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Recent years have seen rapid development of hybrid optical-acoustic imaging modalities with broad applications in research and clinical imaging, including photoacoustic tomography (PAT), photoacoustic microscopy, and ultrasound-modulated optical tomography. Tissue-mimicking phantoms are an important tool for objectively and quantitatively simulating in vivo imaging system performance. However, no standard tissue phantoms exist for such systems. One major challenge is the development of tissue-mimicking materials (TMMs) that are both highly stable and possess biologically realistic properties. To address this need, we have explored the use of various formulations of PVC plastisol (PVCP) based on varying mixtures of several liquid plasticizers. We developed a custom PVCP formulation with optical absorption and scattering coefficients, speed of sound, and acoustic attenuation that are tunable and tissue-relevant. This TMM can simulate different tissue compositions and offers greater mechanical strength than hydrogels. Optical properties of PVCP samples with varying composition were characterized using integrating sphere spectrophotometry and the inverse adding-doubling method. Acoustic properties were determined using a broadband pulse-transmission technique. To demonstrate the utility of this bimodal TMM, we constructed an image quality phantom designed to enable quantitative evaluation of PAT spatial resolution. The phantom was imaged using a custom combined PAT-ultrasound imaging system. Results indicated that this more biologically realistic TMM produced performance trends not captured in simpler liquid phantoms. In the future, this TMM may be broadly utilized for performance evaluation of optical, acoustic, and hybrid optical-acoustic imaging systems.

We present our activities on the development of narrow linewidth tunable optical parametric sources and their integration in gas sensing instruments. In particular, we have introduced the nested cavity optical parametric oscillator (NesCOPO) scheme that enables to implement very compact devices. The NesCOPO was successfully demonstrated in the microsecond to nanosecond regime and in spectral ranges from short- to long-wave infrared. Its high potential was demonstrated both for local photoacoustic spectroscopy and standoff detection using lidar instruments. We also present our recent advances on rapidly tunable picosecond OPOs based on aperiodic quasi-phase matching and their application to gas detection.

In this presentation, we report on the high-sensitivity and high-selectivity measurement of HONO by off-beam quartz-enhanced photoacoustic spectroscopy (QEPAS) in a very small gas sample volume (of ~ 40 mm3) resulting in a ultrashort residence time of less than 10 ms (compared to ~ 7 min for a conventional 210 m multipass cell or ~ 10-min. integration time for currently used chemical analytical instruments). A minimum detection limit of 66 ppbv (1σ) HONO was achieved at 70 mbar using a laser output power of 50 mW and 1 s integration time. This MDL was down to 7 ppbv at the optimal integration time of 150 s.

We report here an analysis of the performance of a quartz-enhanced photoacoustic (QEPAS) system operating in a pulsed mode by employing a quantum cascade laser (QCL). The QEPAS system is based on a quartz tuning fork (QTF) having fundamental resonance frequency of 4.2 kHz and a first overtone resonance of 25.4 KHz. Water vapor was used as a target gas by selecting its absorption line falling at 1296.5 cm-1 with a line strength of 1.69⋅10-22 cm/molecule. The QEPAS signal was investigated, while varying the QCL duty-cycle from continuous wave operation, down to 5%, which corresponds to a laser power consumption of 0.17 mW and a pulse-width of 4 μs.

A photoacoustic (PA) spectrophone was developed for filter-free measurement of black carbon (BC) mass absorption coefficient (MAC) in the spectral region of ~ 442 nm using a blue diode laser. The PA sensor was characterized and calibrated using NO2 at standard calibrated concentrations, as well as at indoor and outdoor air concentrations via a side-by-side intercomparison with a commercial NOx analyzer. Black carbon (graphite) and volcanic ash samples were measured under laboratory condition. MAC of BC and volcanic ash sample were determined based on the measured particles optical absorption coefficient by the PA spectrophone, in combination with the mass concentration measured using a scanning mobility particle sizer (SMPS). A minimum detectable absorption coefficient (1σ) of ~ 1.2 Mm-1 for BC was achieved with a time solution of 1 second.

We report here on the realization of a single-tube on-beam quartz-enhanced photoacoustic (QEPAS) spectroscopy sensor employing a custom-made quartz tuning fork (QTF) with a large prong spacing. The prongs of the QTF have been designed in order to provide a quality factor twice higher when the QTF operates in the first overtone flexural mode than in the fundamental mode. The influence of the microresonator tube on the main parameters characterizing the sensing performance of the QEPAS spectrophone, including the quality factor, the magnitude of the QEPAS signal and the associated background noise was investigated in detail.

We report on a novel quantum cascade laser (QCL) capable of operating in pure amplitude or wavelength modulation configuration thereby allowing the acquisition of background-free gas absorption-line profiles using quartz-enhanced photoacoustic spectroscopy (QEPAS). The QCL is composed of three electrically independent sections: Gain, Phase (PS) and Master Oscillator (MO). The non-uniform pumping of these three QCL sections allows laser wavelength tuning with constant optical power and vice-versa. Pure QEPAS amplitude modulation operating conditions were obtained by modulating the PS current, while pure wavelength modulation was obtained by modulating the MO section and slowly scanning the PS current.

Photo-acoustic spectroscopy gas detection technology has the advantages of high sensitivity, good selectivity, small size and real time monitoring and has been widely used in environmental monitoring, industrial production, medical diagnosis, biological technology and monitoring of power facilities. In this paper, a method to improve the sensitivity of photo-acoustic spectroscopy system is presented, which is combined with the technique of Herriott type multiple pass cell. In this experimental apparatus, the design of the experimental device can make the beam pass the cell 18 times. By comparing the signal of one time pass through the photoacoustic cell and the signal of 18 times passes pass through the photoacoustic cell, we can confirm that the signal is increased and this method is feasible.

