OBJECTIVE: Electron paramagnetic resonance (EPR) imaging is an advanced in vivo oxygen imaging modality. The main drawback of EPR imaging is the long scanning time. Sparse-view projections collection is an effective fast scanning pattern. However, the commonly-used filtered backprojection (FBP) algorithm is not competent to accurately reconstruct images from sparse-view projections because of the severe streak artifacts. The aim of this work is to develop an advanced algorithm for sparse reconstruction of 3D EPR imaging. METHODS: The optimization based algorithms including the total variation (TV) algorithm have proven to be effective in sparse reconstruction in EPR imaging. To further improve the reconstruction accuracy, we propose the directional TV (DTV) model and derive its Chambolle-Pock (CP) solving algorithm. RESULTS: After the algorithm correctness validation on simulation data, we explore the sparse reconstruction capability of the DTV algorithm via a simulated six-sphere phantom and two real bottle phantoms filled with OX063 trityl solution and scanned by an EPR imager with a magnetic field strength of 250G. CONCLUSION: Both the simulated and real data experiments show that the DTV algorithm is superior to the existing FBP and TV-type algorithms and a deep learning based method according to visual inspection and quantitative evaluations in sparse reconstruction of EPR imaging. SIGNIFICANCE: These insights gained in this work may be used in the development of fast EPR imaging workflow of practical significance.
We report the development of a high-sensitivity and high-resolution PET subsystem for a next-generation preclinical PET/EPR hybrid scanner for investigating and improving hypoxia imaging with PET. The PET subsystem consists of 14 detector modules (DM) installed within a cylindrical supporting frame whose outer and inner diameters are 115mm and 60mm, respectively. Each DM contains eight detector units (DU) in a row and each DU is made of a 12×12 array of 1×1×10mm3 LYSO crystals (with a 1.05mm pitch) coupled to a 4×4 silicon photomultiplier (SiPM) array that has a 3.2mm pitch (Hamamatsu multi-pixel photon counter (MPPC) array 14161-3050HS-04). The PET subsystem has a 104mm axial field-of-view (AFOV) that is sufficient for full-body mouse imaging, therefore enabling temporal and spatial correlation studies of tumor hypoxia between PET and EPR. It employs 1mm-width crystals to support sub-millimeter image resolution that is desired for mouse imaging. Al-though a DM contains 1,152 LYSO crystals, by use of a newly devised signal readout method only six outputs are produced. Recently a partial prototype of this subsystem consisting of four DMs is built. In this paper, we present performance measurement results obtained for the developed DMs and initial imaging results obtained by the prototype. The developed DMs show uniformly superior performance in identifying the hit crystal and detector unit, in energy resolution, and in coincidence time resolution. The images obtained for a 22Na point source and a 18F-filled U-shaped tube source show an image resolution of about 1.1mm and 1.2mm FWHM in the transverse and axial directions respectively, and demonstrate successful imaging over the entire 104mm AFOV of the prototype. This estimated image resolution however includes the contribution by the source size.
Precise radiation guided by oxygen images has demonstrated superiority over the traditional radiation methods. Electron paramagnetic resonance (EPR) imaging has proven to be the most advanced oxygen imaging modality. However, the main drawback of EPR imaging is the long scan time. For each projection, we usually need to collect the projection many times and then average them to achieve high signal-to-noise ratio (SNR). One approach to fast scan is to reduce the repeating time for each projection. While the projections would be noisy and thus the traditional commonly-use filtered backprojection (FBP) algorithm would not be capable of accurately reconstructing images. Optimization-based iterative algorithms may accurately reconstruct images from noisy projections for they may incorporate prior information into optimization models. Based on the total variation (TV) algorithms for EPR imaging, in this work, we propose a directional TV (DTV) algorithm to further improve the reconstruction accuracy. We construct the DTV constrained, data divergence minimization (DTVcDM) model, derive its Chambolle-Pock (CP) solving algorithm, validate the correctness of the whole algorithm, and perform evaluations via simulated and real data. The experimental results show that the DTV algorithm outperforms the existing TV and FBP algorithms in fast EPR imaging. Compared to the standard FBP algorithm, the proposed algorithm may achieve 10 times of acceleration.
