Refraction-enhanced x-ray imaging of mouse lung using synchrotron radiation source.

The low divergent x-ray beam from the third-generation synchrotron radiation source such as SPring-8 enables us to observe refraction of x rays that is in the range of microradians. Under an experimental condition for which ray optics is a good approximation, we found that the refraction produces a high-contrast projection image of a mouse when it was recorded at 6.5 m behind the specimen. Especially, the lung is visualized far better than with the conventional imaging which utilizes absorption of x rays. This is a promising new technique for the diagnosis of diseases in the human lung with a low radiation dose.     

Contrast agent CT imaging in variable sized organs using single energy synchrotron radiation.

A theoretical and experimental study has been performed to determine which element, when used as a contrast agent in CT, requires the lowest concentration when delivered to various sized organs. Iodine is at present the primary contrast agent used in contrast enhanced CT imaging. The results presented here show that iodine is not the optimum element to use in terms of concentration needed for visibility. When administered to very small organs, the use of gadolinium reduces the concentration required for visibility by at least a factor of 3 over that required when using iodine.     

Curved optics for x-ray phase contrast imaging by synchrotron radiation

Conventional radiographic techniques have strong limitations when low-absorption contrast samples are imaged. Phase contrast radiography has been shown to produce high-quality images of soft tissues. In this technique the recorded intensity patterns are related to gradients in the refractive index of the sample. A critical point of this new technique is the need to employ crystal analysers, which results in an appreciable reduction in the beam intensity and consequently in rather long exposure times. In this paper the use of focused beams is suggested to overcome this aspect. Biological samples with small structures and low absorption variations were imaged using both flat and curved monochromator crystals, demonstrating that the use of curved optics leads to a decrease in the exposure time with only a limited degradation of the spatial resolution. This opens up the possibility of using the phase contrast technique with laboratory sources.     

Microbubble-based synchrotron radiation phase contrast imaging: basic study and angiography applications

The purpose of the study was to evaluate the feasibility of microbubbles as phase contrast imaging (PCI) agents for angiography applications. The hypothesis was that the introduction of microbubbles into tissue produces a significant change in the refractive index and highlights the lumen of the vessel in PCI. The absorption and phase contrast images of commercially available microbubbles were obtained and compared in vitro. A further increase in contrast was observed in PCI. Microbubbles highlighted the lumen of the renal microvessels, acting as a positive contrast medium in ex vivo imaging. In addition, home-made microbubbles with larger diameters were introduced for image contrast enhancement in living tumor-bearing mice, demonstrating the feasibility of microbubble-based x-ray phase-contrast imaging for tumor vasculature in vivo.     

Quantitative measurement of regional lung gas volume by synchrotron radiation computed tomography

The aim of this study was to assess the feasibility of a novel respiration-gated spiral synchrotron radiation computed tomography (SRCT) technique for direct quantification of absolute regional lung volumes, using stable xenon (Xe) gas as an inhaled indicator. Spiral SRCT with K-edge subtraction using two monochromatic x-ray beams was used to visualize and directly quantify inhaled Xe concentrations and airspace volumes in three-dimensional (3D) reconstructed lung images. Volume measurements were validated using a hollow Xe-filled phantom. Spiral images spanning 49 mm in lung height were acquired following 60 breaths of an 80% Xe-20% O2 gas mixture, in two anaesthetized and mechanically ventilated rabbits at baseline and after histamine aerosol inhalation. Volumetric images of 20 mm lung sections were obtained at functional residual capacity (FRC) and at end-inspiration. 3D images showed large patchy filling defects in peripheral airways and alveoli following histamine provocation. Local specific lung compliance was calculated based on FRC/end-inspiration images in normal lung. This study demonstrates spiral SRCT as a new technique for direct determination of regional lung volume, offering possibilities for non-invasive investigation of regional lung function and mechanics, with a uniquely high spatial resolution. An example of non-uniform volume distribution in rabbit lung following histamine inhalation is presented.     

