beam (670-680 nm) and the OCT probe beam (1050 nm) to be transmitted through the sensor head and into the underlying tissue thus providing a backward mode imaging configuration. The respective OCT and PAT axial resolutions were 8 and 20 µm and the lateral resolutions were 18 and 50-100 µm. The system provides greater penetration depth than previous combined PA/OCT devices due to the longer wavelength of the OCT beam (1050 nm rather than 829-870 nm) and by operating in the tomographic rather than the optical resolution mode of photoacoustic imaging. Three-dimensional in vivo images of the vasculature and the surrounding tissue micro-morphology in murine and human skin were acquired. These studies demonstrated the complementary contrast and tissue information provided by each modality for high-resolution 3D imaging of vascular structures to depths of up to 5 mm. Potential applications include characterizing skin conditions such as tumors, vascular lesions, soft tissue damage such as burns and wounds, inflammatory conditions such as dermatitis and other superficial tissue abnormalities.

Three-dimensional noninvasive imaging of the vasculature in the mouse brain using a high resolution photoacoustic scanner.

The application of a novel photoacoustic imaging instrument based on a Fabry-Perot polymer film sensing interferometer to imaging the small animal brain is described. This approach provides a convenient backward mode sensing configuration that offers the prospect of overcoming the limitations of existing piezoelectric based detection schemes for small animal brain imaging. Noninvasive images of the vasculature in the mouse brain were obtained at different wavelengths between 590 and 889 nm, showing that the cerebral vascular anatomy can be visualized with high contrast and spatial resolution to depths up to 3.7 mm. It is considered that the instrument has a role to play in characterizing small animal models of human disease and injury processes such as stroke, epilepsy, and traumatic brain injury.

Quantitative determination of chromophore concentrations from 2D photoacoustic images using a nonlinear model-based inversion scheme

A model-based inversion scheme was used to determine absolute chromophore concentrations from multiwavelength photoacoustic images. The inversion scheme incorporated a forward model, which predicted 2D images of the initial pressure distribution as a function of the spatial distribution of the chromophore concentrations. It comprised a multiwavelength diffusion based model of the light transport, a model of acoustic propagation and detection, and an image reconstruction algorithm. The model was inverted by fitting its output to measured photoacoustic images to determine the chromophore concentrations. The scheme was validated using images acquired in a tissue phantom at wavelengths between 590 nm and 980 nm. The phantom comprised a scattering emulsion in which up to four tubes, filled with absorbing solutions of copper and nickel chloride at different concentration ratios, were submerged. Photoacoustic signals were detected along a line perpendicular to the tubes from which images of the initial pressure distribution were reconstructed. By varying the excitation wavelength, sets of multiwavelength photoacoustic images were obtained. The majority of the determined chromophore concentrations were within +/-15% of the true value, while the concentration ratios were determined with an average accuracy of -1.2%.

A miniature all-optical photoacoustic imaging probe

A miniature (250 μm outer diameter) photoacoustic probe for endoscopic applications has been developed. It comprises a single delivery optical fibre with a transparent Fabry Perot (FP) ultrasound sensor at its distal end. The fabrication of the sensor was achieved by depositing a thin film multilayer structure comprising a polymer spacer sandwiched between a pair of dichroic dielectric mirrors on to the tip of a single mode fiber. The probe was evaluated in terms of its acoustic bandwidth and sensitivity. Ultra high acoustic sensitivity has been achieved with a concave FP interferometer cavity design, which effectively suppresses the phase dispersion of multiple reflected beam within the cavity to achieve high finesse. The noise equivalent noise (NEP) achieved is 8 Pa over a 20 MHz bandwidth. Backward mode operation of the probe is demonstrated by detecting photoacoustic signals in a variety of phantoms designed to simulate endoscopic applications. A side-viewing probe is also demonstrated illustrating an all-optical design for intravascular imaging applications.

Evaluation of Absorbing Chromophores Used in Tissue Phantoms for Quantitative Photoacoustic Spectroscopy and Imaging

In this paper, the optical properties of absorbing compounds that are often used to construct tissue phantoms for quantitative photoacoustic spectroscopy and imaging are investigated. The wavelength dependence of the optical absorption of inorganic chromophores, such as copper and nickel chloride, and organic chromophores, such as cyanine-based near infrared dyes, was measured using transmittance spectroscopy and compared with that determined using photoacoustic spectroscopy. In addition, the relative change in the Grüneisen coefficient of these solutions with concentration was determined. The sound speed of aqueous gels and lipid emulsions as a function of concentration was also measured. It was found that copper and nickel chloride are suitable chromophores for the construction of photoacoustic tissue phantoms due to their photostability. By contrast, organic dyes were found unsuitable for quantitative photoacoustic measurements due to optically induced transient changes to their absorption spectrum and permanent oxidative photobleaching.