Optical imaging has long been hindered by the high absorption and scattering of light in biological tissue. This makes it difficult to probe beyond a few millimeters beneath the surface without sacrificing image resolution and quantitative accuracy. Strong scattering and the inherent nature of the inverse problem makes fluorescence diffuse optical tomography (FT) extremely challenging. To this end, multi-modality techniques that combine anatomical imaging with the functional optical information have been used to improve the resolution and accuracy of FT. Previously, we have reported on the feasibility of a new imaging method, "Thermal Outlining using Focused Ultrasound" (TOFU), which combines the sensitivity of FT with the resolution of focused ultrasound using temperature reversible fluorescent probes. In this method, the position of the temperature reversible fluorescent probes is localized by an increase in fluorescent signal when the hot spot of the focused ultrasound beam is scanned over the medium. This a priori information is then utilized to guide and constrain conventional reconstruction algorithm to recover the position and concentration of the probes more accurately. The small size of the focal spot (~1.4 mm) up to a depth of 6 cm, allows imaging the distribution of these temperature sensitive agents with not only high spatial resolution but also high quantitative accuracy in deep tissue. In this work, the performance of the system will be evaluated using simulation and phantoms to investigate the dependence that size of the fluorescent distribution has on the TOFU system performance.
We present experimental results that validate our imaging technique termed photomagnetic imaging (PMI). PMI illuminates the medium under investigation with a near-infrared light and measures the induced temperature increase using magnetic resonance imaging. A multiphysics solver combining light and heat propagation is used to model spatiotemporal distribution of temperature increase. Furthermore, a dedicated PMI reconstruction algorithm has been developed to reveal high-resolution optical absorption maps from temperature measurements. Being able to perform measurements at any point within the medium, PMI overcomes the limitations of conventional diffuse optical imaging. We present experimental results obtained on agarose phantoms mimicking biological tissue with inclusions having either different sizes or absorption contrasts, located at various depths. The reconstructed images show that PMI can successfully resolve these inclusions with high resolution and recover their absorption coefficient with high-quantitative accuracy. Even a 1-mm inclusion located 6-mm deep is recovered successfully and its absorption coefficient is underestimated by only 32%. The improved PMI system presented here successfully operates under the maximum skin exposure limits defined by the American National Standards Institute, which opens up the exciting possibility of its future clinical use for diagnostic purposes.
Multi-modality imaging leverages the competitive advantage of different imaging systems to improve the overall resolution
and quantitative accuracy. Our new technique, Photo-Magnetic Imaging (PMI) is one of these true multi-modality imaging
approaches, which can provide quantitative optical absorption map at MRI spatial resolution. PMI uses laser light to
illuminate tissue and elevate its temperature while utilizing MR thermometry to measure the laser-induced temperature
variation with high spatial resolution. The high-resolution temperature maps are later converted to tissue absorption maps by
a finite element based inverse solver that is based on modeling of photon migration and heat diffusion in tissue. Previously,
we have demonstrated the feasibility of PMI with phantom studies. Recently, we have managed to reduce the laser power
under ANSI limit for maximum skin exposure therefore, we have well positioned PMI for in vivo imaging. Currently we are
expanding our system by adding multi-wavelength imaging capability. This will allow us not only to resolve spatial
distribution of tissue chromophores but also exogenous contrast agents. Although we test PMIs feasibility with animal
studies, our future goal is to use PMI for breast cancer imaging due to its high translational potential.
To overcome the strong scattering in biological tissue that has long afflicted fluorescence tomography, we have
developed a novel technique, "temperature-modulated fluorescence tomography" (TM-FT) to combine the sensitivity of
fluorescence imaging with focused ultrasound resolution. TM-FT relies on two key elements: temperature sensitive ICG
loaded pluronic nanocapsules we termed ThermoDots and high intensity focused ultrasound (HIFU). TM-FT localizes
the position of the fluorescent ThermoDots by irradiating and scanning a HIFU beam across the tissue while
conventional fluorescence tomography measurements are acquired. The HIFU beam produces a local hot spot, in which
the temperature suddenly increases changing the quantum efficiency of the ThermoDots. The small size of the focal spot
(~1 mm) up to a depth of 6 cm, allows imaging the distribution of these temperature sensitive agents with not only high
spatial resolution but also high quantitative accuracy in deep tissue using a proper image reconstruction algorithm.
