Xinming Liu

Size and shape effects in the biodistribution of intravascularly injected particles

Understanding how size and shape can affect the biodistribution of intravascularly injected particles is of fundamental importance both for the rational design of delivery systems and from a standardization and regulatory view point. In this work, uncoated silica spherical beads, with a diameter ranging from 700 nm to 3 microm, and uncoated non-spherical silicon-based particles, with quasi-hemispherical, cylindrical and discoidal shapes, have been injected into tumor bearing mice. The number of particles accumulating in the major organs and within the tumor mass has been measured through elemental silicon (Si) analysis. For the spherical beads, it has been found that the number of particles accumulating in the non-RES organs reduces monotonically as the diameter d increases, suggesting the use of smaller particles to provide a more uniform tissue distribution. However, discoidal particles have been observed to accumulate more than others in most of the organs but the liver, where cylindrical particles are deposited at a larger extent. These preliminary results support the notion of using sub-micrometer discoidal particles as intravascular carriers to maximize accumulation in the target organ whilst reducing sequestration by the liver.

The effect of shape on the margination dynamics of non-neutrally buoyant particles in two-dimensional shear flows

The margination dynamics of microparticles with different shapes has been analyzed within a laminar flow mimicking the hydrodynamic conditions in the microcirculation. Silica spherical particles, quasi-hemispherical and discoidal silicon particles have been perfused in a parallel plate flow chamber. The effect of the shape and density on their margination propensity has been investigated at different physiologically relevant shear rates S. Simple scaling laws have been derived showing that the number n of marginating particles scales as S(-0.63) for the spheres; S(-0.85) for discoidal and S(-1) for quasi-hemispherical particles, regardless of their density and size. Within the range considered for the shear rate, discoidal particles marginate in a larger number compared to quasi-hemispherical and spherical particles. These results may be of interest in drug delivery and bio-imaging applications, where particles are expected to drift towards and interact with the walls of the blood vessels.

Comparison of an amorphous silicon/cesium iodide flat-panel digital chest radiography system with screen/film and computed radiography systems--a contrast-detail phantom study.

Flat-panel (FP) based digital radiography systems have recently been introduced as a new and improved digital radiography technology; it is important to evaluate and compare this new technology with currently widely used conventional screen/film (SF) and computed radiography (CR) techniques. In this study, the low-contrast performance of an amorphous silicon/cesium iodide (aSi/Csl)-based flat-panel digital chest radiography system is compared to those of a screen/film and a computed radiography system by measuring their contrast-detail curves. Also studied were the effects of image enhancement in printing the digital images and dependence on kVp and incident exposure. It was found that the FP system demonstrated significantly better low-contrast performance than the SF or CR systems. It was estimated that a dose savings of 70%-90% could be achieved to match the low-contrast performance of the FP images to that of the SF images. This dose saving was also found to increase with the object size. No significant difference was observed in low-contrast performances between the SF and CR systems. The use of clinical enhancement protocols for printing digital images was found to be essential and result in better low-contrast performance. No significant effects were observed for different kVps. From the results of this contrast-detail phantom study, the aSi/CsI-based flat-panel digital chest system should perform better under clinical situations for detection of low-contrast objects such as lung nodules. However, proper processing prior to printing would be essential to realizing this better performance.

In vivo evaluation of safety of nanoporous silicon carriers following single and multiple dose intravenous administrations in mice

Porous silicon (pSi) is being extensively studied as an emerging material for use in biomedical applications, including drug delivery, based on the biodegradability and versatile chemical and biophysical properties. We have recently introduced multistage nanoporous silicon microparticles (S1MP) designed as a cargo for nanocarrier drug delivery to enable the loaded therapeutics and diagnostics to sequentially overcome the biological barriers in order to reach their target. In this first report on biocompatibility of intravenously administered pSi structures, we examined the tolerability of negatively (-32.5±3.1mV) and positively (8.7±2.5mV) charged S1MP in acute single dose (10(7), 10(8), 5×10(8) S1MP/animal) and subchronic multiple dose (10(8) S1MP/animal/week for 4 weeks) administration schedules. Our data demonstrate that S1MP did not change plasma levels of renal (BUN and creatinine) and hepatic (LDH) biomarkers as well as 23 plasma cytokines. LDH plasma levels of 145.2±23.6, 115.4±29.1 vs. 127.0±10.4; and 155.8±38.4, 135.5±52.3 vs. 178.4±74.6 were detected in mice treated with 10(8) negatively charged S1MP, 10(8) positively charged S1MP vs. saline control in single and multiple dose schedules, respectively. The S1MPs did not alter LDH levels in liver and spleen, nor lead to infiltration of leukocytes into the liver, spleen, kidney, lung, brain, heart, and thyroid. Collectively, these data provide evidence of a safe intravenous administration of S1MPs as a drug delivery carrier.

