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Hypofractionated stereotactic body radiotherapy treatments (SBRT) have demonstrated impressive results for the treatment of a variety of solid tumors. The role of tumor supporting vasculature damage in treatment outcome for SBRT has been intensely debated and studied. Fast, non-invasive, longitudinal assessments of tumor vasculature would allow for thorough investigations of vascular changes correlated with SBRT treatment response. In this paper, we present a novel theranostic system which incorporates a fluorescence molecular imager into a commercial, preclinical, microCT-guided, irradiator and was designed to quantify tumor vascular response (TVR) to targeted radiotherapy. This system overcomes the limitations of single-timepoint imaging modalities by longitudinally assessing spatiotemporal differences in intravenously-injected ICG kinetics in tumors before and after high-dose radiation. Changes in ICG kinetics were rapidly quantified by principle component (PC) analysis before and two days after 10 Gy targeted tumor irradiation. A classifier algorithm based on PC data clustering identified pixels with TVR. Results show that two days after treatment, a significant delay in ICG clearance as measured by exponential decay (40.5± 16.1% P = 0.0405 Paired t-test n = 4) was observed. Changes in the mean normalized first and second PC feature pixel values (PC1 & PC2) were found (P = 0.0559, 0.0432 paired t-test), suggesting PC based analysis accurately detects changes in ICG kinetics. The PC based classification algorithm yielded spatially-resolved TVR maps. Our first-of-its-kind theranostic system, allowing automated assessment of TVR to SBRT, will be used to better understand the role of tumor perfusion in metastasis and local control.

Multiwavelength photo-magnetic imaging (PMI) is a novel combination of diffuse optics and magnetic resonance imaging, to the best of our knowledge, that yields tissue chromophore concentration maps with high resolution and quantitative accuracy. Here, we present the first experimental results, to the best of our knowledge, obtained using a spectrally constrained PMI image reconstruction method, where chromophore concentration maps are directly recovered, unlike the conventional two-step approach that requires an intermediate step of reconstructing wavelength-dependent absorption coefficient maps. The imposition of the prior spectral information into the PMI inverse problem improves the reconstructed image quality and allows recovery of highly quantitative concentration maps, which are crucial for effective cancer detection and characterization. The obtained results demonstrate the higher performance of the direct reconstruction method. Indeed, the reconstructed concentration maps are not only of higher quality but also obtained approximately 2 times faster than the conventional method.

Background and objectives In photothermal therapy, cancerous tissue is treated by the heat generated from absorbed light energy. For effective photothermal therapy, the parameters affecting the induced temperature should be determined before the treatment by modeling the increase in temperature via numerical simulations. However, accurate simulations can only be achieved when utilizing the accurate optical, thermal, and physiological properties of the treated tissue. Here, we propose a multi-wavelength photo-magnetic imaging (PMI) technique that provides quantitative and spatially resolved tissue optical absorption maps at any wavelength within the near-infrared (NIR) window to assist accurate photothermal therapy planning. Study design/materials and methods The study was conducted using our recently developed multi-wavelength PMI system, which operates at four laser wavelengths (760, 808, 860, and 980 nm). An agar tissue-simulating phantom containing water, lipid, and ink was illuminated using these wavelengths, and the slight internal laser-induced temperature rise was measured using magnetic resonance thermometry (MRT). The phantom optical absorption was recovered at the used wavelengths using our dedicated PMI image reconstruction algorithm. These absorption maps were then used to resolve the concentration of the tissue chromophores, and thus deduce its optical absorption spectrum in the NIR region based on the Beer-Lambert law. Results The optical absorption of the phantom was successfully recovered at the used four wavelengths with an average error of ~1.9%. The recovered absorption coefficient was then used to simulate temperature variations inside the phantom. A comparison between the modeled temperature maps and the MRT measured ones showed that these maps are in a good agreement with an average pseudo R2 statistic of 0.992. These absorption values were used to successfully recover the concentration of the used chromophores. Finally, these concentrations are used to accurately calculate the total absorption spectrum of the phantom in the NIR spectral window with an average error as low as ~2.3%. Conclusions Multi-wavelength PMI demonstrated a great ability to assess the distribution of tissue chromophores, thus providing its total absorption at any wavelength within the NIR spectral range. Therefore, applications of photothermal therapy applied at NIR wavelengths can benefit from the absorption spectrum recovered by PMI to determine important parameters such as laser power as well as the laser exposure time needed to attain a specific increase in temperature prior to treatment. Lasers Surg. Med. 00:00-00, 2020. © 2020 Wiley Periodicals LLC.

Photo-Magnetic Imaging (PMI) is a novel multimodality imaging technique that provides optical absorption maps with high-resolution and quantitative accuracy. Here, we present the preliminary experimental validation results obtained using our new multi-wavelength PMI system.

