The evolution of civilization is driven by the need for extending our capabilities. A most important way for us to sense the world is by vision. Biomedical imaging systems outperform our natural vision and become indispensible “eyes” in the fields of biology and medicine. A fascinating puzzle in history was how to achieve “an inner vision” of opaque objects. X-ray computed tomography (CT) is the first imaging modality to enable non-destructive sectional or volumetric image reconstruction of an object from x-ray shadows. Since the introduction of x-ray CT, biomedical imaging technology has been under rapid development for predictive, preventive and personalized medicine and should dramatically improve our longevity and quality of life. Our currently funded projects target x-ray CT and optical molecular tomography, multimodality and emerging possibilities.
X-ray CT Projects – We are prototyping the next generation x-ray nano-CT system for ROI-focused scanning and theoretically exact interior reconstruction (NSF/MRI 0923297, 2009-2012). Filling the performance gap between light and electron microscopic techniques, our x-ray nano-CT platform depicts details with resolution down to 50nm and has emerged as a powerful tool in various applications. However, a primary barrier to realizing the full potential of nano-CT is the aforementioned interior problem that prevents us from handling large objects and the intensive x-ray beam that may damage biological samples. To overcome these challenges, we are developing interior tomography/compressive sensing techniques. Our proposed interior nano-CT system should accelerate progress in diverse fields, such as medicine, biology, nanotechnology, material science, and energy physics. Upon completion of our project, the proposed system will be commercialized in collaboration with Xradia. In combination with our existing micro-CT and CT scanners, our multi-scale CT facility, one of the best in the world, covers 6 orders of magnitude in terms of image resolution and sample size with unique interior reconstruction capabilities.
Also, we are working on the next-generation cardiac CT architecture for better detection and quantification of cardiovascular diseases (NIH/NIBIB R01 EB011785, 2009-2012). Cardiovascular diseases are pervasive with high mortality and morbidity. There are urgent needs for significantly higher fidelity cardiac CT with substantially lower radiation dose. Although CT technology has improved from 16 to 320 detector rows and from single to dual sources, there remain challenges in terms of temporal resolution, spatial resolution and radiation dose. Based on an academic-industrial partnership between Virginia Tech and the GE Global Research Center, the goal of this project is to develop and analyze novel cardiac CT architectures and algorithms to define the next-generation cardiac CT concepts. On completion of this project, we will provide specifications and feasibility data for the most promising cardiac CT architecture(s) capable of achieving 16cm coverage, 50ms temporal resolution, 20lp/cm spatial resolution, 10HU noise level, and 5mSv effective dose simultaneously for an entire examination, This will set the stage for the second phase of the project: Actual prototyping of a next-generation cardiac CT system.
Optical Imaging BRP – Regenerative medicine devises new ways to repair or replace damaged tissues and organs for millions of patients who cannot receive transplants. A core technology is the bioengineering of a functional tissue or organ by seeding living cells onto a biodegradable scaffold and surgically implanting the construct into a patient. Tissue engineering involves extensive remodeling of cells and scaffolds. A primary barrier to progress has been the inability to monitor this dynamic complex biological process in real-time, which presents an outstanding biomedical imaging research opportunity. The NIH roadmap highlights molecular imaging that plays an instrumental role in the advancement of medicine. Now, optical molecular imaging tools have found major preclinical and clinical applications but they have not been effectively used for regenerative medicine. Therefore, we are motivated to integrate two forefront technologies – tissue engineering and optical molecular imaging – in a unified framework, and drive a paradigm shift from static assays of cellular function in biopsied tissue or 2D culture models towards systematic tomographic analysis of 3D systems.
Our BRP (Bioengineering Research Partnership) project will develop a first-of-its-kind multi-probe multi-modal optical molecular tomography system for regenerative medicine, and demonstrate its utility in assessing bioengineered blood vessels at pre- and post-implantation stages (NIH/NHLBI R01 HL098912, 2009-2014). Fluorescent probes will be used to label the tubular scaffold and two main cell types of blood vessels (endothelial cells lining the lumen, and smooth muscle cells in the wall). Optical fibers within the scaffold will deliver laser light for optical coherence tomography and excite the fluorescent probes. Innovative algorithms will be developed for fluorescence tomography. Initially, the proposed imaging system will track the development of bioengineered vessels in a bioreactor mimicking blood flow conditions. The engineered vessels will then be implanted as interposition grafts in the carotid arteries of living sheep and imaged to follow the tissue regeneration and function. This project will optimize new optical molecular imaging tools for vessel engineering and have major impacts on other areas in regenerative medicine.