Indocyanine-green-embedded PEBBLEs as a contrast agent for photoacoustic imaging

Nanoparticles 100 nm in diameter containing indocyanine green (ICG) have been developed as a contrast agent for photoacoustic (PA) imaging based on (photonic explorers for biomedical use by biologically localized embedding PEBBLE) technology using organically modified silicate (ormosil) as a matrix. ICG is an FDA-approved dye with strong optical absorption in the near-infrared (NIR) region, where light can penetrate deepest into biological tissue. A photoacoustic imaging system was used to study image contrast as a function of PEBBLE concentration in phantom objects. ICG-embedded ormosil PEBBLEs showed improved stability in aqueous solution compared with free ICG dye. The particles were conjugated with HER-2 antibody for breast cancer and prostate cancer cell targeting. Initial in vitro characterization shows high contrast and high efficiency for binding to prostate cancer cells. ICG can also be used as a photosensitizer (generating toxic oxygen by illumination) for photodynamic therapy. We have measured the photosensitization capability of ICG-embedded ormosil nanoparticles. This feature can be utilized to combine detection and therapeutic functions in a single agent.     

基于Amira的小鼠肺部同步辐射图像的三维重建

医学图像的三维重建为医学人员提供了真实、直观的反映,便于对病灶的观察及手术的进行.本文采用MATLAB软件中的图像处理工具箱,结合Amira软件,实现了通过同步辐射X线相位衬度成像方法 ,获得了小鼠肺部投影图像的三维显示.应用MATLAB编程实现方便,Amira软件三维重建简易可行,显示效果良好.     

Optical molecular imaging of lymph nodes using a targeted vascular contrast agent

We develop a highly specific antibody-dye conjugate for optical imaging of peripheral lymph nodes. The contrast agent consists of the monoclonal antibody recognizing endothelial ligands for the lymphocyte homing receptor L-selectin, MECA-79, and a near-infrared (near-IR) fluorescent indotricarbocyanine dye. The targeting and biodistribution behavior of MECA-79 is studied after radio-iodination and intravenous injection into mice demonstrating specific uptake in lymph nodes and accumulation in high endothelial venules (HEV). After conjugation of MECA-79 with indotricarbocyanine dye, the fluorescence imaging properties of the MECA-79 dye conjugate are examined by intravenous injection in nude mice and laser-induced fluorescence whole-body imaging in vivo. The MECA-79 antibody-dye conjugate accumulates in peripheral lymph nodes, whereas an isotype antibody-dye conjugate does not. Specific lymph node near-IR fluorescent signals become detectable within minutes after injection, and stable imaging persists for more than 24 h. The results demonstrate that vascular targeting of endothelial expression of glyocproteins is feasible to visualize the accumulation of near-IR fluorescent MECA-79 in lymph nodes, making this technology potentially useful to characterize processes of inflammation.     

Manganese ferrite nanoparticle micellar nanocomposites as MRI contrast agent for liver imaging

Iron oxide nanoparticles are effective contrast agents for enhancement of magnetic resonance imaging at tissue, cellular or even molecular levels. In this study, manganese doped superparamagnetic iron oxide (Mn-SPIO) nanoparticles were used to form ultrasensitive MRI contrast agents for liver imaging. Hydrophobic Mn-SPIO nanoparticles are synthesized in organic phase and then transferred into water with the help of block copolymer mPEG-b-PCL. These Mn-SPIO nanoparticles are self-assembled into small clusters (mean diameter ≈ 80 nm) inside micelles as revealed by transmission electron microscopy. Mn-SPIO nanoparticles inside micelles decrease PCL crystallization temperatures, as verified from differential scanning calorimetry and Fourier transform infrared spectroscopy. The Mn-SPIO based nanocomposites are superparamagnetic at room temperature. At the magnetic field of 1.5 T, Mn-SPIO nanoparticle clustering micelles have a T₂ relaxivity of 270 (Mn + Fe) mM^?1 s^?1, which is much higher than single Mn-SPIO nanoparticle containing lipid–PEG micelles. This clustered nanocomposite has brought significant liver contrast with signal intensity changes of ?80% at 5 min after intravenous administration. The time window for enhanced-MRI can last about 36 h with obvious contrast on liver images. This sensitive MRI contrast agent may find applications in identification of small liver lesions, evaluation of the degree of liver cirrhosis, and differential diagnosis of other liver diseases.     