This article presents the experimental and modeling study of quartz-enhanced photoacoustic detection of nitrogen monoxide (NO) using the off-beam configuration and a distributed-feedback (DFB) quantum cascade laser (QCL) at 5.26 μm as the excitation source. Trace gas monitoring of NO is one of the important subjects for both environmental protection and human health monitoring. Quartz-enhanced photoacoustic spectroscopy (QEPAS) with on-beam configuration is mostly adopted for gas detection. In comparison, the off-beam approach has not only comparative detection sensitivity but also significant advantage of simpler installation and optical alignment. We optimized the sensor performance by adjusting the horizontal and vertical distances between the micro-resonator (mR) and the QTF prongs. Pressure and humidity are two important factors affecting the photoacoustic signal. The effects of both parameters on the NO concentration determination were investigated.

We will report on new developments of quartz-enhanced photo-acoustic (QEPAS) sensor employing THz quantum cascade laser (QCLs). The extension of the QEPAS technique in the THz range was made possible by the realization of custom made QTFs. With the aim to improve the QTF acousto-electric transduction efficiency, we designed and realized new QTF designs. A detailed analysis of the quality factor, the resonance frequency and the electrical resistance of custom quartz tuning forks (QTFs) with different geometrical parameters is reported. The custom QTFs were employed in QEPAS sensors using THz QCLs as the laser excitation sources and targeting CH3OH and H2S. Minimum detection limits of a few tens of ppb and normalized noise equivalent absorption factors down to 3.75×10-11 cm-1W/Hz½ were achieved. © (2016) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

Photoacoustic imaging (PAI) involves both optical and ultrasound imaging, owing to this combination the system is capable of generating high resolution images with good penetration depth. With the growing applications of PAI in neurology, vascular biology, dermatology, ophthalmology, tissue engineering, angiogenesis etc., there is a need to make the system more compact, cheap and effective. Therefore we designed an economical and compact version of PAI systems by replacing expensive and sophisticated lasers with a robust pulsed laser diode of 905 nm wavelength. In this study, we determine the feasibility of the Photoacoustic imaging with a very low excitation energy of 0.1uJ in Photoacoustic microscopy. We developed a low cost portable Photoacoustic Imaging including microscopy (both reflection) Phantom study was performed in this configuration and also ex-vivo image was obtained from mouse skin.

The Army is investigating several spectroscopic techniques (e.g., infrared spectroscopy) that could allow for an adaptable sensor platform. Current sensor technologies, although reasonably sized, are geared to more classical chemical threats, and the ability to expand their capabilities to a broader range of emerging threats is uncertain. Recently, photoacoustic spectroscopy (PAS), employed in a sensor format, has shown enormous potential to address these ever-changing threats. PAS is one of the more flexible IR spectroscopy variants, and that flexibility allows for the construction of sensors that are designed for specific tasks. PAS is well suited for trace detection of gaseous and condensed media. Recent research has employed quantum cascade lasers (QCLs) in combination with MEMS-scale photoacoustic cell designs. The continuous tuning capability of QCLs over a broad wavelength range in the mid-infrared spectral region greatly expands the number of compounds that can be identified. We will discuss our continuing evaluation of QCL technology as it matures in relation to our ultimate goal of a universal compact chemical sensor platform. Finally, expanding on our previously reported photoacoustic detection of condensed phase samples, we are investigating standoff photoacoustic chemical detection of these materials. We will discuss the evaluation of a PAS sensor that has been designed around increasing operator safety during detection and identification of explosive materials by performing sensing operations at a standoff distance. We investigate a standoff variant of PAS based upon an interferometric sensor by examining the characteristic absorption spectra of explosive hazards collected at 1 m.

Photoacoustic spectroscopy (PAS) is a useful technique that suitable for trace detection of chemicals and explosives. Normally a high-sensitive microphone or a quartz tuning fork is used to detect the signal in photoacoustic cell. In recent years, laser Doppler vibrometer (LDV) is proposed to remote-sense photoacoustic signal on various substrates. It is a high-sensitivity sensor with a displacement resolution of

Photoacoustics is a novel medical imaging technique with high potential for early detection of different diseases such as skin cancer or rheumatology. It is a hybrid modality with pulsed laser light for excitation of the tissue, and ultrasound as response. One of the hurdles for its introduction into the clinic, or even in clinical pilot studies and larger trials, is the bulkiness and price of existing photoacoustic systems. This presentation describes how recent developments in diode laser technology lead to a compact ultrasound scanner with built-in photoacoustic functionality. This is a key for the introduction of photoacoustic technology in the clinic and future point of care systems. We have developed a diode laser system and driver that deliver pulse energies which up to now were only achievable with Nd:YAG lasers. The efficiency and compactness allows integration in a handheld probe. The paper will highlights the laser technology and its radical integration with a medical ultrasound scanner, leading to a first prototype for clinical pilot studies.

Many types of cancer therapies target the tumor microenvironment, causing biochemical and morphological changes in tissues. In therapies using ultrasound activated microbubbles, vascular collapse is typically reported. Red blood cells (RBCs) that leak out of the vasculature become exposed to the ceramide that is released from damaged endothelial cells. Ceramide can induce programmed cell death in RBCs (eryptosis), and is characterized by cell shrinkage, membrane blebbing and scrambling. Since the effect of eryptotic cells on generated photoacoustics (PA) signals has not been reported, we investigated the potential PA may have for cancer treatment monitoring by using PA spectral analysis to sense eryptosis. To induce eryptosis, C2-ceramide was added to RBC suspensions and that were incubated for 24 hours at 37°C. A control and ceramide-induced sample was imaged in a vessel phantom using a high frequency PA system (VevoLAZR, 10 – 45 MHz bandwidth) irradiated with multiple wavelengths ranging from 680 to 900 nm. PA spectral parameters were measured and linked to changes in RBCs as it underwent eryptosis. These samples were examined using optical microscopy, a blood gas analyzer and an integrating sphere setup to measure optical properties (wavelengths 600 – 900 nm). The results of the experiment demonstrate how PA spectral analysis can be used to identify eryptosis at a depth of more than 1 cm into the phantom using ultrasound derived the y-intercept and mid bandfit (MBF) parameters at optical wavelengths of 800 – 900 nm. These parameters were correlated to the morphological and biochemical changes that eryptotic RBCs display. The results establish the potential of PA in cancer treatment monitoring through sensing treatment induced eryptosis.