Cardiovascular diseases are pervasive with high mortality and morbidity at tremendous social and healthcare costs. There are urgent needs for significantly higher fidelity cardiac CT with substantially lower radiation dose, which is currently not possible because of technical limitations. Although cardiac CT technology has improved significantly from 16 to 320 detector rows and from single to dual source, there remain technical challenges in terms of temporal resolution, spatial resolution, radiation dose, and so on. Based on an ideal academic-industrial partnership between Virginia Tech and the GE Global Research Center (GEGR), we are motivated to advance the state-of-the-art in cardiac CT.
The overall goal of this project is to develop novel cardiac CT architectures and the associated reconstruction algorithms, and define the next-generation cardiac CT system. The specific aims are to (1) design, analyze and compare novel cardiac CT architectures with novel sources and scanning trajectories; (2) develop analytic and iterative cardiac CT reconstruction algorithms for ROI-oriented scanning and dynamic imaging for the proposed cardiac CT architectures; and (3) evaluate and validate the proposed architectures and algorithms in theoretical studies, numerical simulations, phantom experiments and observer studies.
On completion of this project, we will have singled out the most promising cardiac CT architectures and algorithms to achieve 16cm coverage, 50ms temporal resolution, 20lp/cm spatial resolution, 10HU noise level, and 1mSv effective dose simultaneously for the entire examination, with detailed specifications and performance evaluation, setting the stage for prototyping a next-generation cardiac CT system in a Phase-II project. This project will enable significantly better diagnostic performance and bring major therapeutic benefits that affect over 60 million Americans.
Key Components:
Distributed x-ray source technology developed by GE Global Research Center. (a) Diagram of a multi-source electron gun topology, (b) drawing and picture of a high-voltage standoff insulator, and (c) a fast-switching x-ray cathode with 4 focal spots, with measurement of a focal spot.
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Distributed x-ray source technology
Triple-source helical cone-beam tomography formulated by Lv Y, Katsevich A, Zhao J, Yu H and Wang G (2010). (a) An intersection line of an osculation plane and the detector plane and (b) representative filtering lines.
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Triple-source helical cone-beam tomography
Interior tomography of the sheep chest performed by Virginia Tech and Univ. of Iowa (2007). (a) The image reconstructed by the global FBP, (b) that reconstructed by a local FBP after smooth data extrapolation, and (c) that by compressive-sensing-inspired interior tomography without precise knowledge of a subregion in the ROI.
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Interior tomography
Statistical reconstruction performed by GE Healthcare. (a) A slice reconstructed with FBP and (b) the counterpart by statistical reconstruction (Courtesy of Jean-Baptiste Thibault, GE Healthcare).
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Statistical reconstruction
Dynamic reconstruction at end-systole performed by GE Global Research Center. (a) and end-diastole (b) based on PW-MLTR using 50 views per phase.
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Dynamic reconstruction
Candidate Architectures
Baseline Architectures: This includes all commercially available CT architectures. Most commercial CT scanners use the third-generation geometry. The Siemens dual-source system has been well received for its improved temporal resolution and dual-energy imaging potential. The best temporal resolution today is achieved with the EBCT scanner.
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Baseline Architectures
Saddle-curve Architectures: Line sources with longitudinally offset focal spots were proposed by GE Global Research Center and can be used to implement a saddle trajectory. A composite-circling scanning mode was proposed by Virginia Tech as an alternative to solve the short object problem. The saddle-curve scanning mode is feasible for multi-source systems too.
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Saddle-curve Architectures
Triple-source Architecture: A triple-source cone-beam CT (CBCT) is being developed by Shanghai Jiaotong Univ., Central Florida Univ. and Virginia Tech. The apparent merit is a good improvement in temporal resolution at an incremental cost.
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Triple-source Architecture
Inverse Geometry Architecture: Inverse-geometry CT (IGCT) developed by Stanford Univ. and GE Global Research Center consists of multiple focal spots each emitting a relatively narrow x-ray beam through a small portion of the field-of-view. By scanning the source and detector configuration, a complete dataset can be collected.
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Inverse Geometry Architecture
Interior CT Schemes: An easy way to implement interior CT is to collimate x-rays to an ROI. This requires centering the ROI. More ideas were proposed by us and others including aggressive and dynamic bowties.
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Interior CT Schemes
Hybrid CT Schemes: A spectral detector can be embedded in a conventional detector array to implement color interior CT for characterization of plaques and other features.
