Deepening optical imaging with next-generation photoacoustic computed tomography - Abstract Deep-tissue imaging remains a fundamental challenge in biomedical optics due to light scattering, limiting high- resolution optical imaging to depths of approximately 1 mm, also referred to as the optical diffusion limit due to the use of ballistic or quasi-ballistic photons. Photoacoustic tomography (PAT) uniquely circumvents this limitation by using deep penetrating diffuse light to excite photoacoustic waves, which are then detected ultrasonically, leveraging the low scattering of sound in biological tissues to provide high spatial resolution. This proposal aims to push the imaging depth of PAT from the current limit to 6 cm while providing high spatial resolution. Achieving this ambition requires fundamental improvements across the entire imaging chain, from optical excitation to ultrasonic detection and image reconstruction. We propose the following advancements: (1) optimizing SNR by scanning laser pulses with a higher repetition rate to satisfy both ANSI safety limits and incorporating ultrasonic excitation for accurate acoustic speed-of- sound imaging and de-aberration, (2) enhancing ultrasonic detection by maximizing the detection solid angle and packing density (i.e., fill factor) while providing spatial Nyquist sampling with coded masking, (3) refining joint reconstruction augmented by ultrasonic excitation to de-aberrate acoustic blurring and tailoring motion correction to mitigate motion artifacts over extended acquisition times, and (4) performing in vivo imaging of human breasts to validate the proposed technology using contrast-enhanced MRI as the gold standard owing to its shared ability with PAT to image blood vessels. The team has achieved multiple milestones in PAT, including the first in vivo functional PAT, the first 3D pho- toacoustic microscopy with cellular resolution, and the most widely adopted PAT reconstruction method. These foundational contributions have established PAT as the leading high-resolution optical imaging technique in terms of deep-tissue penetration. Despite its success, further technical breakthroughs are required to address the challenges of providing even greater penetration. This proposal introduces a synergistic approach by optimizing laser delivery, ultrasonic detection, acoustic de- aberration, and advanced reconstruction algorithms to achieve a quantum leap in PAT. The proposed innovations will significantly enhance PAT’s diagnostic potential in biomedicine, particularly in breast cancer detection, where deep-tissue visualization is critical for early detection and treatment monitoring. The impact of this research extends to a broad range of biomedical applications. In summary, by systematically improving PAT from excitation to detection and reconstruction, this work will es- tablish the next-generation PAT, capable of transforming clinical imaging. The proposed research aligns with the long-term goal of developing PAT into a widely accessible, non-invasive imaging tool that provides greater imaging depths with high resolution.