In this study, we present some examples of waveform engineering applications in frequency-domain photoacoustics (PA). An example of using linear frequency modulation (LFM) for PA spectroscopy is the capability of simultaneous probing/imaging with multiple wavelengths. Use of mismatched coded waveforms enables encoding the signal sources and, therefore, facilitates simultaneous probing and imaging. This method enables high frame rate functional imaging with reduced motion artifacts. Furthermore, it is shown than that phase of the PA cross-correlation induced with a LFM can yield the absolute absorption coefficient of the chromophores. This method is not affected by fluence attenuation or variation due to the absorption and scattering of the overlayer material.

The field of Optical Fiber Sensors (OFS) is gaining tremendous popularity in recent years. OFS natural immunity to electromagnetic disturbances, inherent biocompatibility and compactness making them highly attractive for ultrasound sensing. Moreover, their compatibility with photoacoustics can make them useful in situations where traditional piezoelectric probes are inadequate. However, the issue of multiplexing individual OFS into an array remains a challenging and costly task. In this work, we demonstrate a straightforward approach for multiplexing multiple broadband OFS for ultrasound sensing by exploiting most of the photoreceiver's bandwidth. The design is based on a recently developed system in which all sensing elements are connected to a single interrogator and to a single digitizing circuit. To mitigate aliasing, the system employs I/Q coherent detection. Synchronization of the sensor interrogation with the excitation enables very high repetition rates (kHz) making it ideal for applications where imaging of dynamic processes is desired.

A flow cytometer that uses sound waves to determine the size of biological cells is presented. In this system, a microfluidic device made of polydimethylsiloxane (PDMS) was developed to hydrodynamically flow focus cells in a single file through a target area. Integrated into the microfluidic device was an ultrasound transducer with a 375 MHz center frequency, aligned opposite the transducer was a pulsed 532 nm laser focused into the device by a 10x objective. Each passing cell was insonfied with a high frequency ultrasound pulse, and irradiated with the laser. The resulting ultrasound and photoacoustic waves from each cell were analyzed using signal processing methods, where features in the power spectra were compared to theoretical models to calculate the cell size. Two cell lines with different size distributions were used to test the system: acute myeloid leukemia cells (AML) and melanoma cells. Over 200 cells were measured using this system. The average calculated diameter of the AML cells was 10.4 ± 2.5 μm using ultrasound, and 11.4 ± 2.3 μm using photoacoustics. The average diameter of the melanoma cells was 16.2 ± 2.9 μm using ultrasound, and 18.9 ± 3.5 μm using photoacoustics. The cell sizes calculated using ultrasound and photoacoustic methods agreed with measurements using a Coulter Counter, where the AML cells were 9.8 ± 1.8 μm and the melanoma cells were 16.0 ± 2.5 μm. These results demonstrate a high speed method of assessing cell size using sound waves, which is an alternative method to traditional flow cytometry techniques.

Cardiovascular related diseases are ranked as the second highest cause of death in Canada. Among the most important cardiovascular diseases is atherosclerosis. Current methods of diagnosis of atherosclerosis consist of angiography, intravascular ultrasound (IVUS) and optical coherence tomography (OCT). None of these methods possesses adequate sensitivity, as the ideal technique should be capable of both depth profiling, as well as functional imaging. An alternative technique is photoacoustics (PA) which can perform deep imaging and spectroscopy. The presented study explores the application of wavelength-modulated differential photoacoustic radar (WM-DPAR) for characterizing arterial vessels. The wavelength-modulated differential photoacoustic technique was shown to be able to substantially increase the dynamic range and sensitivity of hemoglobin oxygenation level detection. In this work the differential PA technique was used with a very high frequency modulation range. To perform spectroscopic PA imaging, at least two wavelengths are required. The selected wavelengths for this work are 1210 nm and 980 nm. 1210 nm corresponds to the maximum optical absorption coefficient of cholesterol and cholesteryl esters which are the main constituents of plaques. Since water, elastin and collagen also have high absorption coefficients at 1210 nm, this wavelength alone cannot provide very high sensitivity and specificity. The additional wavelength, 980 nm corresponds to high absorption coefficient of those constituents of healthy artery tissue. The simultaneous application of the abovementioned wavelengths can provide higher sensitivity and improved specificity in detecting lipids in the arterial vessels.

Patients affected by diseases caused by arteriosclerosis are increasing. Atherosclerosis, which is becoming an especially difficult health problem, forms plaques from lipids such as cholesterol located in walls of the aorta, cerebral artery, and coronary artery. Because lipid-rich plaques are vulnerable and because arterial rupture causes acute vascular occlusion, early detection is crucially important to prevent plaque growth and rupture. Ultrasound systems can detect plaques but cannot discriminate between vulnerable and equable plaques. To evaluate plaques non-invasively and easily, we developed a handheld photoacoustic imaging device. Its usefulness was verified in phantom experiments with a bovine aorta in which mimic plaque had been embedded. Photoacoustic images taken at wavelengths that produce high light absorbance by lipids show strong photoacoustic signals from the boundary of the mimic plaque. Results confirmed that our system can evaluate plaque properties by analysis with the photoacoustic spectrum. The effects of surrounding tissues and tissue components on plaque evaluation were investigated using a layered phantom. The mimic plaque located under a 6 mm blood layer was also evaluated. Results of these analyses demonstrate the system’s usefulness.

