Conventional Photoacoustic Imaging Research Articles

A multi-aperture encoding scheme for increased SNR in photoacoustic Imaging

Photoacoustic imaging creates light-induced ultrasonic signals to provide valuable information on internal body structures and tissue morphology non-invasively. A multi-aperture photoacoustic imaging (MP-PAI) system is an improvement over conventional photoacoustic imaging (PAI) systems in terms of resolution, contrast, and field of view. Previously, a prototype MP-PAI system was introduced based on multiple capacitive micromachined ultrasound transducers (CMUTs) with shared channels, such that each element in a CMUT shares its channel with its counterpart in other CMUTs. The system uses the biasing voltages of the CMUTs to switch between them and multiplex the received signals in time. Notwithstanding all the enhancements, the signal-to-noise ratio (SNR) remains limited in PAI. To address this issue, we are proposing a multi-aperture encoding scheme (MAES) to further increase the SNR in a multi-aperture PAI system. The proposed method involves receiving signals with multiple CMUTs simultaneously based on an encoding matrix, instead of switching between individual CMUTs. As a result, shared channels contain a superposition of signals, which are later recovered by applying a decoding matrix. Here, an analytical model for computing SNR with an arbitrary encoding sequence is presented, and the method is validated through numerical simulations and in an experimental study. Bipolar and unipolar encoding sequences were considered for the experiments. The numerical results show, in comparison to conventional MP-PAI, that MAES will obtain an SNR gain of 5.8 and 8.8 dB for S-sequence and truncated Hadamard encodings, respectively, when using 15 transducers. In experiments, three transducers are encoded by S-sequences and show 1.5 dB improvement in SNR over conventional MP-PAI method, which aligns well with the analytical model.

Transparent Dual-Frequency CMUT Arrays for Photoacoustic Imaging.

The opaque ultrasound transducers used in conventional photoacoustic imaging systems necessitate oblique light delivery, which gives rise to some disadvantages such as inefficient target illumination and bulky system size. This work proposes a transparent capacitive micromachined ultrasound transducer (CMUT) linear array with dual-band operation for through-illumination photoacoustic imaging. Fabricated using an adhesive wafer bonding method, the array consists of optically transparent conductors [indium tin oxide (ITO)] as both top and bottom electrodes, a transparent polymer [bisbenzocyclobutene (BCB)] as the sidewall and adhesive material, and largely transparent silicon nitride as the membrane. The fabricated device had a maximum optical transparency of 76.8% in the visible range. Furthermore, to simultaneously maintain higher spatial resolution and deeper imaging depth, this dual-frequency array consists of low- and high-frequency channels with 4.2- and 9.3-MHz center frequencies, respectively, which are configured in an interlaced architecture to minimize the grating lobes in the receive point spread function (PSF). With a wider bandwidth compared to the single-frequency case, the fabricated transparent dual-frequency CMUT array was used in through-illumination photoacoustic imaging of wire targets demonstrating an improved spatial resolution and imaging depth.

Mitigating skin tone bias in linear array in vivo photoacoustic imaging with short-lag spatial coherence beamforming

Photoacoustic (PA) imaging has the potential to deliver non-invasive diagnostic information. However, skin tone differences bias PA target visualization, as the elevated optical absorption of melanated skin decreases optical fluence within the imaging plane and increases the presence of acoustic clutter. This paper demonstrates that short-lag spatial coherence (SLSC) beamforming mitigates this bias. PA data from the forearm of 18 volunteers were acquired with 750-, 810-, and 870-nm wavelengths. Skin tones ranging from light to dark were objectively quantified using the individual typology angle (ITA°). The signal-to-noise ratio (SNR) of the radial artery (RA) and surrounding clutter were measured. Clutter was minimal (e.g., −16 dB relative to the RA) with lighter skin tones and increased to −8 dB with darker tones, which compromised RA visualization in conventional PA images. SLSC beamforming achieved a median SNR improvement of 3.8 dB, resulting in better RA visualization for all skin tones.

Temperature difference effect of biological tissues induced by low-intensity unfocused ultrasound

Low-intensity unfocused ultrasound (LIUU) is proposed for producing a temperature difference (TD) effect in biological tissues. A finite-element simulation model has been established to validate the method’s rationality, and its effectiveness in practical applications is further discussed through phantom experiments. Experimental results indicate that LIUU under suitable conditions can result in discrepancy of temperature increases in biological tissues with complex compositions. For photoacoustic imaging, the method leverages differences in acoustic absorption coefficients of biological tissues and extracts the TD as an imaging contrast, offering the potential to enhance tissue discrimination in conventional photoacoustic imaging with low light absorption coefficients.

