Summary

This dissertation is focused on exploring co-registered photoacoustic and ultrasound tomographic imaging on two fatal cancers: ovarian cancer and colorectal cancer. It is composed of three main parts: light delivery optimization/fiber optics, system development and optimization, and pilot patient and sample study. First project described in chapter two is related to the light delivery optimization/fiber optics part. We designed and evaluated an optimized hand-held photoacoustic and ultrasound probe suitable for endo-cavity tumor subsurface imaging. Compared to previous designs, the prototype probe, consisting of four 1 mm multi-mode optical fibers attached with 1.5 mm diameter ball-shaped fiber tips sandwiched between a transvaginal ultrasound transducer and a custom-made sheath, demonstrated a higher light output and better beam homogeneity on tissue subsurface. The simulations and experiments demonstrated that ball-shaped fiber tip design can achieve homogeneous fluence distribution on tissue subsurface with acceptable light output efficiency, suggesting its clinical potential for in-vivo endo-cavity imaging. Based on the ball lens design, we made an improved version of design in chapter three in which we developed an effective fiber diffuser tip to reduce the fluence on the target tissue surface while injecting more laser energy and enhancing the photoacoustic signal generated from the tissue. The fiber diffuser tip is made of silica microspheres mixed with UV adhesive. We compared the light diffusion effects of different microsphere materials, sizes, and concentrations, and find 10 μm silica microspheres provide the best light scattering with minimal 5% output energy loss. With Zemax simulation and experimental validation, we show this fiber diffuser tip could be a valuable tool for endo-cavity photoacoustic imaging.

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In chapter four, we proposed an improved beamformer named lag-based delay multiply and sum combined with coherence factor (DMAS-LAG-CF). Simulations and phantom experiments demonstrate that compared with the conventional DAS, the proposed algorithm can provide 1.39 times better resolution and 10.77 dB higher contrast. With a cohort of 28 patient data, similar performance on contrast ratios have been observed. However, since the diagnostic accuracy between cancer and benign/normal groups is the significant measure, we have extracted photoacoustic histogram features of mean, kurtosis and skewness. DMAS-LAG-CF can improve cancer diagnosis with an AUC of 0.91 for distinguishing malignant vs. benign ovarian lesions when mean and skewness are used as features.

Continuing the pilot clinical patient/sample study, we have conducted a pilot study on 23 ex-vivo human colorectal tissue samples immediately after the surgical resection to investigate the ability of co-registered photoacoustic and ultrasound tomographic imaging to assess human colorectal cancer in chapter five. Co-registered photoacoustic images of malignancies showed significantly increased PAT signal compared to normal regions of the same sample. The quantitative relative total hemoglobin concentration (rHbT) computed from four optical wavelengths, the spectral features, such as the mean spectral slope, and 0.5 MHz intercept extracted from PAT and US spectral data, and image features, such as the first and second order statistics along with the standard deviation of the mean radon transform of PAT images, have shown statistical significance between untreated colorectal tumors and the normal tissue. Using either a logistic regression model or a support vector machine, the best set of parameters of rHbT and PAT intercept has achieved AUC values of 0.97 and 0.95 for both training and testing data sets respectively for prediction of histologically confirmed invasive carcinoma.

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One limitation of the current system is the poor image resolution (~ 250 μm axial resolution) due to the commercial endo-cavity ultrasound transducer array (6 MHz central frequency, 80%

bandwidth). To solve the problem of image resolution, we firstly decoded the pin configuration of a high-frequency transducer array (15 MHz central frequency, 9-18 MHz bandwidth) and adapted it to our home-made 128 channels ultrasound pulsing and receiving system (sampling rate: 40 MHz) to perform high frequency PAT/US imaging. To further improve the performance of photoacoustic data acquisition suitable for high-frequency transducer array, we are building a 64-channel FPGA based high frequency photoacoustic imaging system with a sampling rate of 80 MHz and signal-to-noise ratio (SNR) of 40 dB, and adapting this system to an endo-rectal probe with a side-firing fiber tip for in-vivo patient study.

In chapter six, since we did a lot clinical applications on human ovarian cancer and colorectal cancer, we'd like to investigate the laser safety of photoacoustic imaging especially before its adoption by clinical reproductive medicine. Potential DNA damage of photoacoustic laser exposure on preimplantation mouse blastocyst stage embryos was examined. Different embryos groups were exposed to either 5- or 10- minute 15-Hz laser doses (typical clinical doses), and 1-minute 1-kHz laser dose (significantly higher dose), respectively. We demonstrated that typical lasers and exposure times used for photoacoustic imaging do not induce increased cell death in mouse blastocysts.

In chapter seven, we presented a novel fiber endface photoacoustic generator using IR 144 dispersed within an UV adhesive. The generator provides wide acoustic bandwidth in the transducer frequency range of 2-7MHz, high thermal conversion efficiency (> 90%), good PA intensity controllability (well controlled IR 144 concentration), and high feasibility (simple procedures). Through a series of experimental validations, we show this fiber endface photoacoustic

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generator can be a useful tool for a broad range of biomedical applications, such as calibrating the local absorption coefficient of biological tissue towards quantitative photoacoustic tomography.