Near-infrared diffuse optical tomography (DOT) has demonstrated a great potential as an adjunct modality for differentiation of malignant and benign breast lesions and for monitoring treatment response in patients with locally advanced breast cancers. The path toward commercialization of DOT techniques depends upon the improvement of robustness and user-friendliness of this technique in hardware and software. In this study, we introduce our recently developed ultrasound-guided DOT system, which has been improved in system compactness, robustness, and user-friendliness by custom-designed electronics, automated data preprocessing, and implementation of a new two-step reconstruction algorithm. The system performance has been tested with several sets of solid and blood phantoms and the results show accuracy in reconstructed absorption coefficients as well as blood oxygen saturation. A clinical example of a breast cancer patient, who was undergoing neoadjuvant chemotherapy, is given to demonstrate the system performance.
According to the World Health Organization, breast cancer is the most common cancer among women worldwide, claiming the lives of hundreds of thousands of women each year. Near infrared diffuse optical tomography (DOT) has demonstrated a great potential as an adjunct modality for differentiation of malignant and benign breast lesions and for monitoring treatment response of patients with locally advanced breast cancers. The path toward commercialization of DOT techniques depends upon the improvement of robustness and user-friendliness of this technique in hardware and software. In the past, our group have developed three frequency domain prototype systems which were used in several clinical studies. In this study, we introduce our newly under development US-guided DOT system which is being improved in terms of size, robustness and user friendliness by several custom electronic and mechanical design. A new and robust probe designed to reduce preparation time in clinical process. The processing procedure, data selection and user interface software also updated. With all these improvements, our new system is more robust and accurate which is one step closer to commercialization and wide use of this technology in clinical settings. This system is aimed to be used by minimally trained user in the clinical settings with robust performance. The system performance has been tested in the phantom experiment and initial results are demonstrated in this study. We are currently working on finalizing this system and do further testing to validate the performance of this system. We are aiming toward use of this system in clinical setting for patients with breast cancer.
Near infrared (NIR) diffuse optical tomography has demonstrated great potential in the initial diagnosis of tumor and the assessment of tumor vasculature response to neoadjuvant chemotherapy. A fast and robust data processing is critical to move this technique from lab research to bench-side application. Our lab developed frequency-domain diffuse optical tomography system for clinical applications. So far, we still collect data at hospital and do the data processing off-line. In this paper, a robust calibration procedure and fast processing program were developed to overcome this limitation. Because each detection channel had its own electronic delay, the calibration procedure measured amplitude linearity and phase linearity of each channel, and formed a look-up table. The experimental measurements were corrected by the table and the fitting accuracy improved by 45.8%. To further improve the processing speed, the data collection and processing program were converted to C++ from matlab program. The overall processing speed was improved by two times. We expect the new processing program can move diffuse optical tomography one step close to bench-side clinical applications.
Near infrared (NIR) diffuse optical tomography has demonstrated great potential in the initial diagnosis of tumor and in the assessment of tumor vasculature response to neoadjuvant chemotherapy. To reconstruct the absorption map of a breast lesion, perturbation is needed which is the normalized difference between the measurements of lesion-side breast and contralateral reference breast. However, the heterogeneity in the reference breast can produce unwanted perturbation which will result in distortion of the reconstructed target absorption map. This report introduces a filtering method to overcome the reference heterogeneity. This method corrects affected source-detector measurements obtained from the reference side by using averages of unaffected measurements. As a result, the filtered perturbation has decreased the effect of heterogeneity on the reconstructed absorption maps. To evaluate the performance of this filtering method, we have compared the reconstructed results with and without the filtering algorithm using simulated heterogeneous reference with heterogeneous absorbers ranging from 0.05 to 0.20 cm-1 and heterogeneous scatters ranging from 10 to 20cm-1. The results show that the algorithm can improve the maximum reconstructed target value up to 99% of the value with homogeneous reference. In the worst case of high absorption heterogeneity in reference breast, the maximum reconstructed value was around 30.85% of the true absorption without filtering correction and was improved to 60.4% of the true absorption value, which is 95% of the reconstructed value when using the homogeneous reference.