We present a multimodal optical setup, allowing non-contact photoacoustic imaging, optical coherence tomography (OCT), and non-contact mid-infrared photoacoustic spectroscopy. Photoacoustic signals are generated using a Nd:YAG laser and a tunable quantum cascade laser for photoacoustic imaging and spectroscopy, respectively. Photoacoustic signals are acquired by measuring the surface displacement of a specimen using a fiber-optic Mach-Zehnder interferometer. In the same fiber-optic network a spectral-domain OCT system is realized. Light from the photoacoustic detection laser and the OCT source are multiplexed into one fiber and the same objective is used for both imaging modalities. Light reflected from specimens is demultiplexed and guided to the respective imaging systems. To allow fast non-contact PAI and OCT imaging the detection spot is scanned across the specimens’ surface using a galvanometer scanner. As the same fiber-network and optical components are used for photoacoustic and OCT imaging the obtained images are co-registered intrinsically. Imaging is demonstrated on tissue mimicking and biological samples; spectral information is obtained for polystyrene and hemoglobin.

The Methylene Blue loaded Polyacrylamide Nanoparticles (MB-PAA NPs) are used for oxygen sensing and Photodynamic therapy (PDT), a promising therapeutic modality employed for various tumors, with distinct advantages of delivery of biomedical agents and protection from other bio-molecules overcoming inherent limitations of molecular dyes. Lifetime-resolved photoacoustic spectroscopy using quenched-phosphorescence method is applied with MB-PAA NPs so as to sense oxygen, while the same light source is used for PDT. The dye is excited by absorbing 650 nm wavelength light from a pump laser to reach triplet state. The probe laser at 810 nm wavelength is used to excite the first triplet state at certain delayed time to measure the dye lifetime which indicates oxygen concentration. The 9L cells (106 cells/ml) incubated with MB-PAA NP solution are used for monitoring oxygen level change during PDT in situ test. The oxygen level and PDT efficacy are confirmed with a commercial oximeter, and fluorescence microscope imaging and flow cytometry results. This technique with the MB-PAA NPs allowed us to demonstrate a potential non-invasive theragnostic operation, by monitoring oxygen depletion during PDT in situ, without the addition of secondary probes. Here, we demonstrate this theragnostic operation, in vitro, performing PDT while monitoring oxygen depletion. We also show the correlation between O2 depletion and cell death.

Optical imaging beyond a few mm inside biological tissue is a challenging task due to the light scattering inside the biological tissue. Photoacoustic tomography (PAT) breaks this depth limit of optical imaging by combining light and sound. Over the last few years PAT has emerged as a viable deep tissue imaging modality and created lot of attention to the medical imaging community. However, the cost, size and time consuming image acquisition of the PAT system is deterrent to its translation to real clinical applications. So, there is a need for inexpensive, compact, simple, fast PAT imaging system for easy adoption by the clinical practitioners. Nanosecond pulsed laser diodes could help to bring down the cost, size and image acquisition time and make PAT attractive for deep tissue imaging of optical contrast with high resolution. In this work, we present our findings on using a low-cost pulsed diode laser for deep tissue imaging with photoacoustics. The PAT system was tested on tissue phantoms to verify its potential imaging depth demonstration. Up to 3 cm deep inside chicken breast tissue we were able to see photoacoustic signals and up to 2 cm deep we were able to image successfully. Published version

Photoacoustic imaging can provide high resolution images of tissue structure, pathology and function. As these images can be obtained at multiple wavelengths, quantitatively accurate, spatially resolved, estimates for chromophore concentration, for example, may be obtainable. Such a capability would find a wide range of clinical and pre-clinical applications. However, despite a growing body of theoretical papers on how this might be achieved, there is a noticeable lack of studies providing validated evidence that it can be achieved experimentally, either in vitro or in vivo. Well-defined, versatile and stable phantom materials are essential to assess the accuracy, robustness and applicability of multispectral Quantitative Photoacoustic Imaging (qPAI) algorithms in experimental scenarios. This study assesses the potential of polyvinyl chloride plastisol (PVCP) as a phantom material for qPAI, building on previous work that focussed on using PVCP for quality control. Parameters that might be controlled or tuned to assess the performance of qPAI algorithms were studied: broadband acoustic properties, multiwavelength optical properties with added absorbers and scatterers, and photoacoustic effciency. The optical and acoustic properties of PVCP can be tuned to be broadly representative of soft tissue. The Gruneisen parameter is larger than expected in tissue, which is an advantage as it increases the signal-to-noise ratio of the photoacoustic measurements. Interestingly, when the absorption was altered by adding absorbers, the absorption spectra measured using high peak power nanosecond-pulsed sources (typical in photoacoustics) were repeatably different from the ones measured using the low power source in the spectrophotometer, indicative of photochemical reactions taking place.

Photoacoustic spectroscopy (PAS) is a versatile tool that is well suited for the ranged interrogation of layered samples. We have previously demonstrated standoff photoacoustic (PA) chemical detection of condensed phase samples at one meter distance using an interferometric sensing platform. Current research investigates layered solid samples constructed from a thin layer of energetic material deposited on a substrate. The PA signal from the system, as measured by the interferometer, changes based on the differing optical and mechanical properties of the substrate. This signal variance must be understood in order to develop a sensor capable of detecting trace quantities of hazardous materials independent of the surface. Optical absorption and modal excitation are the two biggest sources of PA signal generated in the sample/substrate system. Finally, the mode of operation of the excitation source is investigated. Most PA sensing paradigms use a quantum cascade laser (QCL) operating in either pulsed or modulated CW mode. We will discuss photoacoustic signal generation with respect to these different operating modes.

In this paper, we describe a narrow-bandwidth generation and detection of photoacoustic (PA) signals in biological specimens using frequency-domain photoacoustics. An intensity-modulated laser was used for PA generation, and a homodyne Michelson interferometer coupled to a lock-in amplifier was used for optical PA detection. The amplitude and phase of the PA signal were measured at the modulation frequency as the frequency was swept over the bandwidth of interest. A synthesized pulse response was obtained using time-domain reconstruction and the absorber map was estimated using k-space reconstruction methods. Experimental results obtained from 500-μm graphite rods embedded in tissue-mimicking phantoms and slide-mounted tissue samples are presented along with their respective time-domain and time-reversal reconstruction maps.

