Photoacoustic Elastography and Next-generation Photoacoustic Tomography Techniques Towards Clinical Translation

Ultrasonically probing optical absorption, photoacoustic tomography (PAT) combines rich optical contrast with high ultrasonic resolution at depths beyond the optical diffusion limit. With consistent optical absorption contrast at different scales and highly scalable spatial resolution and penetration depth, PAT holds great promise as an important tool for both fundamental research and clinical application. Despite tremendous progress, PAT still encounters certain limitations that prevent it from becoming readily adopted in the clinical settings. This dissertation aims to advance both the technical development and application of PAT towards its clinical translation. The first part of this dissertation describes the development of photoacoustic elastography techniques, which complement PAT with the capability to image the elastic properties of biological tissue and detect pathological conditions associated with its alterations. First, I demonstrated vascular-elastic PAT (VE-PAT), capable of quantifying blood vessel compliance changes due to thrombosis and occlusions. Then, I developed photoacoustic elastography to noninvasively map the elasticity distribution in biological tissue. Third, I further enhanced its performance by combing conventional photoacoustic elastography with a stress sensor having known stress–strain behavior to achieve quantitative photoacoustic elastography (QPAE). QPAE can quantify the Young’s modulus of biological tissues on an absolute scale. The second part of this dissertation introduces technical improvements of photoacoustic microscopy (PAM). First, by employing near-infrared (NIR) light for illumination, a greater imaging depth and finer lateral resolution were achieved by near-infrared optical-resolution PAM (NIR-OR-PAM). In addition, NIR-OR-PAM was capable of imaging other tissue components, including lipid and melanin. Second, I upgraded a high-speed functional OR-PAM (HF-OR-PAM) system and applied it to image neurovascular coupling during epileptic seizure propagation in mouse brains in vivo with high spatio-temporal resolution. Last, I developed a single-cell metabolic PAM (SCM-PAM) system, which improves the current single-cell oxygen consumption rate (OCR) measurement throughput from ~30 cells over 15 minutes to ~3000 cells over 15 minutes. This throughput enhancement of two orders of magnitude achieves modeling of single-cell OCR distribution with a statistically meaningful cell count. SCM-PAM enables imaging of intratumoral metabolic heterogeneity with single-cell resolution. The third part of this dissertation introduces the application of linear-array-based PAT (LA-PAT) in label-free high-throughput imaging of melanoma circulating tumor cells (CTCs) in patients in vivo. Taking advantage of the strong optical absorption of melanin and the unique capability of PAT to image optical absorption, with 100% relative sensitivity, at depths with high ultrasonic spatial resolution, LA-PAT is inherently suitable for melanoma CTC imaging. First, with a center ultrasonic frequency of 21 MHz, the LA-PAT system was able to detect melanoma CTCs clusters and quantify their sizes based on the contrast-to-noise ratio (CNR). Second, I developed an LA-PAT system with a center ultrasonic frequency of 40 MHz and imaged melanoma CTCs in patients in vivo with a CNR greater than 12. We successfully imaged 16 melanoma patients and detected melanoma CTCs in 3 of them. Among the CTC-positive patients, 67% had disease progression despite systemic therapy. In contrast, only 23% of the CTC-negative patients showed disease progression. This study lays a solid foundation for translating CTC detection to bedside for clinical care and decision-making

Label-free high-throughput photoacoustic tomography of suspected circulating melanoma tumor cells in patients in vivo

Significance: Detection and characterization of circulating tumor cells (CTCs), a key determinant of metastasis, are critical for determining risk of disease progression, understanding metastatic pathways, and facilitating early clinical intervention. Aim: We aim to demonstrate label-free imaging of suspected melanoma CTCs. Approach: We use a linear-array-based photoacoustic tomography system (LA-PAT) to detect melanoma CTCs, quantify their contrast-to-noise ratios (CNRs), and measure their flow velocities in most of the superficial veins in humans. Results: With LA-PAT, we successfully imaged suspected melanoma CTCs in patients in vivo, with a CNR >9. CTCs were detected in 3 of 16 patients with stage III or IV melanoma. Among the three CTC-positive patients, two had disease progression; among the 13 CTC-negative patients, 4 showed disease progression. Conclusions: We suggest that LA-PAT can detect suspected melanoma CTCs in patients in vivo and has potential clinical applications for disease monitoring in melanoma