Previously we have demonstrated this technique with a phantom study with ThermoDots sensitive in the 20-25°C range.
We recently optimized the ThermoDots for physiological temperatures. In this work, we will demonstrate a new HIFU
scanning method which is optimized for in vivo studies. The performance of the system is tested using a phantom that
resembles a small animal bearing a small tumor targeted by ThermoDots.
We introduce an entirely new technique, termed Photo-Magnetic Imaging (PMI), which overcomes the limitation of pure optical imaging and provides optical absorption at MRI spatial resolution. PMI uses laser light to heat the medium under investigation and employs MR thermometry for the determination of spatially resolved optical absorption in the probed medium. A FEM-based PMI forward solver has been developed by modeling photon migration and heat diffusion in tissue to compare simulation results with measured MRI maps. We have successfully performed PMI using 2.5 cm diameter agar phantom with two low optical absorption contrast (x 4) inclusions under the ANSI limit. Currently, we are developing the PMI inverse solver and undertaking further phantom and in vivo experiments.
KEYWORDS: Luminescence, Fluorescence tomography, Ultrasonography, Modulation, Tissues, In vivo imaging, Image resolution, Signal detection, Temperature metrology, Transducers
Low spatial resolution due to strong tissue scattering is one of the main barriers that prevent the wide-spread use of fluorescence tomography. To overcome this limitation, we previously demonstrated a new technique, temperature modulated fluorescence tomography (TM-FT), which relies on key elements: temperature sensitive ICG loaded pluronic nanocapsules and high intensity focused ultrasound (HIFU), to combine the sensitivity of fluorescence imaging with focused ultrasound resolution. While conventional fluorescence tomography measurements are acquired, the tissue is scanned by a HIFU beam and irradiated to produce a local hot spot, in which the temperature increases nearly 5K. The fluorescence emission signal measured by the optical detectors varies drastically when the hot spot overlays onto the location of the temperature dependent nanocapsules. The small size of the focal spot (~1.4 mm) up to a depth of 6 cm, allows imaging the distribution of these temperature sensitive agents with not only high spatial resolution but also high quantitative accuracy in deep tissue using a proper image reconstruction algorithm. Previously we have demonstrated this technique with a phantom study with nanocapsules sensitive to 20-25°C range. In this work, we will show the first nanocapsules optimized for in vivo animal imaging.
Since diffuse optical tomography (DOT) is a low spatial resolution modality, it is desirable to validate its quantitative accuracy with another well-established imaging modality, such as magnetic resonance imaging (MRI). In this work, we have used a polymer based bi-functional MRI-optical contrast agent (Gd-DTPA-polylysine-IR800) in collaboration with GE Global Research. This multi-modality contrast agent provided not only co-localization but also the same kinetics, to cross-validate two imaging modalities. Bi-functional agents are injected to the rats and pharmacokinetics at the bladder are recovered using both optical and MR imaging. DOT results are validated using MRI results as "gold standard"
This study focuses on a multimodal imaging technique that integrates both structural and functional information using a
priori ultrasound (US) information to assist near-infrared (NIR) diffuse optical tomography (DOT). Up to date, handheld
systems that integrates DOT and US have been demonstrated. Our system is designed to be fully-automated and
non-contact. Our aim is to build an interface, in which the optical source and detector fibers will rotate around the breast
together with the US transducer. However, in this study we built a prototype system, which rotated the phantom and kept
the transducers stationary for simplicity. Simulation and experimental studies were performed using a variety of sourcedetector
configurations. The reconstruction results were compared with and without US a priori information. To collect
the a priori US information, the multi-modality agar phantom was rotated 360° using a computer controlled rotational
stage. The multi-modality phantom had an inclusion that had both optical absorption and US contrast. 360 US images
were collected in 1° increments covering the entire phantom volume. The DOT data was also collected while the
phantom is rotated with particular source-detector configurations. These results have shown that when the detectors were
π /8 apart, and the phantom is rotating at π /16 increments with a total of 32 views provide the optimum image
reconstruction. As expected, US a priori information further improved the quantification accuracy.