Blood oxygen saturation (SO2) reflects the oxygenation level in blood transport and tissue. Previous studies have shown the capability of non-invasive quantitative measurements of SO2 by multi-wavelength photoacoustic (PA) spectroscopy for diagnosis of brain, tumor hemodynamics and other pathophysiological phenomena. However, those multi-wavelength methods require a tunable laser or multiple lasers which are relatively expensive and bulky for filed measurement environment and applications. Besides, the operation of multiple wavelengths, calibration procedures and data processing gets system complicated, which reduces the feasibility and flexibility for continuous real-time monitoring. Here we report a newly proposed method by combining PA and scattered light signals wherein imposing a hypothesis that scattering intensity is linear to the concentrations of oxygenated hemoglobin and deoxygenated hemoglobin weighed by blood scattering coefficients. A rigorous theoretical relationship between PA and scattering signals is thus established, making it possible that SO2 can be measured with only one excitation wavelength. To verify the theory basis, both dual-ink phantoms and fresh porcine blood sample have been employed in the experiments. The phantom experiment is able to quantify the concentration of mixed red-green ink that is in precise agreement with pre-set values. The ex vivo experiment with fresh porcine blood was conducted and the results of the proposed single-wavelength method achieved high accuracy of 1% - 4% errors. These demonstrated that the proposed single-wavelength SO2 detection is able to provide non-invasive, accurate measurement of blood oxygenation, and herein create potential for applying it to real clinical applications with low cost and high flexibility. Published version

Osteoporosis is a widespread disease that has a catastrophic impact on patient's lives and overwhelming related healthcare costs. In recent works, we have developed a multi-spectral, frequency domain photoacoustic method for the evaluation of bone pathologies. This method has great advantages over pure ultrasonic or optical methods as it provides both molecular information from the bone absorption spectrum and bone mechanical status from the characteristics of the ultrasound propagation. These characteristics include both the Speed of Sound (SOS) and Broadband Ultrasonic Attenuation (BUA). To test the method's quantitative predictions, we have constructed a combined ultrasound and photoacoustic setup. Here, we experimentally present a dual modality system, and compares between the methods on bone samples in-vitro. The differences between the two modalities are shown to provide valuable insight into the bone structure and functional status.

In this study, a photoacoustic detector integrated with Fourier-transform infrared spectroscopy was used to measure biomarkers in gas samples independently. Simulated exhaled breath samples were created by mixing varying concentrations of acetone, ammonia and ethane. The results of these measurements demonstrate the potential of photoacoustic spectroscopy to detect biomarkers from human breath.

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.

In this paper, wavelength selection for multispectral photoacoustic/ultrasound tomography was optimized to obtain accurate images of hemoglobin oxygen saturation (sO 2 ) in vivo . Although wavelengths can be selected by theoretical methods, in practice the accuracy of reconstructed images will be affected by wavelength-specific and system-specific factors such as laser source power and ultrasound transducer sensitivity. By performing photoacoustic spectroscopy of mouse tumor models using 14 different wavelengths between 710 and 840 nm, we were able to identify a wavelength set which most accurately reproduced the results obtained using all 14 wavelengths via selection criteria. In clinical studies, the optimal wavelength set was successfully used to image human ovaries in vivo and noninvasively. Although these results are specific to our co-registered photoacoustic/ultrasound imaging system, the approach we developed can be applied to other functional photoacoustic and optical imaging systems.

Elastography is implemented by applying a mechanical force to a specimen and visualizing the resulting displacement. As a basis of elastographic imaging typically ultrasound, optical coherence tomography or magnetic resonance imaging are used. Photoacoustics has not been viewed as a primary imaging modality for elastography, but only as a complementary method to enhance the contrast in ultrasound elastography. The reason is that photoacoustics is considered speckle free [3], which hinders application of speckle tracking algorithms. However, while conventional ultrasound only uses a single frequency, photoacoustics utilizes a broad frequency spectrum. We are therefore able to generate artificial texture by using a frequency band limited part of the recorded data. In this work we try to assess the applicability of this technique to photoacoustic tomography. We use Agar phantoms with predefined Young's moduli and laterally apply a 50μm static compression. Pre- and post compression data are recorded via a Fabry Perot interferometer planar sensor setup and reconstructed via a non-uniform-FFT reconstruction algorithm. A displacement vector field, between pre- and post compressed data is then determined via optical flow algorithms. While the implementation of texture generation during post processing reduces image quality overall, it turns out that it improves the detection of moving patterns and is therefore better suited for elastography.

Photoacoustic imaging is emerging as a bioimaging technique. The development of contrast agents extend the potential towards novel application. The design of stable phantoms is needed to achieve a semi-quantitative evaluation of the performance of contrast agents. The aim of this study was to investigate the PA signal generated from gold nanorods (GNRs) loaded in custom made phantoms. VevoLAZR (VisualSonics Inc., Toronto) was used with custom made agar phantom, with 5 parallel polyethylene tubes (with 0.58mm internal and 0.99mm external diameter), and a PDMS phantom, with six parallel channels with sizes from 50 μm to 500 μm, loaded with two different types of GNRs: PEGGNRs (53nm length and 11nm axial diameter, plasmon resonance at 840nm, 87nM (15mM Au equivalent)); and gold nanorods (NPZ) coated in a dense layer of hydrophilic polymers by Nanopartz Inc., Loveland, CO (41nm length and 10nm axial diameter, plasmon resonance at 808nm, 83 nM (14mM Au equivalent)). The absorption spectra acquired with the PA system and the spectrophotometer were compared. The reproducibility and stability of the PA signal were evaluated at different dilutions. The dynamic variation of the PA signal was evaluated as function of the number of the GNRs. The SNR and the contrast were measured across the range of concentrations studied. The custom made agar phantom demonstrated suitable for the characterization of PA contrast agents such as PEG-GNRs and NPZ. The PDMS phantom is promising in the field of photoacoustics, therefore future works will conducted exploiting its precise and controlled geometry.

