Truncated correlation photoacoustic coherence tomography: An axial resolution enhancement imaging modality.

In this report we present a novel photoacoustic (PA) modality using pulsed chirp excitation at a fixed wavelength and spectral analysis based on frequency-domain (FD) processing. We introduce Truncated Correlation Photoacoustic Coherence Tomography (TC-PACT), a PA axial resolution enhancement methodology, with an application to closely stacked subsurface multilayers of plexiglass coated with a thin layer of graphite acting as surface absorber. The experimental results demonstrated that the SNR and the axial resolution were higher in TC-PACT than in conventional FD photoacoustics. A ns pulsed laser was also used as PA excitation source with axial resolution results found to be commensurate with TC-PACT. However, the separation distance between adjacent absorbers when the latter approached the axial resolution limit of the transducer was only resolved in TC-PACT compared to pulsed laser PA owing to the lower uncertainty in the former modality involved in determining the location of the absorbers.

Interference-free Detection of Lipid-laden Atherosclerotic Plaques by 3D Co-registration of Frequency-Domain Differential Photoacoustic and Ultrasound Radar Imaging.

As lipid composition of atherosclerotic plaques is considered to be one of the primary indicators for plaque vulnerability, a diagnostic modality that can sensitively evaluate their necrotic core is highly desirable in atherosclerosis imaging. In this regard, intravascular photoacoustic (IVPA) imaging is an emerging plaque detection modality that provides lipid-specific chemical information of arterial walls. Within the near-infrared window, a 1210-nm optical source is usually chosen for IVPA applications because lipid exhibits a strong absorption peak at that wavelength. However, other arterial tissues also show some degree of absorption near 1210 nm and generate undesirable interfering PA signals. In this study, a novel wavelength-modulated Intravascular Differential Photoacoustic Radar (IV-DPAR) modality was introduced as an interference-free detection technique for a more accurate and reliable diagnosis of plaque progression. By using two low-power continuous-wave laser diodes in a differential manner, IV-DPAR could efficiently suppress undesirable absorptions and system noise, while dramatically improving system sensitivity and specificity to cholesterol, the primary ingredient of plaque necrotic core. When co-registered with intravascular ultrasound imaging, IV-DPAR could sensitively locate and characterize the lipid contents of plaques in human atherosclerotic arteries, regardless of their size and depth.

Frequency-domain differential photoacoustic radar: theory and validation for ultrasensitive atherosclerotic plaque imaging.

Lipid composition of atherosclerotic plaques is considered to be highly related to plaque vulnerability. Therefore, a specific diagnostic or imaging modality that can sensitively evaluate plaques' necrotic core is desirable in atherosclerosis imaging. In this regard, intravascular photoacoustic (IVPA) imaging is an emerging plaque detection technique that provides lipid-specific chemical information from an arterial wall with great optical contrast and long acoustic penetration depth. While, in the near-infrared window, a 1210-nm optical source is usually chosen for IVPA applications since lipids exhibit a strong absorption peak at that wavelength, the sensitivity problem arises in the conventional single-ended systems as other arterial tissues also show some degree of absorption near that spectral region, thereby generating undesirably interfering photoacoustic (PA) signals. A theory of the high-frequency frequency-domain differential photoacoustic radar (DPAR) modality is introduced as a unique detection technique for accurate and molecularly specific evaluation of vulnerable plaques. By assuming two low-power continuous-wave optical sources at ∼1210 and ∼970 nm in a differential manner, DPAR theory and the corresponding simulation/experiment studies suggest an imaging modality that is only sensitive and specific to the spectroscopically defined imaging target, cholesterol.

The application of frequency-domain photoacoustics to temperature-dependent measurements of the Grüneisen parameter in lipids.

The Grüneisen parameter is an essential factor in biomedical photoacoustic (PA) diagnostics. In most PA imaging applications, the variation of the Grüneisen parameter with tissue type is insignificant. This is not the case for PA imaging and characterization of lipids, as they have a very distinct Grüneisen parameter compared with other tissue types. One example of PA applications involving lipids is the imaging and characterization of atherosclerotic plaques. Intravascular photoacoustic (IVPA) imaging is a promising diagnostic tool that can evaluate both plaque severity and composition. The literature for IVPA has mainly focused on using the difference in absorption coefficients between plaque components and healthy arterial tissues. However, the Grüneisen parameters for lipids and their behavior with temperature have not been well established in the literature. In this study we employ frequency-domain photoacoustic measurements to estimate the Grüneisen parameter by virtue of the ability of this modality to independently measure both the absorption coefficient and the Grüneisen parameter through the use of the phase channel. The values of the Grüneisen parameters of some lipids are calculated as functions of temperature in the range 25-45 °C.