We have developed a hybrid frequency domain fluorescence tomography and magnetic resonance imaging system (MRI) for small animal imaging. The main purpose of this system is to obtain quantitatively accurate fluorescence concentration and lifetime images using a multi-modality approach. In vivo experiments are undertaken to evaluate the system. We compare the recovered fluorescence parameters with and without MRI structural a priori information. In addition, we compare two optical background heterogeneity correction methods: Born normalization and utilizing diffuse optical tomography (DOT) functional a priori information. The results show that the concentration and lifetime of a 4.2-mm diameter indocyanine green inclusion located 15 mm deep inside a rat can be recovered with less than a 5% error when functional a priori information from DOT and structural a priori information from MRI are utilized.
A graphics processing unit-based parallel multigrid solver for a radiative transfer equation with vacuum boundary condition or reflection boundary condition is presented for heterogeneous media with complex geometry based on two-dimensional triangular meshes or three-dimensional tetrahedral meshes. The computational complexity of this parallel solver is linearly proportional to the degrees of freedom in both angular and spatial variables, while the full multigrid method is utilized to minimize the number of iterations. The overall gain of speed is roughly 30 to 300 fold with respect to our prior multigrid solver, which depends on the underlying regime and the parallelization. The numerical validations are presented with the MATLAB codes at https://sites.google.com/site/rtefastsolver/.
It is challenging to image fluorescence objects with high spatial resolution in a highly scattering medium. Recently reported temperature-sensitive indocyanine green-loaded pluronic nanocapsules can potentially alleviate this problem. Here we demonstrate a frequency-domain temperature-modulated fluorescence tomography system that could acquire images at high intensity-focused ultrasound resolution with use of these nanocapsules. The system is experimentally verified with a phantom study, where a 3-mm fluorescence object embedded 2 cm deep in a turbid medium is successfully recovered based on both intensity and lifetime contrast.
We present a magnetic resonance (MR)-guided near-infrared dynamic contrast enhanced diffuse optical tomography (DCE-DOT) system for characterization of tumors using an optical contrast agent (ICG) and a MR contrast agent [Gd-diethylenetriaminepentaacetic acid (DTPA)] in a rat model. Both ICG and Gd-DTPA are injected and monitored simultaneously using a combined MRI-DOT system, resulting in accurate co-registration between two imaging modalities. Fisher rats bearing R3230 breast tumor are imaged using this hybrid system. For the first time, enhancement kinetics of the exogenous contrast ICG is recovered from the DCE-DOT data using MR anatomical a priori information. As tumors grow, they undergo necrosis and the tissue transforms from viable to necrotic. The results show that the physiological changes between viable and necrotic tissue can be differentiated more accurately based on the ICG enhancement kinetics when MR anatomical information is utilized.
Local fine representation of the fluorescence map on the standard mesh can be redundant in the sense that the
reconstruction resolution is usually limited in such a severely ill-posed problem. Using global characteristic shape
functions that can approximately capture the major structural information, we study fluorescence tomography with a new
shape-guided representation based on some underlying mesh. Moreover, the proposed method can naturally enforce the
prior coexistence of fluorescence yield and lifetime when fluorescence maps are formulated in complex sources. The
simulation results suggest that, compared with standard pixel-wise representation, the shape-guided representation offers
better localization of inclusions with improved quantitative accuracy, particularly in the case with inclusions of low
fluorescence contrast, such as 2:1 inclusion-to-background ratio, and is more robust to the initial guess and the noise.