An evaluation of three commercially available metal artifact reduction methods for CT imaging

Three commercial metal artifact reduction methods were evaluated for use in computed tomography (CT) imaging in the presence of clinically realistic metal implants: Philips O-MAR, GEs monochromatic gemstone spectral imaging (GSI) using dual-energy CT, and GSI monochromatic imaging with metal artifact reduction software applied (MARs). Each method was evaluated according to CT number accuracy, metal size accuracy, and streak artifact severity reduction by using several phantoms, including three anthropomorphic phantoms containing metal implants (hip prosthesis, dental fillings and spinal fixation rods). All three methods showed varying degrees of success for the hip prosthesis and spinal fixation rod cases, while none were particularly beneficial for dental artifacts. Limitations of the methods were also observed. MARs underestimated the size of metal implants and introduced new artifacts in imaging planes beyond the metal implant when applied to dental artifacts, and both the O-MAR and MARs algorithms induced artifacts for spinal fixation rods in a thoracic phantom. Our findings suggest that all three artifact mitigation methods may benefit patients with metal implants, though they should be used with caution in certain scenarios.

Visibility of microcalcification in cone beam breast CT: Effects of x-ray tube voltage and radiation dose

Mammography is the only technique currently used for detecting microcalcification (MC) clusters, an early indicator of breast cancer. However, mammographic images superimpose a three-dimensional compressed breast image onto two-dimensional projection views, resulting in overlapped anatomical breast structures that may obscure the detection and visualization of MCs. One possible solution to this problem is the use of cone beam computed tomography (CBCT) with a flat-panel (FP) digital detector. Although feasibility studies of CBCT techniques for breast imaging have yielded promising results, they have not shown how radiation dose and x-ray tube voltage affect the accuracy with which MCs are detected by CBCT experimentally. We therefore conducted a phantom study using a FP-based CBCT system with various mean glandular doses and kVp values. An experimental CBCT scanner was constructed with a data acquisition rate of 7.5 frames/s. 10.5 and 14.5 cm diameter breast phantoms made of gelatin were used to simulate uncompressed breasts consisting of 100% glandular tissue. Eight different MC sizes of calcium carbonate grains, ranging from 180-200 microm to 355-425 microm, were used to simulate MCs. MCs of the same size were arranged to form a 5 x 5 MC cluster and embedded in the breast phantoms. These MC clusters were positioned at 2.8 cm away from the center of the breast phantoms. The phantoms were imaged at 60, 80, and 100 kVp. With a single scan (360 degrees), 300 projection images were acquired with 0.5 x, 1x, and 2x mean glandular dose limit for 10.5 cm phantom and with 1x, 2x, and 4x for 14.5 cm phantom. A Feldkamp algorithm with a pure ramp filter was used for image reconstruction. The normalized noise level was calculated for each x-ray tube voltage and dose level. The image quality of the CBCT images was evaluated by counting the number of visible MCs for each MC cluster for various conditions. The average percentage of the visible MCs was computed and plotted as a function of the MGD, the kVp, and the average MC size. The results showed that the MC visibility increased with the MGD significantly but decreased with the breast size. The results also showed that the x-ray tube voltage affects the detection of MCs under different circumstances. With a 50% threshold, the minimum detectable MC sizes for the 10.5 cm phantom were 348(+/-2), 288(+/-7), 257(+/-2) microm at 3, 6, and 12 mGy, respectively. Those for the 14.5 cm phantom were 355 (+/-1), 307 (+/-7), 275 (+/-5) microm at 6, 12, and 24 mGy, respectively. With a 75% threshold, the minimum detectable MC sizes for the 10.5 cm phantom were 367 (+/-1), 316 (+/-7), 265 (+/-3) microm at 3, 6, and 12 mGy, respectively. Those for the 14.5 cm phantom were 377 (+/-3), 334 (+/-5), 300 (+/-2) microm at 6, 12, and 24 mGy, respectively.

A post-reconstruction method to correct cupping artifacts in cone beam breast computed tomography

In cone beam breast computed tomography (CT), scattered radiation leads to nonuniform biasing of CT numbers known as a cupping artifact. Besides being visual distractions, cupping artifacts appear as background nonuniformities, which impair efficient gray scale windowing and pose a problem in threshold based volume visualization/segmentation. To overcome this problem, we have developed a background nonuniformity correction method specifically designed for cone beam breast CT. With this technique, the cupping artifact is modeled as an additive background signal profile in the reconstructed breast images. Due to the largely circularly symmetric shape of a typical breast, the additive background signal profile was also assumed to be circularly symmetric. The radial variation of the background signals was estimated by measuring the spatial variation of adipose tissue signals in front view breast images. To extract adipose tissue signals in an automated manner, a signal sampling scheme in polar coordinates and a background trend fitting algorithm were implemented. The background fits compared with targeted adipose tissue signal value (constant throughout the breast volume) to get an additive correction value for each tissue voxel. To test the accuracy, we applied the technique to cone beam CT images of mastectomy specimens. After correction, the images demonstrated significantly improved signal uniformity in both front and side view slices. The reduction of both intraslice and interslice variations in adipose tissue CT numbers supported our observations.

