Three-dimensional diffuse optical tomography of osteoarthritis: initial results in the finger joints

This work presents a pilot study to show the potential of an emerging imaging modality, near-infrared diffuse optical tomography (DOT), for the diagnosis of osteoarthritis (OA). We report quantitative absorption and scattering images of joint tissue that allow for differentiation between diseased and healthy joints. An automatic, multichannel optical imaging system is used to image finger joints from two OA patients and three healthy volunteers. 3-D optical images of the joint tissue are recovered using a finite-element-based reconstruction algorithm. The reconstructed images demonstrate differences in optical properties at the joint region (cartilage/synovial fluid) between the OA and healthy joints. Quantitative analysis from the patients and healthy volunteers also indicate that the recovered joint sizes are consistent with those from x-ray findings. The results of this pilot study show potential for quantitative imaging and diagnosis of early OA by DOT.     

Near-infrared diffuse optical tomography

Diffuse optical tomography (DOT) is emerging as a viable new biomedical imaging modality. Using near-infrared (NIR) light, this technique probes absorption as well as scattering properties of biological tissues. First commercial instruments are now available that allow users to obtain cross-sectional and volumetric views of various body parts. Currently, the main applications are brain, breast, limb, joint, and fluorescence/bioluminescence imaging. Although the spatial resolution is limited when compared with other imaging modalities, such as magnetic resonance imaging (MRI) or X-ray computerized tomography (CT), DOT provides access to a variety of physiological parameters that otherwise are not accessible, including sub-second imaging of hemodynamics and other fast-changing processes. Furthermore, DOT can be realized in compact, portable instrumentation that allows for bedside monitoring at relatively low cost. In this paper, we present an overview of current state-of-the -art technology, including hardware and image-reconstruction algorithms, and focus on applications in brain and joint imaging. In addition, we present recent results of work on optical tomographic imaging in small animals.     

Mesh-based enhancement schemes in diffuse optical tomography

Two mesh-based methods including dual meshing and adaptive meshing are developed to improve the finite element-based reconstruction of both absorption and scattering images of heterogeneous turbid media. The idea of dual meshing scheme is to use a fine mesh for the solution of photon propagation and a coarse mesh for the inversion of optical property distributions. The adaptive meshing method is accomplished by the automatic mesh refinement in the region of heterogeneity during reconstruction. These schemes are validated using tissue-like phantom measurements. Our results demonstrate the capabilities of the dual meshing and adaptive meshing in both qualitative and quantitative improvement of optical image reconstruction.     

Image analysis methods for diffuse optical tomography

Three major analytical tools in imaging science are summarized and demonstrated relative to optical imaging in vivo. Standard resolution testing is optimal when infinite contrast is used and hardware evaluation is the goal. However, deep tissue imaging of absorption or fluorescent contrast agents in vivo often presents a different problem, which requires contrast-detail analysis. This analysis shows that the minimum detectable sizes are in the range of 1/10 the outer diameter, whereas minimum detectable contrast values are in the range of 10 to 20% relative to the continuous background values. This is estimated for objects being in the center of the domain being imaged, and as the heterogeneous region becomes closer to the surface, the lower limit on size and contrast can become arbitrarily low and more dictated by hardware specifications. Finally, if human observer detection of abnormalities in the images is the goal, as is standard in most radiological practice, receiver operating characteristic (ROC) curve and location receiver operating characteristic curve (LROC) are used. Each of these three major areas of image interpretation and analysis are reviewed in the context of medical imaging as well as how they are used to quantify the performance of diffuse optical imaging of tissue.     

Fundamental study on diffuse reflective optical tomography

We report a simulation study on diffuse reflective optical computed tomography, in which continuous-wave sources and detectors are placed on the plane surface of a semi-infinite body. We adopted a simple Tikhonov regularization in the inverse problem and demonstrated the feasibility of three-dimensional reconstruction of the absorption coefficient change. The spatial resolution of the reconstructed image was shown to be degrading markedly with the depth. The regularization parameter should be chosen appropriately considering the trade-off between the reconstructed image noise and the spatial resolution. We analysed the dependence of the spatial resolution of the reconstructed image on the regularization parameter and the depth, and also the behaviour of the reconstructed image noise on the regularization parameter and the depth.     

Three-dimensional optical tomography of the premature infant brain

For the first time, three-dimensional images of the newborn infant brain have been generated using measurements of transmitted light. A 32-channel time-resolved imaging system was employed, and data were acquired using custom-made helmets which couple source fibres and detector bundles to the infant head. Images have been reconstructed using measurements of mean flight time relative to those acquired on a homogeneous reference phantom, and using a head-shaped 3D finite-element-based forward model with an external boundary constrained to match the measured positions of the sources and detectors. Results are presented for a premature infant with a cerebral haemorrhage predominantly located within the left ventricle. Images representing the distribution of absorption at 780 nm and 815 nm reveal an asymmetry consistent with the haemorrhage, and corresponding maps of blood volume and fractional oxygen saturation are generally within expected physiological values.     