Photoacoustic resonance by spatial filtering of focused ultrasound transducers.

The effect of a spherically focused ultrasound (US) transducer (TD) on photoacoustic (PA) measurements is analytically investigated using the concept of a virtual point detector. The derived analytical results indicate that the limited numerical aperture (NA) of the PA detector takes on the role of spatial filtering of the induced PA waves, which leads to the occurrence of a peak frequency in the PA spectrum. The mathematical description of this phenomenon is similar to the result of resonance peaks of light propagation in dielectrics. This PA resonance peak depends on the NA of the US TD and the absorption coefficient of the PA source. Experimentally measured PA spectra from an ink solution using a frequency-domain PA system verify the PA resonance effect. Finally, we discuss the possibility that previously reported PA resonances interpreted as PA source viscosity might be actually caused by the US TD's spatial filtering.

Coded excitation waveform engineering for high frame rate synthetic aperture ultrasound imaging.

Coded excitation was initially introduced to ultrasound imaging as a method for enhancing the signal-to-noise ratio (SNR). However, this method was also shown to be helpful in conjunction with synthetic aperture transmission for high frame rate imaging. Recently, we introduced two families of mismatched coded excitations based on frequency modulation chirp and combined frequency modulation and Golay code. Here "mismatched" indicates that the coded excitations generate very small cross-correlations among themselves while each has a very strong autocorrelation. Employing weakly correlated coded excitations enables performing simultaneous insonifications from several elements of the ultrasonic transducer and receiving distinguishable responses to each code. In this work, we propose and experimentally demonstrate another set of mismatched correlated coded excitations based on Golay codes. The generated phase codes share identical duration and center frequency which results in similar SNR and image resolution.

Quantitative phase-filtered wavelength-modulated differential photoacoustic radar tumor hypoxia imaging toward early cancer detection.

Overcoming the limitations of conventional linear spectroscopy used in multispectral photoacoustic imaging, wherein a linear relationship is assumed between the absorbed optical energy and the absorption spectra of the chromophore at a specific location, is crucial for obtaining accurate spatially-resolved quantitative functional information by exploiting known chromophore-specific spectral characteristics. This study introduces a non-invasive phase-filtered differential photoacoustic technique, wavelength-modulated differential photoacoustic radar (WM-DPAR) imaging that addresses this issue by eliminating the effect of the unknown wavelength-dependent fluence. It employs two laser wavelengths modulated out-of-phase to significantly suppress background absorption while amplifying the difference between the two photoacoustic signals. This facilitates pre-malignant tumor identification and hypoxia monitoring, as minute changes in total hemoglobin concentration and hemoglobin oxygenation are detectable. The system can be tuned for specific applications such as cancer screening and SO2 quantification by regulating the amplitude ratio and phase shift of the signal. The WM-DPAR imaging of a head and neck carcinoma tumor grown in the thigh of a nude rat demonstrates the functional PA imaging of small animals in vivo. The PA appearance of the tumor in relation to tumor vascularity is investigated by immunohistochemistry. Phase-filtered WM-DPAR imaging is also illustrated, maximizing quantitative SO2 imaging fidelity of tissues. Oxygenation levels within a tumor grown in the thigh of a nude rat using the two-wavelength phase-filtered differential PAR method.

Wavelength-modulated differential photoacoustic radar imager (WM-DPARI): accurate monitoring of absolute hemoglobin oxygen saturation.

Accurate monitoring of blood oxy-saturation level (SO2 ) in human breast tissues is clinically important for predicting and evaluating possible tumor growth at the site. In this work, four different non-invasive frequency-domain photoacoustic (PA) imaging modalities were compared for their absolute SO2 characterization capability using an in-vitro sheep blood circulation system. Among different PA modes, a new WM-DPAR imaging modality could estimate the SO2 with great accuracy when compared to a commercial blood gas analyzer. The developed WM-DPARI theory was further validated by constructing SO2 tomographic images of a blood-containing plastisol phantom.

High-Frame-Rate Synthetic Aperture Ultrasound Imaging Using Mismatched Coded Excitation Waveform Engineering: A Feasibility Study.