Photoacoustic spectroscopy, a hybrid of optics and acoustics has been gaining popularity in the biomedical field very fast. The main aim in the present study was to apply this technique to detect and distinguish breast tumor tissues from normal and hence develop a tool for clinical applications. There were 224 photoacoustic spectra recorded from 28 normal and 28 breast tumor tissues using PZT detector at 281nm pulsed laser excitations from Nd-YAG laser pumped frequency doubled dye laser system. The recorded time domain photoacoustic spectra were fast Fourier transformed into frequency domain patterns in the frequency region 0-1250kHz and from each pattern, 7 features (mean, median, mode, variance, standard deviation, area under the curve & spectral residual after fitting with 10 th degree polynomial) were extracted using MATLAB algorithms. These features were then tested for their significance between normal and malignant conditions using Student T-test and two of them (variance, std. deviation) showing significant variation were selected for further discrimination analysis using supervised quadratic discriminate analysis (QDA). In QDA, 60 spectra from each of the normal and malignant were used for making the respective calibration sets and the remaining 52 spectra from each were used for the validation. The performance of the analysis tested for the frequency region 406.25 - 625.31 kHz, showed specificity and sensitivity values of 100% and 88.46% respectively suggesting possible application of the technique in breast tumor detection.

Breast cancer is the second most common cancer all over the world. Heterogeneity in breast cancer makes it a difficult task to detect with the existing serum markers at an early stage. With an aim to detect the disease early at the pre-malignant level, MCF-7 cells xenografts were developed using female nude mice and blood serum were extracted on days 0 th , 10 th , 15 th & 20 th post tumor cells injection (N=12 for each time point). Photoacoustic spectra were recorded on the serum samples at 281nm pulsed laser excitations. A total of 144 time domain spectra were recorded from 48 serum samples belonging to 4 different time points. These spectra were then converted into frequency domain (0–1250kHz) using MATLAB algorithms. Subsequently, seven features (mean, median, mode, variance, standard deviation, area under the curve & spectral residuals after 10 th degree polynomial fit) were extracted from them and used for PCA. Further, using the first three Principal components (PCs) of the data, Linear Discriminate Analysis has been carried out. The performance of the analysis showed 82.64% accuracy in predicting various time points under study. Further, frequency-region wise analysis was also performed on the data and found 95 - 203.13 kHz region most suitable for the discrimination among the 4 time points. The analysis provided a clear discrimination in most of the spectral features under study suggesting that the photoacoustic technique has the potential to be a diagnostic tool for early detection of breast tumor development

Real-time monitoring of blood glucose concentration (BGC) is a great important procedure in controlling diabetes mellitus and preventing the complication for diabetic patients. Noninvasive measurement of BGC has already become a research hotspot because it can overcome the physical and psychological harm. Photoacoustic spectroscopy is a well-established, hybrid and alternative technique used to determine the BGC. According to the theory of photoacoustic technique, the blood is irradiated by plused laser with nano-second repeation time and micro-joule power, the photoacoustic singals contained the information of BGC are generated due to the thermal-elastic mechanism, then the BGC level can be interpreted from photoacoustic signal via the data analysis. But in practice, the time-resolved photoacoustic signals of BGC are polluted by the varities of noises, e.g., the interference of background sounds and multi-component of blood. The quality of photoacoustic signal of BGC directly impacts the precision of BGC measurement. So, an improved wavelet denoising method was proposed to eliminate the noises contained in BGC photoacoustic signals. To overcome the shortcoming of traditional wavelet threshold denoising, an improved dual-threshold wavelet function was proposed in this paper. Simulation experimental results illustrated that the denoising result of this improved wavelet method was better than that of traditional soft and hard threshold function. To varify the feasibility of this improved function, the actual photoacoustic BGC signals were test, the test reslut demonstrated that the signal-to-noises ratio(SNR) of the improved function increases about 40-80%, and its root-mean-square error (RMSE) decreases about 38.7-52.8%.

Noninvasive blood glucose level (BGL) monitoring has recently become a research hotspot in the world. Photoacoustic spectroscopy is a well-established, hybrid and promising noninvasive technique, which has already drawn many researchers’ attentions in recent years due to the advantage of overcoming the scattering light interference. As the preliminary exploration of photoacoustic BGL monitoring, a photoacoustic BGL monitoring set-up based on nanosecond pulsed laser with repetition rate of 20Hz and ultrasound transducer with central frequency of 9.55MHz was established in this paper. To explore the mechanism of the time resolved BGL photoacoustic signal, a series of in vitro experiments of glucose aqueous solutions were tested, the time resolved photoacoustic signals for different concentrations of glucose solutions under different output wavelengths were captured with the data average of 512 times. The peak-to-peak values of each solution were gotten at the wavelength interval of 10nm. Difference with the peak-to-peak value of pure water via subtractive spectroscopy, the characteristic wavelengths of glucose were gotten, and the optimum characteristic wavelengths were determined via data pre-processing and principle component analysis(PCA) algorithm, the calibration equation between concentration and the peak-to-peak value was gotten via multiple linear regression(MLR), and the calibration root mean square error(CRMSE) and the prediction root mean square error(PRMSE) of glucose level is all less than 10mg/dl under the correction equation.

Photoacoustic spectroscopy (PAS) is a useful monitoring technique that is well suited for trace gas detection. This method routinely exhibits detection limits at the parts-per-million (ppm) or parts-per-billion (ppb) level for gaseous samples. PAS also possesses favorable detection characteristics when the system dimensions are scaled to a microelectromechanical system (MEMS) design. One of the central issues related to sensor miniaturization is optimization of the photoacoustic cell geometry, especially in relationship to high acoustical amplification and reduced system noise. Previous work relied on a multiphysics approach to analyze the resonance structures of the MEMS scale photo acoustic cell. This technique was unable to provide an accurate model of the acoustic structure. In this paper we describe a method that relies on techniques developed from musical instrument theory and electronic transmission line matrix methods to describe cylindrical acoustic resonant cells with side branches of various configurations. Experimental results are presented that demonstrate the ease and accuracy of this method. All experimental results were within 2% of those predicted by this theory.