Three-dimensional cellular-level imaging using full-field optical coherence tomography

An ultrahigh-resolution full-field optical coherence tomography (OCT) system has been developed for cellular-level imaging of biological media. The system is based on a Linnik interference microscope illuminated with a tungsten halogen lamp, associated with a high-resolution CCD camera. En face tomographic images are produced in real time, with the best spatial resolution ever achieved in OCT (0.7 microm x 0.9 microm, axial x transverse). A shot-noise limited detection sensitivity of 80 dB can be reached with an acquisition time per image of 1 s. Images of animal ophthalmic biopsies and vegetal tissues are shown.     

Contrast-detail analysis characterizing diffuse optical fluorescence tomography image reconstruction

Contrast-detail analysis is used to evaluate the imaging performance of diffuse optical fluorescence tomography (DOFT), characterizing spatial resolution limits, signal-to-noise limits, and the trade-off between object contrast and size. Reconstructed images of fluorescence yield from simulated noisy data were used to determine the contrast-to-noise ratio (CNR). A threshold of CNR=3 was used to approximate a lowest acceptable noise level in the image, as a surrogate measure for human detection of objects. For objects 0.5 cm inside the edge of a simulated tissue region, the smallest diameter that met this criteria was approximately 1.7 mm, regardless of contrast level, and test field diameter had little impact on this limit. Object depth had substantial impact on object CNR, leading to a limit of 4 mm for objects near the center of a 51-mm test field and 8.5 mm for an 86-mm test field. Similarly, large objects near the edge of both test fields required a minimum contrast of 50% to achieve acceptable image CNR. The minimum contrast for large, centered objects ranged between 50% and 100%. Contrast-detail analysis using human detection of lower contrast limits provides fundamentally important information about the performance of reconstruction algorithms, and can be used to compare imaging performance of different systems.     

A soft deformable tissue-equivalent phantom for diffuse optical tomography

A recipe is presented for the manufacture of highly compressible phantoms for diffuse optical tomography. The recipe is based on polyvinyl alcohol (PVA) slime, a viscoelastic fluid which readily deforms under moderate pressure. Scattering particles and absorbing compounds can be added to provide a uniform material with stable and reproducible optical properties. A linear relationship between the concentration of scattering particles (either titanium dioxide or microspheres) and the transport scatter coefficient is demonstrated. Phantoms of an arbitrary size and shape may be produced by containing the slime within a thin latex shell, and a stability over a period of at least 3 months has been established. The deformable phantoms may be used to test and calibrate optical tomography systems designed for use on patients with irregular or variable geometries.     

Gauss-Newton method for image reconstruction in diffuse optical tomography

We present a regularized Gauss-Newton method for solving the inverse problem of parameter reconstruction from boundary data in frequency-domain diffuse optical tomography. To avoid the explicit formation and inversion of the Hessian which is often prohibitively expensive in terms of memory resources and runtime for large-scale problems, we propose to solve the normal equation at each Newton step by means of an iterative Krylov method, which accesses the Hessian only in the form of matrix-vector products. This allows us to represent the Hessian implicitly by the Jacobian and regularization term. Further we introduce transformation strategies for data and parameter space to improve the reconstruction performance. We present simultaneous reconstructions of absorption and scattering distributions using this method for a simulated test case and experimental phantom data.     

Design and implementation of a multifrequency near-infrared diffuse optical tomography system

The design and implementation of a multifrequency and multispectral diffuse optical tomography system is described. Four wavelengths are utilized: 665, 785, 808, and 830 nm. The system is based on a network analyzer, which provides rf modulation signals for the laser diodes, as well as measures the amplitude and the phase of the detected signals. Six different modulation frequencies ranging from 110 to 280 MHz are used. The details of instrumentation, calibration, data acquisition, and performance of the system are given. 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. Data acquisition for one wavelength is completed in less than 2.5 min for a single modulation frequency. The measurement repeatability is 0.5% in ac intensity and 0.2 deg in phase. The performance of the system is evaluated with phantom studies. A multifrequency reconstruction algorithm is used, in which a single absorption and scattering image pair is obtained using the whole dataset obtained at different modulation frequencies. It is shown that the multifrequency reconstruction approach provides superior image quality compared to the single frequency counterpart.     