It has been reported that acoustic waves are generated when a high-energy pulsed proton beam is deposited in a small volume within tissue. One possible application of proton-induced acoustics is to get real-time feedback for intra-treatment adjustments by monitoring such acoustic waves. A high spatial resolution in ultrasound imaging may reduce proton range uncertainty. Thus, it is crucial to understand the dependence of the acoustic waves on the proton beam characteristics. In this manuscript, firstly, an analytic solution for the proton-induced acoustic wave is presented to reveal the dependence of the signal on the beam parameters; then it is combined with an analytic approximation of the Bragg curve. The influence of the beam energy, pulse duration and beam diameter variation on the acoustic waveform are investigated. Further analysis is performed regarding the Fourier decomposition of the proton-acoustic signals. Our results show that the smaller spill time of the proton beam upsurges the amplitude of the acoustic wave for a constant number of protons, which is hence beneficial for dose monitoring. The increase in the energy of each individual proton in the beam leads to the spatial broadening of the Bragg curve, which also yields acoustic waves of greater amplitude. The pulse duration and the beam width of the proton beam do not affect the central frequency of the acoustic wave, but they change the amplitude of the spectral components.

Background Bone metastases are common and devastating to cancer patients. Existing treatments do not specifically target the disease sites and are therefore ineffective and systemically toxic. Here we present a new strategy to treat bone metastasis by targeting both the cancer cells (“the seed”), and their surrounding niche (“the soil”), using stem cells engineered to home to the bone metastatic niche and to maximise local delivery of multiple therapeutic factors. Methods We used mesenchymal stem cells engineered using mRNA to simultaneously express P-selectin glycoprotein ligand-1 (PSGL-1)/Sialyl-Lewis X (SLEX) (homing factors), and modified versions of cytosine deaminase (CD) and osteoprotegerin (OPG) (therapeutic factors) to target and treat breast cancer bone metastases in two mouse models, a xenograft intratibial model and a syngeneic model of spontaneous bone metastasis. Findings We first confirmed that MSC engineered using mRNA produced functional proteins (PSGL-1/SLEX, CD and OPG) using various in vitro assays. We then demonstrated that mRNA-engineered MSC exhibit enhanced homing to the bone metastatic niche likely through interactions between PSGL-1/SLEX and P-selectin expressed on tumour vasculature. In both the xenograft intratibial model and syngeneic model of spontaneous bone metastasis, engineered MSC can effectively kill tumour cells and preserve bone integrity. The engineered MSC also exhibited minimal toxicity in vivo, compared to its non-targeted chemotherapy counterpart (5-fluorouracil). Interpretation Our combinatorial targeting of both the cancer cells and the niche represents a simple, safe and effective way to treat metastatic bone diseases, otherwise difficult to manage with existing strategies. It can also be applied to other cell types (e.g., T cells) and cargos (e.g., genome editing components) to treat a broad range of cancer and other complex diseases. Fund National Institutes of Health, National Cancer Institute of the National Institutes of Health, Department of Defense, California Institute of Regenerative Medicine, National Science Foundation, Baylx Inc., and Fondation ARC pour la recherche sur le cancer.

High scattering in biological tissues severely degrades the spatial resolution of optical fluorescence imaging in thick tissue. As one of the most sensitive in vivo molecular imaging modalities, Fluorescence Tomography plays an essential role in preclinical studies. To overcome the limitations of FT, we introduced a novel method termed, temperature modulated fluorescence tomography (TMFT). TMFT is based on two key elements: 1) temperature sensitive fluorescent agent (ThermoDots) and 2) high intensity focused ultrasound (HIFU). TMFT localizes the position of the fluorescent ThermoDots by scanning a HIFU beam across the tissue while monitoring the variation in the measured fluorescence signals. Actually, a binary mask is built by monitoring the sudden jumps in the fluorescence signal corresponding to the HIFU scan over a position containing ThermoDots. This binary map is used as functional a priori during the FT image reconstruction process. TMFT not only allowed us to resolve ThermoDots with high spatial resolution (~1.3 mm), deep in tissue (~ 60 mm) but with high quantitative accuracy as well (< 3% error). In this paper, we present the latest prototype of TMFT. Here, the fluorescence signals are acquired using a CCD camera, which increases the sensitivity of the system compared to the previous fiber-based system.

Although diffuse optical tomography (DOT) is able to obtain valuable functional information, its routine use in clinic is hampered by its poor spatial resolution and quantitative accuracy. Previously, our team introduced Photo-Magnetic Imaging (PMI) to overcome the limitation of DOT. PMI is a hybrid modality that synergistically utilizes optics and Magnetic Resonance Imaging (MRI). While illuminating the imaged medium by near-infrared laser, the induced internal temperature increase is measured using Magnetic Resonance Thermometry (MRT). Using these MRT maps, optical absorption maps at the laser's wavelength can be recovered using the dedicated PMI image reconstruction algorithm. In this paper, we present the result of the first validation simulation study of multi-wavelength PMI that utilizes five different laser wavelengths ranging between 760 and 980 nm. Using the high resolution wavelength specific absorption maps, PMI successfully recovered the concentration of three dyes, used as chromophore in the composition of our phantom, with high spatial resolution and quantitative accuracy. By providing functional information at high resolution, multi-wavelength PMI will be a valuable tool for monitoring tissue physiology, cancer detection and monitoring.