Photoacoustic spectroscopy (PAS) is a useful monitoring technique that is well suited for trace detection of gaseous and condensed media. We have previously demonstrated favorable PAS gas detection characteristics when the system dimensions are scaled to a micro-system design. This design includes quantum cascade laser (QCL)-based microelectromechanical systems (MEMS)-scale photoacoustic sensors that provide detection limits at parts-per-billion (ppb) levels for chemical targets. Current gas sensing research utilizes an ultra compact QCL, SpriteIR, in combination with a MEMS-scale photoacoustic cell for trace gas detection. At approximately one tenth the size of a standard commercially available QCL, SpriteIR is an essential element in the development of an integrated sensor package. We will discuss these results as well as the envisioned sensor prototype. Finally, expanding on our previously reported photoacoustic detection of condensed phase samples, we are investigating standoff photoacoustic chemical detection of these materials and will discuss preliminary results.

Quantitative photoacoustics is emerging as a new hybrid modality to investigate diseases and cells in human pathology and cytology studies. Optical absorption of light is the predominant mechanism behind the photoacoustic effect. Therefore, a need exits to characterize the optical properties of specimens and to identify the relevant operating wavelengths for photoacoustic imaging. We have developed a custom low-cost spectrophotometer to measure the optical properties of human axillary lymph nodes dissected for breast-cancer staging. Optical extinction curves of positive and negative nodes were determined in the spectral range of 400 to 1000 nm. We have developed a model to estimate tissue optical properties, taking into account the role of fat and saline. Our results enabled us to select the optimal optical wavelengths for maximizing the imaging contrast between metastatic and noncancerous tissue in axillary lymph nodes.

We present two-photon absorption-induced photoacoustic measurements. Since two-photon photoacoustics is a nonlinear effect numerous physical effects might lead to similar observations. In the presented paper we focus on the effect of the temperature dependent Gruneisen coefficient of water. We discuss the expected theoretical behavior and compare measurements with theoretical predictions. Finally, we demonstrate multimodal photoacoustic and luminescence microscopy via two-photon absorption, and show that it is possible to image objects with localized dyes. Excitation is performed using a femtosecond laser with a wavelength of 800nm. The photoacoustic signals, the luminescence intensity and its spectrum were detected simultaneously.

Photoacoustic (PA) measurements on confined and unconfined hemoglobin molecules are presented. In vitro experiments were performed with porcine red blood cells ( RBCs) at 532 and 1064 nm at various laser fluences. Fluence was gradually changed from 8 to 21 mJ/cm 2 /pulse for 532 nm and 353 to 643 mJ/cm 2 /pulse for 1064 nm. PA signals from suspended RBCs (SRBCs) and hemolyzed RBCs (HRBCs) were measured using a needle hydrophone at hematocrits ranging from 10 to 60%. PA amplitude was found to be varied linearly with the laser fluence for each type of samples at the above two optical radiations. At 532 nm, PA signals from SRBCs and HRBCs were measured to be nearly equal, whereas, at 1064 nm, signal amplitude for SRBCs was approximately 2 times higher than that of HRBCs. The results suggest that it may be feasible to detect hemolysis with PAs. Keywords: Red blood cells, hemoglobin, hemolysis, photoacoustics 1. INTRODUCTION 1.1 Hemolysis and its detection Under various circumstances red blood cell (RBC) membrane may get ruptured resulting in the release of cellular content [i.e. hemoglobin (Hb)] into the ambient medium, known as hemolysis

Although molecularly targeted cancer therapies have shown great promise, it is now evident that responses are dependent upon the molecular genetic context. Spatial and temporal tumour heterogeneity renders biopsy of solid tumours unsuitable for determining the genetic profile of the disease, making adaptation of appropriate therapy difficult. We have utilized the tunable optical absorption characteristic of gold nanorods to assess the potential of photoacoustics for non-invasive multiplexed molecular imaging. Gold nanorods with resonance peaks at 700nm and 900nm were functionalised with in-house antibodies ICR55 and ICR62, targeted to HER2 and EGFR transmembrane receptors, respectively. Three human squamous carcinoma cell lines (LICR-LON-HN4 expressing high HER2 and low EGFR, LICR-LON-HN3 expressing intermediate levels of HER2 and EGFR and A431 expressing high EGFR and low HER2) were incubated with the targeted nanorods for 24 hours. Cells were then incorporated as simulated tumours in tissue-like phantoms composed of 7.5% gelatin containing 0.5% Intralipid® for optical scattering and imaged at a depth of 2.5 cm, using a new clinical in-house multi-spectral photoacoustic imaging system. Images were obtained from the cell inclusions for wavelengths ranging from 710 to 950 nm at 40 nm intervals, and the mean amplitude of the photoacoustic image was computed for each wavelength, to determine their relative receptor expression levels. The molecular profile of the cells obtained using multi-wavelength photoacoustics had substantial similarity to that obtained using flow cytometry. These preliminary results confirm selective uptake of the functionalised nanorods, which reflects the cellular expression of therapeutically important oncoproteins, and give an indication of the potential of photoacoustics for multiplexed molecular profiling.