Fluorescence diffuse optical tomography (FT) is a molecular imaging technique that can create images of
spatially resolved fluorophore concentrations and fluorescence lifetimes. One problem faced by FT is that the recovered
fluorophore parameters greatly depend on the size and depth of the inclusion due to the ill-posedness of the FT inverse
problem. Structural a priori information from imaging modalities with high spatial resolution is demonstrated to
significantly improve the accuracy of the FT reconstruction. We have constructed a hybrid FT/MRI system for small
animal imaging in this study. Near-infrared light was delivered and collected by optical fibers that connect the FT/MRI
system to the interface in the MRI bore. We investigated the feasibility of a photo-multiplier tube (PMT) based detection
system that acquired time-resolved data in the frequency domain. Phantom studies were used to evaluate the
performance of the combined system. The concentration and lifetime maps were reconstructed with and without the
structural a priori information obtained from MRI. ICG and DTTCI, two fluorophores with similar excitation and
emission spectra but different lifetimes, were used in this evaluation. Specifically, we showed that the PMT-based
frequency domain hybrid system was capable of differentiating between two fluorophores with different fluorescence
lifetimes. Furthermore, this process was shown to be more accurate when MR a priori is used.
KEYWORDS: Tumors, Magnetic resonance imaging, Chromophores, Tissues, In vivo imaging, Diffuse optical tomography, Data acquisition, Imaging systems, Interfaces, Sensors
In vivo experiments using a hybrid DOT and MRI system are undertaken on small animals in this study. MRI
structural a priori information is utilized for constraining and guiding DOT chromophore reconstruction. Even though in
the past, multi-wavelength DOT has been extensively evaluated with phantom and clinical studies, there have been very
few small animal studies reported in literature. In this small animal study, chromophore reconstruction results for
different tumor types are presented and compared. The goal of this study is to evaluate the performance of the hybrid
MRI-DOT system in vivo.
Dynamic contrast enhanced MRI (DCE-MRI) has been proven to be the most sensitive modality in detecting breast
lesions. Currently available MR contrast agent, Gd-DTPA, is a low molecular weight extracellular agent and can
diffuse freely from the vascular space into interstitial space. Due to this reason, DCE-MRI has low sensitivity in
differentiating benign and malignant tumors. Meanwhile, diffuse optical tomography (DOT) can be used to provide
enhancement kinetics of an FDA approved optical contrast agent, ICG, which behaves like a large molecular weight
optical agent due to its binding to albumin. The enhancement kinetics of ICG may have a potential to distinguish
between the malignant and benign tumors and hence improve the specificity. Our group has developed a high speed
hybrid MRI-DOT system. The DOT is a fully automated, MR-compatible, multi-frequency and multi-spectral
imaging system. Fischer-344 rats bearing subcutaneous R3230 tumor are injected simultaneously with Gd-DTPA
(0.1nmol/kg) and IC-Green (2.5mg/kg). The enhancement kinetics of both contrast agents are recorded
simultaneously with this hybrid MRI-DOT system and evaluated for different tumors.
A fully integrated trimodality fluorescence, diffuse optical, and x-ray computed tomography (FT/DOT/XCT) system for small animal imaging is reported in this work. The main purpose of this system is to obtain quantitatively accurate fluorescence concentration images using a multimodality approach. XCT offers anatomical information, while DOT provides the necessary background optical property map to improve FT image accuracy. The quantitative accuracy of this trimodality system is demonstrated in vivo. In particular, we show that a 2-mm-diam fluorescence inclusion located 8 mm deep in a nude mouse can only be localized when functional a priori information from DOT is available. However, the error in the recovered fluorophore concentration is nearly 87%. On the other hand, the fluorophore concentration can be accurately recovered within 2% error when both DOT functional and XCT structural a priori information are utilized together to guide and constrain the FT reconstruction algorithm.
A gantry-based hybrid fluorescence and x-ray computed tomography (FT/CT) system is developed for quantitative
molecular imaging. The performance of the dual modality FT/CT system is evaluated using an irregular shaped phantom
with an inclusion containing Indocyanine-Green (ICG). The anatomical data from CT provides structural a priori
information for the FT inverse problem. Although a 4.2 mm diameter inclusion can be resolved in the reconstructed
concentration image without any a priori information, ICG concentration in the inclusion is recovered with 75% error.
