The purpose of this study is to develop an alternate empirical approach to estimate near-infra-red (NIR) photon propagation and quantify optically induced drug release in brain metastasis, without relying on computationally expensive Monte Carlo techniques (gold standard). Targeted drug delivery with optically induced drug release is a noninvasive means to treat cancers and metastasis. This study is part of a larger project to treat brain metastasis by delivering lapatinib-drug-nanocomplexes and activating NIR-induced drug release. The empirical model was developed using a weighted approach to estimate photon scattering in tissues and calibrated using a GPU based 3D Monte Carlo. The empirical model was developed and tested against Monte Carlo in optical brain phantoms for pencil beams (width 1mm) and broad beams (width 10mm). The empirical algorithm was tested against the Monte Carlo for different albedos along with diffusion equation and in simulated brain phantoms resembling white-matter (μs’=8.25mm-1, μa=0.005mm-1) and gray-matter (μs’=2.45mm-1, μa=0.035mm-1) at wavelength 800nm. The goodness of fit between the two models was determined using coefficient of determination (R-squared analysis). Preliminary results show the Empirical algorithm matches Monte Carlo simulated fluence over a wide range of albedo (0.7 to 0.99), while the diffusion equation fails for lower albedo. The photon fluence generated by empirical code matched the Monte Carlo in homogeneous phantoms (R2=0.99). While GPU based Monte Carlo achieved 300X acceleration compared to earlier CPU based models, the empirical code is 700X faster than the Monte Carlo for a typical super-Gaussian laser beam.
Purpose: The objective is to develop a multivariate in vivo hemodynamic model of tissue oxygenation
(MiHMO2) based on 3D photoacoustic spectroscopy.
Introduction: Low oxygen levels, or hypoxia, deprives cancer cells of oxygen and confers resistance to
irradiation, some chemotherapeutic drugs, and oxygen-dependent therapies (phototherapy) leading to
treatment failure and poor disease-free and overall survival. For example, clinical studies of patients with
breast carcinomas, cervical cancer, and head and neck carcinomas (HNC) are more likely to suffer local
reoccurrence and metastasis if their tumors are hypoxic. A novel method to non invasively measure tumor
hypoxia, identify its type, and monitor its heterogeneity is devised by measuring tumor hemodynamics,
MiHMO2.
Material and Methods: Simulations are performed to compare tumor pO2 levels and hypoxia based on
physiology - perfusion, fractional plasma volume, fractional cellular volume - and its hemoglobin status -
oxygen saturation and hemoglobin concentration - based on in vivo measurements of breast, prostate, and
ovarian tumors. Simulations of MiHMO2 are performed to assess the influence of scanner resolutions and
different mathematic models of oxygen delivery.
Results: Sensitivity of pO2 and hypoxic fraction to photoacoustic scanner resolution and dependencies on
model complexity will be presented using hemodynamic parameters for different tumors.
Conclusions: Photoacoustic CT spectroscopy provides a unique ability to monitor hemodynamic and
cellular physiology in tissue, which can be used to longitudinally monitor tumor oxygenation and its
response to anti-angiogenic therapies.
Purpose: Our purpose is to develop and test a molecular probe that can detect the expression of neutropilin-1 receptor
(NPR-1) in vivo using fluorescence imaging and photoacoustic spectroscopy.
Introduction: NPR-1 is expressed on endothelial cells and some breast cancer cells, and binds to vascular endothelial
growth factor VEGF165, a growth factor associated with pathological tumor angiogenesis. This receptor is coexpressed
with VEGFR2 and shown to enhance the binding of VEGF165; therefore, it has the potential to be used as a
marker of angiogenic activity and targeted for therapy.
Material and Methods: A peptide specific to NPR-1 receptor was synthesized and conjugated to a NIR fluorochrome
(IRDye800CW) and was intravenously injected into mice with breast tumors (MCF7VEGF). Probe kinetics was
monitored in vivo via near infrared fluorescence (NIRF) within an optical imager for up to 72 hours within the tumor
and compared to other organs (liver, muscle) for binding specificity. A multivariate fitting algorithm was used to
spectrally deconvolve the IRDye800CW from endogenous hemoglobin signature (hemoglobin concentration and
oxygen saturation).