Comparison of diffuse optical tomography of human breast with whole-body and breast-only positron emission tomography

We acquire and compare three-dimensional tomographic breast images of three females with suspicious masses using diffuse optical tomography (DOT) and positron emission tomography (PET). Co-registration of DOT and PET images was facilitated by a mutual information maximization algorithm. We also compared DOT and whole-body PET images of 14 patients with breast abnormalities. Positive correlations were found between total hemoglobin concentration and tissue scattering measured by DOT, and fluorodeoxyglucose (18F-FDG) uptake. In light of these observations, we suggest potential benefits of combining both PET and DOT for characterization of breast lesions.     

Sagittal laser optical tomography for imaging of rheumatoid finger joints

We present a novel optical tomographic imaging system that was designed to determine two-dimensional spatial distribution of optical properties in a sagittal plane through finger joints. The system incorporates a single laser diode and a single silicon photodetector into a scanning device that records spatially resolved light intensities as they are transmitted through a finger. These data are input to a model-based iterative image reconstruction (MOBIIR) scheme, which uses the equation of radiative transfer (ERT) as a forward model for light propagation through tissue. We have used this system to obtain tomographic images of six proximal interphalangeal finger joints from two patients with rheumatoid arthritis. The optical images were compared to clinical symptoms and ultrasound images.     

Improved quantification of small objects in near-infrared diffuse optical tomography

Diffuse optical tomography allows quantification of hemoglobin, oxygen saturation, and water in tissue, and the fidelity in this quantification is dependent on the accuracy of optical properties determined during image reconstruction. In this study, a three-step algorithm is proposed and validated that uses the standard Newton minimization with Levenberg-Marquardt regularization as the first step. The second step is a modification to the existing algorithm using a two-parameter regularization to allow lower damping in a region of interest as compared to background. This second stage allows the recovery of the actual size of an inclusion. A region-based reconstruction is the final third step, which uses the estimated size and position information from step 2 to yield quantitatively accurate average values for the optical parameters. The algorithm is tested on simulated and experimental data and is found to be insensitive to object contrast and position. The percentage error between the true and the average recovered value for the absorption coefficient in test images is reduced from 47 to 27% for a 10-mm inclusion, from 38 to 13% for a 15-mm anomaly, and from 28 to 5.5% for a 20-mm heterogeneity. Simulated data with absorbing and scattering heterogeneities of 15 mm diam located in different positions show recovery with less than 15% error in absorption and 6% error in reduced scattering coefficients. The algorithm is successfully applied to clinical data from a subject with a breast abnormality to yield quantitatively increased absorption coefficients, which enhances the contrast to 3.8 compared to 1.23 previously.     

Genetic diseases of bones and joints

Genetic factors play roles in many diseases. Often these factors are ill defined and unpredictable. Other diseases are caused by specific single gene mutations and are passed to offspring in Mendelian inheritance patterns. There are over 5000 documented Mendelian disorders; over 500 of these affect bones and joints. Some of these single gene disorders affect many tissues, and the skeletal system is one of many organ systems involved. The surgical pathologist must often diagnose these disorders. Important examples are neurofibromatosis, Gaucher's disease, and alkaptonuria. Other single gene disorders almost exclusively affect the skeleton. These disorders are the skeletal dysplasias and 372 have been documented. These disorders are classified using radiographic, clinical, and molecular data. The most common dysplasias are osteogenesis imperfecta, achondroplasia, and osteopetrosis. The surgical pathologist usually does not play a role in the diagnosis of skeletal dysplasias. However, histologic studies often elucidate the pathophysiologic basis of these diseases and proper collection of tissues is important for the evolving understanding of the molecular basis of these disorders.     

Experimental measurement of time-dependent photon scatter for diffuse optical tomography

Time-resolved measurement of early arriving photons through diffusive media has been shown to effectively reduce the high degree of light scatter in biological tissue. However, the experimentally achievable reduction in photon scatter and the impact of time-gated detection on instrument noise performance is not well understood. We measure time-dependent photon density sensitivity functions (PDSFs) between a pulsed laser source and a photomultiplier tube operating in time-correlated single-photon-counting mode. Our data show that with our system, measurement of early arriving photons reduces the full width half maximum of PDSFs on average by about 40 to 60% versus quasicontinuous wave photons over a range of experimental conditions similar to those encountered in small animal tomography, corresponding to a 64 to 84% reduction in PDSF volume. Factoring in noise considerations, the optimal operating point of our instrument is determined to be about the 10% point on the rising edge of the transmitted intensity curve. Time-dependent Monte Carlo simulations and the time-resolved diffusion approximation are used to model photon propagation and are evaluated for agreement with experimental data.     