To overcome the intensive light scattering in biological tissue, diffuse optical tomography (DOT) in the near-infrared range for breast lesion detection is usually combined with other imaging modalities, such as ultrasound, x-ray, and magnetic resonance imaging, to provide guidance. However, these guiding imaging modalities may depend on different contrast mechanisms compared to the optical contrast in the DOT. As a result, they cannot provide reliable guidance for DOT because some lesions may not be detectable by a nonoptical modality but may have a high optical contrast. An imaging modality that relies on optical contrast to provide guidance is desirable for DOT. We present a system that combines a frequency-domain DOT and real-time photoacoustic tomography (PAT) systems to detect and characterize deeply seated targets embedded in a turbid medium. To further improve the contrast, the exogenous contrast agent, indocyanine green (ICG), is used. Our experimental results show that the combined system can detect a tumor-mimicking phantom, which is immersed in intralipid solution with the concentrations ranging from 100 to 10 μM and with the dimensions of 0.8 cm×0.8 cm×0.6 cm , up to 2.5 cm in depth. Mice experiments also confirmed that the combined system can detect tumors and monitor the ICG uptake and washout in the tumor region. This method can potentially improve the accuracy to detect small breast lesions as well as lesions that are sensitive to background tissue changes, such as the lesions located just above the chest wall.
To overcome the intensive light scattering in the biological tissue, diffuse optical tomography (DOT) in the near infrared range for breast lesion detection usually is combined with other imaging modalities such as ultrasound, X-ray, and MRI, to provide guidance. However, the guided imaging modalities may depend on different contrast mechanics compared to the optical contrast in the DOT. As a result, they can’t provide reliable guidance for diffuse optical tomography because some lesions may not be detectable by a non-optical modality but yet have high optical contrast. An imaging modality which can provide the guidance from optical contrast is desirable for DOT. In this paper, we present a system that combines diffuse optical tomography and photoacoustic tomography (PAT), to detect and characterize the deeply-seated targets embedded in a turbid medium. Photoacoustic tomography utilizes a short-pulsed laser beam to penetrate into tissue diffusively. 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. The combined system used in the experiment combines a 64-channel photoacoustic system with a frequency-domain diffused optical system. To further improve the contrast, the exogenous contrast agent, indocyanine green (ICG) is used. Our experiment results show that the combined system can detect a tumormimicking phantom up to 2.5 cm in depth and 10 μM in concentration. Mice experiments also confirmed that the combined system can detect the tumor region and monitor the ICG uptake and washout in the tumor region. This method can potentially improve the accuracy to detect the small breast lesions or any lesions which are sensitive to the reference change, such as the lesions located on the chest wall.
Photoacoustic tomography provides the distribution of absorbed optical energy density, which is the product of optical absorption coefficient and optical fluence distribution. We report the experimental investigation of a novel fitting procedure that quantitatively determines the optical absorption coefficient of chromophores. The experimental setup consisted of a hybrid system of a 64-channel photoacoustic imaging system with a frequency-domain diffused optical measurement system. The fitting procedure included a complete photoacoustic forward model and an analytical solution of a target chromophore using the diffusion approximation. The fitting procedure combines the information from the photoacoustic image and the background information from the diffuse optical measurements to minimize the photoacoustic measurements and forward model data and recover the target absorption coefficient quantitatively. 1-cm-cube phantom absorbers of high and low contrasts were imaged at depths of up to 3.0 cm. The fitted absorption coefficient results were at least 80% of their true values. The sensitivities of this fitting procedure to target location, target radius, and background optical properties were also investigated. We found that this fitting procedure was most sensitive to the accurate determination of the target radius and depth. Blood sample in a thin tube of radius 0.58 mm, simulating a blood vessel, was also studied. The photoacoustic images and fitted absorption coefficients are presented. These results demonstrate the clinical potential of this fitting procedure to quantitatively characterize small lesions in breast imaging.
Traditional Photoacoustic tomography provides the distribution of absorbed optical
energy densities which are the products of the optical absorption coefficients and fluences.
However, the absorption coefficient is the only functional parameter that is related to disease
diagnosis, such as cancer. In this paper, we report the experimental investigation of an improved
fitting procedure which can quantitatively characterize optical absorption coefficients of multiple
targets. The original fitting procedure was proposed by us and used for a single target. The fitting
procedure included a complete photoacoustic forward model, which incorporated an analytical
model of light transport and a model of acoustic propagation. Using the target information from
the PAT images and the background information from diffuse optical measurements (DOM), the
fitting method minimizes the photoacoustic measurements and forward model data and recovers
the target absorption coefficient quantitatively. The fitting errors in the absorption coefficients
can reach 20% to 100% if the original fitting procedure is directly used on multiple targets. In
our improved fitting method, the ratio between the photoacoustic intensities is introduced and
served as extra input to the fitting procedure. As a result, the total number of unknown
parameters is reduced and fitting accuracy is improved. The hybrid system used in the
experiment combines a 64-channel photoacoustic system with a frequency-domain diffused
optical system. The experiment was performed in the reflection geometry suitable for breast
imaging. Phantom experiments include the combination of high contrast and low contrast targets
with absorption coefficients ranging from 0.07 to 0.28 cm-1 and with different spatial separations.