Mismatched coded excitation (CE) can be employed to increase the frame rate of synthetic aperture ultrasound imaging. The high autocorrelation and low cross correlation (CC) of transmitted signals enables the identification and separation of signal sources at the receiver. Thus, the method provides B-mode imaging with simultaneous transmission from several elements and capability of spatial decoding of the transmitted signals, which makes the imaging process equivalent to consecutive transmissions. Each transmission generates its own image and the combination of all the images results in an image with a high lateral resolution. In this paper, we introduce two different methods for generating multiple mismatched CEs with an identical frequency bandwidth and code length. Therefore, the proposed families of mismatched CEs are able to generate similar resolutions and signal-to-noise ratios. The application of these methods is demonstrated experimentally. Furthermore, several techniques are suggested that can be used to reduce the CC between the mismatched codes.

Wavelength-Modulated Differential Photoacoustic Spectroscopy (WM-DPAS) for noninvasive early cancer detection and tissue hypoxia monitoring.

This study introduces a novel noninvasive differential photoacoustic method, Wavelength Modulated Differential Photoacoustic Spectroscopy (WM-DPAS), for noninvasive early cancer detection and continuous hypoxia monitoring through ultrasensitive measurements of hemoglobin oxygenation levels (StO2 ). Unlike conventional photoacoustic spectroscopy, WM-DPAS measures simultaneously two signals induced from square-wave modulated laser beams at two different wavelengths where the absorption difference between maximum deoxy- and oxy-hemoglobin is 680 nm, and minimum (zero) 808 nm (the isosbestic point). The two-wavelength measurement efficiently suppresses background, greatly enhances the signal to noise ratio and thus enables WM-DPAS to detect very small changes in total hemoglobin concentration (CHb ) and oxygenation levels, thereby identifying pre-malignant tumors before they are anatomically apparent. The non-invasive nature also makes WM-DPAS the best candidate for ICU bedside hypoxia monitoring in stroke patients. Sensitivity tunability is another special feature of the technology: WM-DPAS can be tuned for different applications such as quick cancer screening and accurate StO2 quantification by selecting a pair of parameters, signal amplitude ratio and phase shift. The WM-DPAS theory has been validated with sheep blood phantom measurements. Sensitivity comparison between conventional single-ended signal and differential signal.

Photoacoustic and ultrasound imaging of cancellous bone tissue.

We used ultrasound (US) and photoacoustic (PA) imaging modalities to characterize cattle trabecular bones. The PA signals were generated with an 805-nm continuous wave laser used for optimally deep optical penetration depth. The detector for both modalities was a 2.25-MHz US transducer with a lateral resolution of ~1 mm at its focal point. Using a lateral pixel size much larger than the size of the trabeculae, raster scanning generated PA images related to the averaged values of the optical and thermoelastic properties, as well as density measurements in the focal volume. US backscatter yielded images related to mechanical properties and density in the focal volume. The depth of interest was selected by time-gating the signals for both modalities. The raster scanned PA and US images were compared with microcomputed tomography (µCT) images averaged over the same volume to generate similar spatial resolution as US and PA. The comparison revealed correlations between PA and US modalities with the mineral volume fraction of the bone tissue. Various features and properties of these modalities such as detectable depth, resolution, and sensitivity are discussed.

Frequency-domain photothermoacoustic and ultrasonic imaging of blood and opto-thermal effects of plasmonic nanoparticle concentrations.

We describe the use of combined ultrasonic imaging (USI) and photoacoustic radar imaging (PARI) with linear chirp laser modulation to provide visualization of blood with and without the use of gold nanoparticles. A blood vessel simulating sample (S1) containing pure sheep blood was shown to be an optically weak absorbing medium which satisfies thermal but not acoustic confinement. On the contrary, the blood-gold combinations (S2) using 10% and S3 (20%) Au concentrations behaved as optically strongly absorbing media. A heating efficiency of 0.54 to 8.60×10(3) K cm(2) (-1) was determined for Au NPs. The optimal optical power modulation spectral density was determined to be in the range of 0.5 to 0.8 MHz and 0.3 to 1.0 MHz for USI and PARI, respectively. USI produced a better structural image while PARI produced a better functional image of the simulated blood vessel in the order of S2>S3>S1 due to enhanced signal-to-noise ratio. Two-dimensional images of the simulated blood vessel were also obtained. In summary, the PA signal does not increase linearly with Au NP concentration and the change of blood osmolarity due to temperature increase can cause thermo-hemolysis of red blood cells which in turn degrades the PA signal and thus the blood imaging quality. On the other hand, USI produced the best structural image, S4, due to the strong US reflection response from Au NPs and its insensitivity to the presence of blood.

