Photoacoustic Reporter Gene Imaging And Optical Coherence Computed Tomography

Advances in imaging technologies have always been the major driving forces for the evolution of biomedical research. Compared with other modalities, optical imaging possesses several prominent merits. Because light interacts with tissue at the microscopic level through many distinct physical mechanisms, optical methods allow sensitive exploration of various aspects of the life down to the single-molecule level. From the technical perspective, optical systems utilize safe non-ionizing radiation, could be implemented at relatively low cost, also have the potential to be miniaturized for portable or endoscopic applications. As a result, optical imaging tools are playing an increasingly important role in both laboratorial research and clinical practice. Among them, photoacoustic imaging: PAI) and optical coherence tomography: OCT) are the two fastest growing branches. PAI measures the laser-induced acoustic wave, and produces high-resolution images of the optically absorbing features of tissue at multiple length-scales. OCT detects singly backscattered photons, and enables real-time high-resolution in vivo biopsy of tissue up to an optical transport mean-free-path. My doctoral research is focused on developing three novel optical imaging techniques based on the spirits of PAI and OCT. In the first part of this study, we established a new paradigm to visualize gene expression in vivo based on optical absorption. In the post-genomic era, we are now being challenged to develop novel molecular imaging methods to identify the functions of genes. PAI can detect specific molecules according to their characteristic absorption spectra, thus is a promising candidate for molecular imaging of gene expression. The full potential of photoacoustic molecular imaging still remains to be explored. For the first time, we demonstrated imaging gene expression by PAI in living mice and rats, using a chromogenic lacZ/X-gal reporter gene system. We demonstrated the expression of the lacZ reporter gene can be detected by PAI as deep as 5 cm inside tissue. In addition, we showcased that PAI could follow gene expression from the microscopic to the macroscopic level. This work represents one of the pioneering efforts to extend photoacoustic methods for molecular imaging. In the second part of this study, we developed a novel multimodal microscope, called the integrated photoacoustic and optical coherence microscope: iPOM), which combines PAI and OCT in a single imaging platform. PAI is predominantly sensitive to optical absorption, while OCT exploits optical scattering. By combining their naturally complementary imaging contrasts, iPOM can provide comprehensive information about biological tissue. We designed and built a reflection-mode prototype of iPOM, which fuses optical-resolution photoacoustic microscopy with spectral-domain optical coherence tomography. The potential applications of iPOM in studying cutaneous and ocular microcirculation, and tissue engineering were demonstrated. Finally, we invented a new optical tomography, named optical coherence computed tomography: optical CCT), which overcomes several major limitations of OCT. OCT relies on singly backscattered photons to obtain high-resolution images. Its image quality degrades fast with the increase of the depth, because the multiply scattered photons quickly become dominant at a penetration larger than 500 &mum. As a result, OCT can only effectively penetrate ~1 mm into highly scattering tissue like skin. In addition, OCT is mainly sensitive to optical scattering, which does not reflect the molecular content of tissue directly. Optical CCT measures both singly and multiply scattered photons using a low-coherence interferometer. We make use of both types of photons by adopting a model-based reconstruction algorithm. The light-tissue interaction model was established using the time-resolved Monte Carlo method. The optical properties of the tissue were reconstructed from measurements by solving the inverse radiative transport problem under the first Born approximation. As a result, optical CCT could image deeper than OCT, and provide extra molecule-specific contrasts, such as optical absorption. We designed and built the first optical CCT system. In experiments, absorbing inclusions of 100 &mum diameter were imaged with consistent quality through a 2.6-mm-thick: equivalent to ~3 transport mean-free-paths) tissue-mimicking phantom

An ionizing radiation acoustic imaging (iRAI) technique for real‐time dosimetric measurements for FLASH radiotherapy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163494/2/mp14358_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163494/1/mp14358.pd