Algorithms , Imaging, Three-Dimensional , Electron Spin Resonance Spectroscopy/methods , Phantoms, Imaging , Imaging, Three-Dimensional/methods , Oxygen , Image Processing, Computer-Assisted/methods
In continuous-wave electron paramagnetic resonance imaging (CW EPRI), data are collected generally at densely sampled views sufficient for achieving accurate reconstruction of a four dimensional spectral-spatial (4DSS) image by use of the conventional filtered-backprojection (FBP) algorithm. It is desirable to minimize the scan time by collection of data only at sparsely sampled views, referred to as sparse-view data. Interest thus remains in investigation of algorithms for accurate reconstruction of 4DSS images from sparse-view data collected for potentially enabling fast data acquisition in CW EPRI. In this study, we investigate and demonstrate optimization-based algorithms for accurate reconstruction of 4DSS images from sparse-view data. Numerical studies using simulated and real sparse-view data acquired in CW EPRI are conducted that reveal, in terms of image visualization and physical-parameter estimation, the potential of the algorithms developed for yielding accurate 4DSS images from sparse-view data in CW EPRI. The algorithms developed may be exploited for enabling sparse-view scans with minimized scan time in CW EPRI for yielding 4DSS images of quality comparable to, or better than, that of the FBP reconstruction from data collected at densely sampled views.
PURPOSE: The determination of blood-brain barrier (BBB) integrity and partial pressure of oxygen (pO2) in the brain is of substantial interest in several neurological applications. This study aimed to assess the feasibility of using trityl OX071-based pulse electron paramagnetic resonance imaging (pEPRI) to provide a quantitative estimate of BBB integrity and pO2 maps in mouse brains as a function of neuroinflammatory disease progression. METHODS: Five Connexin-32 (Cx32)-knockout (KO) mice were injected with lipopolysaccharide to induce neuroinflammation for imaging. Three wild-type mice were also used to optimize the imaging procedure and as control animals. An additional seven Cx32-KO mice were used to establish the BBB leakage of trityl using the colorimetric assay. All pEPRI experiments were performed using a preclinical instrument, JIVA-25 (25 mT/720 MHz), at times t = 0, 4, and 6 h following lipopolysaccharide injection. Two pEPRI imaging techniques were used: (a) single-point imaging for obtaining spatial maps to outline the brain and calculate BBB leakage using the signal amplitude, and (b) inversion-recovery electron spin echo for obtaining pO2 maps. RESULTS: A statistically significant change in BBB leakage was found using pEPRI with the progression of inflammation in Cx32 KO animals. However, the change in pO2 values with the progression of inflammation for these animals was not statistically significant. CONCLUSIONS: For the first time, we show the ability of pEPRI to provide pO2 maps in mouse brains noninvasively, along with a quantitative assessment of BBB leakage. We expect this study to open new queries from the field to explore the pathology of many neurological diseases and provide a path to new treatments.
Blood-Brain Barrier , Neuroinflammatory Diseases , Mice , Animals , Blood-Brain Barrier/diagnostic imaging , Mice, Knockout , Electron Spin Resonance Spectroscopy/methods , Lipopolysaccharides , Brain/diagnostic imaging , Brain/pathology , Inflammation/diagnostic imaging , Connexins
Cellular therapies for type-1 diabetes can leverage cell encapsulation to dispense with immunosuppression. However, encapsulated islet cells do not survive long, particularly when implanted in poorly vascularized subcutaneous sites. Here we show that the induction of neovascularization via temporary controlled inflammation through the implantation of a nylon catheter can be used to create a subcutaneous cavity that supports the transplantation and optimal function of a geometrically matching islet-encapsulation device consisting of a twisted nylon surgical thread coated with an islet-seeded alginate hydrogel. The neovascularized cavity led to the sustained reversal of diabetes, as we show in immunocompetent syngeneic, allogeneic and xenogeneic mouse models of diabetes, owing to increased oxygenation, physiological glucose responsiveness and islet survival, as indicated by a computational model of mass transport. The cavity also allowed for the in situ replacement of impaired devices, with prompt return to normoglycemia. Controlled inflammation-induced neovascularization is a scalable approach, as we show with a minipig model, and may facilitate the clinical translation of immunosuppression-free subcutaneous islet transplantation.
