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Prostate-specific membrane antigen (PSMA) is a promising diagnostic and therapeutic target for prostate cancer (PC). Poly(amidoamine) [PAMAM] dendrimers serve as versatile scaffolds for imaging agents and drug delivery that can be tailored to different sizes and compositions depending upon the application. We have developed PSMA-targeted PAMAM dendrimers for real-time detection of PC using fluorescence (FL) and photoacoustic (PA) imaging. A generation-4, ethylenediamine core, amine-terminated dendrimer was consecutively conjugated with on average 10 lysine-glutamate-urea PSMA targeting moieties and a different number of sulfo-cyanine7.5 (Cy7.5) near-infrared dyes (2, 4, 6 and 8 denoted as conjugates II, III, IV and V, respectively). The remaining terminal primary amines were capped with butane-1,2-diol functionalities. We also prepared a conjugate composed of Cy7.5-lysine-suberic acid-lysine glutamate-urea (I) and control dendrimer conjugate (VI). Among all conjugates, IV showed superior in vivo target specificity in male NOD-SCID mice bearing isogenic PSMA+ PC3 PIP and PSMA- PC3 flu xenografts and suitable physicochemical properties for FL and PA imaging. Such agents may prove useful in PC cancer detection and subsequent surgical guidance during excision of PSMA-expressing lesions.

Photoacoustic (PA) imaging has attracted much attention as a new biomedical imaging modality due to its ultrasonic spatial resolution, optical contrast resolution, and deeper imaging depth than oth...

The multi-bounce laser microphone utilizes optical methods to detect the displacement of a gold-covered thin film diaphragm caused by ultrasound signal pressure waves. This sensitive all-optical sensing technique provides new opportunities for advanced ultrasound imaging as it is expected to achieve a higher detection signal-to-noise ratio (SNR) in a broader spectrum, as compared to conventional ultrasonic transducers. The technique does not involve signal time-averaging and the real-time enhancement in detection SNR stems from the amplification of signal strength due to multiple bouncing off the diaphragm. The system was previously developed for detecting acoustic signatures generated by explosives and were limited to lower than 10 kHz in frequency. To demonstrate its feasibility for biomedical imaging applications, preliminary experiments were conducted to show high fidelity detection of ultrasound waves with frequencies ranging from 100 kHz to in excess of 1 MHz. Experimental results are also presented in this work demonstrating the improved detection sensitivity of the multi-bounce laser microphone in detecting ultrasound signals when compared with a commercial Fabry-Perot type optical hydrophone. Furthermore, we also applied the multi-bounce laser microphone to detect photoacoustic signatures emitted by India ink when a LED bar is used as the excitation source without signal averaging.

We hypothesize that noninvasive photoacoustic imaging can accurately measure cerebral venous oxyhemoglobin saturation (So2) in a neonatal model of hypoxia-ischemia. In neonatal piglets, which have a skull thickness comparable to that of human neonates, we compared the photoacoustic measurement of sagittal sinus So2 against that measured directly by blood sampling over a wide range of conditions. Systemic hypoxia was produced by decreasing inspired oxygen stepwise (i.e., 100, 21, 19, 17, 15, 14, 13, 12, 11, and 10%) with and without unilateral or bilateral ligation of the common carotid arteries to enhance hypoxia-ischemia. Transcranial photoacoustic sensing enabled us to detect changes in sagittal sinus O2 saturation throughout the tested range of 5–80% without physiologically relevant bias. Despite lower cortical perfusion and higher oxygen extraction in groups with carotid occlusion at equivalent inspired oxygen, photoacoustic measurements successfully provided a robust linear correlation that approached the line of identity with direct blood sample measurements. Receiver-operating characteristic analysis for discriminating So2 2 noninvasively over a wide range and support its use for early detection of neonatal hypoxia-ischemia. NEW & NOTEWORTHY We present data to validate the noninvasive photoacoustic measurement of sagittal sinus oxyhemoglobin saturation. In particular, this paper demonstrates the robustness of this methodology during a wide range of hemodynamic and physiological changes induced by the stepwise decrease of fractional inspired oxygen to produce hypoxia and by unilateral and bilateral ligation of the common carotid arteries preceding hypoxia to produce hypoxia-ischemia. This technique may be useful for diagnosing risk of neonatal hypoxic-ischemic encephalopathy.

In this paper, we present a novel system-on-chip (SOC) solution for a portable ultrasound imaging system (PUS) for point-of-care applications. The PUS-SOC includes all of the signal processing modules (i.e., the transmit and dynamic receive beamformer modules, mid- and back-end processors, and color Doppler processors) as well as an efficient architecture for hardware-based imaging methods (e.g., dynamic delay calculation, multi-beamforming, and coded excitation and compression). The PUS-SOC was fabricated using a UMC 130-nm NAND process and has 16.8 GFLOPS of computing power with a total equivalent gate count of 12.1 million, which is comparable to a Pentium-4 CPU. The size and power consumption of the PUS-SOC are $27\times 27~{\rm mm}^{2}$ and 1.2 W, respectively. Based on the PUS-SOC, a prototype hand-held US imaging system was implemented. Phantom experiments demonstrated that the PUS-SOC can provide appropriate image quality for point-of-care applications with a compact PDA size ( $200\times 120\times 45~{\rm mm}^{3}$ ) and 3 hours of battery life.