Simultaneous dual-wavelength photoacoustic radar imaging using waveform engineering with mismatched frequency modulated excitation.

The spectroscopic imaging capability of photoacoustics (PA) without the depth limitations of optical methods offers a major advantage in preclinical and clinical applications. Consecutive PA measurements with properly chosen wavelengths allow composition related information about blood or tissue. In this work, we propose and experimentally introduce modulation waveform engineering through the use of mismatched (uncorrelated or weakly correlated) linear frequency modulated signals for PA characterization and imaging. The feasibility of the method was tested on oxygen saturated hemoglobin and deoxygenated hemoglobin in vitro in a blood circulating rig. The method was also employed for in vivo imaging of a neck carcinoma tumor grown in a mouse thigh. The proposed method can increase the accuracy and speed of functional imaging by simultaneous PA probing with two wavelengths using portable laser-diode based PA imaging systems.

Photoacoustic radar phase-filtered spatial resolution and co-registered ultrasound image enhancement for tumor detection.

Co-registered ultrasound (US) and frequency-domain photoacoustic radar (FD-PAR) imaging is reported for the first time in this paper. The merits of ultrasound and cross-correlation (radar) frequency-domain photoacoustic imaging are leveraged for accurate tumor detection. Commercial US imagers possess sophisticated, optimized software for rapid image acquisition that could dramatically speed-up PA imaging. The PAR image generated from the amplitude of the cross-correlation between detected and input signals was filtered by the standard deviation (SD) of the phase of the correlation signal, resulting in strong improvement of image spatial resolution, signal-to-noise ratio (SNR) and contrast. Application of phase-mediated image improvement is illustrated by imaging a cancer cell-injected mouse. A 14-15 dB SNR gain was recorded for the phase-filtered image compared to the amplitude and phase independently, while ~340 µm spatial resolution was seen for the phase PAR image compared to ~840 µm for the amplitude image.

The application of backscattered ultrasound and photoacoustic signals for assessment of bone collagen and mineral contents.

BACKGROUND: This study examines the backscattered ultrasound (US) and back-propagating photoacoustic (PA) signals from trabecular bones, and their variations with reduction in bone minerals and collagen content. While the collagen status is directly related to the strength of the bone, diagnosis of its condition using US remains a challenge. METHODS: For both PA and US methods, coded-excitation signals and matched filtering were utilized to provide high sensitivity of the detected signal. The optical source was a 805-nm CW laser and signals were detected employing a 2.2-MHz ultrasonic transducer. Bone decalcification and decollagenization were induced with mild ethylenediaminetetraacetic acid (EDTA) and sodium hypochlorite solutions, respectively. RESULTS: The PA and US signals were measured on cattle bones, and apparent integrated backscatter/back-propagating (AIB) parameters were compared before and after demineralization and decollagenization. CONCLUSIONS: The results show that both PA and US are sensitive to mineral changes. In addition, PA is also sensitive to changes in the collagen content of the bone, but US is not significantly sensitive to these changes.

On estimating the directionality distribution in pedicle trabecular bone from micro-CT images.

Our interest in the trabecular alignment within bone stems from the need to better understand the manner in which it can affect ultrasound propagation, particularly in pedicles. Within long bones it is well established that trabecular structures are aligned in an organized manner associated with the direction of load distribution; however, for smaller bones there are limited alignment studies. To investigate the directionality distribution in a quantitative manner we used a micro-CT to obtain three-dimensional (3D) structural data and developed analytical methods based on the special properties of Gabor filters. Implementation of these techniques has been developed and tested on a variety of simulated images as well as on 3D structures whose geometry is well-defined. To test the use of this technique we compared the results obtained on vertebral body trabecular bone with visual directionality and previous measurements by others. The method has been applied to six human pedicle samples in two orthogonal planes with results that provide reasonable proof-of-principle evidence that the method is well suited for estimating the directionality distribution within pedicle bones.

Coregistered photoacoustic and ultrasonic signatures of early bone density variations.