[This corrects the article DOI: 10.3389/fmed.2023.1269689.].
PURPOSE: This study aimed to develop a biocompatible oximetric electron paramagnetic resonance (EPR) spin probe with reduced self-relaxation, and sensitivity to oxygen for a higher signal-to-noise ratio and longer relaxation times at high oxygen concentration, compared to the reference spin probe OX071. PROCEDURES: SOX71 was synthesized by succinylation of the twelve alcohol groups of OX071 spin probe and characterized by EPR at X-Band (9.5 GHz) and at low field (720 MHz). The biocompatibility of SOX71 was tested in vitro and in vivo in mice. A pharmacokinetic study was performed to determine the best time frame for EPR imaging. Finally, a proof-of-concept EPR oxygen imaging was performed on a mouse model of a fibrosarcoma tumor. RESULTS: SOX71 was synthesized in one step from OX071. SOX71 exhibits a narrow line EPR spectrum with a peak-to-peak linewidth of 66 mG, similar to OX071. SOX71 does not bind to albumin nor show cell toxicity for the concentrations tested up to 5 mM. No toxicity was observed after systemic delivery via intraperitoneal injection in mice at twice the dose required for EPR imaging. After the injection, the probe is readily absorbed into the bloodstream, with a peak blood concentration half an hour, post-injection. Then, the probe is quickly cleared by the kidney with a half-life of ~ 45 min. SOX71 shows long relaxation times under anoxic condition (T1e = 9.5 µs and T2e = 5.1 µs; [SOX71] = 1 mM in PBS at 37 °C, pO2 = 0 mmHg, 720 MHz). Both the relaxation rates R1e and R2e show a decreased sensitivity to pO2, leading to twice longer relaxation times under room air conditions (pO2 = 159 mmHg) compared to OX071. This is ideal for oxygen imaging in samples with a wide range of pO2. Both the relaxation rates R1e and R2e show a decreased sensitivity to self-relaxation compared to OX071, with a negligible effect of the probe concentration on R1e. SOX71 was successfully applied to image oxygen in a tumor. CONCLUSION: SOX71, a succinylated derivative of OX071 was synthesized, characterized, and applied for in vivo EPR tumor oxygen imaging. SOX71 is highly biocompatible, and shows decreased sensitivity to oxygen and self-relaxation. This first report suggests that SOX71 is superior to OX071 for absolute oxygen mapping under a broad range of pO2 values.
Recent advances in our understanding of hypoxia and hypoxia-mediated mechanisms shed light on the critical implications of the hypoxic stress on cellular behavior. However, tools emulating hypoxic conditions (i.e., low oxygen tensions) for research are limited and often suffer from major shortcomings, such as lack of reliability and off-target effects, and they usually fail to recapitulate the complexity of the tissue microenvironment. Fortunately, the field of biomaterials is constantly evolving and has a central role to play in the development of new technologies for conducting hypoxia-related research in several aspects of biomedical research, including tissue engineering, cancer modeling, and modern drug screening. In this perspective, we provide an overview of several strategies that have been investigated in the design and implementation of biomaterials for simulating or inducing hypoxic conditions-a prerequisite in the stabilization of hypoxia-inducible factor (HIF), a master regulator of the cellular responses to low oxygen. To this end, we discuss various advanced biomaterials, from those that integrate hypoxia-mimetic agents to artificially induce hypoxia-like responses, to those that deplete oxygen and consequently create either transient (<1 day) or sustained (>1 day) hypoxic conditions. We also aim to highlight the advantages and limitations of these emerging biomaterials for biomedical applications, with an emphasis on cancer research.
