Module C: Computed Tomographic Imaging CT Imaging Overview In the middle of the spectrum are heat waves (infrared), visible light and UV rays. The shorter UV rays can be damaging to life. X-rays (Rntgen rays) were discovered and artificially produced in the laboratory towards the end of the 19 th century. can cause serious damage to the macromolecules of life CT: Synthesis of multiple X-ray images of a slice. MRI: Imaging protons excited by radio waves. Ultrasound: High - frequency sound waves reflected from tissue junctions. Basic Difference between Major Modalities All these methods illustrate structure of the body in some form of sectional view. MRICTUS X Rays X-rays are a part of the natural electromagnetic spectrum. All electromagnetic waves travel at the same speed through vacuum 300,000 km/sec. A wave has two attributes wavelength and frequency. The product of the two equals the speed at which it travels. Waves with longer wavelength (lower frequency) have lower energy. The shorter the wavelength, greater the energy of the wave. At one end of the spectrum we have radio waves with wavelengths measured in metres, centimetres or millimetres (frequencies range from few kHz to tens of mHz). Use of X-rays for Various Applications X Ray Tube Principles Artificially X rays are produced by decelerating high- velocity electrons. X-ray tube has a source of electrons, a means of accelerating them to high velocities and something to stop them so that they lose their energy. The electron source is the cathode, heated by a filament. The anode has a positive voltage (thousands of volts) and attracts the electrons so that they reach a high velocity. The disc-like surface of the anode also stops the electrons. The X-rays produced go out through the window. Only a small fraction of the energy is in the form of X- rays, a lot is wasted as heat. The anode is specially designed to withstand the heat and the tube also has a cooling mechanism. Cathode Anode Heater Window Key Point : X-rays are produced by deceleration of high velocity electrons. In a nut shell On films Bone calcium greater attenuation : white image Soft tissues less attenuation gray image Air least attenuation, dark areas However thickness also matters! In fluoroscopy the pattern is reversed. Image Densities A Matter of Contrast! Dark blobs -bubbles of gas in the colon. Ordinarily, the colon is invisible because it blends with the other viscera in an X-ray image. Gas in the colon creates contrast. Vertebrate: Thin shell of solid bone and spongy bone inside Spine of a vertebra is at a lower level than its body Joints between the articular processes A Matter of Contrast Key Point : Contrast can show structures which are otherwise invisible Air under the diaphragm indicates that some abdominal hollow organ has a perforation or rupture, causing gas to escape into the peritoneal cavity Diaphragm blends with the abdominal organs Air between the liver and the right dome of the diaphragm Creating a cross-sectional tomographic plane of a body part A patient is scanned by an X-ray tube rotating around the body A detector assembly measures the radiation exiting the patients Tomo = image // to long axis of the body CT = image is transverse to the body CT Imaging Overview Hounsfield units: Each pixel within the matrix is assigned a number that is related to the linear attenuation coefficient of the tissue within each voxel Each pixel in the image corresponds to the volume of tissue in the body section being imaged. The voxel volume is a product of the pixel area and slice thickness Voxel A relative comparison of x-ray attenuation of a voxel of tissue to an equal volume of water. Water is used because it is in abundance in the body and has a uniform density Water is assigned an arbitrary HU value of 0 Tissue denser than water are given positive CT numbers Tissue with less density than water are assigned negative CT numbers The scale of CT numbers ranges from for air to +14,000 for dense bone Only CT # in the body are Fat, Lung & Air Hounsfield Units (HU) Hounsfield Scale On the CRT or LCD, each pixel within the image is assigned a level of gray The gray level assigned to each pixel corresponds to the CT number or Hounsfield units for that pixel The CT Image A P R L Liver A CT image can be taken as a plain image or with the introduction of a contrast medium. Like conventional X-ray images, bone appears white, air black and soft tissues have intermediate densities depending on their composition and thickness. However, the contrast and resolution is better than in conventional tomography. Air in the stomach- As the patient is supine, the air rises to the anterior side. Pancreas Infvena cava, with left renal vein crossing across aorta Aorta Left Kidney Right Kidney R. Psoas major R. post. vertebral muscles Radio-opaque vs Radioactive Positive contrast media are often described as radio- opaque (Opaque to X-radiation). CT Contrast media are NOT radioactive! The confusion possibly arises from the fact that a radioactive isotope of iodine (atomic mass 131) is often used in diagnostic tests. Iodine is concentrated by the thyroid gland. When it is radioactive iodine, the thyroid gland emits radiation which can be used to create an image of the thyroid gland. Other