Results: Dynamics of the NIR fluorescence signal within the first hour after injection indicates specific binding
compared to muscle, with an average tumor-to-muscle ration of 2.00 (+/- 0.27). Spectral analysis clearly indentified
the presence of the NPR-1 probe. Based on calibration data, the average tumor concentration from both NIRF and
PCT-S was measured to be ~200-300nM.
Conclusion: These preliminary results show the capability of PCT to image an exogenous probe in vivo in addition to
its hemoglobin state.
KEYWORDS: Tumors, Spectroscopy, Photoacoustic spectroscopy, Oxygen, Luminescence, Near infrared, In vivo imaging, Scanners, Data acquisition, Near infrared spectroscopy
Purpose: The purpose of this study is to determine the feasibility of using photacoustic CT spectroscopy(PCT-s) to track
a near infrared dye conjugated with trastuzumab in vivo.
Materials and Methods: An animal model was developed which contained both high and low Her2 expression tumor
xenografts on the same mouse. The tumors were imaged at multiple wavelengths (680- 950nm) in the PCT scanner one
day prior to injection of the near infrared conjugated probe. Baseline optical imaging data was acquired and the probe
was then injected via the tail vein. Fluorescence data was acquired over the next week, PCT spectroscopic data was also
acquired during this timeframe. The mice were sacrificed and tumors were extirpated and sent to pathology for IHC
staining to verify Her2 expression levels. The optical fluorescence images were analyzed to determine probe uptake
dynamics. Reconstructed PCT spectroscopic data was analyzed using IDL routines to deconvolve the probe signal from
endogenous background signals, and to determine oxygen saturation.
Results: The location of the NIR conjugate was able to be identified within the tumor utilizing IDL fitting routines, in
addition oxygen saturation, and hemoglobin concentrations were discernible from the spectroscopic data.
Conclusion: Photacoustic spectroscopy allows for the determination of in vivo tumor drug delivery at greater depths than
can be determined from optical imaging techniques.
Purpose: The purpose of this study is to calibrate the PCT scanner to quantify the hemoglobin status utilizing a blood
flow phantom.
Materials and Methods: A blood circulation system was designed and constructed to control the oxygen saturation and
hemoglobin concentration of blood. As a part of the circulation system, a 1.1mm FEP tube was placed in the center of
imaging tank of PCT scanner as the imaging object. Photoacoustic spectra (690-950 nm) was acquired for different
hemoglobin concentrations (CtHb) and oxygen saturation levels (SaO2), where the formers was formed by diluting
blood samples with PBS and the latter by mixing blood with gases at different oxygen content. Monte Carlo simulations
were performed to calculate the photon energy depositions in the phantom tube, which took into account photon losses in
water and blood. A Kappa value which represents the energy transfer efficiency of hemoglobin molecule was calculated
based on the PCT measurement and simulation result. The final SaO2 value of each blood sample was calculated based
on the PCT spectrum and Kappa value. These oxygen saturation results were compared with co-oximeter measurements
to obtain systematic errors.
Results and Conclusion: The statistic error of calculating Kappa value from hemoglobin concentration experiment was
less than 5%. The systematic error between PCT spectra analysis and co-oximeter analysis for hemoglobin oxygen
saturation was -4.5%. These calibration techniques used to calculate Kappa and hemoglobin absorption spectra would be
used in hypoxia measurements in tumors as well as for endogenous biomarkers studies.
Purpose: The purpose of this study is to use PCT spectroscopy scanner to monitor the hemoglobin concentration and
oxygen saturation change of living mouse by imaging the artery and veins in a mouse tail.
Materials and Methods: One mouse tail was scanned using the PCT small animal scanner at the isosbestic wavelength
(796nm) to obtain its hemoglobin concentration. Immediately after the scan, the mouse was euthanized and its blood was
extracted from the heart. The true hemoglobin concentration was measured using a co-oximeter. Reconstruction
correction algorithm to compensate the acoustic signal loss due to the existence of bone structure in the mouse tail was
developed. After the correction, the hemoglobin concentration was calculated from the PCT images and compared with
co-oximeter result. Next, one mouse were immobilized in the PCT scanner. Gas with different concentrations of oxygen
was given to mouse to change the oxygen saturation. PCT tail vessel spectroscopy scans were performed 15 minutes
after the introduction of gas. The oxygen saturation values were then calculated to monitor the oxygen saturation change
of mouse.
