Vasilis Ntziachristos

Three-dimensional diffuse optical tomography in the parallel plane transmission geometry: evaluation of a hybrid frequency domain/continuous wave clinical system for breast imaging.

Three-dimensional diffuse optical tomography (DOT) of breast requires large data sets for even modest resolution (1 cm). We present a hybrid DOT system that combines a limited number of frequency domain (FD) measurements with a large set of continuous wave (cw) measurements. The FD measurements are used to quantitatively determine tissue averaged absorption and scattering coefficients. The larger cw data sets (10(5) measurements) collected with a lens coupled CCD, permit 3D DOT reconstructions of a 1-liter tissue volume. To address the computational complexity of large data sets and 3D volumes we employ finite difference based reconstructions computed in parallel. Tissue phantom measurements evaluate imaging performance. The tests include the following: point spread function measures of resolution, characterization of the size and contrast of single objects, field of view measurements and spectral characterization of constituent concentrations. We also report in vivo measurements. Average tissue optical properties of a healthy breast are used to deduce oxy- and deoxy-hemoglobin concentrations. Differential imaging with a tumor simulating target adhered to the surface of a healthy breast evaluates the influence of physiologic fluctuations on image noise. This tomography system provides robust, quantitative, full 3D image reconstructions with the advantages of high data throughput, single detector-tissue coupling path, and large (1L) imaging domains. In addition, we find that point spread function measurements provide a useful and comprehensive representation of system performance.

Breast imaging technology: Probing physiology and molecular function using optical imaging - applications to breast cancer

The present review addresses the capacity of optical imaging to resolve functional and molecular characteristics of breast cancer. We focus on recent developments in optical imaging that allow three-dimensional reconstruction of optical signatures in the human breast using diffuse optical tomography (DOT). These technologic advances allow the noninvasive, in vivo imaging and quantification of oxygenated and deoxygenated hemoglobin and of contrast agents that target the physiologic and molecular functions of tumors. Hence, malignancy differentiation can be based on a novel set of functional features that are complementary to current radiologic imaging methods. These features could enhance diagnostic accuracy, lower the current state-of-the-art detection limits, and play a vital role in therapeutic strategy and monitoring.

Hydrophilic Cyanine Dyes as Contrast Agents for Near-infrared Tumor Imaging: Synthesis, Photophysical Properties and Spectroscopic In vivo Characterization¶

Abstract We have synthesized a group of glucamine and gluosamine-substituted cyanine dyes structurally related to indocyanine green (ICG) and have characterized these compounds with regard to their potential as contrast agents for biomedical optical imaging. The compounds reported herein exhibit increased hydrophilicity and less plasma protein binding (<50%), and are thus expected to have different pharmacokinetic properties compared with ICG. Furthermore, we measured enhanced fluorescence quantum yields (7–15%) in a physiological environment with respect to ICG. For the derivative with the highest hydrophilicity (5a) the efflux from tumor and normal tissue was monitored by intensity-modulated diffuse optical spectroscopy after intravenous injection into tumor-bearing rats. In comparison with ICG, 5a exhibited a considerably enhanced tissue-efflux half-life (73 min versus less than 10 min for ICG in tumor tissue), a two-fold higher initial tissue absorption coefficient compared to ICG, and finally, it generated an elevated tumor-to-tissue concentration gradient up to 1 h after injection. In conclusion, compounds such as 5a are promising contrast agents for optical imaging, and could facilitate highly sensitive and specific detection of breast cancer or other malignancies by utilizing mechanisms similar to contrast-enhanced magnetic resonance imaging or computerized tomography.

Optimization of optode arrangements for diffuse optical tomography: A singular-value analysis

We develope a method to optimize the resolution of diffuse optical tomographic instruments. Singular-value analysis of the tomographic weight matrix associated with specific data types, geometries, and optode arrangements is shown to provide a measure of image resolution. We achieve optimization of device configuration by monitoring the resolution measure described. We introduce this idea and demonstrate its utility by optimizing the spatial sampling interval and field-of-view parameters in the parallel-plane transmission geometry employed for diffuse optical breast imaging. We also compare resolution in transmission and remission geometries.

Time-correlated single photon counting imager for simultaneous magnetic resonance and near-infrared mammography

We describe a near infrared (NIR) imager for mammography, designed to work simultaneously with a magnetic resonance (MR) scanner. The imager employs two pulsing laser diodes, with average power of 25 μW, at 780 and 830 nm. The two wavelengths are time multiplexed into 24 source fibers. The detection part consists of eight parallel time-correlated photon-counting channels with overall counting capacity of 106 photons/s. We use long optical fibers to avoid interference with the magnetic field. Specially designed coupling plates, for breast soft compression, bear both the MR radio-frequency coils and the optical source and detector fibers. Capillaries containing water and copper sulfate mark the position of the plates on the MR images for accurate coregistration of NIR and MR images. Instrument compatibility has been successfully tested with volunteers in the MR scanner. The use of gallium arsenide photomultiplier tubes has allowed penetration depths of 10 cm in the human breast. Imaging algorithms, based on...