Developments in PET-MRI for Radiotherapy Planning Applications

The hybridization of magnetic resonance imaging (MRI) and positron emission tomography (PET) provides the benefit of soft-tissue contrast and specific molecular information in a simultaneous acquisition. The applications of PET-MRI in radiotherapy are only starting to be realised. However, quantitative accuracy of PET relies on accurate attenuation correction (AC) of, not only the patient anatomy but also MRI hardware and current methods, which are prone to artefacts caused by dense materials. Quantitative accuracy of PET also relies on full characterization of patient motion during the scan. The simultaneity of PET-MRI makes it especially suited for motion correction. However, quality assurance (QA) procedures for such corrections are lacking. Therefore, a dynamic phantom that is PET and MR compatible is required. Additionally, respiratory motion characterization is needed for conformal radiotherapy of lung. 4D-CT can provide 3D motion characterization but suffers from poor soft-tissue contrast. In this thesis, I examine these problems, and present solutions in the form of improved MR-hardware AC techniques, a PET/MRI/CT-compatible tumour respiratory motion phantom for QA measurements, and a retrospective 4D-PET-MRI technique to characterise respiratory motion. Chapter 2 presents two techniques to improve upon current AC methods that use a standard helical CT scan for MRI hardware in PET-MRI. One technique uses a dual-energy computed tomography (DECT) scan to construct virtual monoenergetic image volumes and the other uses a tomotherapy linear accelerator to create CT images at megavoltage energies (1.0 MV) of the RF coil. The DECT-based technique reduced artefacts in the images translating to improved μ-maps. The MVCT-based technique provided further improvements in artefact reduction, resulting in artefact free μ-maps. This led to more AC of the breast coil. In chapter 3, I present a PET-MR-CT motion phantom for QA of motion-correction protocols. This phantom is used to evaluate a clinically available real-time dynamic MR images and a respiratory-triggered PET-MRI protocol. The results show the protocol to perform well under motion conditions. Additionally, the phantom provided a good model for performing QA of respiratory-triggered PET-MRI. Chapter 4 presents a 4D-PET/MRI technique, using MR sequences and PET acquisition methods currently available on hybrid PET/MRI systems. This technique is validated using the motion phantom presented in chapter 3 with three motion profiles. I conclude that our 4D-PET-MRI technique provides information to characterise tumour respiratory motion while using a clinically available pulse sequence and PET acquisition method

Development and Testing of a High Resolution PET Detector for Prostate Imaging

According to the American Cancer Society one in six men will be diagnosed with prostate cancer in their lifetime. Current methods for screening of prostate cancer including various PSA blood tests, as well as the digital rectal exam, are unreliability while current imaging modalities clinically employed (US, CT, MRI) are unable to localize intraprostatic cancer(s). Consequently, diagnosis via core needle biopsy is problematic and a game of chance at best. Therefore, in response to new radiopharmaceuticals applicable to both internal and external prostate cancer visualization and localization, novel prostate specific nuclear medical imagers are being developed.;The first prototype of a compact prostate specific PET detector utilizing silicon photomultiplier (SiPM) technology has been developed and tested at West Virginia University. The compact detector is proposed as an endorectal probe placed proximally to the rectal wall/prostate interface and operating in coincidence with one or more externally mounted large area gamma detectors or in tandem with a clinical whole body PET scanner. To ensure high reconstruction resolution, the scintillation array of the compact detector will be coupled to SiPMs on both axial ends in a dual ended readout approach. Such an approach allows for the extraction of continuous depth of interaction (DOI) information thus minimizing the effects of parallax error and providing nearly isotropic and uniform spatial resolution throughout the entire detector field of view (FOV).;Two compact DOI based prototype detectors were developed and tested. While both utilize pixelated LYSO scintillation crystal arrays, the first has a crystal pitch of 1.0 mm and is coupled to SensL SiPMs, while the second has a crystal pitch of 0.7mm and is coupled to Hamamatsu SiPMs. Initial proof of concept studies were preformed using the SensL based detector while more extensive and systematic studies were preformed using the Hamamatsu based detector. Ultimately, when averaged over all crystals and all depths the Hamamatsu based detector achieved a depth of interaction resolution of 0.78+/-0.09 mm FWHM and an energy resolution of 13.2+/-0.7 % FWHM. Validation studies with regards to the efficacy of incorporating DOI information extracted from a small compact DOI based PET detector module into image reconstruction algorithms were also preformed