Recent Advances in Contrast-Enhanced Photoacoustic Imaging: Overcoming the Physical and Practical Challenges.

For decades now, photoacoustic imaging (PAI) has been investigated to realize its potential as a niche biomedical imaging modality. Despite its highly desirable optical contrast and ultrasonic spatiotemporal resolution, PAI is challenged by such physical limitations as a low signal-to-noise ratio (SNR), diminished image contrast due to strong optical attenuation, and a lower-bound on spatial resolution in deep tissue. In addition, contrast-enhanced PAI has faced practical limitations such as insufficient cell-specific targeting due to low delivery efficiency and difficulties in developing clinically translatable agents. Identifying these limitations is essential to the continuing expansion of the field, and substantial advances in developing contrast-enhancing agents, complemented by high-performance image acquisition systems, have synergistically dealt with the challenges of conventional PAI. This review covers the past four years of research on pushing the physical and practical challenges of PAI in terms of SNR/contrast, spatial resolution, targeted delivery, and clinical application. Promising strategies for dealing with each challenge are reviewed in detail, and future research directions for next generation contrast-enhanced PAI are discussed.

Quantitative analysis of oxygen partial pressure measurements based on photoacoustic pump-probe imaging

Pump-probe-based photoacoustic imaging is an innovative technique for high-specificity molecular imaging in deep tissues. Compared with conventional photoacoustic imaging, this method effectively eliminates the interference from blood signal and other background signal, enabling the detection of subtle target molecules. Additionally, the manipulating of the time delay between the pump laser and probe laser can facilitate non-invasive mapping of oxygen partial pressure distribution within tissues. To quantify the photoacoustic pump-probe imaging, we use methylene blue as the molecular probe to monitor changes in oxygen partial pressure within a hemoglobin solution. Utilizing a Gaussian noise model, we investigate the relationship between the stability of the triplet-state difference signal and the average number, and also evaluate the error associated with measuring oxygen partial pressure. The results demonstrate that the detection accuracy of the system is better than 33 mmHg (1 mmHg = 133 Pa) in the oxygen partial pressure range of about 300 to 550 mmHg after 200 times of averaging. This research will play a significant role in guiding the further advancement and application of pump-probe-based photoacoustic imaging technology.

Calibrated Photoacoustic Spectrometer Based on a Conventional Imaging System for In Vitro Characterization of Contrast Agents.

Photoacoustic (PA) imaging systems are spreading in the biomedical community, and the development of new PA contrast agents is an active area of research. However, PA contrast agents are usually characterized with spectrophotometry or uncalibrated PA imaging systems, leading to partial assessment of their PA efficiency. To enable quantitative PA spectroscopy of contrast agents in vitro with conventional PA imaging systems, we have developed an adapted calibration method. Contrast agents in solution are injected in a dedicated non-scattering tube phantom imaged at different optical wavelengths. The calibration method uses a reference solution of cupric sulfate to simultaneously correct for the spectral energy distribution of excitation light at the tube location and perform a conversion of the tube amplitude in the image from arbitrary to spectroscopic units. The method does not require any precise alignment and provides quantitative PA spectra, even with non-uniform illumination and ultrasound sensitivity. It was implemented on a conventional imaging setup based on a tunable laser operating between 680 nm and 980 nm and a 5 MHz clinical ultrasound array. We demonstrated robust calibrated PA spectroscopy with sample volumes as low as 15 μL of known chromophores and commonly used contrast agents. The validated method will be an essential and accessible tool for the development of new and efficient PA contrast agents by improving their quantitative characterization.

Advances in Endoscopic Photoacoustic Imaging.

Photoacoustic (PA) imaging is able to provide extremely high molecular contrast while maintaining the superior imaging depth of ultrasound (US) imaging. Conventional microscopic PA imaging has limited access to deeper tissue due to strong light scattering and attenuation. Endoscopic PA technology enables direct delivery of excitation light into the interior of a hollow organ or cavity of the body for functional and molecular PA imaging of target tissue. Various endoscopic PA probes have been developed for different applications, including the intravascular imaging of lipids in atherosclerotic plaque and endoscopic imaging of colon cancer. In this paper, the authors review representative probe configurations and corresponding preclinical applications. In addition, the potential challenges and future directions of endoscopic PA imaging are discussed.