Molecular imaging is becoming essential for precision targeted radiation therapy, yet progress is hindered from a lack of integrated imaging and treatment systems. We report the development of a prototype positron emission tomography (PET) scanner integrated into a commercial cone beam computed tomography (CBCT) based small animal irradiation system for molecular-image-guided, targeted external beam radiation therapy. The PET component consists of two rotating Hamamatsu time-of-flight PET modules positioned with a bore diameter of 101.6 mm and a radial field-of-view of 53.1 mm. The measured energy resolution after linearity correction at 511 KeV was 12.9% and the timing resolution was 283.6 ps. The measured spatial resolutions at the field-of-view center and 5 mm off the radial center were 2.6 mm x 2.6 mm x 1.6 mm and 2.6 mm x 2.6 mm x 2.7 mm respectively. 18F-Fluorodeoxyglucose-based PET imaging of a NEMA NU 4-2008 phantom resolved cylindrical volumes with diameters as small as 3 mm. To validate the system in-vivo, we performed 64Cu-DOTA-M5A PET and computed tomography (CT) imaging of carcinoembryonic antigen (CEA)-positive colorectal cancer in athymic nude mice and compared the results with a commercially available Siemens Inveon PET/CT system. The prototype PET system performed comparably to the Siemens system for identifying the location, size, and shape of tumors. Regions of heterogeneous 64Cu-DOTA-M5A uptake were observed. Using 64Cu-DOTA-M5A PET and CT images, a Monte Carlo-based radiation treatment plan was created to escalate the dose to the 64Cu-DOTA-M5A-based, highly active, biological target volume while largely sparing the normal tissue. Results demonstrate the feasibility of molecular-image-guided treatment plans using the prototype theranostic system.

© 2015 The Authors. Published by Elsevier Inc. Mammographic density has been proven as an independent risk factor for breast cancer. Women with dense breast tissue visible on a mammogram have a much higher cancer risk than women with little density. A great research effort has been devoted to incorporate breast density into risk prediction models to better estimate each individual’s cancer risk. In recent years, the passage of breast density notification legislation in many states in USA requires that every mammography report should provide information regarding the patient’s breast density. Accurate definition and measurement of breast density are thus important, which may allow all the potential clinical applications of breast density to be implemented. Because the two-dimensional mammography-based measurement is subject to tissue overlapping and thus not able to provide volumetric information, there is an urgent need to develop reliable quantitative measurements of breast density. Various new imaging technologies are being developed. Among these new modalities, volumetric mammographic density methods and threedimensional magnetic resonance imaging are the most well studied. Besides, emerging modalities, including different x-ray–based, optical imaging, and ultrasound-based methods, have also been investigated. All these modalities may either overcome some fundamental problems related to mammographic density or provide additional density and/or compositional information. The present review article aimed to summarize the current established and emerging imaging techniques for the measurement of breast density and the evidence of the clinical use of these density methods from the literature.

Photo-magnetic imaging (PMI) is an emerging optical imaging modality that showed great performance on providing absorption maps with high resolution and quantitative accuracy. As a multi-modality technology, PMI warms up the imaged object using a near infrared laser while temperature variation is measured using magnetic resonance imaging. By probing tissue at multiple wavelengths, concentration of the main tissue chromophores such as oxy-and deoxy-hemoglobin, lipid, and water are obtained then used to derive functional parameters such as total hemoglobin concentration and relative oxygen saturation. In this paper, we present a multi-wavelength PMI system that was custom-built to host five different laser wavelengths. After recovering the high-resolution absorption maps, a least-squared minimization process was used to resolve the different chromophore concentration. The performance of the system was experimentally tested on a phantom with two different dyes. Their concentrations were successfully assessed with high spatial resolution and average accuracy of nearly 80%. (C) 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

Photo-Magnetic Imaging (PMI) is a novel diffuse optical imaging technique that yields high resolution optical absorption images. It is based on the measurement of the temperature increase of a given medium after its illumination with a near-infrared laser using Magnetic Resonance Thermometry (MRT). In this paper, we present the first multi-wavelengths PMI system able to provide oxy- and deoxyhemoglobin concentration maps with high spatial and quantitative accuracy.

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. Diffuse optical tomography (DOT) has been studied for use in the detection of breast cancer, cerebral oxygenation, and cognitive brain signals. As optical imaging studies have increased significantly, acquiring imaging data in real time has become increasingly important. We have developed frequency-division multiplexing (FDM) DOT systems to analyze their performance with respect to acquisition time and imaging quality, in comparison with the conventional time-division multiplexing (TDM) DOT. A large tomographic area of a cylindrical phantom 60mmin diameter could be successfully reconstructed using both TDM DOT and FDM DOT systems. In our experiment with 6 source-detector (S-D) pairs, the TDM DOT and FDM DOT systems required 6.18 and 1 s, respectively, to obtain a single tomographic data set. While the absorption coefficient of the reconstruction image was underestimated in the case of the FDM DOT, we experimentally confirmed that the abnormal region can be clearly distinguished from the background phantom using both methods.