Results: The systematic error for hemoglobin concentration measurement was less than 5% based on preliminary
analysis. Same correction technique was used for oxygen saturation calculation. After correction, the oxygen saturation
level change matches the oxygen volume ratio change of the introduced gas.
Conclusion: This living mouse tail experiment has shown that NIR
PCT-spectroscopy can be used to monitor the oxygen
saturation status in living small animals.
Purpose: The purpose of this study is to monitor in vivo the IR dose dependent response of NF-κB and tumor
hemodynamics as a function of time.
Material and Methods: An MDA-231 breast cancer cell line was stably transfected with a firefly luciferase gene
within the NF-kappaB promoter. Tumors on the right flank irradiated with a single fractionated dose of 5Gy or 10Gy.
Over two weeks, photoacoustic spectroscopy (PCT-S), bioluminescence imaging (BLI), and dynamic contrast
enhanced CT (DCE-CT) was used to monitor hemoglobin status, NF-kappaB expression, and physiology, respectively.
Results: From the BLI, an increase in NF-kappaB expression was observed in both the right (irradiation) and left (nonirradiated)
tumors, which peaked at 8-12 hours, returned to basal levels after 24 hours, and increased a second time
from 3 to 7 days. This data identifies both a radiation-induced bystander effect and a bimodal longitudinal response
associated with NF-κB-controlled luciferase promoter. The physiological results from DCE-CT measured an increase
in perfusion (26%) two days after radiation and both a decrease in perfusion and an increase in fp by week 1 (10Gy
cohort). PCT-S measured increased levels of oxygen saturation two days post IR, which did not change after 1 week.
Initially, NF-κB would modify hemodynamics to increase oxygen delivery after IR insult. The secondary response
appears to modulate tumor angiogenesis.
Conclusions: A bimodal response to radiation was detected with NF-kappaB-controlled luciferase reporter with a
concomitant hemodynamic response associated with tumor hypoxia. Experiments are being performed to increase
statistics.
Purpose: The purpose of this study is to develop a new 3-D iterative Monte Carlo algorithm to recover the
heterogeneous distribution of molecular absorbers with a solid tumor.
Introduction: Spectroscopic imaging (PCT-S) has the potential to identify a molecular species and quantify its
concentration with high spatial fidelity. To accomplish this task, tissue attenuation losses during photon propagation in
heterogeneous 3D objects is necessary. An iterative recovery algorithm has been developed to extract 3D
heterogeneous parametric maps of absorption coefficients implementing a MC algorithm based on a single source
photoacoustic scanner and to determine the influence of the reduced scattering coefficient on the uncertainty of
recovered absorption coefficient.
Material and Methods: This algorithm is tested for spheres and ellipsoids embedded in simulated mouse torso with
optical absorption values ranging from 0.01-0.5/cm, for the same objects where the optical scattering is unknown
(μs'=7-13/cm), and for a heterogeneous distribution of absorbers.
Results: Systemic and statistical errors in ma with a priori knowledge of μs' and g are <2% (sphere) and <4%
(ellipsoid) for all ma and without a priori knowledge of ms' is <3% and <6%. For heterogenenous distributions of ma,
errors are <4% and <5.5% for each object with a prior knowledge of ms' and g, and to 7 and 14% when μs' varied
from 7-13/cm.
Conclusions: A Monte Carlo code has been successfully developed and used to correct for photon propagation effects
in simulated objects consistent with tumors.
We have designed and built a prototype PCT (photoacoustic CT) scanner suitable for small animal imaging that acquires
a sparse set of 128 photoacoustic, radial "projections" uniformly distributed over the surface of a hemisphere in response
to optical absorption from a tunable, pulsed NIR (near-infrared) laser. Acquisition of a denser set of projections is
achieved by rotating the hemispherical array about its vertical axis and acquiring additional, interleaved projections.
Each detector in the array is a 3-mm diameter, piezo-composite with a center frequency of 5 MHz and 70% bandwidth.
