Ultrasound/ Photoacoustic Imaging Platform, Tumor Treatment System Development and Their Biomedical Applications


Student thesis: Doctoral Thesis

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Award date23 Jul 2020


Biomedical imaging helps us understand organisms from the macroscopic scale to the microscopic level. The accelerated development of different imaging technologies is not only conducive to cancer diagnosis at an early stage but also valuable for providing suggestions in selecting effective tumor treatment strategy in the next step. However, most single-modality imaging methods are still limited to their drawbacks in terms of imaging mechanism itself. Developing a compatible multi-modal imaging platform that can achieve the most optimized imaging performance is extremely important in oncology diagnostics. Minimal-invasive or non-invasive therapy is now getting more and more attention as it is safe and object-targeted in therapeutics. Therefore, integrating a multi-modal imaging platform with minimal-invasive or non-invasive tumor therapy is focused on this thesis.

The spatiotemporal resolution, contrast ration (CR), signal to noise ratio (SNR), the ratio of the imaging depth to the imaging resolution, the field of view, hardware cost and operation safety are all needed to consider in the biomedical imaging system development. Photoacoustic (PA) computed tomography is a hybrid imaging modality inheriting the merits of ultrasound (US) imaging and optical imaging, which can utilize either exogenous or endogenous contrast agents to realize multi-scale, deep, and dynamic biomedical imaging. It combines the advantages of excellent image contrast in optical imaging as well as the superiority of deeper penetration depth in US imaging. PA imaging is sensitive to the optical-absorbed molecules. The combination of US imaging and PA imaging provides complementary information from a molecule to morphology. Therefore, the US/PA dual-modal imaging may be the most promising technology to achieve the requirements above-mentioned. As PA imaging platforms can share the same data acquisition (DAQ) system with US imaging, they can be integrated conveniently. Therefore, the first step of the research in this thesis is to design a high-speed and dual-mode hardware platform.

In ultrasonography, a linear array transducer is frequently used in the clinic as it is portable and easy to operate for the physician. Furthermore, the external environments little restrict its operation in diagnosis. A linear array transducer integrating with the DAQ, horizontal mechanical scanning, and real-time image reconstruction for the US and PA imaging is convenient to acquire structural or functional features in the 3D space, which is useful for the research in tissue phenotype or dermatology. Therefore, a horizontal hand-hold scanning US/PA system has been developed firstly. However, the advantages will be lost if we want to acquire complete cross-section images or image the protruding features, for example, the animal whole-body imaging or woman's breast tumor screening diagnosis. The horizontal scanning linear array system has the drawbacks of the limited view or under-spatial sampling. The problems are especially severe for the PA imaging, which are the main reasons to degrade reconstructed image quality. However, the issues can be alleviated by designing a rotating scanning system. In the rotating scanning system, the transducer stays at a different rotating angle to receive signals. And then a whole image can be combined from all sub-images. Although the scanning process will increase the PA signal acquisition time, the advantage of this kind of rotating scanning system is low hardware cost. Therefore, a rotating scanning US/PA system has also been developed. However, to capture in vivo physiological change in real-time, the rotating method is not the most optimized. To synchronize the pulse repetition frequency of laser source with the imaging rate, we expect to acquire a complete PA image in a single laser shot. A dedicated custom-built ring-array transducer is an ideal choice. A system adopting ring-array transducer can achieve real-time and high-fidelity imaging results, whether in the US or PA images. Therefore, a system adopting a ring-array transducer has been developed to supplement the functionality of the linear array imaging system. Finally, both in vitro experiments and in vivo experiments have demonstrated all the designed imaging systems' performance and efficacy.

Software design is implemented in this thesis. The reconstruction algorithm is vitally important to improve the US or PA image. The next step of this thesis is to focus on the imaging reconstruction algorithm, especially in PA imaging reconstruction. Delay and sum (DAS) or filter back-projection (FBP) are popularly used algorithms in PA computed tomography reconstruction because of light implementation, even on a standard personal computer. However, due to lacking analyzing enough raw signals information from time domain or frequency domain, the reconstructed image is often contaminated by noise or interference from other absorbers. Two kinds of adaptive algorithms have been developed to improve image quality in terms of resolution, SNR, and CR. The first algorithm is developed by utilizing signal eigenspace clutter elimination, and the imaging quality is improved significantly. The second algorithm is developed by spatial frequency and magnitude filter, which can also enhance the quality of the image.