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Hybrid CT Schemes
Instant CT Scheme: Similar to EBCT, an instant CT scanner is optimized for temporal resolution. We recently introduced a stationary interior cardiac CT concept according to interior tomography and compressive sensing. This scheme is conceivable with a cardiac ROI of 10cm, a magnification of 2, and a detector width of 20cm, and an architecture with tens of source-detector pairs. Scattering can be addressed by collimation, multiplexing and spectral imaging.
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Instant CT Scheme
Evaluation Strategy
Numerical Simulation: GE Global Research Center developed a simulation environment CatSim for x-ray CT and licensed to Virginia Tech. The well-known NCAT and UCAIR phantoms will be used to generate realistic datasets.
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Numerical Simulation
Phantom Experiments: GE Global Research Center has an experimental platform capable of emulating a very wide range of CT geometries. A cardiac CT phantom with beating heart inserts will be used, along with a CT performance phantom and a dosimeter.
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Phantom Experiments
Approach for Initial Evaluation: Modified Completeness Maps based on the Tuy’s condition and interior tomography theory respectively.
Approach for General Evaluation: Traditional image quality matrix and radiation dose indexes.
Approach for Specific Evaluation: Mathematical and human observer studies will compare both imaging performance and system superiority.
Project Timeline:
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Timeline
Project Website:
Click here for the GRC Site [password protected]
The attenuation-contrast mechanism underlying clinical and pre-clinical x-ray imaging has remained essentially the same since Roentgen’s revolutionary discovery. As a consequence, improvements in image contrast resolution are limited by the required increase in radiation dose. Alternatively, the phase-contrast mechanism, using the wave nature of the x-ray beam, is sensitive to the refractive index of the tissue rather than the attenuation coefficient. Since many soft tissues have quite different refractive indices but very similar attenuation coefficients, phase contrast imaging provides a thousand-fold improvement in contrast resolution with lower radiation dose. This has numerous major biomedical applications, such as x-ray phase-contrast in vitro characterization, small animal imaging, and mammography.
X-ray phase imaging with a synchrotron radiation source provides outstanding soft tissue contrast and information on a par with histological staining methods. Phase imaging is usually conducted with a synchrotron radiation source or a micro-focus tube. Synchrotron sources, of which there are fewer than 30 worldwide, require multi-million-dollar facilities. Micro-focus sources, while significantly less expensive, are severely limited by anode heating and have long imaging times, yet are unable to compete with synchrotron sources in terms of image quality. In 2006, Pfeiffer et al. reported groundbreaking results that x-ray phase-contrast imaging can be done using a hospital-grade x-ray tube instead of a synchrotron facility or micro-focus tube. The design, as a novel application of the Talbot effect, uses three gratings to produce coherent wavelets from a hospital-grade x-ray tube, construct interference patterns at an appropriate distance, extract the differential phase of wave-fronts distorted by an object irradiated by these wavelets, and finally form phase-contrast images in terms of the refractive index.
Recognizing the great potential of their work as the foundation of a less expensive and smaller in vitro and preclinical imaging system, supported by internal funding from Dr. Wang’s institution and in a newly established collaboration with NIST’s neutron phase imaging group (see Dr. Arif’s Letter), we are close to completing a 1D grating-based x-ray imaging platform as described in C.1. This revised proposal is to upgrade the current 1D-grating-based system with 2D-gratings to provide imaging performance similar to that obtained with a synchrotron source, but in an exceedingly cost-effective manner. The general hypothesis is that 2D grating-based phase-contrast imaging techniques can be developed to produce more accurate and robust phase-contrast images of biomedical interest than the competing 1D techniques. The overall goal is to develop the 2D-grating-based x-ray phase-contrast technology into a preclinical imaging tool. The specific aims are as follows.
Specific Aim 1 – Theory & Methods: Develop novel theory and methods for 2D grating-based x-ray phase-contrast imaging. Task 1.1 – Forward Modeling: The forward model for 2D grating-based x-ray phase-contrast imaging will be formulated. Initially, only a weakly absorbing object is considered. Then, the model will be refined to take absorption and scattering into account. Task 1.2 – Inversion Schemes: Based on the forward model, phase retrieval and tomographic reconstruction algorithms will be developed. Practical factors will be taken into account such as system calibration, data preprocessing and computational efficiency.