Dual-modal imaging with non-contact photoacoustic microscopy and fluorescence microscopy.

Simultaneous imaging of complementary absorption and fluorescence contrasts with high spatial resolution is useful for biomedical studies. However, conventional dual-modal photoacoustic (PA) and fluorescence imaging systems require the use of acoustic coupling media due to the contact operation of PA imaging, which causes issues and complicates the procedure in certain applications such as cell imaging and ophthalmic imaging. We present a novel dual-modal imaging system which combines non-contact PA microscopy (PAM) based on PA remote sensing and fluorescence microscopy (FLM) into one platform. The system enables high lateral resolution of 2 and 2.7 µm for PAM and FLM modes, respectively. In vivo imaging of a zebrafish larva injected with a rhodamine B solution is demonstrated, with PAM visualizing the pigment and FLM revealing the injected rhodamine B.

Sensing non-light-absorbing media via thermally modulated photoacoustic measurements

In conventional photoacoustic (PA) imaging, the imaging contrast is largely determined by the difference in optical absorption of the targets. Therefore, to distinguish non-light-absorbing media using these optical methods presents practical difficulties. It has been shown that the difference in thermodynamic properties is more obvious in certain situations. Further, it has been found experimentally that the PA response of a probe is significantly different due to the thermodynamic action of the surrounding medium, for example, there is a reverse trend for lipid and collagen. In this Letter, an optical method using a PA-responsive external probe to sense the difference in thermodynamic properties of non-light-absorbing media is proposed. The experimental results demonstrate that the proposed method provides a scheme to solve the challenges encountered by traditional PA technologies and has significant potential in biomedical applications.

Photoacoustic Imaging of Human Vasculature Using LED versus Laser Illumination: A Comparison Study on Tissue Phantoms and In Vivo Humans

Vascular diseases are becoming an epidemic with an increasing aging population and increases in obesity and type II diabetes. Point-of-care (POC) diagnosis and monitoring of vascular diseases is an unmet medical need. Photoacoustic imaging (PAI) provides label-free multiparametric information of deep vasculature based on strong absorption of light photons by hemoglobin molecules. However, conventional PAI systems use bulky nanosecond lasers which hinders POC applications. Recently, light-emitting diodes (LEDs) have emerged as cost-effective and portable optical sources for the PAI of living subjects. However, state-of-art LED arrays carry significantly lower optical energy (<0.5 mJ/pulse) and high pulse repetition frequencies (PRFs) (4 KHz) compared to the high-power laser sources (100 mJ/pulse) with low PRFs of 10 Hz. Given these tradeoffs between portability, cost, optical energy and frame rate, this work systematically studies the deep tissue PAI performance of LED and laser illuminations to help select a suitable source for a given biomedical application. To draw a fair comparison, we developed a fiberoptic array that delivers laser illumination similar to the LED array and uses the same ultrasound transducer and data acquisition platform for PAI with these two illuminations. Several controlled studies on tissue phantoms demonstrated that portable LED arrays with high frame averaging show higher signal-to-noise ratios (SNRs) of up to 30 mm depth, and the high-energy laser source was found to be more effective for imaging depths greater than 30 mm at similar frame rates. Label-free in vivo imaging of human hand vasculature studies further confirmed that the vascular contrast from LED-PAI is similar to laser-PAI for up to 2 cm depths. Therefore, LED-PAI systems have strong potential to be a mobile health care technology for diagnosing vascular diseases such as peripheral arterial disease and stroke in POC and resource poor settings.

Compensating for visibility artefacts in photoacoustic imaging with a deep learning approach providing prediction uncertainties

Conventional photoacoustic imaging may suffer from the limited view and bandwidth of ultrasound transducers. A deep learning approach is proposed to handle these problems and is demonstrated both in simulations and in experiments on a multi-scale model of leaf skeleton. We employed an experimental approach to build the training and the test sets using photographs of the samples as ground truth images. Reconstructions produced by the neural network show a greatly improved image quality as compared to conventional approaches. In addition, this work aimed at quantifying the reliability of the neural network predictions. To achieve this, the dropout Monte-Carlo procedure is applied to estimate a pixel-wise degree of confidence on each predicted picture. Last, we address the possibility to use transfer learning with simulated data in order to drastically limit the size of the experimental dataset.