Tumor therapy is the next step after completing the imaging diagnosis. Compared with surgery therapy, minimal-invasive or non-invasive therapies are more attractive in tumor therapy fields. Therefore, they are focused on this research. Photothermal therapy (PTT) and high intensity focused ultrasound (HIFU) therapy, which are two representative therapy methods, are the choice in this thesis. The third step is to integrate these two therapeutic technologies with the developed US/PA imaging platform.

PTT is one kind of minimally invasive therapy. With the aid of specially designed photothermal agents, PTT can only be explicitly heating the tumor site and has a decent therapeutic outcome. It is challenging when a tumor situates in a deep position if using visible or near-infrared first window wavelength (650nm – 950nm). The near-infrared second window (1000nm – 1700nm) is extensively used in recent years because the therapy depth can be improved significantly. The 1064nm, as a characteristic wavelength, has many advantages. For example, it has a higher maximum permissible exposure (MPE) and reduced tissue scattering. Besides, PA imaging can also use 1064nm due to these advantages. Therefore, the same laser can be acted as an excitation source for PA imaging as well as a thermal source for PTT, which can reduce the hardware cost-efficiently. In this thesis, tumor therapy on tumor-xenografted mice has been well demonstrated using the US/PA imaging-guided PTT combining with a designed conjugated small molecule.

Even though using long-wavelength in PTT, light scattering event still exists. HIFU tumor ablation is a promising non-invasive therapeutic method to alleviate this challenge. HIFU only generates high-intensity energy on the focus position and treats the tumor by one kind of thermal ablation. Compared with light propagation, acoustic signal propagation has fewer scatter in biological tissue. For US/PA imaging-guided HIFU therapy, a developed tri-modal system has been developed in this thesis. Here, an array-based transducer is used, whose phase can be changed in the 3D space. Therefore, the focus of the HIFU transducer can be guided using the US/PA image at high speed. Besides, the PA image can be acted as thermometry, which enables to evaluate the temperature changing on the tumor region. Therefore, treatment can be controlled in real-time by image feedback. In vitro experiments have well demonstrated the developed system in this thesis.

Guiding microrobot in deep tissue is hard to track in real-time when using traditional optical imaging or US imaging methods. The thesis attempt to address this challenge. The developed US/PA imaging system is adapted to guide magnetic-driven microrobot. The microrobot is biodegradable and carrying with engineered stem cells. It is expected that the microrobot can be guided into the tumor region according to the US/PA imaging, while the microrobot is actuated under the magnetic fields. We have successfully demonstrated that microrobot in deep tissue can be guided in vivo in real-time using the developed US/PA dual-modal system.

In summary, from the hardware design, three kinds of US/PA dual-modal systems have been developed in this thesis, including hand-hold linear-array based horizontal scanning system, linear-array based rotating scanning system, and ring-array based system. Besides, PTT is well integrated with the developed system using only one laser equipment. A tri-modal system, which combines a dual-modal imaging system and an array-based HIFU transducer, has also been developed. In a summary of the software design, different time sequence control schemes, as well as two PA reconstruction algorithms, have been developed. Both in vitro experiments and in vivo experiments have well demonstrated the system's ability in terms of structural imaging, functional imaging, and molecular imaging. For tumor ablation, the US/PA imaging-guiding PTT has been shown in vitro experiments and in vivo experiments. The US/PA imaging-guided HIFU therapy and monitor has also been well demonstrated in vitro experiments. In the last, the imaging system has proved the ability to guide microrobot to move in the portal vein of the mouse, which paves a new way to deliver drugs by guiding microrobot in vivo accurately.

    Research areas

  • Biomedical imaging, Ultrasound imaging, Photoacoustic imaging, Linear array transducer, Horizontal scanning, Rotating scanning, Ring array transducer, Delay and sum, Filter back-projection, Adaptive image reconstruction, Near-infrared second window imaging, Photothermal treatment, High intensity focused ultrasound, Microrobot guiding