Coherent manipulation of light-matter interactions is pivotal to the advancement of nanophotonics. Conventionally, the non-resonant optical Stark effect is harnessed for band engineering by intense laser pumping. However, this method is hindered by the transient Stark shifts and the high-energy laser pumping which, by itself, is precluded as a nanoscale optical source due to light diffraction. As an analog of photons in a laser, surface plasmons are uniquely positioned to coherently interact with matter through near-field coupling, thereby, providing a potential source of electric fields. Herein, the first demonstration of plasmonic Stark effect is reported and attributed to a newly uncovered energy-bending mechanism. As a complementary approach to the optical Stark effect, it is envisioned that the plasmonic Stark effect will advance fundamental understanding of coherent light-matter interactions and will also provide new opportunities for advanced optoelectronic tools, such as ultrafast all-optical switches and biological nanoprobes at lower light power levels.

The implementation of dynamic delay calculations (DDCs) is challenging for ultra-compact ultrasound imaging due to the enormous computation and power consumption requirements. Here, we present an efficient pseudo-DDC method based on optimal zone segmentation (PDC-Optimal), which significantly decreases these requirements relative to an unconstrained DDC method: reductions in flip-flops of 84.35% and in look-up tables of 94.19%, respectively. The reductions lead to an up to 94.53% lower dynamic power consumption and provide image quality comparable to the unconstrained DDC method. The proposed PDC-Optimal method also provides adaptive flexibility between beamforming accuracy and battery life using the delay error allowance, a user-definable parameter. A conventional pseudo-DDC method using uniform zone segmentation (PDC-Conv) presented substantial image degradation in the near imaging field when the same number of zone segments was used. Therefore, the PDC-Optimal method provides an efficient yet flexible DDC solution to improve the experiences for ultra-compact ultrasound imaging system users.

We present a proof-of-concept of an automatic integration of photoacoustic (PA) imaging on clinical ultrasound (US) imaging platforms. Here we tackle two critical challenges: the laser synchronization and the inaccessibility to the beamformer core embedded in commercial US imaging platform. In particular, the line trigger frequency (LTF) estimation and the asynchronous synthetic aperture inverse beamforming (ASAIB) were developed and evaluated in both k-Wave simulation and phantom experiment. The proposed method is an economical solution to enable PA imaging on a greater number of US equipment to further thrive the PA imaging research community.

A sensitive, non-invasive method to detect localized prostate cancer, particularly for early detection and repetitive study in patients undergoing active surveillance, remains an unmet need. Here we propose a molecular photoacoustic (PA) imaging approach by targeting the prostate-specific membrane antigen (PSMA), which is over-expressed in the vast majority of prostate cancers. We performed spectroscopic PA imaging in an experimental model of prostate cancer, namely, in immunocompromised mice bearing PSMA+ (PC3 PIP) and PSMA− (PC3 flu) tumors through administration of the known PSMA-targeted fluorescence agent, YC-27. Differences in contrast between PSMA+ and isogenic control tumors were observed upon PA imaging, with PSMA+ tumors showing higher contrast in average of 66.07-fold with five mice at the 24-hour post-injection time points. These results were corroborated using standard near-infrared fluorescence imaging with YC-27, and the squared correlation between PA and fluorescence intensities was 0.89. Spectroscopic PA imaging is a new molecular imaging modality with sufficient sensitivity for targeting PSMA in vivo, demonstrating the potential applications for other saturable targets relevant to cancer and other disorders.

Quantification of brain function is a significant milestone towards understanding of the underlying workings of the brain. Photoacoustic (PA) imaging is the emerging brain sensing modality by which the molecular light absorptive contrast can be non-invasively quantified from deep-lying tissue (~several cm). In this BRAIN initiative effort, we propose high-speed transcranial PA imaging using a novel, compact pulsed LED illumination system (Prexion Inc., Japan) with 200-uJ pulse energy for 75-ns duration, and pulse repetition frequency (PRF) up to 4kHz at near-infrared (NIR) wavelengths of 690-nm and 850-nm switchable in real-time. To validate the efficacy of the proposed system, preliminary ex vivo experiments were conducted with mice skull and human temporal bone, which included vessel-mimicking tubes filled with 10% Indian Ink solution and light absorptive rubber material, respectively. The results indicated that significant PA contrast, 150% signal-to-noise ratio (SNR), can be achieved through the mice skull only with 64 subsequent frame averaging. The minimal number of frames for averaging required was only 16 to generate signal above background noise, leading to 250 Hz frame rate in the strictest temporal frame separation. Furthermore, distinguishable PA contrast was achieved with human temporal bone with 64-frame averaging. Overall, the preliminary results indicate that the LED illumination system can be a cost-effective solution for high-speed PA brain imaging in preclinical and clinical applications, compared to expansive and bulky Nd:YAG laser systems commonly used in PA imaging.

