Photoacoustic imaging (also called optoacoustic or thermoacoustic imaging) has the potential to image animal or human organs, such as the breast and the brain, with simultaneous high contrast and high spatial resolution. This article provides an overview of the rapidly expanding field of photoacoustic imaging for biomedical applications. Imaging techniques, including depth profiling in layered media, scanning tomography with focused ultrasonic transducers, image forming with an acoustic lens, and computed tomography with unfocused transducers, are introduced. Special emphasis is placed on computed tomography, including reconstruction algorithms, spatial resolution, and related recent experiments. Promising biomedical applications are discussed throughout the text, including (1) tomographic imaging of the skin and other superficial organs by laser-induced photoacoustic microscopy, which offers the critical advantages, over current high-resolution optical imaging modalities, of deeper imaging depth and higher absorptioncontrasts, (2) breast cancerdetection by near-infrared light or radio-frequency–wave-induced photoacoustic imaging, which has important potential for early detection, and (3) small animal imaging by laser-induced photoacoustic imaging, which measures unique optical absorptioncontrasts related to important biochemical information and provides better resolution in deep tissues than optical imaging.

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Photoacoustic imaging in biomedicine

Author(s): Vogel, Alfred; Venugopalan, Vasan | Abstract: The mechanisms of pulsed laser ablation of biological tissues were studied. The transiently empty space created between the fiber tip and the tissue surface improved the optical transmission to the target and thus increased the ablation efficiency. It was found that the structure and morphology also affect the energy transport among tissue constituents.

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Mechanisms of pulsed laser ablation of biological tissues.

Imaging techniques based on optical contrast analysis can be used to visualize dynamic and functional properties of the nervous system via optical signals resulting from changes in blood volume, oxygen consumption and cellular swelling associated with brain physiology and pathology. Here we report in vivo noninvasive transdermal and transcranial imaging of the structure and function of rat brains by means of laser-induced photoacoustic tomography (PAT). The advantage of PAT over pure optical imaging is that it retains intrinsic optical contrast characteristics while taking advantage of the diffraction-limited high spatial resolution of ultrasound. We accurately mapped rat brain structures, with and without lesions, and functional cerebral hemodynamic changes in cortical blood vessels around the whisker-barrel cortex in response to whisker stimulation. We also imaged hyperoxia- and hypoxia-induced cerebral hemodynamic changes. This neuroimaging modality holds promise for applications in neurophysiology, neuropathology and neurotherapy.

Noninvasive laser-induced photoacoustic tomography for structural and functional in vivo imaging of the brain

We review recent advances in laser cell surgery, and investigate the working mechanisms of femtosecond laser nanoprocessing in biomaterials with oscillator pulses of 80-MHz repetition rate and with amplified pulses of 1-kHz repetition rate. Plasma formation in water, the evolution of the temperature distribution, thermoelastic stress generation, and stress-induced bubble formation are numerically simulated for NA=1.3, and the outcome is compared to experimental results. Mechanisms and the spatial resolution of femtosecond laser surgery are then compared to the features of continuous-wave (cw) microbeams. We find that free electrons are produced in a fairly large irradiance range below the optical breakdown threshold, with a deterministic relationship between free-electron density and irradiance. This provides a large ‘tuning range’ for the creation of spatially extremely confined chemical, thermal, and mechanical effects via free-electron generation. Dissection at 80-MHz repetition rate is performed in the low-density plasma regime at pulse energies well below the optical breakdown threshold and only slightly higher than used for nonlinear imaging. It is mediated by free-electron-induced chemical decomposition (bond breaking) in conjunction with multiphoton-induced chemistry, and hardly related to heating or thermoelastic stresses. When the energy is raised, accumulative heating occurs and long-lasting bubbles are produced by tissue dissociation into volatile fragments, which is usually unwanted. By contrast, dissection at 1-kHz repetition rate is performed using more than 10-fold larger pulse energies and relies on thermoelastically induced formation of minute transient cavities with lifetimes <100 ns. Both modes of femtosecond laser nanoprocessing can achieve a 2–3 fold better precision than cell surgery using cw irradiation, and enable manipulation at arbitrary locations.

Mechanisms of femtosecond laser nanosurgery of cells and tissues

High-resolution volumetric optical imaging modalities,
such as confocal microscopy, two-photon microscopy, and
optical coherence tomography, have become increasingly
important in the biomedical imaging field. However, due to
strong light scattering, the penetration depths of these
imaging modalities are limited to the optical transport mean
free path in biological tissues, for example, ∼1 mm in the
skin. Photoacoustic tomography (PAT), an emerging hybrid
imaging modality that can provide strong endogenous and
exogenous optical absorption contrasts with high ultrasonic
spatial resolution using the photoacoustic (PA) effect, has
overcome the fundamental depth limitation. The image
resolution is scalable with the ultrasonic frequency. The
imaging depth is limited to the reach of photons and up to
a few centimeters deep in biological tissues. This Review
will focus on the following aspects of PAT described in
works published from 2003 to 2009: (1) multiscale PAT
systems, (2) morphological and functional PAT using
intrinsic contrasts (hemoglobin or melanin), and (3) functional
and molecular PAT using exogenous contrast agents
(organic dyes, nanoparticles, reporter genes, or fluorescence
proteins).