We report the design and experimental validation of a compact positron emission tomography (PET) detector module (DM) intended for building a preclinical PET and electron-paramagnetic-resonance-imaging hybrid system that supports sub-millimeter image resolution and high-sensitivity, whole-body animal imaging. The DM is eight detector units (DU) in a row. Each DU contains 12×12 lutetium-yttrium oxyorthosilicate (LYSO) crystals having a 1.05 mm pitch read by 4×4 silicon photomultipliers (SiPM) having a 3.2 mm pitch. A small-footprint, highly-multiplexing readout employing only passive electronics is devised to produce six outputs for the DM, including two outputs derived from SiPM cathodes for determining event time and active DU and four outputs derived from SiPM anodes for determining energy and active crystal. Presently, we have developed two DMs that are 1.28×10.24 cm2 in extent and approximately 1.8 cm in thickness, with their outputs sampled at 0.7 GS/s and analyzed offline. For both DMs, our results show successfully discriminated DUs and crystals. With no correction for SiPM nonlinearity, the average energy resolution for crystals in a DU ranges from 14% to 16%. While not needed for preclinical imaging, the DM may support 300-400 ps time-of-flight resolution.
Background: Clinical attempts to find benefit from specifically targeting and boosting resistant hypoxic tumor subvolumes have been promising but inconclusive. While a first preclinical murine tumor type showed significant improved control with hypoxic tumor boosts, a more thorough investigation of efficacy from boosting hypoxic subvolumes defined by electron paramagnetic resonance oxygen imaging (EPROI) is necessary. The present study confirms improved hypoxic tumor control results in three different tumor types using a clonogenic assay and explores potential confounding experimental conditions. Materials and methods: Three murine tumor models were used for multi-modal imaging and radiotherapy: MCa-4 mammary adenocarcinomas, SCC7 squamous cell carcinomas, and FSa fibrosarcomas. Registered T2-weighted MRI tumor boundaries, hypoxia defined by EPROI as pO2 ≤ 10 mmHg, and X-RAD 225Cx CT boost boundaries were obtained for all animals. 13 Gy boosts were directed to hypoxic or equal-integral-volume oxygenated tumor regions and monitored for regrowth. Kaplan-Meier survival analysis was used to assess local tumor control probability (LTCP). The Cox proportional hazards model was used to assess the hazard ratio of tumor progression of Hypoxic Boost vs. Oxygenated Boost for each tumor type controlling for experimental confounding variables such as EPROI radiofrequency, tumor volume, hypoxic fraction, and delay between imaging and radiation treatment. Results: An overall significant increase in LTCP from Hypoxia Boost vs. Oxygenated Boost treatments was observed in the full group of three tumor types (p < 0.0001). The effects of tumor volume and hypoxic fraction on LTCP were dependent on tumor type. The delay between imaging and boost treatments did not have a significant effect on LTCP for all tumor types. Conclusion: This study confirms that EPROI locates resistant tumor hypoxic regions for radiation boost, increasing clonogenic LTCP, with potential enhanced therapeutic index in three tumor types. Preclinical absolute EPROI may provide correction for clinical hypoxia images using additional clinical physiologic MRI.
PURPOSE: Progress toward developing a novel radiocontrast agent for determining pO2 in tumors in a clinical setting is described. The imaging agent is designed for use with electron paramagnetic resonance imaging (EPRI), in which the collision of a paramagnetic probe molecule with molecular oxygen causes a spectroscopic change which can be calibrated to give the real oxygen concentration in the tumor tissue. PROCEDURES: The imaging agent is based on a nanoscaffold of aluminum hydroxide (boehmite) with sizes from 100 to 200 nm, paramagnetic probe molecule, and encapsulation with a gas permeable, thin (10-20 nm) polymer layer to separate the imaging agent and body environment while still allowing O2 to interact with the paramagnetic probe. A specially designed deuterated Finland trityl (dFT) is covalently attached on the surface of the nanoparticle through 1,3-dipolar addition of the alkyne on the dFT with an azide on the surface of the nanoscaffold. This click-chemistry reaction affords 100% efficiency of the trityl attachment as followed by the complete disappearance of the azide peak in the infrared spectrum. The fully encapsulated, dFT-functionalized nanoparticle is referred to as RADI-Sense. RESULTS: Side-by-side in vivo imaging comparisons made in a mouse model made between RADI-Sense and free paramagnetic probe (OX-071) showed oxygen sensitivity is retained and RADI-Sense can create 3D pO2 maps of solid tumors CONCLUSIONS: A novel encapsulated nanoparticle EPR imaging agent has been described which could be used in the future to bring EPR imaging for guidance of radiotherapy into clinical reality.