Breast cancer is the most frequently diagnosed cancer type a nd its detection at an early stage can reduce the mortality rate substantially. With the aim to detect breast cancer early , by studying tumor progression in nude mice, a pulsed laser induced photoacoustic spectroscopy set up has been designed and developed. MCF-7 cells xenografts were developed using six to eight weeks old female nude mice and tumor tissues were extracted on different days (10th, 15th & 20th Day) post injection and the corresponding photoacoustic spectra were recorded at 281nm excitation. A total of 144 time domain spectra were recorded from 36 animals belonging to the three time points (10th, 15th and 20th day post injection) and converted into frequency domains by Fast Fourier Transform (FFT) tools of the MATLAB algorithms and analyzed. The frequency patterns of the tumor masses on 10th, 15th and 20th day of tumor development showed a gradual increase in intensity at certain frequencies, 5.93 x10

Due to the high scattering coefficient of tissue over the wavelength range used for photoacoustic (PA) imaging, most studies employ bulky, low repetition rate lasers to provide sufficient pulse energies at depth to image within the body. The size and cost of these lasers has impeded integration of photoacoustics into conventional, routinely-used ultrasound (US) scanners. Here, we present an approach leveraging the capabilities of modern, high repetition rate fiber lasers to produce a clinically translatable system providing integrated US/PA images at frame rates > 30 Hz. The system uses a portable, low-cost, low pulse-energy (1 mJ/pulse), high repetition rate (1 kHz), 1064 nm laser and is designed for integrated US/PA imaging of the peripheral vasculature or any relevant diseased region, such as a tumor. Using a rotating galvo-mirror system, the incident laser beam is quickly scanned over the imaging area. Multiple PA images covering the scan area are integrated to form a single PA image. Additionally, ultrasound firings are integrated into the scan sequence to provide an US image reconstructed over the same frame period. We acquired PA images of a 1.5-mmdiameter cylindrical absorber (absorption coefficient 5 cm -1 ) embedded in a tissue-mimicking gelatin phantom at 6-cm depth. A 2 cm × 1 cm (depth × lateral) area was reconstructed. We obtained a signal-to-noise ratio of more than 30 dB, comparable to conventional PA methods using high energy, low repetition rate lasers. The current system produces an integrated US/PA frame at a 32 Hz rate, and 100 Hz frame rates are possible with our present approach.

The purpose of this article is to present a sensitive optical system for immediate detection of traces of ammonia by means of photoacoustic spectroscopy and study some properties with both a pulsed CO 2 laser (TEA) and a CW CO 2 laser. The laser beam is aimed to an innovative dual resonator differential cell, which lowest resonant frequency is the first longitudinal mode at 1205 Hz, filled with a flowing NH 3 and N 2 mixture. The chosen cell’s material is polypropylene, suitable for reducing the effects of adsorption. As a result of physical adsorption-desorption studies, based on a pulsed CO 2 laser, 5 % PA signal decay from an enclosed sample of 248 ppmV of NH 3 in N 2 is recorded within 1 hour. The setup for CW CO 2 laser excitation takes advantage of a differential microphone connected to both resonators by picking up out of phase signals. For this purpose, the beam is modulated at the cell’s resonance by means of a chopper with a special blade which allows both reflection and transmission of the laser beam; the direct and the reflected beam are alternatively aimed to one resonator and the other. The measurements show that for the double resonator configuration a signal increase is achieved, as expected from the study of the sensitivity of both resonators separately, which have been previously characterized. Measurements with this system indicate a limit of detection of 13ppbV at the 10P(32) laser line, deduced from one standard deviation of the PA signal from pure N 2 .

Photoacoustic spectroscopy (PAS) is a powerful tool for the study of the absorption spectra of solid samples. Scattered light, which used to be a main error source in conventional absorption spectroscopy, is not a problem for PAS, and furthermore, in this paper it is helpful for photoacoustic spectroscopy measurement. In this work, the photoacoustic spectra of an olanzapine tablet and its powder have been investigated. Differential analysis was used to eliminate the background signal generated by the photoacoustic cell. It is found that the photoacoustic spectrum of olanzapine in the powdered olanzapine tablet has the same spectral features as that of the pure olanzapine powder, while the photoacoustic spectrum of the olanzapine tablet does not have, although the ingredients in both are completely the same. This phenomenon can be interpreted as the light scattering effects in the powdered olanzapine tablet. The light scattering effects in a solid mixture amplify the photoacoustic spectral features of the main light-absorbing ingredient in the mixture, rather than enhance the measured photoacoustic signal over the whole measured wavelength range, which is different from the influence of light scattering effects on a single-ingredient solid powder. Based on this work, a method is proposed to preliminarily fast identify the light-absorbing ingredient in a solid mixture. Using the method, a drug tablet can be measured directly in solid state and hardly need sample preprocessing, and thus the time for composition analyses will be reduced significantly.

Nonlinear optical materials are important to extend the spectral coverage of existing lasers, mainly via frequency doubling and with optical parametric oscillators. The quality of the materials and components, e.g. in terms of residual absorption, is pivotal for the performance of the devices. The paper presents high-sensitivity absorption measurements of nonlinear optical materials. They were performed using a photoacoustic spectrometer which combines high sensitivity with broad spectral coverage. This allows one not only to quantify the level of residual absorption but also to assist in the characterization of the materials in terms of optically relevant impurities and imperfections. The spectrometer covers the wavelength range between 407 and 2600 nm using a pulsed optical parametric oscillator as excitation source. Pulse energies up to 100 mJ allow one to record absorption spectra with a sensitivity down to 10 ppm/cm. The paper presents spectra of lithium niobate and lithium triborate crystals which are important for highpower nonlinear optical applications. The results are discussed with respect to material impurities and the suitability of individual samples for frequency conversion.

This study examines the application of backscattered ultrasound (US) and photoacoustics (PA) for assessment of bone structure and density variations. Both methods are applied in the frequency-domain, employing linear frequency modulation chirps. An 800-nm CW laser and a 3.5-MHz ultrasonic transducer are used for transmitting the signal. The backscattered pressure waves are detected with a 2.2-MHz US transducer. Experiments are focused on detection and evaluation of PA and US signals from in-vitro animal and human bones with cortical and trabecular sublayers. Osteoporotic changes in the bone are simulated by using a very mild demineralization solution (EDTA). Changes in the time-domain signal as well as integrated backscattering spectra are compared for each sample before and after demineralization. Results show the ability of US to generate detectable signals from deeper bone sublayers, whereas the PA signals show higher sensitivity to the variation in bone density. While US signal variation with changes in the cortical layer is insignificant, PA has proven to be able to detect minor variation of the cortical bone density.