Photoacoustic fluctuation imaging: theory and application to blood flow imaging

Photoacoustic fluctuation imaging, which exploits randomness in photoacoustic generation, provides enhanced images in terms of resolution and visibility, as compared to conventional photoacoustic images. While a few experimental demonstrations of photoacoustic fluctuation imaging have been reported, it has to date not been described theoretically. In the first part of this work, we propose a theory relevant to fluctuations induced either by random illumination patterns or by random distributions of absorbing particles. The theoretical predictions are validated by Monte Carlo finite-difference time-domain simulations of photoacoustic generation in random particle media. We provide a physical insight into why visibility artefacts are absent from second-order fluctuation images. In the second part, we demonstrate experimentally that harnessing randomness induced by the flow of red blood cells produce photoacoustic fluctuation images free of visibility artefacts. As a first proof of concept, we obtain two-dimensional images of blood vessel phantoms. Photoacoustic fluctuation imaging is finally applied in vivo to obtain 3D images of the vascularization in a chicken embryo.

Self‐Reporting Gold Nanourchins for Tumor‐Targeted Chemo‐Photothermal Therapy Integrated with Multimodal Imaging

AbstractIn search of facile yet efficient therapeutic and imaging nanoagents for cancer treatment, versatile self‐reporting gold nanourchins (AuNUs) featuring synergic chemo‐photothermal therapies and multimodal imaging are fabricated. AuNUs are synthesized using a surfactant‐free approach, and then functionalized with a Raman reporter 4‐mercaptophenylboronic acid (4‐MPBA) and dopamine to form adenosine triphosphate (ATP)‐cleavable boronate ester bonds prior to further immobilization with hyaluronic acid (HA) for cancer targeting. Controlled release of an anticancer drug, doxorubicin (DOX), loaded in the interstices of AuNUs, is achieved upon exposure to the overproduced hyaluronidase (HAase) in a tumor microenvironment. The spiny exterior of AuNUs enables their optophysical conversion of near‐infrared (NIR) light (808 nm) to heat for photothermal therapy and IR imaging. The surface enhanced Raman scattering (SERS) of AuNUs also allows sensitive and reliable Raman mapping of their cellular uptake in vitro, and intratumoral accumulation in vivo, complementary to conventional photoacoustic imaging (PAI). With a demonstrated ability to eradicate tumors and enable multimodal imaging, AuNUs exemplify ongoing efforts in design and utility of multifunctional nanoplatforms.

Single-Cell Photoacoustic Microrheology.

Rheological properties, such as elasticity and viscosity, are fundamental biomechanical parameters that are related to the function and pathological status of cells and tissues. In this paper, an innovative photoacoustic microrheology (PAMR), which utilized the time and phase characteristics of photoacoustic (PA) response, was proposed to extract elastic modulus and viscosity. The feasibility and accuracy of the method were validated by tissue-mimicking agar-gelatin phantoms with various viscoelasticity values. PAMR realized single cell elasticity and viscosity mappings on the adipocyte and myocyte with micrometer scale. In clinical samples, normal blood cells and iron deficiency anemia cells were successfully distinguished due to their various rheological properties. This method expands the scope of conventional PA imaging and opens new possibilities for developing microrheological technology, prefiguring great clinical potential for interrogating mechanocellular properties.

Three-dimensional interventional photoacoustic imaging for biopsy needle guidance with a linear array transducer.

Needle placement is important for many clinical interventions, such as tissue biopsy, regional anesthesia and drug delivery. It is essential to visualize the spatial position of the needle and the target tissue during the interventions using appropriate imaging techniques. Based on the contrast of optical absorption, photoacoustic imaging is well suited for the guidance of interventional procedures. However, conventional photoacoustic imaging typically provides two-dimensional (2D) slices of the region of interest and could only visualize the needle and the target when they are within the imaging plane of the probe at the same time. This requires great alignment skill and effort. To ease this problem, we developed a 3D interventional photoacoustic imaging technique by fast scanning a linear array ultrasound probe and stitching acquired image slices. in vivo sentinel lymph node biopsy experiment shows that the technique could precisely locate a needle and a sentinel lymph node in a tissue volume while a perfusion experiment demonstrates that the technique could visualize the 3D distribution of injected methylene blue dye underneath the skin at high temporal and spatial resolution. The proposed technique provides a practical way for photoacoustic image-guided interventions.