Spatial resolution is < 300 μm and nearly isotropic, owing to the array geometry. Preliminary results acquired at half of
the allowable laser power and with no system optimizations show a low contrast sensitivity sufficient to detect a 350 nM
concentration of a NIR-absorbing organic dye embedded in 12.5 mm of soft tissue. This scanner design will allow our
group to take advantage of HYPR (HighlY constrained backPRojection) reconstruction techniques, which can
significantly improve temporal (or spectral) resolution, without sacrificing signal-to-noise or spatial resolution. We will
report how these accelerated reconstruction techniques can be implemented with this PCT scanner design. Using this
approach, we may be able to achieve 100-ms temporal resolution for dynamic studies throughout a 20-mm-diameter
imaging volume.
KEYWORDS: Monte Carlo methods, Tumors, Blood, Photoacoustic spectroscopy, Absorption, Near infrared, Tissue optics, Photon transport, Acoustics, Signal attenuation
Purpose: The purpose of this study is to evaluate the influence of photon propagation on the NIR spectral features associated with photoacoustic imaging.
Introduction: Photoacoustic CT spectroscopy (PCT-S) has the potential to identify molecular properties of tumors while overcoming the limited depth resolution associated with optical imaging modalities (e.g., OCT and DOT). Photoacoustics is based on the fact that biological tissue generates high-frequency acoustic signals due to volume of expansion when irradiated by pulsed light. The amplitude of the acoustic signal is proportional to the optical absorption properties of tissue, which varies with wavelength depending on the molecular makeup of the tissue. To obtain quantifiable information necessitate modeling and correcting for photon and acoustic propagation in tumors.
Material and Methods: A Monte Carlo (MC) algorithm based on MCML (Monte Carlo for Multi-Layered edia) has been developed to simulate photon propagation within objects comprised of a series of complex 3D surfaces (Mcml3D). This code has been used to simulate and correct for the optical attenuation of photons in blood, and for subcutaneous tumors with homogenous and radially heterogeneous vascular distributions.
Results: The NIR spectra for oxygenated and deoxygenated blood as determined from Monte Carlo simulated photoacoustic data matched measured data, and improving oxygen saturation calculations. Subcutaneous tumors with a homogeneous and radially heterogeneous distribution of blood revealed large variations in photon absorption as a function of the scanner projection angle. For select voxels near the periphery of the tumor, this angular profile between the two different tumors appeared similar.
Conclusions: A Monte Carlo code has been successfully developed and used to correct for photon propagation effects in blood phantoms and restoring the integrity of the NIR spectra associated with oxygenated and deoxygenated blood. This code can be used to simulate the influence of intra-tumor heterogeneity on the molecular identification via NIR spectroscopy.
Purpose: The purpose of this study is to calibrate the PCT small animal scanner system with a blood phantom and to measure the blood hemoglobin concentration and oxygen saturation level in mouse tail vein and tumors.
Methods and Materials: A blood phantom with variable blood flow and oxygen content was integrated into the PCT scanner with a circulation system. The circulation system consisted of a pump, an oxygen electrode detector and a tonometer. The SaO2 values were determined based on a linear combination model of oxy-hemoglobin and deoxy-hemoglobin absorption spectrum curves. Hemoglobin concentration (CHb) was determined by measuring the linear relationship for different blood dilutions. SaO2 and CHb as measured in vivo for the artery and vein in a mouse tail were also measured.
Results: The PCT spectra of blood phantom samples were measured and compared with hemoglobin optical absorption spectra. The linear relationship between hemoglobin concentration and PCT intensities were observed by phantom study. The hemoglobin concentration of mouse is ~9.7g/dL. The saturation difference between arteries and veins in mouse tail is also measured by PCT scan.
Conclusions: Both the phantom and living mouse tail vessel scans have shown that NIR PCT-spectroscopy can be used to measure the hemoglobin saturation level and hemoglobin concentration in small animal for future tumor hypoxia study.
Purpose: To evaluate photoacoustic CT spectroscopy (PCT-S) and dynamic contrast-enhanced CT (DCE-CT) ability to measure parameters - oxygen saturation and vascular physiology - associated with the intra-tumor oxygenation status.