radioactive isotopes are similarly used to scan other organs, notably the liver. Purpose of Contrast Media To enhance subject contrast or render high subject contrast in a tissue that normally has low subject contrast. Atomic Number Fat = 6.46 Water = 7.51 Muscle = 7.64 Bone = 12.31 Radiographic Contrast : Influenced by Radiation Quality (KVP) Film Contrast Radiographic object (Patient) KVP TYPE OF CONTRAST USED DETERMINES KVP RANGE BARIUM 90 120 kVp IODINES 70 80 kVp (Ionic / Nonionic Water or Oil) Contrast Media Negative contrast Negative contrast (AIR OR CO2) Radiolucent Low atomic # material Black on film Positive contrast Positive contrast (all others) Radiopaque High atomic # material White on film Types of Contrast Media Radiolucent- negative contrast agent x-rays easily penetrate areas- appear dark on films Negative Contrast Media Air and gas complications emboli-air pockets in vessels lack of oxygen Radiopaque- positive contrast agent- absorbs x-rays appears light Positive Contrast Agents BARIUM IODINES BISMUTH GOLD GADOLINUM Both + & - can be used in same study Most Common TYPES OF CONTRAST material BARUIM BARUIM Z# 56 NON WATER SOLUABLE GI TRACT ONLY INGESTED OR RECTALLY KVP 90 120* IODINE Z# 53 WATER SOLUABLE POWDER LIQUID INTRAVENOUS OR Intrathecal GI TRACT Also OIL based KVP BELOW 90* avb Barium Meal This is an oblique view of a barium swallow. Note the ribs on far side and the vertebrae at lower right. At the upper end of the picture the barium paste mass is narrow, indicating that the oesophageal muscle is contracting to push the bolus down. At lower left notice that some barium has entered the stomach and shows as a larger mass. Barium Meal - Stomach The outline of the stomach is obvious. Observe the air bubble in the fundus (F). The blue arrow shows the pylorus. F Urography Key Points : In intravenous urography, the medium is injected through a vein. It is too dilute in the bloodstream. It is concentrated in the urine by the kidneys. This imaging method also indicates that the kidney is functional! These pictures show intravenous urography. Note the lumbar vertebrae, the outlines of the cavities (calyces) of the kidney and the ureters, as also the course of the ureter. In about an hours time all the iodine compound will be in the urinary bladder. Blood pool CT contrast agents (Confined to the intravascular space, highlighting blood vessels) Passive targeting agents (Reticulo-endothelial system (RES) or through the enhanced permeability and retention (EPR) effect) Active targeting agents (Selectively accumulate on specific cells and tissue by conjugation of antibodies, peptides, or other ligands onto the surface of nanoparticles) Broad Categories of CT Contrast Agents CT Contrast Agents Small Molecule Nanoparticle Macromolecules Structural Functional Molecular Broadening the Horizon The ability of the CT to distinguish between different tissues is based on the fact that different tissues provide different degrees of x-ray attenuation. I 0 =incident x-ray intensity; I = transmitted x-ray intensity = thickness of the absorber medium = mass attenuation coefficient. The most dominant factor impacting the mass attenuation coefficient is the photoelectric effect, which is proportional to the third power of the atomic number of the material (Z 3 ). Sensitivity of the MRI to micro molar contrast agents' concentration Sensitivity of the CT to millimolar contrast agents' concentration Mass attenuation coefcients of iodine and a selection of high-Z materials looking at energies above the K-edge energy of a given high-Z element, these elements exhibit a mass attenuation coefcient much higher than iodine. CM based on high-Z materials may yield an increased contrast-to-noise ratio at equal dose, which would allow for signicant dose reduction when aiming for equal constant contrast-to-noise ratio. Clinically Approved CT Contrast Agents Low-osmolality, nonionic contrast agents Tissue Specific Small Molecule CT Contrast Agents Representative upper GI canine radiograph following oral administration of a conventional barium sulfate suspension Representative upper GI canine radiograph following oral administration of an oil-in-water emulsion of compound 17 (formulated at 22.0% w/v oil, 118 mg I/mL) compound 17 Extensive, uniform, mucosal detail and persistent coating of the small intestines after oral administration. J. Med. Chem., 2000, 43 (10), pp 19401948 Novel tissue-specic small-molecule iodinated CT contrast agents: (a) an anionic Ca2+ chelating contrast agent for bone micro-damage imaging Glycosaminoglycan (GAG) in cartilage is an indicator of cartilage health Anionic CECT in bovine osteochondral plugs. (A) Representative CECT images of control and degraded samples (exposure to chondroitinase ABC for 8 h and for 30 h) demonstrate an increase in CT attenuation of articular cartilage with increased exposure to chondroitinase ABC. (B) Representative Toludine-blue stained sections indicate a progressive loss of GAG (blue staining) from the ECM as indicated by CECT in (A). Structures of a novel tissue-specic small-molecule iodinated CT contrast agent a cationic contrast agent CA4+ for cartilage tissue imaging Cationic 3D reconstruction of femur after exposure to CA 4+. In direct comparisons with