Electron density measurement with dual-energy x-ray CT using synchrotron radiation

Monochromatic x-ray computed tomography (CT) at two different energies provides information about electron density of human tissue without ambiguity due to the beam hardening effect. This information makes the treatment planning for proton and heavy-ion radiotherapy more precise. We have started a feasibility study on dual energy x-ray CT by using synchrotron radiation. A translation-rotation scanning CT system was developed for quantitative measurement in order to clarify what precision in the measurement was achieved. Liquid samples of solutions of K2HPO4 and solid samples of tissue equivalent materials were used to simulate human tissue. The experiments were carried out using monochromatic x-rays with energies of 40, 70 and 80 keV produced by monochromatizing synchrotron radiation. The solid samples were also measured in a complementary method using high-energy carbon beams to evaluate the electron densities. The measured electron densities were compared with the theoretical values or the values measured in the complementary method. It was found that these values were in agreement in 0.9% on average. Effective atomic numbers were obtained as well from dual-energy x-ray CT. The tomographic image based on each of the electron densities and the effective atomic number presents a different feature of the material, and its contrast drastically differs from that in a conventional CT image.     

Preliminary study on extremely small angle x-ray scatter imaging with synchrotron radiation

Among the medical physics community, there is nowadays a great interest in the possible implementation of scatter imaging techniques, especially in the field of breast imaging. It is well known that malignant lesions and normal tissue differ in their scattering signatures, and thus scattered radiation can provide a powerful tool to distinguish between the two cases. Up to now, most of the proposed techniques rely on the detection of radiation scattered at angles of the order of a few degrees, which in most cases results in very high contrast values. On the other hand, at those relatively large angles the scattered flux is relatively low with respect to the primary, which often implies the necessity of increasing the dose delivered to the sample in order to achieve sufficient statistics. Furthermore, most of these techniques are based on pencil beam set-ups, which results in an increase of the overall duration of the examination. We propose here an alternative approach based on the detection of radiation scattered at extremely small angles, of the order of approximately 100-200 microrad. This results in a relatively high scattered flux (5-10% of the primary) and in the possibility of utilizing a fan beam geometry, which reduces the acquisition times with respect to pencil beam set-ups. Images of several samples have been acquired, demonstrating that the proposed technique results in an increased contrast with respect to absorption imaging. Possible in vivo implementations of the technique at no dose expense are finally discussed.     

Dynamic measures of regional lung air volume using phase contrast x-ray imaging

Phase contrast x-ray imaging can provide detailed images of lung morphology with sufficient spatial resolution to observe the terminal airways (alveoli). We demonstrate that quantitative functional and anatomical imaging of lung ventilation can be achieved in vivo using two-dimensional phase contrast x-ray images with high contrast and spatial resolution (<100 microm) in near real time. Changes in lung air volume as small as 25 microL were calculated from the images of term and preterm rabbit pup lungs (n = 28) using a single-image phase retrieval algorithm. Comparisons with plethysmography and computed tomography showed that the technique provided an accurate and robust method of measuring total lung air volumes. Furthermore, regional ventilation was measured by partitioning the phase contrast images, which revealed differences in aeration for different ventilation strategies.     