Material and Methods: Breast (VEGF165 enhance MCF-7) and ovarian (SKOV3x) cancer cells were implanted into the fat pads and flanks of immune deficient mice and allowed to grow to a diameter of 8-15 mm. CT was used to determine physiological parameters by acquiring a sequence of scans over a 10 minute period after an i.v. injection of a radio-opaque contrast agent (Isovue). These time-dependent contrast-enhanced curves were fit to a two-compartmental model determining tumor perfusion, fractional plasma volume, permeability-surface area produce, and fractional interstitial volume on a voxel-by-voxel basis. After which, the tumors were imaged using photoacoustic CT (Optosonics, Inc., Indianapolis, IN 46202). The near infrared spectra (700-910 nm) within the vasculature was fit to linear combination of measured oxy- and deoxy-hemoglobin blood samples to obtain oxygen saturation levels (SaO2).
Results: The PCT-S scanner was first calibrated using different samples of oxygenated blood, from which a statistical error ranging from 2.5-6.5% was measured and a plot of the hemoglobin dissociation curve was consistent with empirical formula. In vivo determination of tumor vasculature SaO2 levels were measurably tracked, and spatially correlated to the periphery of the tumor. Tumor depend variations in SaO2 - 0.32 (ovarian) and 0.60 (breast) - and in vascular physiology - perfusion, 1.03 and 0.063 mL/min/mL, and fractional plasma volume, 0.20 and 0.07 - were observed.
Conclusion: Combined, PCT-S and CED-CT has the potential to measure intra-tumor levels of tumor oxygen saturation and vascular physiology, key parameters associated with hypoxia.
Initial animal study for quantifying myocardial physiology through contrast-enhanced dynamic x-ray CT suggested that beam hardening is one of the limiting factors for accurate regional physiology measurement. In this study, a series of simulations were performed to investigate its deterioration effects and two correction algorithms were adapted to evaluate for their efficiency in improving the measurements.
The simulation tool consists of a module simulating data acquisition of a real polyenergetic scanner system and a heart phantom consisting of simple geometric objects representing ventricles and myocardium. Each phantom component was modeled with time-varying attenuation coefficients determined by ideal iodine contrast dynamic curves obtained from experimental data or simulation. A compartment model was used to generate the ideal myocardium contrast curve using physiological parameters consistent with measured values. Projection data of the phantom were simulated and reconstructed to produce a sequence of simulated CT images. Simulated contrast dynamic curves were fitted to the compartmental model and the resultant physiological parameters were compared with ideal values to estimate the errors induced by beam hardening artifacts.
The simulations yielded similar deterioration patterns of contrast dynamic curves as observed in the initial study. Significant underestimation of left ventricle curves and corruption of regional myocardium curves result in systematic errors of regional perfusion up to approximately 24% and overestimates of fractional blood volume (fiv) up to 13%. The correction algorithms lead to significant improvement with errors of perfusion reduced to 7% and errors of fiv within 2% which shows promise for more robust myocardial physiology measurement.
Purpose: The purpose of this study is to evaluate PCT Imaging technique to classify tissue and extract kidney cysts in pcy mice model of human adolescent nephronophthisis. Method: Four mice with late stages of nephronophthisis with polycystic kidney disease-PKD and one normal mouse were scanned in the PCT Small Animal Scanner. Both vivo and ex-vivo images of mice kidney were taken at wavelength from 680 nm to 940 nm. The ex-vivo PCT images were compared with histology photographs to check the sensitivity of detecting cysts. Histograms of kidney images were generated over slices and fitted to Gaussian-curve model for volumetric analysis. The portions of cysts in kidneys were estimated and kidney images were segmented by three different colors to present the distribution of different tissues. Result: A good correspondence between PCT imaging findings and PKD histology result was observed. Histogram curves from images of pcy kidneys and normal kidneys were fitted to Gaussian-curve model. Portions of cysts, parenchyma and area of high level hemoglobin were estimated according to the curve fit result. A growth of cysts associated with relatively volume decrease of parenchyma and tissues with high perfusion of hemoglobin was observed. Conclusion: The PCT enabled visualization of renal cysts for mouse model and had the potential for volumetric measurements of kidney.