Type 1 diabetes (T1D) is an autoimmune disease that leads to the loss of insulin-producing beta cells. Bioartificial pancreas (BAP) or beta cell replacement strategies have shown promise in curing T1D and providing long-term insulin independence. Hypoxia (low oxygen concentration) that may occur in the BAP devices due to cell oxygen consumption at the early stages after implantation damages the cells, in addition to imposing limitations to device dimensions when translating promising results from rodents to humans. Finding ways to provide cells with sufficient oxygenation remains the major challenge in realizing BAP devices' full potential. Therefore, in vitro oxygen imaging assessment of BAP devices is crucial for predicting the devices' in vivo efficiency. Electron paramagnetic resonance oxygen imaging (EPROI, also known as electron MRI or eMRI) is a unique imaging technique that delivers absolute partial pressure of oxygen (pO2) maps and has been used for cancer hypoxia research for decades. However, its applicability for assessing BAP devices has not been explored. EPROI utilizes low magnetic fields in the mT range, static gradients, and the linear relationship between the spin-lattice relaxation rate (R1) of oxygen-sensitive spin probes such as trityl OX071 and pO2 to generate oxygen maps in tissues. With the support of the Juvenile Diabetes Research Foundation (JDRF), an academic-industry partnership consortium, the "Oxygen Measurement Core" was established at O2M to perform oxygen imaging assessment of BAP devices originated from core members' laboratories. This article aims to establish the protocols and demonstrate a few examples of in vitro oxygen imaging of BAP devices using EPROI. All pO2 measurements were performed using a recently introduced 720 MHz/25 mT preclinical oxygen imager instrument, JIVA-25™. We began by performing pO2 calibration of the biomaterials used in BAPs at 25 mT magnetic field since no such data exist. We compared the EPROI pO2 measurement with a single-point probe for a few selected materials. We also performed trityl OX071 toxicity studies with fibroblasts, as well as insulin-producing cells (beta TC6, MIN6, and human islet cells). Finally, we performed proof-of-concept in vitro pO2 imaging of five BAP devices that varied in size, shape, and biomaterials. We demonstrated that EPROI is compatible with commonly used biomaterials and that trityl OX071 is nontoxic to cells. A comparison of the EPROI with a fluorescent-based point oxygen probe in selected biomaterials showed higher accuracy of EPROI. The imaging of typically heterogenous BAP devices demonstrated the utility of obtaining oxygen maps over single-point measurements. In summary, we present EPROI as a quality control tool for developing efficient cell transplantation devices and artificial tissue grafts. Although the focus of this work is encapsulation systems for diabetes, the techniques developed in this project are easily transferable to other biomaterials, tissue grafts, and cell therapy devices used in the field of tissue engineering and regenerative medicine (TERM). In summary, EPROI is a unique noninvasive tool to experimentally study oxygen distribution in cell transplantation devices and artificial tissues, which can revolutionize the treatment of degenerative diseases like T1D.