Smartphone Spectrometers

Smartphones are playing an increasing role in the sciences, owing to the ubiquitous proliferation of these devices, their relatively low cost, increasing processing power and their suitability for integrated data acquisition and processing in a 'lab in a phone' capacity. There is furthermore the potential to deploy these units as nodes within Internet of Things architectures, enabling massive networked data capture. Hitherto, considerable attention has been focused on imaging applications of these devices. However, within just the last few years, another possibility has emerged: to use smartphones as a means of capturing spectra, mostly by coupling various classes of fore-optics to these units with data capture achieved using the smartphone camera. These highly novel approaches have the potential to become widely adopted across a broad range of scientific e.g., biomedical, chemical and agricultural application areas. In this review, we detail the exciting recent development of smartphone spectrometer hardware, in addition to covering applications to which these units have been deployed, hitherto. The paper also points forward to the potentially highly influential impacts that such units could have on the sciences in the coming decades

Medical Imaging of Microrobots: Toward In Vivo Applications

Medical microrobots (MRs) have been demonstrated for a variety of non-invasive biomedical applications, such as tissue engineering, drug delivery, and assisted fertilization, among others. However, most of these demonstrations have been carried out in in vitro settings and under optical microscopy, being significantly different from the clinical practice. Thus, medical imaging techniques are required for localizing and tracking such tiny therapeutic machines when used in medical-relevant applications. This review aims at analyzing the state of the art of microrobots imaging by critically discussing the potentialities and limitations of the techniques employed in this field. Moreover, the physics and the working principle behind each analyzed imaging strategy, the spatiotemporal resolution, and the penetration depth are thoroughly discussed. The paper deals with the suitability of each imaging technique for tracking single or swarms of MRs and discusses the scenarios where contrast or imaging agent's inclusion is required, either to absorb, emit, or reflect a determined physical signal detected by an external system. Finally, the review highlights the existing challenges and perspective solutions which could be promising for future in vivo applications

Reconstruction algorithms for multispectral diffraction imaging

Thesis (Ph.D.)--Boston UniversityIn conventional Computed Tomography (CT) systems, a single X-ray source spectrum is used to radiate an object and the total transmitted intensity is measured to construct the spatial linear attenuation coefficient (LAC) distribution. Such scalar information is adequate for visualization of interior physical structures, but additional dimensions would be useful to characterize the nature of the structures. By imaging using broadband radiation and collecting energy-sensitive measurement information, one can generate images of additional energy-dependent properties that can be used to characterize the nature of specific areas in the object of interest. In this thesis, we explore novel imaging modalities that use broadband sources and energy-sensitive detection to generate images of energy-dependent properties of a region, with the objective of providing high quality information for material component identification. We explore two classes of imaging problems: 1) excitation using broad spectrum sub-millimeter radiation in the Terahertz regime and measure- ment of the diffracted Terahertz (THz) field to construct the spatial distribution of complex refractive index at multiple frequencies; 2) excitation using broad spectrum X-ray sources and measurement of coherent scatter radiation to image the spatial distribution of coherent-scatter form factors. For these modalities, we extend approaches developed for multimodal imaging and propose new reconstruction algorithms that impose regularization structure such as common object boundaries across reconstructed regions at different frequencies. We also explore reconstruction techniques that incorporate prior knowledge in the form of spectral parametrization, sparse representations over redundant dictionaries and explore the advantage and disadvantages of these techniques in terms of image quality and potential for accurate material characterization. We use the proposed reconstruction techniques to explore alternative architectures with reduced scanning time and increased signal-to-noise ratio, including THz diffraction tomography, limited angle X-ray diffraction tomography and the use of coded aperture masks. Numerical experiments and Monte Carlo simulations were conducted to compare performances of the developed methods, and validate the studied architectures as viable options for imaging of energy-dependent properties