Purpose. To evaluate photoacoustic spectroscopy as a potential imaging modality capable of measuring intra-tumor heterogeneity and spectral features associated with hemoglobin and the molecular probe indocyanine green (ICG). Material and Methods. Immune deficient mice were injected with wildtype and VEGF enhanced MCF-7 breast cancer cells or SKOV3x ovarian cancer cells, which were allowed to grow to a size of 6-12 mm in diameter. Two mice were imaged alive and after euthanasia for (oxy/deoxy)-hemoglobin content. A 0.4 mL volume of 1 μg/mL concentration of ICG was injected into the tail veins of two mice prior to imaging using the photoacoustic computed tomography (PCT) spectrometer (Optosonics, Inc., Indianapolis, IN 46202) scanner. Mouse images were acquired for wavelengths spanning 700-920 nm, after which the major organs were excised, and similarly imaged. A histological study was performed by sectioning the organ and optically imaging the fluorescence distribution. Results. Calibration of PCT-spectroscopy with different samples of oxygenated blood reproduced a hemoglobin dissociation curve consistent with empirical formula with an average error of 5.6%. In vivo PCT determination of SaO2 levels within the tumor vascular was measurably tracked, and spatially correlated to the periphery of the tumor. Statistical and systematic errors associated with hypoxia were estimated to be 10 and 13%, respectively. Measured ICG concentrations determined by contrast-differential PCT images in excised organs (tumor, liver) were approximately 0.8 μg/mL, consistent with fluorescent histological results. Also, the difference in the ratio of ICG concentration in the gall bladder-to-vasculature between the mice was consistent with excretion times between the two mice. Conclusion. PCT spectroscopic imaging has shown to be a noninvasive modality capable of imaging intra-tumor heterogeneity of (oxy/deoxy)-hemoglobin and ICG in vivo, with an estimated error in SaO2 at 17% and in ICG at 0.8 μg/mL in excised tissue. Ongoing development of spectroscopic analysis techniques, probe development, and calibration techniques are being developed to improve sensitivity to both exogenous molecular probes and (oxy/deoxy)-hemoglobin fraction.
Purpose: The purpose of this study is to evaluate multi-slice computed tomography technology to quantify functional and physiologic changes in rats with pulmonary emphysema. Method: Seven rats were scanned using a 16-slice CT (Philips MX8000 IDT) before and after artificial inducement of emphysema. Functional parameters i.e. lung volumes were measured by non-contrast spiral scan during forced breath-hold at inspiration and expiration followed by image segmentation based on attenuation threshold. Dynamic CT imaging was performed immediately following the contrast injection to estimate physiology changes. Pulmonary perfusion, fractional blood volume, and mean transit times (MTTs) were estimated by fitting the time-density curves of contrast material using a compartmental model. Results: The preliminary results indicated that the lung volumes of emphysema rats increased by 3.52±1.70mL (p<0.002) at expiration and 4.77±3.34mL (p<0.03) at inspiration. The mean lung densities of emphysema rats decreased by 91.76±68.11HU (p<0.01) at expiration and low attenuation areas increased by 5.21±3.88% (p<0.04) at inspiration compared with normal rats. The perfusion for normal and emphysema rats were 0.25±0.04ml/s/ml and 0.32±0.09ml/s/ml respectively. The fractional blood volumes for normal and emphysema rats were 0.21±0.04 and 0.15±0.02. There was a trend toward faster MTTs for emphysema rats (0.42±0.08s) than normal rats (0.89±0.19s) with p<0.006, suggesting that blood flow crossing the capillaries increases as the capillary volume decreases and which may cause the red blood cells to leave the capillaries incompletely saturated with oxygen if the MTTs become too short. Conclusion: Quantitative measurement using CT of structural and functional changes in pulmonary emphysema appears promising for small animals.