We present the feasibility of structured-light-based diffuse optical tomography (DOT) to quantify the breast density with an extensive simulation study. This study is performed on multiple numerical breast phantoms built from magnetic resonance imaging (MRI) images. These phantoms represent realistic tissue morphologies and are given typical breast optical properties. First, synthetic data are simulated at five wavelengths using our structured-light-based DOT forward problem. Afterwards, the inverse problem is solved to obtain the absorption images and subsequently the chromophore concentration maps. Parameters, such as segmented volumes and mean concentrations, are extracted from these maps and used in a regression model to estimate the percent breast densities. These estimations are correlated with the true values from MRI, r = 0.97, showing that our new technique is promising in measuring breast density.

We recently introduced a new high-resolution diffuse optical imaging technique termed photo-magnetic imaging (PMI), which utilizes magnetic resonance thermometry (MRT) to monitor the 3D temperature distribution induced in a medium illuminated with a near-infrared light. The spatiotemporal temperature distribution due to light absorption can be accurately estimated using a combined photon propagation and heat diffusion model. High-resolution optical absorption images are then obtained by iteratively minimizing the error between the measured and modeled temperature distributions. We have previously demonstrated the feasibility of PMI with experimental studies using tissue simulating agarose phantoms. In this Letter, we present the preliminary ex vivo PMI results obtained with a chicken breast sample. Similarly to the results obtained on phantoms, the reconstructed images reveal that PMI can quantitatively resolve an inclusion with a 3 mm diameter embedded deep in a biological tissue sample with only 10% error. These encouraging results demonstrate the high performance of PMI in ex vivo biological tissue and its potential for in vivo imaging. (C) 2017 Optical Society of America.

Previously, we demonstrated that temperature-modulated fluorescence tomography (TM-FT) could provide fluorescence images with high quantitative accuracy and the spatial resolution of focused ultrasound. TM-FT is based on scanning the focused ultrasound across the medium to activate temperature-reversible fluorescent nanoprobes (ThermoDots). This technique can resolve small fluorescent targets located several centimeters deep in turbid media with millimeter resolution. Our past studies with this multimodality technique used agar phantoms, which could not represent the true heterogeneous nature of the acoustic and optical properties of biological tissue. In this work, we report the results of the first TM-FT study performed on ex vivo chicken breast tissue. In order to improve the spatial resolution of this technique, diffuse optical tomography is also used to better estimate the optical property maps of the tissue, which is utilized as functional a priori for the TM-FT reconstruction algorithm. These ex vivo results show that TM-FT can accurately recover the concentration and position of a 1.5 mm×5 mm inclusion filled with ThermoDots. Since the inclusion is embedded 2cm deep in the chicken breast sample, these results demonstrate the great potential of TM-FT for future in vivo small animal imaging.

Fluorescence diffuse optical tomography (FDOT) has been widely used for in vivo small animal studies and the illposed problem in reconstruction can be eased by utilizing structural a priori obtained from an anatomic imaging modality. In this study, a multispectral fluorescence tomography (FT) is used, which has shown the ability to detect subtle shifts in the ICG absorption spectrum in our previous study. The imaging system is in trans-illumination mode with a swept-wavelength laser and a CCD on a rotation gantry and the structural image from the X-ray computed tomography is used to guide and constrain the FT reconstruction algorithm. In this work, a phantom with two inclusions filled with different fluorophores is utilized to evaluate whether the spectral information obtained using sweptwavelength laser can distinguish these two inclusions. The images are captured from 8 different views with three different wavelengths.

In this study, we present a fast analytical approach for laser induced temperature increase in biological tissue. The whole problem consists of two main steps. These steps are the light propagation and heat transfer in tissue. We first obtain a detailed analytical solution for the diffusion equation based on an integral approach for specific boundary conditions. Secondly, we also solve the Pennes' bio-heat transfer equation analytically using the separation of variables technique and obtain the temperature induced by optical absorption of tissue. Here, heat source term consists of the local absorption and photon density, which will be determined from the diffusion equation. We find a very comprehensive solution for the diffusion equation by using an integral method for the Robin boundary condition. In other words, we obtain a particular Green's function in a different way. Next, we use this solution as a source term in the Pennes’ bio-heat equation by utilizing the heat convection boundary condition. It is important to note that these boundary conditions are good approximations for imaging of biological tissue. As a result, we obtain spatio-temporal temperature distribution inside the medium. First, our approach is validated by a numerical approach using a Finite Element Method (FEM). Next, we also validate our method by performing phantom and tissue experiments. Experimental data corresponding to spatio-temporal temperature distribution are recorded using magnetic resonance thermometry. The analytical results obtained by our method are in a very good agreement with ones obtained by the FEM and experiment.