Molecular contrast optical coherence tomography: A pump-probe scheme using indocyanine green as a contrast agent

The use of indocyanine green (ICG), a U.S. Food and Drug Administration approved dye, in a pump-probe scheme for molecular contrast optical coherence tomography (MCOCT) is proposed and demonstrated for the first time. In the proposed pump-probe scheme, an optical coherence tomography (OCT) scan of the sample containing ICG is first acquired. High fluence illumination (approximately 190 kJ/cm2) is then used to permanently photobleach the ICG molecules--resulting in a permanent alteration of the overall absorption of the ICG. A second OCT scan is next acquired. The difference of the two OCT scans is used to determine the depth resolved distribution of ICG within a sample. To characterize the extent of photobleaching in different ICG solutions, we determine the cumulative probability of photobleaching, phi(B,cum), defined as the ratio of the total photobleached ICG molecules to the total photons absorbed by the ground state molecules. An empirical study of ICG photobleaching dynamics shows that phi(B,cum) decreases with fluence as well as with increasing dye concentration. The quantity phi(B,cum) is useful for estimating the extent of photobleaching in an ICG sample (MCOCT contrast) for a given fluence of the pump illumination. The paper also demonstrates ICG-based MCOCT imaging in tissue phantoms as well as within stage 54 Xenopus laevis.     

Peptide-conjugated polyamidoamine dendrimer as a nanoscale tumor-targeted T1 magnetic resonance imaging contrast agent

A tumor-targeting carrier, peptide HAIYPRH (T7)-conjugated polyethylene glycol-modified polyamidoamine dendrimer (PAMAM-PEG-T7) was explored to deliver magnetic resonance imaging (MRI) contrast agents targeting to the tumor cells specifically. Two different types of tumors, liver cancer and early brain glioma model (involved with the blood-brain barrier), were chosen to evaluate the imaging capacity of this contrast agent. PAMAM-PEG-T7 was synthesized, conjugated with diethylene triamine pentaacetic acid (DTPA) and further chelated gadolinium (Gd), yielding GdDTPA-PAMAM-PEG-T7. The result of ICP-AES showed that about 92 Gd ions could be loaded per PAMAM molecule. The calculated longitudinal relaxivity R1 of the GdDTPA-PAMAM-PEG-T7 was 10.7 mm(-1) S(-1) per Gd (984.4 mm(-1) S(-1) per PAMAM), while that of GdDTPA was only 4.8 mm(-1) S(-1). PAMAM-PEG-T7 had better targeting capacity to the liver cancer cells in vitro and in vivo, compared with PAMAM-PEG. The accumulation of PAMAM-PEG-T7 was 162.5% times that of PAMAM-PEG. But for glioma cells, PAMAM-PEG-T7 did not show its specificity. Furthermore, GdDTPA-PAMAM-PEG-T7 could improve the diagnostic efficiency of liver cancer with the enhanced signal (187%), compared to 130% for PAMAM-PEG and 121% for GdDTPA. GdDTPA-PAMAM-PEG-T7 could selectively identify liver cancer but not early glioma. This nanoscaled MRI contrast agent GdDTPA-PAMAM-PEG-T7 might allow for selective and efficient diagnosis of tumors without the natural barrier including liver cancer.     

Quantitative myocardial perfusion magnetic resonance imaging: the impact of pulsatile flow on contrast agent bolus dispersion

Myocardial blood flow (MBF) can be quantified using T1-weighted first-pass magnetic resonance imaging (MRI) in combination with a tracer-kinetic model, like MMID4. This procedure requires the knowledge of an arterial input function which is usually estimated from the left ventricle (LV). Dispersion of the contrast agent bolus may occur between the LV and the tissue of interest. The aim of this study was to investigate the dispersion under conditions of physiological pulsatile blood flow, and to simulate its effect on MBF quantification. The dispersion was simulated in coronary arteries using a computational fluid dynamics (CFD) approach. Simulations were accomplished on straight vessels with stenosis of different degrees and shapes. The results show that dispersion is more pronounced under resting conditions than during hyperemia. Stenosis leads to a reduction of dispersion. In consequence, dispersion results in a systematic MBF underestimation between -0.4% and -9.3%. The relative MBF error depends not only on the dispersion but also on the actual MBF itself. Since MBF under rest is more underestimated than under stress, myocardial perfusion reserve is overestimated between 0.1% and 4.5%. Considering other sources of errors in myocardial perfusion MRI, systematic errors of MBF by bolus dispersion are relatively small.     