This study examines the application of backscattered ultrasound (US) and photoacoustic (PA) signals for assessment of bone structure and density variations. Both methods were applied in the frequency-domain, employing linear frequency modulation chirps. A near-IR laser (800 nm) was used for inducing the PA signal. The backscattered pressure waves were detected with a 2.2-MHz US transducer. Experiments were focused on detection and evaluation of PA and US signals from in-vitro animal and human bones with cortical and trabecular sublayers. It was shown that PA signals can be detected as deep as a few millimeters below trabecular and cortical layers. The occurrence of multiple scattering was demonstrated in PA detected signals from cancellous bone. Osteoporotic changes in the bone were simulated by using a very mild demineralization ethylenediaminetetraacetic acid solution. Changes in the time-domain signals as well as integrated backscattering spectra were compared for the samples before and after demineralization. The results demonstrated the sensitivity of PA to variations in bone minerals. In comparison to PA, US was capable of generating detectable signals from deeper bone sublayers (few centimeters). However, while US signal variations with changes in the cortical layer were insignificant, PA proved to be sensitive even to minor variations of the cortical bone density.

Slow and fast ultrasonic wave detection improvement in human trabecular bones using Golay code modulation.

The identification of fast and slow waves propagating through trabecular bone is a challenging task due to temporal wave overlap combined with the high attenuation of the fast wave in the presence of noise. However, it can provide valuable information about bone integrity and become a means for monitoring osteoporosis. The objective of this work is to apply different coded excitation methods for this purpose. The results for single-sine cycle pulse, Golay code, and chirp excitations are compared. It is shown that Golay code is superior to the other techniques due to its signal enhancement while exhibiting excellent resolution without the ambiguity of sidelobes.

Comparison between pulsed laser and frequency-domain photoacoustic modalities: signal-to-noise ratio, contrast, resolution, and maximum depth detectivity.

In this work, a detailed theoretical and experimental comparison between various key parameters of the pulsed and frequency-domain (FD) photoacoustic (PA) imaging modalities is developed. The signal-to-noise ratios (SNRs) of these methods are theoretically calculated in terms of transducer bandwidth, PA signal generation physics, and laser pulse or chirp parameters. Large differences between maximum (peak) SNRs were predicted. However, it is shown that in practice the SNR differences are much smaller. Typical experimental SNRs were 23.2 dB and 26.1 dB for FD-PA and time-domain (TD)-PA peak responses, respectively, from a subsurface black absorber. The SNR of the pulsed PA can be significantly improved with proper high-pass filtering of the signal, which minimizes but does not eliminate baseline oscillations. On the other hand, the SNR of the FD method can be enhanced substantially by increasing laser power and decreasing chirp duration (exposure) correspondingly, so as to remain within the maximum permissible exposure guidelines. The SNR crossover chirp duration is calculated as a function of transducer bandwidth and the conditions yielding higher SNR for the FD mode are established. Furthermore, it was demonstrated that the FD axial resolution is affected by both signal amplitude and limited chirp bandwidth. The axial resolution of the pulse is, in principle, superior due to its larger bandwidth; however, the bipolar shape of the signal is a drawback in this regard. Along with the absence of baseline oscillation in cross-correlation FD-PA, the FD phase signal can be combined with the amplitude signal to yield better axial resolution than pulsed PA, and without artifacts. The contrast of both methods is compared both in depth-wise (delay-time) and fixed delay time images. It was shown that the FD method possesses higher contrast, even after contrast enhancement of the pulsed response through filtering.

Linear frequency modulation photoacoustic radar: optimal bandwidth and signal-to-noise ratio for frequency-domain imaging of turbid media.

The development of the pulse compression photoacoustic (PA) radar using linear frequency modulation (LFM) demonstrated experimentally that spectral matching of the signal to the ultrasonic transducer bandwidth does not necessarily produce the best PA signal-to-noise ratio, and it was shown that the optical and acoustic properties of the absorber will modify the optimal bandwidth. The effects of these factors are investigated in frequency-domain (FD) PA imaging by employing one-dimensional and axisymmetric models of the PA effect, and a Krimholtz-Leedom-Matthaei model for the employed transducers. LFM chirps with various bandwidths were utilized and transducer sensitivity was measured to ensure the accuracy of the model. The theory was compared with experimental results and it was shown that the PA effect can act as a low-pass filter in the signal generation. Furthermore, with the PA radar, the low-frequency behavior of two-dimensional wave generation can appear as a false peak in the cross correlation signal trace. These effects are important in optimizing controllable features of the FD-PA method to improve image quality.