The strong scattering and absorption of light in biological tissue makes it challenging to model the propagation of light, especially in deep tissue. This is especially true in fluorescent tomography, which aims to recover the internal fluorescence source distribution from the measured light intensities on the surface of the tissue. The inherently ill-posed and underdetermined nature of the inverse problem along with strong tissue scattering makes Fluorescence Tomography (FT) extremely challenging. Previously, multispectral detection fluorescent tomography (FT) has been shown to improve the image quality of FT by incorporating the spectral filtering of biological tissue to provide depth information to overcome the inherent absorption and scattering limitations. We investigate whether multi-wavelength fluorescent tomography can be used to distinguish the signals from multiple fluorophores with overlapping fluorescence spectrums using a unique near-infrared (NIR) swept laser. In this work, a small feasibility study was performed to see whether multi-wavelength FT can be used to detect subtle shifts in the absorption spectrum due to differences in fluorophore microenvironment.

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.

Breast density is an independent risk factor for breast cancer, where women with denser breasts are more likely to develop cancer. By identifying women at higher risk, healthcare providers can suggest screening at a younger age to effectively diagnose and treat breast cancer in its earlier stages. Clinical risk assessment models currently do not incorporate breast density, despite its strong correlation with breast cancer. Current methods to measure breast density rely on mammography and MRI, both of which may be difficult to use as a routine risk assessment tool. We propose to use diffuse optical tomography with structured-light to measure the dense, fibroglandular (FGT) tissue volume, which has a different chromophore signature than the surrounding adipose tissue. To test the ability of this technique, we performed simulations by creating numerical breast phantoms from segmented breast MR images. We looked at two different cases, one with a centralized FGT distribution and one with a dispersed distribution. As expected, the water and lipid volumes segmented at half-maximum were overestimated for the dispersed case. However, it was noticed that the recovered water and lipid concentrations were lower and higher, respectively, than the centralized case. This information may provide insight into the morphological distribution of the FGT and can be a correction in estimating the breast density.

We introduce a new Photo-Magnetic Imaging image reconstruction algorithm that uses analytical methods to solve both its forward and inverse problem, making it 33 times faster than a single iteration of our previous FEM-based algorithm.

Laser induced thermal ablation is a minimally invasive alternative to conventional surgery and can provide faster recovery times as well as reduction in complication rates. In this study, our purpose is to develop a simulation tool for therapy planning to determine important laser parameters that govern the magnitude of temperature rise and its duration in the tissue. This tool is based on the use of a new analytical approach to model laser induced temperature in turbid media. First, the diffusion equation is used for the light propagation and a comprehensive solution is derived analytically by obtaining a special Greens’ function. Next, the heat equation is also solved analytically for a source term given by the product of the solution of the diffusion equation and the local optical absorption. The results obtained with our theoretical model are successfully validated using experimental data.

In this work, we present a new analytical approach to model continuous wave laser induced temperature in highly homogeneous turbid media. First, the diffusion equation is used to model light transport and a comprehensive solution is derived analytically by obtaining a special Greens' function. Next, the time-dependent bio-heat equation is used to describe the induced heat increase and propagation within the medium. The bio-heat equation is solved analytically utilizing the separation of variables technique. Our theoretical model is successfully validated using numerical simulations and experimental studies with agarose phantoms and ex-vivo chicken breast samples. The encouraging results show that our method can be implemented as a simulation tool to determine important laser parameters that govern the magnitude of temperature rise within homogenous biological tissue or organs. (c) 2015 Optical Society of America

Fluorescence tomography (FT) is a promising molecular imaging technique that can spatially resolve both fluorophore concentration and lifetime parameters. However, recovered fluorophore parameters highly depend on the size and depth of the object due to the ill-posedness of the FT inverse problem. Structural a priori information from another high spatial resolution imaging modality has been demonstrated to significantly improve FT reconstruction accuracy. In this study, we have constructed a combined magnetic resonance imaging (MRI) and FT system for small animal imaging. A photo-multiplier tube (PMT) is used as the detector to acquire frequency domain FT measurements. This is the first MR-compatible time-resolved FT system that can reconstruct both fluorescence concentration and lifetime maps simultaneously. The performance of the hybrid system is evaluated with phantom studies. Two different fluorophores, Indocyanine Green (ICG) and 3-3′ Diethylthiatricarbocyanine Iodide (DTTCI), which have similar excitation and emission spectra but different lifetimes, are utilized. The fluorescence concentration and lifetime maps are both reconstructed with and without the structural a priori information obtained from MRI for comparison. We show that the hybrid system can accurately recover both fluorescence intensity and lifetime within 10% error for two 4.2 mm-diameter cylindrical objects embedded in a 38 mm-diameter cylindrical phantom when MRI structural a priori information is utilized.

In this paper we present first-of-its-kind spatially resolved enhancement kinetics of optical and magnetic resonance (MR) agents obtained by a combined MR and Diffuse Optical Tomography (MR-DOT) animal imaging system. A unique MR compatible fiber optic interface allows co-registration of MR and DOT data in space and time. High temporal resolution of the hybrid system permits acquisition of data in dynamic mode. Rats bearing a R3230 AC breast cancer tumor model are used for in vivo studies. Thirty-two optical and thirty MR images are acquired during a single imaging session that lasts nearly ten minutes. Both optical, indocyanine green (ICG), and MR contrast agents, gadolinium-DTPA (Gd-DTPA), are injected simultaneously after the acquisition of several baseline frames. Contrast enhancement time curves obtained by MR and DOT systems both indicate higher average enhancement in tumor regions, up to ten-fold for MRI and 3-fold for DOT, compared to close by non-tumor regions. This feasibility study is the first step towards clinical translation of this hybrid imaging platform. The ultimate aim is to use the enhancement kinetics of the optical agent ICG, which binds to plasma proteins, as complementary information to the kinetics of the MR agent Gd-DTPA, a small molecular agent that does not bind to plasma proteins, to better differentiate benign and malignant lesions.