The phantoms were inserted into a chicken breast tissue. The fitting errors of multiple targets
were reduced to less than 20% for both high and low contrast targets. These results illustrate the
potential application of this quantitative DOM-assisted photoacoustic fitting procedure to image
and diagnose breast cancer having multiple and complex tumor distribution.
Clustered small breast lesions may be present in the neighboring areas and are difficult to accurately resolve and quantify in diffuse optical tomography. In addition, larger cancers are often accompanied by clustered satellite lesions in the neighboring areas, which are also difficult to resolve and quantify. To improve the light quantification of clustered lesions, a new multi-zone reconstruction algorithm guided by co-registered ultrasound (US) was investigated using simulations, phantoms, and clinical examples. This method separated one larger region-of-interest (ROI) into several ROIs based on the location information provided by co-registered US. In general, the single-ROI method cannot resolve two smaller targets when their separations were less than 2.5 cm and the depth was greater than 2.0 cm. The multi-zone reconstruction method improved the resolving ability and reconstruction accuracy. As a result, two targets located at 2.5 cm depth with separation greater than 2.0 cm could be distinguished, and reconstruction improved by more than 20% as compared with that of the single-ROI method. When two targets, one larger and one smaller, were located closer to each other, the location of the reconstructed absorption mass was shifted toward the larger target and the quantification of the smaller target was limited.
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.
A handheld photoacoustic tomography-guided diffuse optical tomography system for imaging deeply-seated targets in
scattering media is presented. This hybrid imager consists of a probe with an ultrasound transducer in the center and
straddled by two optical fibers for taking photoacoustic images. The diffuse optical tomography component comprises of
9 light-source fibers for delivering light to the imaged tissue, and 14 detector fibers for collecting the light. Single- and
two-phantom targets of high and low optical contrasts were immersed in a scattering intralipid solution to depths of up to
3cm and imaged. The reconstructed absorption coefficients of the targets with guidance from photoacoustic tomography
were compared to those obtained with a-priori depth-only information, and no a-priori information. The reconstructed
absorption maps yielded as much as 2.6-fold improvement in the quantification accuracy compared to the cases with no
guidance from photoacoustic tomography.
To improve the light quantification of clustered lesions, a multi-zone reconstruction algorithm guided by co-registered
ultrasound image was investigated using simulations and phantoms. The performance of the algorithm was demonstrated
using clinical examples.
In this paper, we report the experimental investigation of a novel fitting procedure which can
detect and quantitatively characterize the optical contrasts of targets using diffuse optical
tomography (DOT)-assisted photoacoustic tomography. The hybrid system combines a 64-channel
photoacoustic system with a 9-source, 14-detector frequency-domain DOT system. A white probe
was used to house the ultrasound transducer, the optical sources and detectors. The experiment was
performed in the reflection mode which is more realistic to clinical applications. The fitting
procedure included a complete photoacoustic forward model, which incorporated an analytical
model of light transport and a model of acoustic propagation. Using the structural information from
the PAT images and the background information from DOT measurements, the photoacoustic
forward model was used to recover the target absorption coefficient quantitatively. Phantom
absorbers, 1 cm in diameter, with absorption coefficients ranging from 0.08 to 0.28 cm-1 were
imaged at depths of up to 3.0 cm. The fitting results were at least 85% of their true values for both
high and low contrast targets. Blood sample in a thin tube of radius 0.6 mm, that was simulating a
blood vessel, was also imaged, and the reconstructed images and fitted absorption coefficients are
presented. These results illustrate the promising application of this fitting procedure for tissue
absorption coefficient characterization and consequently breast cancer diagnosis.
