Multiscale Photoacoustic Imaging from Microscopy to Clinical Applications

Abstract

Photoacoustic imaging (PAI) is a non-invasive and non-ionizing biomedical imaging technique that combines the advantages of optical and ultrasound (US). When a pulsed laser illuminates the biological tissues, the endogenous chromophores of those tissues absorb light. Some of the light energy delivered to the tissue is rapidly converted into thermal energy, inducing to instantaneous thermoelastic expansion, which leads to broadband US emission. The US wave is called a photoacoustic (PA) wave, and the PA waves are properly processed and reconstructed into a PA image. The beauty of PAI is the scalability originated from its optical and acoustic focusing. Depending on the type of foci, PAI can be classified into two categories: optical-resolution photoacoustic imaging (OR-PAI) and acoustic-resolution photoacoustic imaging (AR-PAI). Within the optical diffusion limits (~1 mm depth), the optical beam of OR-PAI can be tightly focused, boasting a great spatial resolution. Beyond the optical diffusion limit, the AR-PAI can achieve relatively better acoustic beam focus in deep tissues (up to several centimeters). Thanks to the multi-scalability, PAI is widely used in a variety of biomedical imaging from laboratory research to clinical applications. The main goal of this dissertation is to evaluate the scalability of PAI from nanoscale to macroscale. The specific aims are as follows: (1) developing a Bessel-beam based sub-wavelength photoacoustic microscope (to reach the abbe’s diffraction limit) and overcoming a limited depth-of-field (DOF) of the microscope; (2) simulating a super-resolution photoacoustic microscope (beyond the diffraction limit), and (3) evaluating PAI in deep tissue of small animals (to aim a deepest imaging depth) and humans (to contribute human clinical research) in vivo. The first part of this thesis describes the study of PAI within the optical diffusion limit. This part covers a sub-wavelength photoacoustic microscope (SW-PAM) with an extended DOF. SW-PAM theoretically has the highest level of resolution, but due to its compromise, the DOF is extremely short. To solve this problem, a SW-PAM applied with a Bessel-beam, a non-diffraction beam, was developed and evaluated. Next, simulation study to develop a PA microscope that exceed abbe's diffraction limits is covered. A few nm-scale optical focus was obtained from the near-field localized nanoaperture by surface plasmon resonance. Through this, super-resolution PAI simulation was performed and evaluated. The second part of the thesis describes the findings of deep tissue PAI studies that go beyond optical diffusion limits. Firstly, the study of a novel exogenous agent with strong absorption properties in the second near-infrared window is introduced. To evaluate the agent, PA images were acquired and analyzed from the sentinel lymph nodes, gastrointestinal, and bladder of small animals. Next, human clinical applications of deep tissue PAI such as cutaneous melanoma with various sizes and types and thyroid cancers are covered. After analyzing the depth of human melanoma by PAI, it was found that physicians could assist patients with staging. Lastly, novel criteria for evaluating thyroid nodules was proposed to minimize biopsy by analyzing human thyroid benign and cancer nodules. In the last part, the dissertation summarizes the conclusion of research. This thesis deals with the multi-scalability of PAI from high-resolution PAI to deep tissue PAI. PAI based on the scalability is expected to be effectively applied not only to laboratory-based research from nanometer to micrometer scale, but also to clinical applications.