Dynamic contrast-enhanced diffuse optical tomography (DCE-DOT) can provide spatially resolved enhancement kinetics of an optical contrast agent. We undertook a systematic phantom study to evaluate the effects of the geometrical parameters such as the depth and size of the inclusion as well as the optical parameters of the background on the recovered enhancement kinetics of the most commonly used optical contrast agent, indocyanine green (ICG). For this purpose a computer-controlled dynamic phantom was constructed. An ICG-intralipid-water mixture was circulated through the inclusions while the DCE-DOT measurements were acquired with a temporal resolution of 16 s. The same dynamic study was repeated using inclusions of different sizes located at different depths. In addition to this, the effect of non-scattering regions was investigated by placing a second inclusion filled with water in the background. The phantom studies confirmed that although the peak enhancement varied substantially for each case, the recovered injection and dilution rates obtained from the percentage enhancement maps agreed within 15% independent of not only the depth and the size of the inclusion but also the presence of a non-scattering region in the background. Although no internal structural information was used in these phantom studies, it may be necessary to use it for small objects buried deep in tissue. However, the different contrast mechanisms of optical and other imaging modalities as well as imperfect co-registration between both modalities may lead to potential errors in the structural a priori. Therefore, the effect of erroneous selection of structural priors was investigated as the final step. Again, the injection and dilution rates obtained from the percentage enhancement maps were also immune to the systematic errors introduced by erroneous selection of the structural priors, e.g. choosing the diameter of the inclusion 20% smaller increased the peak enhancement 60% but changed the injection and dilution rates only less than 10%.

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 investigate the performance of a frequency-domain FT system for small inclusions that are embedded in a heterogeneous background. The results demonstrate that functional and structural a priori information is crucial to be able to recover both parameters with high accuracy. The functional a priori information is defined by the absorption and scattering maps at both excitation and emission wavelengths. Similarly, the boundaries of the small inclusion and different regions in the background are utilized as the structural a priori information. Without a priori information, the fluorophore concentration of a 5 mm inclusion in a 40 mm medium is recovered with 50% error, while the lifetime cannot be recovered at all. On the other hand, when both functional and structural information are available, the true lifetime can be recovered and the fluorophore concentration can be estimated only with 5% error. This study shows that a hybrid system that can acquire diffuse optical absorption tomography (DOT), FT and anatomical images in the same setting is essential to be able to recover the fluorophore concentration and lifetime accurately in vivo.

Conventional fluorescence tomography (FT) can recover the distribution of fluorescent agents within a highly scattering medium. However, poor spatial resolution remains its foremost limitation. Previously, we introduced a new fluorescence imaging technique termed "temperature-modulated fluorescence tomography" (TM-FT), which provides high-resolution images of fluorophore distribution. TM-FT is a multimodality technique that combines fluorescence imaging with focused ultrasound to locate thermo-sensitive fluorescence probes using a priori spatial information to drastically improve the resolution of conventional FT. In this paper, we present an extensive simulation study to evaluate the performance of the TM-FT technique on complex phantoms with multiple fluorescent targets of various sizes located at different depths. In addition, the performance of the TM-FT is tested in the presence of background fluorescence. The results obtained using our new method are systematically compared with those obtained with the conventional FT. Overall, TM-FT provides higher resolution and superior quantitative accuracy, making it an ideal candidate for in vivo preclinical and clinical imaging. For example, a 4mm diameter inclusion positioned in the middle of a synthetic slab geometry phantom (D:40 mm×W:100 mm) is recovered as an elongated object in the conventional FT (x=4.5 mm; y=10.4 mm), while TM-FT recovers it successfully in both directions (x=3.8 mm; y=4.6 mm). As a result, the quantitative accuracy of the TM-FT is superior because it recovers the concentration of the agent with a 22% error, which is in contrast with the 83% error of the conventional FT.

We are developing a ballistic-photon based approach for improving the spatial resolution of fluorescence tomography using time-domain measurements. This approach uses early photon information contained in measured time-of-fight distributions originating from fluorescence emission. The time point spread functions (TPSF) from both excitation light and emission light are acquired with gated single photon Avalanche detector (SPAD) and time-correlated single photon counting after a short laser pulse. To determine the ballistic photons for reconstruction, the lifetime of the fluorophore and the time gate from the excitation profiles will be used for calibration, and then the time gate of the fluorescence profile can be defined by a simple time convolution. By mimicking first generation CT data acquisition, the sourcedetector pair will translate across and also rotate around the subject. The measurement from each source-detector position will be reshaped into a histogram that can be used by a simple back-projection algorithm in order to reconstruct high resolution fluorescence images. Finally, from these 2D sectioning slides, a 3D inclusion can be reconstructed accurately. To validate the approach, simulation of light transport is performed for biological tissue-like media with embedded fluorescent inclusion by solving the diffusion equation with Finite Element Method using COMSOL Multiphysics simulation. The reconstruction results from simulation studies have confirmed that this approach drastically improves the spatial resolution of fluorescence tomography. Moreover, all the results have shown the feasibility of this technique for high resolution small animal imaging up to several centimeters.