The purpose of this study is to demonstrate that dynamic CT provides the necessary sensitivity to quantify tumor physiology and differences in chemotherapeutic response. A compartmental mouse model utilizing measured contrast-enhanced dynamic CT scans is used to simulate systematic and statistical errors associated with tumor physiology: perfusion, permeability (PS), fractional plasma volume (fp), and fractional interstitial volume. The solute utilized is a small molecular weight radio-opaque contrast agent (isovue). For such an intravascular-interstitial medium, the kinematics simplifies to a two compartmental diffusive dominated set of coupled differential equations. Each combination of physiological parameters is repeatedly simulated fifteen times from which statistical errors calculated. The fractional change relative to the true value (systematic error) and standard deviation (statistical error) are plotted as a function of PS, fp, scanner temporal resolution and noise, and contrast media injection rates. By extrapolating from experimental data found in literature, a relative change in PS and fp of approximately 40% is required. Thus, the longitudinal response of two chemotherapeutic drugs under investigation - proteasome and IMPDH inhibitors - are hypothesized to induce different physiological responses. The first set of simulations varies PS from 0.05 to 0.40 mL/min/mL and fp from 0.01 to 0.07 mL/mL while holding all other physiological parameters constant. Errors in PS remain below 3% while statistical errors for fp increase significantly as the volume decreases toward 1-2%: errors remain less than 6% for fp>0.03 while increasing to above 15% for fp<0.02. The second set of simulations are performed quantifying the relationship between scanner temporal resolution and contrast media injection rate for various tumor permeabilities. For the majority of cases, the errors remain below 5%. As PS approaches perfusion, a total error less than 6% can be maintained for a temporal resolution less than or equal to 3 seconds, and an error less than 9% up to 5-7 seconds. As the injection rate decreases from 2 mL/min down to 0.25 mL/min, inadequate sampling of the contrast dynamics necessary to decouple the physiological parameters is lost increasing both systematic and statistical errors from 10% when sampling at 5 seconds in excess of 20-25% at a 9 second sampling rate. In each case, dynamic CT provides the necessary sensitivity to distinguish between the differing therapeutic reponses of proteasome and IMPDH inhibitors.
High-speed X-ray computed tomography (CT) has the potential to observe the transport of iodinated radio-opaque contrast agent (CA) through tissue enabling the quantification of tissue physiology in organs and tumors. The concentration of Iodine in the tissue and in the left ventricle is extracted as a function of time and is fit to a compartmental model for physiologic parameter estimation. The reproducibility of the physiologic parameters depend on the (1) The image-sampling rate. According to our simulations 5-second sampling is required for CA injection rates of 1.0ml/min (2) the compartmental model should reflect the real tissue function to give meaning results. In order to verify these limits a functional CT study was carried out in a group of 3 mice. Dynamic CT scans were performed on all the mice with 0.5ml/min, 1ml/min and 2ml/min CA injection rates. The physiologic parameters were extracted using 4 parameter and 6 parameter two compartmental models (2CM). Single factor ANOVA did not indicate a significant difference in the perfusion, in the kidneys for the different injection rates. The physiologic parameter obtained using the 6-parameter 2CM model was in line with literature values and the 6-parameter significantly improves chi-square goodness of fits for two cases.
Purpose: To evaluate whether functional multi-slice computed tomography (MSCT) can identify regional areas of normally perfused and ischemic myocardium in a porcine model.
Material and Methods: Three out bred pigs, two of which had ameroids surgically implanted to constrict flow within the LAD and LCx coronary arteries, were injected with 25 mL of iopromide (Isovue) at a rate of 5 mL/second via the femoral or jugular vein. Sixty axial scans along the short axis of the heart was acquired on a 16-slice CT scanner (Philips MX8000-IDT) triggered at end-diastole of the cardiac cycle and acquiring an image within 270 msec. A second series of scans were taken after an intravenous injection of a vasodilator, 150 μg/kg/min of adenosine. ROIs were drawn around the myocardial tissue and the resulting time-density curves were used to extract perfusion values.
Results: Determination of the myocardial perfusion and fractional blood volume implementing three different perfusion models. A 5-point averaging or 'smoothing' algorithm was employed to effectively filter the data due to its noisy nature. The (preliminary) average perfusion and fractional blood volume values over selected axial slices for the pig without an artificially induced stenosis were measured to be 84 ± 22 mL/min/100g-tissue and 0.17 ± 0.04 mL/g-tissue, the former is consistent with PET scan and EBCT results. The pig with a stenosis in the left LAD coronary artery showed a reduced global perfusion value -- 45 mL/min/100g-tissue. Correlations in regional perfusion values relative to the stenosis were weak. During the infusion of adenosine, averaged perfusion values for the three subjects increased by 46 (±45) percent, comparable to increases measured with PET.
Conclusion: Quantifying global perfusion values using MDCT appear encouraging. Future work will focus resolving the systematic effects from noise due to signal fluctuation from the porcine tachyardia (80-93 BPM) and provide a more robust measurement of regional myocardial perfusion throughout the heart.