Microcalcification detectability for four mammographic detectors: Flat‐panel, CCD, CR, and screen/film

Amorphous silicon/cesium iodide (a-Si:H/CsI:Tl) flat-panel (FP)-based full-field digital mammography systems have recently become commercially available for clinical use. Some investigations on physical properties and imaging characteristics of these types of detectors have been conducted and reported. In this perception study, a phantom containing simulated microcalcifications (microCs) of various sizes was imaged with four detector systems: a FP system, a small field-of-view charge coupled device (CCD) system, a high resolution computed radiography (CR) system, and a conventional mammography screen/film (SF) system. The images were reviewed by mammographers as well as nonradiologist participants. Scores reflecting confidence ratings were given and recorded for each detection task. The results were used to determine the average confidence-rating scores for the four imaging systems. Receiver operating characteristics (ROC) analysis was also performed to evaluate and compare the overall detection accuracy for the four detector systems. For calcifications of 125-140 microm in size, the FP system was found to have the best performance with the highest confidence-rating scores and the greatest detection accuracy (Az = 0.9) in the ROC analysis. The SF system was ranked second while the CCD system outperformed the CR system. The p values obtained by applying a Student t-test to the results of the ROC analysis indicate that the differences between any two systems are statistically significant (p<0.005). Differences in microC detectability for the large (150-160 microm) and small (112-125 microm) size microC groups showed a wider range of p values (not all p values are smaller than 0.005, ranging from 0.6 to <0.001) compared to the p values obtained for the medium (125-140 microm) size microC group. Using the p values to assess the statistical significance, the use of the average confidence-rating scores was not as significant as the use of the ROC analysis p value for p value.

Feasibility of volume-of-interest (VOI) scanning technique in cone beam breast CT-a preliminary study

This work is to demonstrate that high quality cone beam CT images can be generated for a volume of interest (VOI) and to investigate the exposure reduction effect, dose saving, and scatter reduction with the VOI scanning technique. The VOI scanning technique involves inserting a filtering mask between the x-ray source and the breast during image acquisition. The mask has an opening to allow full x-ray exposure to be delivered to a preselected VOI and a lower, filtered exposure to the region outside the VOI. To investigate the effects of increased noise due to reduced exposure outside the VOI on the reconstructed VOI image, we directly extracted the projection data inside the VOI from the full-field projection data and added additional data to the projection outside the VOI to simulate the relative noise increase due to reduced exposure. The nonuniform reference images were simulated in an identical manner to normalize the projection images and measure the x-ray attenuation factor for the object. Regular Feldkamp-Davis-Kress filtered backprojection algorithm was used to reconstruct the 3D images. The noise level inside the VOI was evaluated and compared with that of the full-field higher exposure image. Calcifications phantom and low contrast phantom were imaged. Dose reduction was investigated by estimating the dose distribution in a cylindrical water phantom using Monte Carlo simulation based Geant4 package. Scatter reduction at the detector input was also studied. Our results show that with the exposure level reduced by the VOI mask, the dose levels were significantly reduced both inside and outside the VOI without compromising the accuracy of image reconstruction, allowing for the VOI to be imaged with more clarity and helping to reduce the breast dose. The contrast-to-noise ratio inside the VOI was improved. The VOI images were not adversely affected by noisier projection data outside the VOI. Scatter intensities at the detector input were also shown to decrease significantly both inside and outside the VOI in the projection images, indicating potential improvement of image quality inside the VOI and contribution to dose reduction both inside and outside the VOI.

A-Si:H/CsI(Tl) flat-panel versus computed radiography for chest imaging applications: image quality metrics measurement.

Amorphous silicon (a-Si:H) flat-panel (FP) imaging systems have recently become commercially available for both chest and mammographic imaging applications. It has been shown that this new detector technology offers better image quality and various operational advantages over the computed radiography (CR) which to date has been the most widely implemented and used digital radiography technique. However, most image quality measurements reported on flat-panel systems have been performed on prototype systems in laboratories while those for CR systems were typically independently performed and reported on in separate studies. To directly compare the two technologies, we have measured the image properties for a commercial amorphous silicon/cesium iodide [a-Si:H/CsI(Tl)] flat-panel based digital chest system and a commercial CR system under clinical imaging conditions. In this paper, measurements of image quality metrics, including the modulation transfer functions (MTFs), noise power spectra (NPSs), and detective quantum efficiencies (DQEs), for the FP and CR systems are presented and compared. Methods and issues related to these measurements are discussed. The results show that the flat-panel system has slightly lower MTF but significantly higher DQEs than the CR system. The DQEs of the flat-panel system were found to increase with the exposure while those of the CR system decrease slightly with the exposure.