anionic contrast agents, the cationic contrast agents afforded higher equilibrium concentrations in the articular cartilage of ex vivo rabbit femurs and thus greater imaging sensitivity. Linear regression analysis of average CT attenuation (in HU) vs GAG content of cartilage (reported as [mg of GAG]/[mg of hydrated cartilage]) using the CA4+ contrast agent. Nonspecific bio-distribution, Relatively small size -tend to undergo rapid renal clearance from the body High osmolality and/or high viscosity of the contrast media formulations can lead to renal toxicity and adverse physiological effects High per dose concentrations are required High rates of extravasation and equilibration between intravascular and extravascular compartments at the capillary level --make it difficult to obtain meaningful and clear CT images Issues? Iohexol Containing Polymeric Nanoparticle (A) Serial fluoroscopic images of C57BL/6 mice following jugular vein injection of 200 L of conventional iodinated contrast agent (iohexol) solution (upper panel) and poly(iohexol) NP solution (lower panel) at 250 mg iohexol/kg, respectively. Images taken at 0 and 60 min after injection were shown. Arrows indicated the enhanced contrast in the bladder regions. (B) In vivo circulation time of poly(iohexol) NP and iohexol. 64 Cu-labeled poly(iohexol) NP and iohexol were injected intravenously through the tail vein of mice. At various time points (5, 15, and 30 min and 1, 2, 4, 6, 8, 12, 24, and 48 h), blood was withdrawn intraorbitally, and the radioactivity was measured by the -counter to evaluate the systemic circulation of the poly(iohexol) NP (red) and iohexol (blue) (n = 3) A Direct Comparison Between Small Molecule and NP Agents Containing Iohexol A) Serial axial CT images of the MCF-7 tumors in mice following intratumoral injection of 200 L of iohexol (upper panel) and poly(iohexol) NPs (lower panel) at 50 mg iohexol/kg. Images were taken before injection as well as 5 min, 1 h, and 4 h post injection. Arrows indicate the enhanced contrast regions in the tumor bed. (B) Serial sections of coronal CT images in MCF-7 xenografts bearing mice following the same treatment as described in (A). Arrows indicate the enhanced contrast regions in the bladder. (C) Enhanced density (HU) of tumors at 5 min, 1 h, and 4 h after injection of poly(iohexol) NPs or iohexol. MCF-7 Xenograft Study High payload (>500k metal atoms/NP) High atomic number (Z) Metal with well-positioned K-edge energy Biocompatible surface Defined in vivo characteristics Bio-elimination Stability (shelf life/in-vivo) Metals for CT Contrast Agents Prerequisite features: Coating High Z metal Homing agent 41 Element Atomic number K-edge energy [keV] X-ray mass attenuation coefficient at 100 keV [cm 2 g 1 ] I Ba Au Pt Gd Yb Dy Lu Ta Bi K-edge energies and X-ray mass attenuation coefficients for heavy elements used in CT imaging Experimental CT opacity of bismuth solutions as a function of concentration. The horizontal dashed lines indicate the opacities of air, water and 2.36 M (300 mg I ml -1 ) iodine contrast agent, for comparison. Inset: X-ray fluoroscopy of tubes containing PBS, 0.5 M Bi 2 S 3 nanoparticle suspension (BPNPs) and 2.36 M iodine contrast agent (Iopromide). Nanoparticle of Bismuth Lymph Node Imaging with Bi 2 S 3 Nanoparticles CT imaging of a lymph node of a mouse with the BPNP imaging agent. a,b, Three-dimensional volume renderings of the CT data set, the length of the reconstruction is 3.8 cm. c, Coronal slice (length of the slice 2.3 cm). d, Transverse slice at the height indicated by the horizontal lines in b. The maximal diameter of the mouse 1.8 cm. In vivo X-ray transverse CT images of tumor (a1 and a2) and 3-D renderings of in vivo CT images (b1 and b2) before (a1 and b1) and after (a2 and b2) intratumoral injection of PEGylated WO 2.9 NRs (20 mg/kg). Tungsten Oxide Nanoparticles Scientific Reports 4, Article number: 3653 doi: /srep03653 CT images of mice before (a, b) and after (c, d) injection of gold nanoparticles. While little contrast enhancement is observed for the mouse administered with nonspecific immunoglobulin G (IgG)-conjugated nanoparticles (a, c), anti-CD-4-targeted nanoparticles show clear contrast enhancement of inguinal lymph nodes (c, d). Anti-CD-4-Targeted Gold Nanoparticles (i) A portion of X-rays is transmitted without interaction. (ii) The energy of the incident X-ray is absorbed by an atom, and then X-ray with the same energy is emitted with a random direction (Coherent scattering). (iii) When the incident X-ray collides with outer-shell electrons, a portion of the X- ray energy is transferred to the electron, and the X-ray photon is deflected with a reduced energy (Compton scattering). (iv) When the incident X-ray transfers its energy to inner-shell electron, the electron is subsequently ejected, and the vacancy of the electron shell is filled by outer- shell electrons, producing a characteristic X-ray (Photoelectron effect). Interactions of X-ray with matters (a) Schematic drawing of third-generation CT. CT images are acquired during the rotation of an X-ray tube and an array of detectors. (b) Schematic attenuation profiles of voxels. Measured X-ray intensity can be expressed as sum of the attenuation along the path of X-ray. Spectra CT