Micro-computed tomography (microCT) is capable of obtaining high-resolution images of skeletal tissues. However its image contrast among soft tissues remains inadequate for tumor detection. High speed functional computed tomography will be needed to image tumors by employing x-ray contrast medium. The functional microCT development will not only facilitate the image contrast enhancement among different tissues but also provide information of tumor physiology. To demonstrate the feasibility of functional CT in mouse imaging, sequential computed tomography is performed in mice after contrast material administration using a high-speed clinical CT scanner. Although the resolution of the clinical scanner is not sufficient to dissolve the anatomic details of rodents, bulky physiological parameters in major organs such as liver, kidney, pancreas, and ovaries (testicular) can be examined. For data analysis, a two-compartmental model is employed and implemented to characterize the tissue physiological parameters (regional blood flow, capillary permeability, and relative compartment volumes.) The measured contrast dynamics in kidneys are fitted with the compartmental model to derive the kidney tissue physiology. The study result suggests that it is feasible to extract mouse tissue physiology using functional CT imaging technology.
We have completed the design and testing of a thermoacoustic computed tomography scanner for whole-breast imaging. We report on the technical changes in this design form our previous TCT scanner, and how these design changes have improved image quality. Improvements to the design include: greater angular coverage of TCT measurements, increased sensitivity of the ultrasound detector array, and improved delivery of radio wave energy. These improvements resulted in higher fidelity 3D reconstructions, reduced scan time, and fewer image artifacts. These improvements were documented by imaging simple, 3D phantoms, formulated from salinated agar spheres. We confirmed improvements in breast image quality by comparing images of patient volunteers taken with our previous TCT scanner and this new TCT scanner.
Measurement and signal intelligence of the battlespace has created new requirements in information management, communication and interoperability as they effect surveillance and situational awareness. In many situations, stand-off remote-sensing and hazard-interdiction techniques over realistic operational areas are often impractical and difficult to characterize. An alternative approach is to implement adaptive remote-sensing techniques with swarms of mobile agents employing collective behavior for optimization of mapping signatures and positional orientation (registration). We have expanded intelligent control theory using physics-based collective behavior models and genetic algorithms to produce a uniquely powerful implementation of distributed ground-based measurement incorporating both local collective behavior, and niter-operative global optimization for sensor fusion and mission oversight. By using a layered hierarchical control architecture to orchestrate adaptive reconfiguration of semi-autonomous robotic agents, we can improve overall robustness and functionality in dynamic tactical environments without information bottlenecking.
Recent attention has been given to the deployment of an adaptable sensor array realized by multi-robotic systems (or swarms). Our group has been studying the collective, autonomous behavior of these such systems and their applications in the area of remote-sensing and emerging threats. To accomplish such tasks, an interdisciplinary research effort at Sandia National Laboratories are conducting tests in the fields of sensor technology, robotics, and multi- agents architectures. Our goal is to coordinate a constellation of point sensors using unmanned robotic vehicles (e.g., RATLERs, Robotic All-Terrain Lunar Exploration Rover- class vehicles) that optimizes spatial coverage and multivariate signal analysis. An overall design methodology evolves complex collective behaviors realized through local interaction (kinetic) physics and artificial intelligence. Learning objectives incorporate real-time operational responses to environmental changes. This paper focuses on our recent work understanding the dynamics of many-body systems according to the physics-based hydrodynamic model of lattice gas automata. Three design features are investigated. One, for single-speed robots, a hexagonal nearest-neighbor interaction topology is necessary to preserve standard hydrodynamic flow. Two, adaptability, defined by the swarm's rate of deformation, can be controlled through the hydrodynamic viscosity term, which, in turn, is defined by the local robotic interaction rules. Three, due to the inherent nonlinearity of the dynamical equations describing large ensembles, stability criteria ensuring convergence to equilibrium states is developed by scaling information flow rates relative to a swarm's hydrodynamic flow rate. An initial test case simulates a swarm of twenty-five robots maneuvering past an obstacle while following a moving target. A genetic algorithm optimizes applied nearest-neighbor forces in each of five spatial regions distributed over the simulation domain. Armed with this knowledge, the swarm adapts by changing state in order to avoid the obstacle. Simulation results are qualitatively similar to a lattice gas.
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