When a large, highly absorbing breast lesion is imaged by optical tomography in reflection geometry, most of the photons are absorbed by the top portion of the lesion. As a result, the lower portion of the lesion is not quantified correctly. This posterior light shadowing effect is similar to the sound shadowing effect frequently seen in pulse-echo ultrasound images. The presence of significant posterior shadowing of a lesion in ultrasound images suggests malignance. The light shadowing effect due to optical contrast is characterized using a simple measure and validated by the Monte Carlo photon-tracking method and phantom experiments. Clinical examples of large malignant and benign lesions are presented to demonstrate the shadowing effect and the utility of the measure. Understanding and quantifying the shadowing effect due to optical contrast is important for characterizing larger malignant cancers from benign lesions.
We develop a new tomographic imaging reconstruction algorithm for a two-layer tissue structure. Simulations and phantom experiments show more accurate reconstruction of target optical properties compared with those results obtained from a semi-infinite tissue model for layered structures. This improvement is mainly attributed to the more accurate estimation of background optical properties and more accurate estimation of weight matrix for imaging reconstruction by considering the light propagation effect in the second layer. Clinical results of breast lesions are also presented to demonstrate the utility of this new imaging algorithm.
Shallow lesions less than 1.5-cm deep are frequently seen in breast patients when they are scanned in reflection geometry. Two boundary conditions are compared for imaging shallow lesions, and a new probe design is introduced. A partial reflection boundary condition is suitable for imaging shallow lesions less than 1.0-cm deep; whereas an absorption boundary condition is desirable for imaging lesions more than 1.5-cm deep. Our new probe design incorporates either a partial reflection boundary or an absorption boundary based on a priori knowledge of lesion depth provided by coregistered real-time ultrasound images. An angled source is introduced to further improve the illumination of the region between 1.0- to 1.5-cm depths. Simulation, phantom, and freshly excised mouse tumor experiments demonstrate that targets located at different depths can be uniformly reconstructed. A clinical example is given to demonstrate the utility of this new approach for optimally probing lesions located at different depths.
A typical perturbation-based image reconstruction technique requires a homogeneous
reference for accurate estimation of target-caused perturbation and accurate
reconstruction of target optical properties. Therefore reference selection is critical. In
this report, we analyze the influence of different references on reconstructed optical
images when a typical perturbation approach, such as Born method, is used for imaging
reconstruction. A new photon tracking method using Monte Carlo simulation is
developed and used to analyze the contributions of a target and a chest-wall layer
underneath the breast tissue to the NIR measurements. We have found that a chest-wall
layer has much larger contribution than the target when the breast-tissue layer thickness
is less than 1.5 to 2.0 cm deep depending on bulk optical properties. Different references,
such as optical property-matched and depth-unmatched reference, depth-matched and
property-unmatched reference, property-unmatched and depth-unmatched reference, and
property-matched and depth-matched reference, are compared and evaluated using the
total perturbation and the reconstructed image quality as quantitative criteria. We have
found that the property-matched and depth-matched reference provides the best result
with error less than 5%, and the depth-matched and property-unmatched reference
provides the worst results with error larger than 60%. Phantom experiments confirm with
the simulation results. As results, we suggest using the measurements from a normal
contralateral site of the same quadrant as the breast lesion with matched propagation
depth as best property-matched and depth-matched reference with the help of co-registered
ultrasound in clinical trials.
Shallow breast lesions less than 1.0 cm deep are frequently seen in patients when they are
scanned in a supine position by a hand-held combined ultrasound and optical probe.
Reflection boundary condition is suitable for imaging shallow lesions, but it is not
sensitive enough for imaging lesions deeper than 1.0 cm. The absorption boundary
condition is more desirable for imaging deeper lesions. However, it is less sensitive to
shallower lesions unless the optical sources are positioned right on top of the lesion
which is unknown in general. To solve this problem, we have designed a new probe
which incorporates three angled sources to improve the illumination of the shallow region
underneath the co-registered ultrasound probe. Monte Carlo method is extended to
include an absorber in the medium and used to evaluate the analytical results.
Simulations have shown that the combination of tilted and peripherally located sources
can improve reconstruction compared with the probe with no tilted sources. Phantom
experiments agree with simulation results.
In this report, clinical examples of using combined ultrasound and optical diffused wave technique to image tumor total hemoglobin concentration and tumor hypoxia are given. These examples demonstrate that the sensitivity and specificity of using tumor hemoglobin level as diagnostic index are much higher than that of tumor
hypoxia.
Angiogenesis in advanced breast cancers is highly distorted and heterogeneous. Non-invasive imaging that can monitor angiogenesis may be invaluable for assessing tumor response to treatment. By combining ultrasound and near infrared optical imaging, a reliable new technique has emerged for predicting tumor angiogenesis within the breast.
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