Target detection and quantification using a hybrid hand-held diffuse optical tomography and photoacoustic tomography system

We present a photoacoustic tomography-guided diffuse optical tomography approach using a hand-held probe for detection and characterization of deeply-seated targets embedded in a turbid medium. Diffuse optical tomography guided by coregistered ultrasound, MRI, and x ray has demonstrated a great clinical potential to overcome lesion location uncertainty and to improve light quantification accuracy. However, due to the different contrast mechanisms, some lesions may not be detectable by a nonoptical modality but yet have high optical contrast. Photoacoustic tomography utilizes a short-pulsed laser beam to diffusively penetrate into tissue. Upon absorption of the light by the target, photoacoustic waves are generated and used to reconstruct, at ultrasound resolution, the optical absorption distribution that reveals optical contrast. However, the robustness of optical property quantification of targets by photoacoustic tomography is complicated because of the wide range of ultrasound transducer sensitivity, the orientation and shape of the targets relative to the ultrasound array, and the uniformity of the laser beam. We show in this paper that the relative optical absorption map provided by photoacoustic tomography can potentially guide the diffuse optical tomography to accurately reconstruct target absorption maps.     

Three-dimensional imaging of xenograft tumors using optical computed and emission tomography

The physical basis and preliminary applications of optical computed tomography (optical-CT) and optical emission computed tomography (optical-ECT) are introduced, as new techniques with potential to provide unique 3D information on a variety of aspects of tumor structure and function. A particular focus here is imaging tumor micro-vasculature, and the spatial distribution of viable tumor cells, although the techniques have the potential for much wider application. The principle attractiveness of optical-CT and optical-ECT are that high resolution (<20 microm) and high contrast co-registered 3D images of structure and function can be acquired for relatively large intact samples. The unique combination of high contrast and resolution offers advantages over micro-CT and micro-MRI, and the lack of requirement for sectioning offers advantages over confocal microscopy, conventional microscopy, and histological sectioning techniques. Optical-CT/ECT are implemented using in-house custom apparatus and a commercial dissecting microscope capable of both transmission and fluorescence imaging. Basic studies to characterize imaging performance are presented. Negligible geometrical distortion and accurate reconstruction of relative attenuation coefficients was observed. Optical-CT and optical-ECT are investigated here by application to high resolution imaging of HCT116 xenograft tumors, about 1 cc in dimension, which were transfected with constitutive red fluorescent protein (RFP). Tumor microvasculature was stained in vivo by tail vein injection of either passive absorbing dyes or active fluorescent markers (FITC conjugated lectin). Prior to imaging, the tumors were removed (ex vivo) and optically cleared in a key process to make the samples amenable to light transmission. The cleared tumors were imaged in three modes (i) optical-CT to image the 3D distribution of microvasculature as indicated by absorbing dye, (ii) optical-ECT using the FITC excitation and emission filter set, to determine microvasculature as indicated by lectin-endothelial binding, and (iii) optical-ECT using the DSRed2 filter set to determine the 3D distribution of viable tumor as indicated by RFP emission. A clear correlation was observed between the independent vasculature imaging modes (i) and (ii) and postimaging histological sections, providing substantial validation of the optical-CT and optical-ECT techniques. Strong correlation was also observed between the RFP imaging of mode iii, and modes i and ii, supporting the intuitive conclusion that well-perfused regions contain significant viable tumor. In summary, optical-CT and optical-ECT, when combined with new optical clearing techniques, represent powerful new imaging modalities with potential for providing unique information on the structure and function of tumors.     

Three-dimensional diffuse optical mammography with ultrasound localization in a human subject

We describe an approach that combines clinical ultrasound and photon migration techniques to enhance the sensitivity and information content of diffuse optical tomography. Measurements were performed on a postmenopausal woman with a single 1.8 x 0.9 cm malignant ductal carcinoma in situ approximately 7.4 mm beneath the skin surface (UCI IRB protocol 95-563). The ultrasound-derived information about tumor geometry enabled us to segment the breast tissue into tumor and background regions. Optical data was obtained with a multifrequency, multiwavelength hand-held frequency-domain photon migration backscattering probe. The optical properties of the tumor and background were then computed using the ultrasound-derived geometrical constraints. An iterative perturbative approach, using parallel processing, provided quantitative information about scattering and absorption simultaneously with the ability to incorporate and resolve complex boundary conditions and geometries. A three to four fold increase in the tumor absorption coefficient and nearly 50% reduction in scattering coefficient relative to background was observed (lambda = 674, 782, 803, and 849 nm). Calculations of the mean physiological parameters reveal fourfold greater tumor total hemoglobin concentration [Hbtot] than normal breast (67 microM vs 16 microM) and tumor hemoglobin oxygen saturation (SOx) values of 63% (vs 73% and 68% in the region surrounding the tumor and the opposite normal tissue, respectively). Comparison of semi-infinite to heterogeneous models shows superior tumor/background contrast for the latter in both absorption and scattering. Sensitivity studies assessing the impact of tumor size and refractive index assumptions, as well as scan direction, demonstrate modest effects on recovered properties.