Quantitative photoacoustic elastography in humans

We report quantitative photoacoustic elastography (QPAE) capable of measuring Young’s modulus of biological tissue in vivo in humans. By combining conventional PAE with a stress sensor having known stress–strain behavior, QPAE can simultaneously measure strain and stress, from which Young’s modulus is calculated. We first demonstrate the feasibility of QPAE in agar phantoms with different concentrations. The measured Young’s modulus values fit well with both the empirical expectation based on the agar concentrations and those measured in an independent standard compression test. Next, QPAE was applied to quantify the Young’s modulus of skeletal muscle in vivo in humans, showing a linear relationship between muscle stiffness and loading. The results demonstrated the capability of QPAE to assess the absolute elasticity of biological tissue noninvasively in vivo in humans, indicating its potential for tissue biomechanics studies and clinical applications

Quantitative photoacoustic elastography of Young’s modulus in humans

Elastography can noninvasively map the elasticity distribution of biological tissue, which is often altered in pathological states. In this work, we report quantitative photoacoustic elastography (QPAE), capable of measuring Young’s modulus of human tissue in vivo. By combining photoacoustic elastography with a stress sensor having known stress-strain behavior, QPAE can simultaneously measure strain and stress, from which Young’s modulus is calculated. We first applied QPAE to quantify the Young’s modulus of tissue-mimicking agar phantoms with different concentrations. The measured values fitted well with both the empirical expectations based on the agar concentrations and those measured in independent standard compression tests. We then demonstrated the feasibility of QPAE by measuring the Young’s modulus of human skeletal muscle in vivo. The data showed a linear relationship between muscle stiffness and loading. The results proved that QPAE can noninvasively quantify the absolute elasticity of biological tissue, thus enabling longitudinal imaging of tissue elasticity. QPAE can be exploited for both preclinical biomechanics studies and clinical applications

Non-reciprocal cavity polariton

Breaking the time-reversal symmetry of light is of great importance for fundamental physics, and also have attracted increasing interests in the study of non-reciprocal photonics for applications. The optical non-reciprocity has been realized by engineering the susceptibility of dielectric, through either magneto-optics effect with bias magnetic field or directional coherent nonlinear optical effects stimulated by external drives. Here, we experimentally demonstrate an inherently non-reciprocal quasiparticle, i.e. the cavity polariton, in a strongly coupled cavity quantum electrodynamics system. Through carefully manipulating the internal quantum state of atoms to break the time-reversal symmetry, the polariton shows non-reciprocal photon emission without bias field. Such non-reciprocal polariton state leads to optical isolation exceeds 30dB on single-quanta level ($\sim0.1$ photon), and also produces non-reciprocal non-classical statistics with coherent probe lights, manifesting the quantum nature of the non-reciprocal polaritons. Such new quasiparticle demonstrated in this work holds great potential for exploring the quantum non-reciprocity in photonics and quantum network applications, and also new topological phases in many-body physics.Comment: 6 pages, 4 figure

Encrypted Three-dimensional Dynamic Imaging using Snapshot Time-of-flight Compressed Ultrafast Photography

Compressed ultrafast photography (CUP), a computational imaging technique, is synchronized with short-pulsed laser illumination to enable dynamic three-dimensional (3D) imaging. By leveraging the time-of-flight (ToF) information of pulsed light backscattered by the object, ToF-CUP can reconstruct a volumetric image from a single camera snapshot. In addition, the approach unites the encryption of depth data with the compressed acquisition of 3D data in a single snapshot measurement, thereby allowing efficient and secure data storage and transmission. We demonstrated high-speed 3D videography of moving objects at up to 75 volumes per second. The ToF-CUP camera was applied to track the 3D position of a live comet goldfish. We have also imaged a moving object obscured by a scattering medium