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In vivo photoacoustic tomography of chemicals: high-resolution functional and molecular optical imaging at new depths

Conversion of energy from a heat pulse to acoustic stress is theoretically and experimentally studied in detail. The heat pulse was generated by laser radiation delivered via an optical fiber into an absorbing liquid. The experimental results indicate that tensile stress and cavitation are induced in front of the fiber tip at a distance far below the optical penetration depth of the laser radiation. The occurrence of tensile stress in the acoustic near field of a submerged fiber is explained by acoustic diffraction of the thermoelastic expansion wave. Good agreement between experimental results and theoretical calculations based on a three-dimensional model was found.

Laser-Generated Cavitation in Absorbing Liquid Induced by Acoustic Diffraction

Irradiation of an absorbing material with a short laser pulse generates a thermoelastic stress wave, from which the distribution of absorbed energy can be derived. This method is ideal to measure the light penetration in biological tissue. Especially for in vivo applications, we developed an optical stress transducer that can be positioned directly in front of the irradiated surface, inside the laser beam, in order to avoid distortion of the stress wave due to acoustic diffraction. The detector is based on stress wave-induced changes of optical reflectance of a glass-water interface, probed with a continuous laser beam that is incident at an angle close to the critical angle of total internal reflection to achieve maximum sensitivity. In this study, we describe the theory for the calibration of the transducer and compare the measured with the theoretically predicted signals. In the experiments, an aqueous dye solution is irradiated with pulses from either a Q-switched, frequency-doubled Nd:yttrium aluminu...

Measurement of laser-induced acoustic waves with a calibrated optical transducer

Photomechanical fracture induced by thermoelastic stress waves is an important mechanism of tissue ablation by short laser pulses. In this study, we present experimental investigations of the fracture process in ductile, water-containing materials and compare the results with a theoretical calculation. The model describes cavitation caused by the negative part of a bipolar thermoelastic stress wave. Pulses from aQ-switched, frequency-doubled Nd:YAG laser with 8 ns duration were used to irradiate dyed water and gelatine with variable absorption coefficient. Cavitation and ablation were observed with various time-resolved methods such as stress detection, video imaging and an optical pump-probe technique for the detection of individual cavities. Quantitative agreement between experiment and simulation could be achieved in the case of cavity lifetimes, especially at low laser fluence where the bubble density is low and no coalescence takes place. An increase of the threshold energy density for ablation with rising absorption coefficient and a distortion of the thermoelastic wave in the presence of cavitation were experimentally observed and could be qualitatively explained by use of the simulation. The results obtained in this study should facilitate the choice of the optimal laser parameters for photomechanical tissue ablation.

Microcavity dynamics during laser-induced spallation of liquids and gels

Laser light from a Q‐switched Nd:yttrium‐aluminum‐garnet laser (λ=1064 nm; pulse duration=20 ns; pulse energies up to 150 mJ) focused into water creates shock waves by rapidly expanding microplasmas. Using piezoelectric, thin‐film polyvinylidenefluoride (PVDF) as a transducer, a broadband hydrophone (100‐MHz bandwidth) was developed to investigate underwater shock waves. The electrical signal is analyzed with respect to reflections of the shock wave within the transducer and the input impedance of the measuring device. The shock waveform is determined, its peak pressure ranging to kbars (108 Pa), decreasing with r−1.12 and increases by the square root of the laser pulse energy. The time resolution of the hydrophone (4 ns) is sufficient to determine the plasma dimensions and the number of shock waves generated by a single laserpulse. Both vary statistically, primarily because of contaminations in the fluid. Because of the length of the region containing plasmas, different peak pressures are found in the di...

Time-resolved investigations of laser-induced shock waves in water by use of polyvinylidenefluoride hydrophones

A method for optimized generation and detection of thermoelastic stress waves for the measurement of tissue optical properties and structure is investigated. The stress waves are formed by short pulsed irradiation of an absorbing dye solution with a Q‐switched Nd:YAG laser at 532 nm. An optical transducer based on pressure‐induced reflectivity changes of a continuous laser beam at a glass‐water interface detects the stress wave in front of the irradiated sample surface. It is shown theoretically and experimentally that this kind of detector, where the active area is a small spot close to the irradiated surface, minimizes signal distortion due to acoustic diffraction. Comparisons of absorption coefficients measured acoustically and from optical transmission show a good agreement between the two methods. The high sensitivity of the detector (1.5 mV/bar) makes it possible to keep the temperature and pressure rise in the investigated target low, which enables in vivo applications of the optical transducer.

Heinz Schmidt-Kloiber

Papers

Laser-Generated Cavitation in Absorbing Liquid Induced by Acoustic Diffraction

Measurement of laser-induced acoustic waves with a calibrated optical transducer

Microcavity dynamics during laser-induced spallation of liquids and gels

Time-resolved investigations of laser-induced shock waves in water by use of polyvinylidenefluoride hydrophones

Light distribution measurements in absorbing materials by optical detection of laser‐induced stress waves