Fluorescence tomography is a non invasive, non ionizing imaging technique able to provide a 3D distribution of fluorescent agents within thick highly scattering mediums, using low cost instrumentation. However, its low spatial resolution due to undetermined and ill-posed nature of its inverse problem has delayed its integration into the clinical settings. In addition, the quality of the fluorescence tomography images is degraded due to the excitation light leakage contaminating the fluorescence measurements. This excitation light leakage results from the excitation photons that cannot be blocked by the fluorescence filters. In this contribution, we present a new method to remove this excitation light leakage noise based on the use of a temperature sensitive fluorescence agents. By performing different sets of measurements using this temperature sensitive agents at multiple temperatures, the excitation light leakage can be estimated and then removed from the measured fluorescence signals . The results obtained using this technique demonstrate its potential for use in in-vivo small animal imaging.

Diffuse optical imaging with structured-light illumination and detection can provide rapid, wide-field anatomical and functional imaging of the breast with an application for breast cancer screening. Our aims for this study were to test the feasibility of structured-light, test our pattern set, and develop and optimize our image reconstruction algorithm. For our phantom studies, we created an agar phantom with dimensions similar to a compressed breast. A cubic inclusion of 30mm by 30mm by 25mm with twice the amount of absorption contrast than the background was placed at the center. Near-infrared light of eleven patterns including a full illumination and single stripes was illuminated onto the breast phantom and detected with a CCD camera, with integration of the signals according to the patterns performed post-data acquisition, with a total of 121 measurements. These measurements were then used in our reconstruction algorithm that iteratively minimized the difference between the collected data and the estimation from our FEM-based forward model of photon diffusion to calculate the absorption values. Reconstructions of the 3D absorption maps detect an inclusion at the center and indicate that our selected set of patterns may be sufficient for structured-light imaging. We are currently improving our instrumentation and testing with additional phantom studies, while also performing simulations of numerical breast phantoms created from MR images to test structured-light’s ability to image complex and realistic breast tissue composition. We hope to use this technique as optical method to image molecular markers, such as hemoglobin, water and lipid, within the breast.

Recently, there has been a great amount of interest in developing multi-modality imaging techniques for oncologic research and clinical studies with the aim of obtaining complementary information and, thus, improving the detection and characterization of tumors. In this present work, the details of a combined MR-diffuse optical imaging system for dual-modality imaging of small animals are given. As a part of this effort, a multi-spectral frequency domain diffuse optical tomography system is integrated with an MRI system. Here, a network analyzer provides the rf modulation signal for the laser diodes and measures the amplitude and the phase of the detected signals. Photomultiplier tubes are utilized to measure low-level signals. The integration of this optical imaging system with the 4T MRI system is realized by incorporating a fiber adaptive interface inside the MR magnet. Coregistration is achieved by a special probe design utilizing fiducial markers. A finite element algorithm is used to solve the diffusion equation and an inverse solver based on this forward solver is implemented to calculate the absorption and scattering maps from the acquired data. The MR a priori information is used to guide the optical reconstruction algorithm. Phantom studies show that the absorption coefficient of a 7 mm inclusion in an irregular object located in 64 mm phantom is recovered with 11% error when MR a priori information is used. ENU induced tumor model is used to test the performance of the system in vivo.

A fibre optic experimental arrangement was used to determine the thermo-optic coefficient (dn/dT) of electron beam deposited titanium dioxide coatings on the cleaved end faces of multimode optical fibres for a wavelength range between 600 and 1050 nm. The temperature-induced change in the index of refraction (n) and extinction coefficient (k) were successfully determined from reflection spectra. Measurements of n and k at various wavelengths for different temperatures enabled the determination of dn/dT and dk/dT. It was found that dn/dT takes different values at different temperature ranges. For example, at 800 nm, dn/dT was (−1.77±0.7)×10 −4 K −1 , between 18°C and 120°C, and took a value of (−3.04±0.7)×10 −4 K −1 between 220°C and 325°C.

We developed a spectrally-resolved fluorescence tomography (FT) system using a new source and detection unit. On the source side, we utilized a near-infrared (NIR) swept laser-based technology and on the detection side, we developed a digital micromirror device (DMD) based spectrally-resolved detection unit. We demonstrated the development of a NIR swept laser centered at 800 nm for FT, which covers the maximum absorption wavelength of a NIR fluorescence dye, indo-cyanine green (ICG) in plasma. Two different ICG samples whose absorption characteristics were slightly different were used to demonstrate the performance of the NIR swept laser-based FT system, and this FT system was able to show the difference of absorption between the ICG samples. In addition, we also developed a prototype spectrally-resolved detection unit based on the DMD. This detection system provided a spectral resolution of 15 nm and the possibility of simultaneous detection of multiple fluorescence spectra.