Imager that combines near-infrared diffusive light and ultrasound

We introduce an imaging technique that combines complementary features of ultrasound and near-infrared diffusive light imaging. We achieve the combined technology experimentally by mounting an ultrasound array together with multiple laser source and optical detector fibers upon a hand-held probe. The technique is demonstrated with tissue phantoms wherein both acoustic and optical sensors image the volume underneath the probe. Coregistration of acoustic and optical images is achieved with an accuracy of 0.27+/-0.20cm, approximately half of the image pixel size of our prototype. Accurate determination of target optical absorption is also achieved by use of image segmentation on the ultrasound reconstruction. The combined technique may provide improved breast-cancer detection sensitivity and specificity.

Multichannel photon counting instrument for spatially resolved near infrared spectroscopy

We have developed a multichannel photon counting instrument for near infrared spatially resolved spectroscopy. The instrument uses two laser diodes at 780 and 830 nm. The two wavelengths are time multiplexed at a rate of 5 MHz for virtually simultaneous measurements at the two wavelengths. The photon pulses are then multiplexed with an optical switch so that the incident optical signals are directed to different source positions. Eight time-correlated channels have been employed for simultaneous acquisition of spectroscopic data at multiple locations. Photon detection is performed by multichannel plate photomultiplier tubes. Robust and accurate data analysis tools to perform deconvolution, data fitting, and absorption change quantification are presented. The instrument has been tested with phantoms simulating tissue optical properties. Absolute optical properties, namely absorption and reduced scattering coefficient, have been determined with an accuracy of ±5%. Quantification of absorption changes can be...

Diffuse optical tomography of highly heterogeneous media

The authors investigate the performance of diffuse optical tomography to image highly heterogeneous media, such as breast tissue, as a function of background heterogeneity. To model the background heterogeneity, they have employed the functional information derived from Gadolinium-enhanced magnetic resonance images of the breast. The authors demonstrate that overall image quality and quantification accuracy worsens as the background heterogeneity increases. Furthermore they confirm the appearance of characteristic artifacts at the boundaries that scale with background heterogeneity. These artifacts are very similar to the ones seen in clinical examinations and can be misinterpreted as actual objects if not accounted for. To eliminate the artifacts and improve the overall image reconstruction, the authors apply a data-correction algorithm that yields superior reconstruction results and is virtually independent of the degree of the background heterogeneity.

Accuracy limits in the determination of absolute optical properties using time‐resolved NIR spectroscopy

We assess typical systematic experimental errors involved in a time-resolvedmeasurement as applied to NIR diffuse optical spectroscopy and investigate their effect on the quantification accuracy of the absorption and the reduced scattering coefficient. We demonstrate that common systematic experimental uncertainties may lead to quantification errors of 10% or more, even when excellent signal to noise ratio conditions exist and accurate photon propagation models are employed. We further demonstrate that the accuracy of the calculation depends nonlinearly on the optical properties of the medium measured. High scattering and low absorbing media can be quantified more accurately than media with low scattering or high absorption using measurements of the same signal to noise ratio. We further discuss curve-shape fitting schemes that aid in improving the quantification accuracy in the presence of experimental errors. Finally, we identify uncertainties that set quantification accuracy limits and we find temporal resolution as the ultimate limiting factor in the quantification accuracy achieved. Our findings suggest that temporal resolution of the order of 10 ps is necessary for quantifying the absorption and reduced scattering coefficient of diffuse media with accuracy better than 5% using curve fitting methods. In that sense this analysis can be used in time-resolved system design and in predicting the expected errors given the technology selected for time-resolvedmeasurements.

Experimental determination of photon propagation in highly absorbing and scattering media

Optical imaging and tomography in tissues can facilitate the quantitative study of several important chromophores and fluorophores. Several theoretical models have been validated for diffuse photon propagation in highly scattering and low-absorbing media that describe the optical appearance of tissues in the near-infrared (NIR) region. However, these models are not generally applicable to quantitative optical investigations in the visible because of the significantly higher tissue absorption in this spectral region compared with that in the NIR. We performed photon measurements through highly scattering and absorbing media for ratios of the absorption coefficient to the reduced scattering coefficient ranging approximately from zero to one. We examined experimentally the performance of the absorption-dependent diffusion coefficient defined by Aronson and Corngold [J. Opt. Soc. Am. A 16, 1066 (1999)] for quantitative estimations of photon propagation in the low- and high-absorption regimes. Through steady-state measurements we verified that the transmitted intensity is well described by the diffusion equation by considering a modified diffusion coefficient with a nonlinear dependence on the absorption. This study confirms that simple analytical solutions based on the diffusion approximation are suitable even for high-absorption regimes and shows that diffusion-approximation-based models are valid for quantitative measurements and tomographic imaging of tissues in the visible.