Diabetes Mellitus, Type 1 , Insulins , Humans , Oxygen , Diabetes Mellitus, Type 1/therapy , Hypoxia , Biocompatible Materials
PURPOSE: Tumor hypoxia contributes to aggressive phenotypes and diminished therapeutic responses to radiation therapy (RT) with hypoxic tissue being 3-fold less radiosensitive than normoxic tissue. A major challenge in implementing hypoxic radiosensitizers is the lack of a high-resolution imaging modality that directly quantifies tissue-oxygen. The electron paramagnetic resonance oxygen-imager (EPROI) was used to quantify tumor oxygenation in two murine tumor models: E0771 syngeneic transplant breast cancers and primary p53/MCA soft tissue sarcomas, with the latter autochthonous model better recapitulating the tumor microenvironment in human malignancies. We hypothesized that tumor hypoxia differs between these models. We also aimed to quantify the absolute change in tumor hypoxia induced by the mitochondrial inhibitor papaverine (PPV) and its effect on RT response. PROCEDURES: Tumor oxygenation was characterized in E0771 and primary p53/MCA sarcomas via EPROI, with the former model also being quantified indirectly via diffuse reflectance spectroscopy (DRS). After confirming PPV's effect on hypoxic fraction (via EPROI), we compared the effect of 0 versus 2 mg/kg PPV prior to 20 Gy on tumor growth delay and survival. RESULTS: Hypoxic sarcomas were more radioresistant than normoxic sarcomas (p=0.0057, 2-way ANOVA), and high baseline hypoxic fraction was a significant (p=0.0063, Cox Regression Model) hazard in survivability regardless of treatment. Pre-treatment with PPV before RT did not radiosensitize tumors in the sarcoma or E0771 model. In the sarcoma model, EPROI successfully identified baseline hypoxic tumors. DRS quantification of total hemoglobin, saturated hemoglobin, changes in mitochondrial potential and glucose uptake showed no significant difference in E0771 tumors pre- and post-PPV. CONCLUSION: EPROI provides 3D high-resolution pO2 quantification; EPR is better suited than DRS to characterize tumor hypoxia. PPV did not radiosensitize E0771 tumors nor p53/MCA sarcomas, which may be related to the complex pattern of vasculature in each tumor. Additionally, understanding model-dependent tumor hypoxia will provide a much-needed foundation for future therapeutic studies with hypoxic radiosensitizers.
PURPOSE: Spatial heterogeneity in tumor hypoxia is one of the most important factors regulating tumor growth, development, aggressiveness, metastasis, and affecting treatment outcome. Most solid tumors are known to have hypoxia or low oxygen levels (pO2 ≤10 torr). Electron paramagnetic resonance oxygen imaging (EPROI) is an emerging oxygen mapping technology. EPROI utilizes the linear relationship between the relaxation rates of the injectable OX071 trityl spin probe and the partial oxygen pressure (pO2). However, most of the EPROI studies have been limited to mouse models of solid tumors because of the instrument-size limitations. The purpose of this work was to develop a human-sized 9-mT (250 MHz resonance frequency, 60 cm bore size) pulse EPROI instrument and evaluate its performance with rabbit VX-2 tumor oxygen imaging. METHODS: A New Zealand white rabbit with a 3.2-cm VX-2 tumor in the calf muscle was imaged using the human-sized EPROI instrument and a 2.25-in. ID volume coil. The animal received a ~8-min intravenous injection of OX071 (5.2 mL total volume at 72 mM concentration) and, after 75 min, an intratumoral injection (120 µL total at 5 mM OX071 concentration) and underwent EPROI. At the end of the experiments, MRI was performed using a preclinical 9.4-T MRI system to outline the tumor boundaries. RESULTS: For the first time, a human-sized pulse EPROI instrument with a 60-cm bore size/250-MHz frequency was built and evaluated using rabbit tumor oxygen imaging. For the first time, the systemic IV injection of the oxygen-sensitive trityl OX071 spin probe was used for an animal of this size. The resulting EPROI image from the IV injection showed complete tumor coverage. The image obtained after intratumoral injection showed localized coverage in the upper lobe of the tumor, demonstrating the need for improved intratumoral injection protocol. CONCLUSIONS: This study demonstrates the performance of the world's first human-sized pulse EPROI instrument. It also demonstrates that the EPROI of larger animals can be performed using the systemic injection of a manageable amount of the spin probe. This brings EPROI one step closer to clinical applications in cancer therapies. Oxygen imaging is a platform technology, and the instrument and techniques developed here will also be useful for other clinical applications.