Breast density is a risk factor for breast cancer and we propose using diffuse optical tomography with structured light illuminations (SLI) to quantify the percentage of the fibroglandular (dense) tissue within the breast. Segmentations of dense tissue from breast MRI cases were used to create a geometric model of the breast. COMSOL-generated Finite Element Method (FEM) meshes were used for simulating photon migration through the breast tissue and reconstructing the absorption maps. In these preliminary simulations, the absorption coefficients of the non-dense and dense tissue were assigned using literature values based on their concentrations of water, lipid, oxy- and deoxyhemoglobin as they are the main chromophores, or absorbers of light, within the breast. Synthetic SLI measurements were obtained using a FEMbased forward solver. During the simulation, 12 distinct patterns consisting of vertical stripes, horizontal stripes, and checkerboard patterns were used for illumination and detection. Using these simulated measurements, FEM-based inverse solvers were used to reconstruct the 3D absorption maps. In this study, the methods are applied to reconstruct the absorption maps for multiple wavelengths (780nm, 830nm, 900nm, 1000nm) using one case as an example. We are currently continuing these simulations with additional cases and reconstructing 3D concentration maps of the chromophores within the dense and non-dense breast tissue.

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.

In this paper, we establish the mathematical framework of a novel imaging technique, namely photo-magnetic imaging (PMI). PMI uses a laser to illuminate biological tissues and measure the induced temperature variations using magnetic resonance imaging (MRI). PMI overcomes the limitation of conventional optical imaging and allows imaging of the optical contrast at MRI spatial resolution. The image reconstruction for PMI, using a finite-element-based algorithm with an iterative approach, is presented in this paper. The quantitative accuracy of PMI is investigated for various inclusion sizes, depths and absorption values. Then, a comparison between conventional diffuse optical tomography (DOT) and PMI is carried out to illustrate the superior performance of PMI. An example is presented showing that two 2 mm diameter inclusions embedded 4.5 mm deep and located side by side in a 25 mm diameter circular geometry medium are recovered as a single 6 mm diameter object with DOT. However, these two objects are not only effectively resolved with PMI, but their true concentrations are also recovered successfully.

The design and implementation of a diffuse optical tomography system using wavelength-swept laser is described. Rapid and continuous wavelength change is utilized for high speed spectral scanning from 775 nm to 875 nm optical wavelength. Maximum speed of wavelength repetition is 1 kHz and averaged output power of the wavelength-swept laser is 20 mW. A fiber-optic Sagnac interferometer is incorporated to conduct passive amplitude modulation of the wavelength-swept laser. It is shown that the wavelength-swept laser can be successfully incorporated to the DOT system, and then reduces wavelength-shifting time and hardware complexity in multi-wavelength DOT implementation.

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.

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.

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.

We present a high-resolution fluorescence imaging technique based on the use of in-vivo temperature sensitive ICG loaded pluronic nanocapsules and the synergistic combination of two imaging techniques: Fluorescence Tomography (FT) and High Intensity Focused Ultrasound (HIFU).

Insight into the vasculature of the tumor in small animals has the potential to impact many areas of cancer research. The heterogeneity of the vasculature of a tumor is directly related to tumor stage and disease progression. In this small scale animal study, we investigated the feasibility of differentiating tumors with different levels of vasculature heterogeneity in vivo using a previously developed hybrid magnetic resonance imaging (MRI) and diffuse optical tomography (DOT) system for small animal imaging. Cross-sectional total hemoglobin concentration maps of 10 Fisher rats bearing R3230 breast tumors are reconstructed using multi-wavelength DOT measurements both with and without magnetic resonance (MR) structural a priori information. Simultaneously acquired MR structural images are used to guide and constrain the DOT reconstruction, while dynamic contrast-enhanced MR functional images are used as the gold standard to classify the vasculature of the tumor into two types: high versus low heterogeneity. These preliminary results show that the stand-alone DOT is unable to differentiate tumors with low and high vascular heterogeneity without structural a priori information provided by a high resolution imaging modality. The mean total hemoglobin concentrations comparing the vasculature of the tumors with low and high heterogeneity are significant (p-value 0.02) only when MR structural a priori information is utilized.

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.

We describe a novel approach termed "temperature-modulated fluorescence tomography" that can acquire fluorescence images at focused ultrasound resolution. By utilizing recently emerged temperature sensitive fluorescence contrast agents, this technique provides fluorescence images with high spatial resolution.

In this paper, we present a novel imaging technique, namely Photo-Magnetic Imaging (PMI), which overcomes the limitation of pure optical imaging and provides optical contrast at MRI spatial resolution.

A priori information can be used to guide near-infrared diffuse optical tomography reconstruction and improve quantification. The goal of this study is to develop a hands-free, fully automatic US-DOT system for quantitative whole breast imaging.

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 .