Specific Aim 2 – System Prototyping: Prototype a 2D-grating-based imaging platform for projective and tomographic imaging. Task 2.1 – 1D-grating-based Configuration: Initially, we will complete the development of our current 1D grating-based phase-contrast imaging system to produce a flexible imaging platform for further R&D. Task 2.2 – 2D-grating-based Configuration: The current 1D-gratings will be replaced by chessboard-like 2D-gratings for extraction of phase information more accurately and robustly than the 1D grating-based system. The entire system will be calibrated and optimized for the highest signal-to-noise ratio and best image quality. Testing, operation and quality assurance procedures will be developed and documented.
Specific Aim 3 – Validation & Application: Evaluate and validate the proposed technology, and demonstrate its utility for in vitro imaging. Task 3.1 – Simulation Studies: The proposed techniques will be evaluated in numerical simulation and validated in phantom experiments with respect to phantom specifications and imaging parameters. Key image quality measures will be determined. Task 3.2 – In vitro Studies: The proposed technology will be applied to in vitro studies with an emphasis on spatial and contrast resolution for visualization of atherosclerotic plaques in vessels from an existing mouse model of differential diet. The imaging results will be compared to their counterparts acquired using state of the art histology, micro-CT and micro-MRI. The data will be systematically analyzed for statistical significance.
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Project Timeline:
By Ge Wang on April 14, 2011
Updated July 23, 2011
The physiome concept was presented to the International Union of Physiological Sciences (IUPS) in 1993, and was designated as a strategic area by IUPS in 2001. A physiome describes physiological processes and their interactions from the scale of genome to organism in a systematic fashion. The IUPS Physiome Project supports a worldwide repository of models and datasets, and represents an integral component of systems biology and modern medicine.
In the medical imaging field, efforts are being made to link molecular assays with diagnostic imaging; however, the success to date has been rather limited. One reason is that medical imaging often times does not offer a sufficient spectrum of information. For example, current x-ray CT scanners only produce gray-scale images, while information from genetic and epigenetic profiling is huge. This imbalance between phenotype descriptions (e.g. CT images) and genome-level tests suggests more independent imaging features are demanded. Indeed, the medical imaging field is rapidly trending in this direction. X-ray CT is in transition from gray-scale to true-color images, thanks to the energy-sensitive photon-counting detection technology. Furthermore, x-ray phase-contrast and dark-field imaging systems are under development. Overall, imaging modalities and contrast agents are constantly being improved to generate more and more information on structural, functional, cellular and molecular characteristics of biological systems.
The holy grail of imaging for diagnosis and intervention would produce simultaneous and dynamic multimodal tomographic in vivo observations of highly complex and interconnected physiological and pathological phenomena. The modality fusion approach has been effective in partially meeting this challenge, as demonstrated by the popularity of PET/CT and other hybrid scanners. I envision that the next stage is to integrate more imaging modalities into a single system, or even perform a grand fusion of tomographic imaging modalities to include CT, MRI, PET, SPECT, US, optical and photoacoustic imaging, and more. However, given the physical size requirements of typical scanners, this grand fusion task appears impractical due to space conflict. We could line up the scanners of different types, but this sequential arrangement would make simultaneous capture impossible, especially when relatively slow modalities are involved (e.g. MRI, PET and SPECT).3rd, 2011
The physiome concept was presented to the International Union of Physiological Sciences (IUPS) in 1993, and was designated as a strategic area by IUPS in 2001. A physiome describes physiological processes and their interactions from the scale of genome to organism in a systematic fashion. The IUPS Physiome Project supports a worldwide repository of models and datasets, and represents an integral component of systems biology and modern medicine.
In the medical imaging field, efforts are being made to link molecular assays with diagnostic imaging; however, the success to date has been rather limited. One reason is that medical imaging often times does not offer a sufficient spectrum of information. For example, current x-ray CT scanners only produce gray-scale images, while information from genetic and epigenetic profiling is huge. This imbalance between phenotype descriptions (e.g. CT images) and genome-level tests suggests more independent imaging features are demanded. Indeed, the medical imaging field is rapidly trending in this direction. X-ray CT is in transition from gray-scale to true-color images, thanks to the energy-sensitive photon-counting detection technology. Furthermore, x-ray phase-contrast and dark-field imaging systems are under development. Overall, imaging modalities and contrast agents are constantly being improved to generate more and more information on structural, functional, cellular and molecular characteristics of biological systems.
Virginia Tech filed a provisional patent application entitled “Tomogranphy – Interior Tomographysiome” (VTIP 11-103, Application Number 61471245) on April 4, 2011.