Background and Objective: Optimization based image reconstruction algorithm is an advanced algorithm in medical imaging. However, the corresponding solving algorithm is challenging because the optimization model is usually large-scale and non-smooth. This work aims to devise a simple but universal solver for optimization models. Methods: The alternating direction method of multipliers (ADMM) algorithm is a simple and effective solver of the optimization models. However, there always exists a sub-problem that has not closed-form solution. One may use gradient descent algorithm to solve this sub-problem, but the step-size selection via line search is time-consuming. Or, one may use fast Fourier transform (FFT) to get a closed-form solution if the system matrix and the sparse transform matrix are both of special structure. In this work, we propose a simple but universal fully linearized ADMM (FL-ADMM) algorithm that avoids line search to determine step-size and applies to system matrix and sparse transform of any structures. Results: We derive the FL-ADMM algorithm instances for three total variation (TV) models in 2D computed tomography (CT). Further, we validate and evaluate one FL-ADMM algorithm and explore how the two important factors impact convergence rate. Also, we compare this algorithm with the Chambolle-Pock algorithm via real CT phantom reconstructions. These studies show that the FL-ADMM algorithm may accurately solve optimization models in image reconstruction. Conclusion: The FL-ADMM algorithm is a simple, effective, convergent and universal solver of optimization models in image reconstruction. Compared to the existing ADMM algorithms, the new algorithm does not need time-consuming step-size line-search or special demand to system matrix and sparse transform. It is a rapid prototyping tool for optimization based image reconstruction.
OBJECTIVE: We investigate and develop optimization-based algorithms for accurate reconstruction of four-dimensional (4D)-spectral-spatial (SS) images directly from data collected over limited angular ranges (LARs) in continuous-wave (CW) electron paramagnetic resonance imaging (EPRI). METHODS: Basing on a discrete-to-discrete data model devised in CW EPRI employing the Zeeman-modulation (ZM) scheme for data acquisition, we first formulate the image reconstruction problem as a convex, constrained optimization program that includes a data fidelity term and also constraints on the individual directional total variations (DTVs) of the 4D-SS image. Subsequently, we develop a primal-dual-based DTV algorithm, simply referred to as the DTV algorithm, to solve the constrained optimization program for achieving image reconstruction from data collected in LAR scans in CW-ZM EPRI. RESULTS: We evaluate the DTV algorithm in simulated- and real-data studies for a variety of LAR scans of interest in CW-ZM EPRI, and visual and quantitative results of the studies reveal that 4D-SS images can be reconstructed directly from LAR data, which are visually and quantitatively comparable to those obtained from data acquired in the standard, full-angular-range (FAR) scan in CW-ZM EPRI. CONCLUSION: An optimization-based DTV algorithm is developed for accurately reconstructing 4D-SS images directly from LAR data in CW-ZM EPRI. Future work includes the development and application of the optimization-based DTV algorithm for reconstructions of 4D-SS images from FAR and LAR data acquired in CW EPRI employing schemes other than the ZM scheme. SIGNIFICANCE: The DTV algorithm developed may be exploited potentially for enabling and optimizing CW EPRI with minimized imaging time and artifacts by acquiring data in LAR scans.
Significance: Fundamental to the application of tissue redox status to human health is the quantification and localization of tissue redox abnormalities and oxidative stress and their correlation with the severity and local extent of disease to inform therapy. The centrality of the low-molecular-weight thiol, glutathione, in physiological redox balance has long been appreciated, but direct measurement of tissue thiol status in vivo has not been possible hitherto. Recent advances in instrumentation and molecular probes suggest the feasibility of real-time redox assessment in humans. Recent Advances: Recent studies have demonstrated the feasibility of using low-frequency electron paramagnetic resonance (EPR) techniques for quantitative imaging of redox status in mammalian tissues in vivo. Rapid-scan (RS) EPR spectroscopy and imaging, new disulfide-dinitroxide spin probes, and novel analytic techniques have led to significant advances in direct, quantitative imaging of thiol redox status. Critical Issues: While novel RS EPR imaging coupled with first-generation molecular probes has demonstrated the feasibility of imaging thiol redox status in vivo, further technical advancements are desirable and ongoing. These include developing spin probes that are tailored for specific tissues with response kinetics tuned to the physiological environment. Equally critical are RS instrumentation with higher signal-to-noise ratio and minimal signal distortion, as well as optimized imaging protocols for image acquisition with sparsity adapted to image information content. Future Directions: Quantitative images of tissue glutathione promise to enable acquisition of a general image of mammalian and potentially human tissue health.