An in vitro study of a microbubble contrast agent using a clinical ultrasound imaging system

Optimal insonation settings for contrast imaging are yet to be specified, mainly due to the lack of good understanding of the behaviour of the microbubbles. A satisfactory model that explains the behaviour of individual contrast agent scatterers has not yet been reported in the literature. An in vitro system based on a commercial scanner (ATL HDI3000) has been developed to investigate the backscatter of such agents. Suspensions of Definity were introduced in an anechoic tank. The frequency of transmitted ultrasound varied from 1 to 5 MHz, pulse period from 2 to 10 periods and peak negative acoustic pressure from 0.08 to 1.7 MPa. The backscatter at the fundamental and second harmonic frequency windows from the agent was normalized in terms of the corresponding components of backscatter from a blood mimicking fluid suspension. The agent provided a dominant resonance effect at 1.6 MHz transmit frequency. Second harmonic normalized backscatter averaged around 9 dB higher than the fundamental. The normalized fundamental backscatter intensity was linear with peak negative pressure. The second harmonic at resonance peaked at 0.5 MPa suggestive of bubble disruption above such pressure. The system proved capable of illustrating the ultrasonic behaviour of Definity in vitro, and the investigation suggested particular insonation conditions for optimal image enhancement using Definity.     

Nanoparticulate carrier containing water-insoluble iodinated oil as a multifunctional contrast agent for computed tomography imaging

Contrast-enhanced computed tomography (CT) imaging is a valuable and routine strategy for the clinical diagnosis of various diseases. However, all current CT contrast agents are liquids, so they flow through the blood vessels and disappear very quickly by extravasation. If it were possible to make a blood-compatible particulate contrast agent, we could highlight a particular tissue by either passive or active targeting. In this work, Pluronic F127 and a naturally iodinated compound, Lipiodol, were used to form radiopaque nanoreservoir structures. The resultant nanoparticles have a stable structure at high concentrations, sufficient X-ray absorption, a safety profile similar to or better than that of Iopromide, and a longer circulation time than commercial iodinated preparations. The utility of the resultant radiopaque nanoparticles as a contrast agent was tested using micro-SPECT/CT imaging in vivo. Together with the very good solubility of hydrophobic drugs (e.g., Taxol) in Lipiodol, these results suggest the possibility that these particulate structures and their bioconjugates could become functional CT contrast agents that could deliver therapeutic agents to a particular tissue.     

Dose measurements in inhomogeneous bone/tissue and lung/tissue phantoms for angiography using synchrotron radiation

For angiography using synchrotron radiation we measured the absorbed dose distribution in inhomogeneous phantoms with thin LiF:Mg, Cu, P, LiF:Mg, Ti thermoluminescent dosimeters (TLDs) in tissue and lung substitutes, and with Mg2SiO4:Tb TLDs in bone substitute for 33.32 keV monoenergetic photons from synchrotron radiation. The energy responses of the TLDs were measured in air for 10-40 keV monoenergetic photons. The values at 30 keV became smaller by 30% for LiF:Mg, Cu, P and larger by 22% for Mg2SiO4:Tb than the ratio of the mass energy absorption coefficients of the TLDs to that of air. These values were used to modify the calculated response of the TLDs in each phantom material. The absorbed dose distribution obtained was compared with that calculated using the Monte Carlo transport code EGS4 expanded to a low-energy region, and their agreement was confirmed taking linear polarization into account. In the bone substitute the dose increased by a factor of 3.9, while behind the bone the dose decreased drastically because of photon attenuation. In the lung substitute a slight dose difference from that in soft tissue was observed because of its different density. The LiF:Mg, Cu, P TLDs exhibited a better energy response, higher sensitivity and wider linear regions than did the other tissue-equivalent TLDs in the low-energy region.