On the other hand, the error in the recovered ICG concentration reduces to 15% when a priori information from CT is
utilized. The results demonstrate that accurate fluorophore concentration can only be obtained when x-ray CT structural
a priori information is available.
KEYWORDS: Magnetic resonance imaging, Tumors, Absorption, Magnetism, Optical imaging, In vivo imaging, Tissue optics, Image enhancement, Signal detection, Fiber optics
Our goal is to assess the feasibility of a bi-functional contrast agent that is intravenously injected to an R3230 induced
small animal breast tumor model. The MR/optical contrast agent was produced by GE Global Research, NY, and it was
available in one size, Dp20. We used a combined frequency domain diffuse optical tomography (DOT) and a 4T
magnetic resonance (MR) scanner to simultaneously measure the kinetics of the contrast agent in vivo. Both systems
detected the signal change in the tumor and the non-tumor region. MR measurements served as a gold standard to
validate the optical kinetics. We present both MR and DOT dynamic curves as well as the reconstructed optical
absorption map.
Fluorescence diffuse optical tomography (FT) is a promising molecular imaging technique that can
spatially resolve both fluorophore concentration and lifetime parameters. In this phantom study, we
built a photo-multiplier tube (PMT) based single detection system that uses fiber bundles to collect
light. Measurements were acquired both with a 1 mm diameter single fiber and a 6 mm diameter fiber
bundle using the very same detection unit for comparison purposes. We demonstratethat the
fluorescence concentration and lifetime can be well recovered for 6 mm diameter objects deeply
embedded in an 80 mm diameter breast-sized phantom when the fiber bundle is utilized.
We demonstrate the feasibility of using a dual-modality fluorescence and x-ray computed tomography (CT)
system for quantitative molecular imaging with phantom studies. A CCD based non-contact FT system,
which can take measurements from multiple views was built.
High-resolution X-Ray CT was used to obtain
structural information from the phantom. A 3.6 mm diameter fluorescence inclusion was deeply embedded
in the heterogeneous optical background. The results demonstrated that the fluorophore concentration can
only be obtained accurately when guided by the a priori information provided by the x-ray CT.
KEYWORDS: Magnetic resonance imaging, Tumors, Absorption, Magnetism, Imaging systems, Image enhancement, In vivo imaging, Optical tomography, Preclinical imaging, Breast cancer
We present simultaneous measurement of enhancement kinetics of an optical and a magnetic resonance (MR) contrast agent in a small animal breast tumor model (R3230 ac) using a combined MR-diffuse optical tomographic (MR-DOT) imaging system. A mixture of a small molecular-weight MR contrast agent gadolinium-diethylene-triamine-pentaacetic acid (Gd-DTPA) and a large molecular-weight optical contrast agent indocyanine green (ICG) was administered intravenously for multimodal dynamic imaging. Coregistration of optical and MR images was accomplished using agar-water–based markers. Using T2 and dynamic T1 weighted MR images, we divided the entire tumor into two regions of interest (ROI): a viable and a nonviable region. The absorption enhancements in the ROIs were calculated. An enhancement of the ICG was observed in the viable region. On the contrary, there was a lower enhancement in the nonviable region.
Fluorescence diffuse optical tomography (FT) is an emerging molecular imaging technique that can
spatially resolve both fluorophore concentration and lifetime parameters. In this study, we investigated the
performance of a frequency domain FT system for inclusions with various sizes and contrast levels. Due to
the ill-posedness of the FT problem, the fluorescence parameters can not be recovered accurately. The
reconstructed fluorescence parameters depend on the signal to background contrast and size of the
compartments containing the fluorophores. Recently, imaging with multiple modalities has become a
popular trend. Different modalities give different information on the subject under investigation. Here, we
evaluated the improvement in FT reconstruction when structural a priori information from a second
imaging modality was incorporated. The results demonstrated that the structural a priori information was
crucial to be able to recover both parameters with high accuracy. Without such a priori information, the
same fluorophore concentration for different object sizes could not be recovered to the same value. On the
other hand, when the structural a priori information was available, both fluorescence parameters could be
recovered within 15% error for all the cases.
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