Electron paramagnetic resonance (EPR) imaging is an advanced oxygen imaging modality for oxygen-image guided radiation. The iterative reconstruction algorithm is the research hot-point in image reconstruction for EPR imaging (EPRI) for this type of algorithm may incorporate image-prior information to construct advanced optimization model to achieve accurate reconstruction from sparse-view projections and/or noisy projections. However, the system matrix in the iterative algorithm needs complicated calculation and needs huge memory-space if it is stored in memory. In this work, we propose an iterative reconstruction algorithm without system matrix for EPRI to simplify the whole iterative reconstruction process. The function of the system matrix is to calculate the projections, whereas the function of the transpose of the system matrix is to perform backprojection. The existing projection and backprojection methods are all based on the configuration that the imaged-object remains stationary and the scanning device rotates. Here, we implement the projection and backprojection operations by fixing the scanning device and rotating the object. Thus, the core algorithm is only the commonly-used image-rotation algorithm, while the calculation and store of the system matrix are avoided. Based on the idea of image rotation, we design a specific iterative reconstruction algorithm for EPRI, total variation constrained data divergence minimization (TVcDM) algorithm without system matrix, and named it as image-rotation based TVcDM (R-TVcDM). Through a series of comparisons with the original TVcDM via real projection data, we find that the proposed algorithm may achieve similar reconstruction accuracy with the original one. But it avoids the complicated calculation and store of the system matrix. The insights gained in this work may be also applied to other imaging modalities, for example computed tomography and positron emission tomography.
Algorithms , Oxygen , Electron Spin Resonance Spectroscopy/methods , Phantoms, Imaging , Image Processing, Computer-Assisted/methods
PURPOSE: To identify the optimal threshold in 18F-fluoromisonidazole (FMISO) PET images to accurately locate tumor hypoxia by using electron paramagnetic resonance imaging (pO2 EPRI) as ground truth for hypoxia, defined by pO2 [Formula: see text] 10 mmHg. METHODS: Tumor hypoxia images in mouse models of SCCVII squamous cell carcinoma (n = 16) were acquired in a hybrid PET/EPRI imaging system 2 h post-injection of FMISO. T2-weighted MRI was used to delineate tumor and muscle tissue. Dynamic contrast enhanced (DCE) MRI parametric images of Ktrans and ve were generated to model tumor vascular properties. Images from PET/EPR/MRI were co-registered and resampled to isotropic 0.5 mm voxel resolution for analysis. PET images were converted to standardized uptake value (SUV) and tumor-to-muscle ratio (TMR) units. FMISO uptake thresholds were evaluated using receiver operating characteristic (ROC) curve analysis to find the optimal FMISO threshold and unit with maximum overall hypoxia similarity (OHS) with pO2 EPRI, where OHS = 1 shows perfect overlap and OHS = 0 shows no overlap. The means of dice similarity coefficient, normalized Hausdorff distance, and accuracy were used to define the OHS. Monotonic relationships between EPRI/PET/DCE-MRI were evaluated with the Spearman correlation coefficient ([Formula: see text]) to quantify association of vasculature on hypoxia imaged with both FMISO PET and pO2 EPRI. RESULTS: FMISO PET thresholds to define hypoxia with maximum OHS (both OHS = 0.728 [Formula: see text] 0.2) were SUV [Formula: see text] 1.4 [Formula: see text] SUVmean and SUV [Formula: see text] 0.6 [Formula: see text] SUVmax. Weak-to-moderate correlations (|[Formula: see text]|< 0.70) were observed between PET/EPRI hypoxia images with vascular permeability (Ktrans) or fractional extracellular-extravascular space (ve) from DCE-MRI. CONCLUSION: This is the first in vivo comparison of FMISO uptake with pO2 EPRI to identify the optimal FMISO threshold to define tumor hypoxia, which may successfully direct hypoxic tumor boosts in patients, thereby enhancing tumor control.
Carcinoma, Squamous Cell , Tumor Hypoxia , Animals , Carcinoma, Squamous Cell/diagnostic imaging , Carcinoma, Squamous Cell/pathology , Cell Hypoxia , Electron Spin Resonance Spectroscopy , Hypoxia/diagnostic imaging , Mice , Misonidazole/analogs & derivatives , Positron-Emission Tomography/methods , Radiopharmaceuticals , Tomography, X-Ray Computed