Precise sentinel lymph node (SLN) identification is crucial not only for accurate diagnosis of micro-metastases at an early stage of cancer progression but also for reducing the number of SLN biopsies (SLNB) to minimize their severe side effects. Furthermore, it is desirable that an SLNB guidance should be as safe as possible in routine clinical use. Although there are currently various SLNB guidance methods for pre-operative or intra-operative assessment, none are ideal. We propose a real-time SLNB guidance method using contrast-enhanced tri-modal images (i.e., ultrasound, photoacoustic, and fluorescence) acquired by a recently developed hand-held tri-modal probe. The major advantage of tri-modal imaging is demonstrated here through an in vivo study of the technically-difficult case of nodal obstruction that frequently leads to false-negative results in patients. The results in a tumor model in rabbits and normal controls showed that tri-modal imaging is capable of clearly identifying obstructed SLNs and of indicating their metastatic involvement. Based on these findings, we propose an SLNB protocol to help surgeons take full advantage of the complementary information obtained from tri-modal imaging, including for pre-operative localization, intra-operative biopsy guidance and post-operative analysis.

The contradictory biological function of eumelanin (photoprotection vs photosensitization) has long been a topic of debate in a wide range of disciplines such as chemistry, physics and biology. For understanding full spectrum of eumelanin's photobiological aspect, revealing how eumelanin's complex structural organization dictates its photophysical properties is critical step. Here, we report a practical approach to controlling the hierarchically assembled structure of natural eumelanin, which leads to disassembly of its structure into subunits and oxidized subunits, respectively. Based on the well-characterized model system, it was possible to systematically determine how the photophysical properties of eumelanin are ruled by its hierarchical assembly organization. Particularly, our experiments reveal that the chemical oxidation of eumelanin's subunits, which leads to delamination of their stacked layer structure, is critical to significantly increase their photochemical reactivity to generate ROS under UV irradiation. This result provides clear experimental evidence that oxidative degradation of eumelanin, which might be induced by phagosomal enzymatic activity in the process of melanomagenesis, is responsible for triggering the negative photobiological role of eumelanin such as ROS source needed for development of malignant melanoma.

We present a new melanin-like nanoparticle (MelNP) and its performance evaluation results. This particle is proposed as an exogenous contrast agent for photoacoustic (PA) imaging. Conventional PA contrast agents are based on non-biological materials. In contrast, the MelNPs are organic nanoparticles inspired by natural melanin. Melanin is an endogenous chromophore that has the ability to produce a PA signal in vivo. The developed MelNPs are capable of aggregating with one another under mildly acidic conditions after introducing hydrolysis-susceptible citraconic amide on the surface of bare MelNPs. We ascertained that the physical aggregation of the MelNPs resulted in an increased PA signal strength in the near-infrared window of biological tissue (i.e., 700 nm) without absorption tuning. This phenomenon is likely because of the overlapping thermal fields of the developed MelNPs. The PA signal produced from the developed MelNPs, after exposure to mildly acidic conditions (i.e., pH 6), is 8.1 times stronger than under neutral conditions. This unique characteristic found in this study can be utilized in a practical strategy for highly sensitive in vivo cancer target imaging in response to its acidic microenvironment. This approach to amplify the PA response of MelNPs in clusters could accelerate the use of MelNPs as an alternative to non-biological nanoprobes, so that MelNPs may be applicable in PA imaging and functional PA imaging such as stimuli sensitive, multimodal, and theranostic imaging.

Recently, a portable US imaging system using smart devices is highlighted for enhancing the portability of diagnosis. Especially, the system combination can enhance the user experience during whole US diagnostic procedures by employing the advanced wireless communication technology integrated in a smart device, e.g., WiFi, Bluetooth, etc. In this paper, an effective post-phase rotation-based dynamic receive beamforming (PRBF-POST) method is presented for wireless US imaging device integrating US probe system and commercial smart device. In conventional, the frame rate of conventional PRBF (PRBF-CON) method suffers from the large amount of calculations for the bifurcated processing paths of in-phase and quadrature signal components as the number of channel increase. Otherwise, the proposed PRBF-POST method can preserve the frame rate regardless of the number of channels by firstly aggregating the baseband IQ data along the channels whose phase quantization levels are identical ahead of phase rotation and summation procedures on a smart device. To evaluate the performance of the proposed PRBF-POST method, the pointspread functions of PRBF-CON and PRBF-POST methods were compared each other. Also, the frame rate of each PRBF method was measured 20-times to calculate the average frame rate and its standard deviation. As a result, the PRBFCON and PRBF-POST methods indicates identical beamforming performance in the Field-II simulation (correlation coefficient = 1). Also, the proposed PRBF-POST method indicates the consistent frame rate for varying number of channels (i.e., 44.25, 44.32, and 44.35 fps for 16, 64, and 128 channels, respectively), while the PRBF-CON method shows the decrease of frame rate as the number of channel increase (39.73, 13.19, and 3.8 fps). These results indicate that the proposed PRBF-POST method can be more advantageous for implementing the wireless US imaging system than the PRBF-CON method.