Dual-Contrast Nonlinear Photoacoustic Sensing and Imaging Based on Single High-Repetition- Rate Pulsed Laser

Photoacoustic imaging (PAI) is a fast-developing non-invasive imaging technique, which provides optical contrast in deep scattering tissue with high spatial resolution. Conventional photoacoustic (PA) imaging has been widely studied based on linear PA effect, which is induced by single short laser pulse. Recently, nonlinear photoacoustic effect has been proposed by using two consecutive laser pulses with two laser sources. In this paper, we report a dual-contrast nonlinear photoacoustic (dNPA) sensing and imaging technique by single high-repetition-rate laser induced nonlinear PA effect. Using the high-repetition-rate pulsed laser, two different kinds of imaging contrasts can be extracted: optical and thermal contrasts. Unlike conventional PA imaging that exhibits optical absorption only, we could extract thermal contrast that is reflected by the rising slope/trend of temperature and consequent PA signals. In this paper, the high-repetition-rate nonlinear PA effect and dual-contrast mechanism were proposed in theory with detailed mathematical modeling. The dual-contrast PA sensing and imaging were demonstrated by experimental results with both in vitro phantom and ex vivo porcine tissues. The results indicate both optical absorption and thermal accumulation properties of different samples, which could enhance the image contrast significantly.

Photoacoustic imaging in the second near-infrared window: a review.

.Photoacoustic (PA) imaging is an emerging medical imaging modality that combines optical excitation and ultrasound detection. Because ultrasound scatters much less than light in biological tissues, PA generates high-resolution images at centimeters depth. In recent years, wavelengths in the second near-infrared (NIR-II) window (1000 to 1700 nm) have been increasingly explored due to its potential for preclinical and clinical applications. In contrast to the conventional PA imaging in the visible (400 to 700 nm) and the first NIR-I (700 to 1000 nm) window, PA imaging in the NIR-II window offers numerous advantages, including high spatial resolution, deeper penetration depth, reduced optical absorption, and tissue scattering. Moreover, the second window allows a fivefold higher light excitation energy density compared to the visible window for enhancing the imaging depth significantly. We highlight the importance of the second window for PA imaging and discuss the various NIR-II PA imaging systems and contrast agents with strong absorption in the NIR-II spectral region. Numerous applications of NIR-II PA imaging, including whole-body animal imaging and human imaging, are also discussed.

Passive ultrasound aided acoustic resolution photoacoustic microscopy imaging for layered heterogeneous media

Photoacoustic imaging reconstructions usually assume a known speed-of-sound (SOS) distribution; however, in most cases, the SOS distribution is not revealed and is difficult to estimate from photoacoustic signals. In this paper, we propose passive ultrasound aided acoustic resolution photoacoustic microscopy which simultaneously reconstructs SOS distributions and photoacoustic images for layered heterogeneous media. The passive ultrasound is a kind of laser-induced acoustic wave generated by a transducer absorbing the backscattered light. It can be used to measure the layer thicknesses due to its sensitivity to structural information and broad bandwidth and further determine the SOS distributions. After estimating the SOS distributions, a phase shift plus interpolation is employed to reconstruct the photoacoustic image for heterogeneous media. Without introducing additional hardware, this method can be conveniently incorporated into a conventional photoacoustic imaging system. A curved shell immersed in water is adopted as a layered heterogeneous phantom, and the proposed method reconstructs the targets (carbon rods) under this shell. Under the test of a 5 MHz focused transducer (NA 0.25), the maximum reconstruction deviation of 1.2 mm carbon rods is only 0.15 mm.

Hybrid multi-wavelength nonlinear photoacoustic sensing and imaging.

Multi-wavelength photoacoustic (PA) imaging has been studied extensively to explore the spectroscopic absorption contrast of biological tissues. To generate strong PA signals, a high-power wavelength tunable pulsed laser source has to be employed, which is bulky and quite expensive. In this Letter, we propose a hybrid multi-wavelength PA imaging (hPAI) method based on the combination of a single-wavelength pulsed laser source and multi-wavelength continuous-wave (CW) laser sources. By carefully controlling the laser illumination sequence (pulse-CW-pulse) and extracting the PA signal difference before and after the heating of CW lasers, the optical absorption property of multi-wavelength light illumination could be obtained. Compared with conventional PA imaging, the proposed hPAI shows a much lower system cost due to the usage of single-wavelength pulsed lasers and multiple inexpensive CW lasers. As the preliminary results show in this Letter, hPAI imaging has the potential to provide another pathway for high spectroscopic optical absorption contrast in PA imaging.