Molecular Contrast Agents for CT and

Next Generation CT Techniques-

MEng in Bioinstrumentation

Examples of plasmonic GNPs: 16-nm Au nanospheres; gold nanorods and gold nanorods with silver coatings (inset); SiO2/Au nanoshells; gold nanostars; silver nanocubes and Au-Ag nanocages obtained from them (insets); nanocomposites containing a gold nanorod or nanocage core and a mesoporous silica shell doped with hematoporphyrin; hollow mesoporous silica spheres and nanorattles containing gold nanocages; plasmonic nanopowders of gold nanospheres, nanorods, nanostars, and Au-Ag nanocages.

Schematic illustration of the preparation of dendrimer-entrapped gold nanoparticles.

Dendrimer-entrapped Gold Nanoparticle

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

Bismuth sulfide (Bi2S3) nanoparticles labeled with the cyclic nine amino acid peptide, CGNKRTRGC (LyP-1)-targeted to 4T1 breast cancer in mice

Targeted Bismuth Nanoparticles

X-ray CT images of tumor-bearing mouse immediately (a), 2 h (b), 4.5 h (c), and 24 (d) after injection of Bi2S3 nanoparticles labeled with LyP-1.

In vivo micro-CT volume reconstructions post–injection polyethylene glycol5000 coated Bi2S3 nanoparticles that do not contain a peptide label.

Serial CT Imaging

(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

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Spectral/multi energy CT has the potential to distinguish different materials by K-edge characteristics.

K-edge imaging involves the two energy bins on both sides of a K-edge.

Energy discriminating photon counting detectors

Advanced Detector Technology

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Mass attenuation coefficients of several materials as function of X-ray energy

Excitation of a 1s electron occurs at the K-edge, while excitation of a 2s or 2p electron occurs at an L-edge

Spectral CT with Energy-Resolving Detector

Energy-resolving detectors discriminate colors

Spectral CT with energy-resolving detector is like the human eye at day

Total attenuation

energy

Compton Scatter

Photo-electric

Emerging Opportunities with Spectral CT

Multicolored or spectral CT has the potential to detect and quantify intraluminal fibrin presented by ruptured plaque in the context of CT angiograms all without calcium interference.

Philips Research, Hamburg, DERelevant Patents: US20110096892;

20110096905 (Philips)

Diagnosis of Chest Pain of Cardiac OriginDiagnostic Imaging – Treatment Planning – Intervention Guidance

Plaque

CoronaryCT Angio

Diagnosis

Cardiac CT angiography (CCTA) Surplant invasive diagnostic cardiac catheterization with a quicker, noninvasive, lower cost procedure

Early DiagnosisStress Test/ Hospitalization

SymptomsPatient presented at ER with chest pain

Detecting Atherosclerotic Plaque

Clinical Significance of Spectral CT

wiki.medpedia.com/Coronary_Calcium_Scan

Negative predictive value of CT angiography established early (non- reimbursable)• Poor anatomic correlation with cath• Cost• Inability to separate coronary Ca

• CORE-64 at the AHA

scientific sessions (2007),

noninvasive 64-slice MDCT

angiography was reported to

have a 91% positive and 83%

negative predictive value in a

large multicenter trial: 89/405

patients were excluded due to

high calcium scores

• Poor anatomic correlation

between CCTA and Cath.

Coronary Thrombus Imaging by Spectral CT

• Nanobeacons (Au, Bi,…) bind to fibrin

• Conventional CT is unable to selectively image materials

• Spectral CT enables material specific imaging of suitable metals

• New Nanobeacons and advances in statistical image reconstruction methods improve coronary fibrin imaging

Nanobeacons target fibrin of thrombus on ruptured plaque

Fibrin

Ca deposit

Plaque formation

non-separated attenuation from nanoparticle and Ca

Selective imaging of nanoparticles

Quantitative Tissue DifferentiationTargeted bismuth nanocolloids distinguishes fibrin microdeposits from calcium

Pan et. al. Angew Chem Int Ed. 9635-9639 (2010)

Spectral CT image of a fibrin clot phantom with embedded calcium chloride (white arrow) targeted (green arrow) in a glass tube (blue arrows denote wall).

Ca-separated

Hospitaltour.com

Calcium red & Bismuth Gold)Soft tissue invisible due to low X-ray attenuation

c

Arterial Lumen

BiNC

Calcium

Photoelectric K-edge

Tubec

Arterial Lumen

BiNC

Calcium

Photoelectric K-edge

TubeTargetedControl TargetedControl

Simultaneous Data Acquisition for Perfect Image Registration

Pan, Schirra et al., ACS Nano. 2012 Apr 24;6(4):3364-70

Ytterbium Nanocolloids for Multicolor CT

Pan, Schirra et al., ACS Nano. 2012 Apr 24;6(4):3364-70

PET-Like “Hot Spot” Imaging with Spectral CT

Simultaneous Data Acquisition for Perfect Image Registration

Spectral CT identifies area of high macrophage activity with Au-HDL contrast

Visualize the Au-HDL along with the iodinated contrast agents and calcified structures in the same scan.

Offers the potential to simultaneously acquire information on stenosis, calcification, and inflammation, three valuable parameters of plaque characterization.

CT techniques require both a pre-injection image and a post-injection image that must be compared—Spectral CT is sufficiently sensitive that it requires only one post-injection image and therefore has potential to use lower doses of contrast.

Contrast agents are visible and there is no need for a contrast pre- and post- because there is no [background] iodine or gold in the body

Micro-CT image of a mouse bearing tumor cells that are visualized using Qdot/Ba-nanoparticle-conjugated tumor-

targeting antibodies

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In K-edge subtraction imaging (KES), two simultaneous CT images are acquired using two x-ray beams at two different energies above and below the K-edge of Xe.

Absolute quantity of the CA is determined directly on any given point of a lung CT image after subtracting these two images on a logarithmic scale.

K-edge subtraction imaging (KES)

Xenon Broncheography

http://www.healthcare.siemens.com/computed-tomography/technologies-innovations/ct-dual-energy/technical-specifications

The Selective Photon Shield ensures dose neutrality by eliminating spectral overlap. This makes Dual Energy as dose-efficient as any single 120 kV scan.

Dual Energy CT

• During a Dual Source Dual Energy scan, two CT datasets are acquired simultaneously with different kV and mA levels, allowing to visualize differences in the energy-dependence of the attenuation coefficients of different materials.

• These images are combined and analyzed to visualize information about anatomical and pathological structures.

One Basic Reason for Use of Dual Energy CT: Material Differentiation• By scanning a patient at two different energy spectra (e.g. at 56 kV and 76 kV), the attenuation difference of the same material is different.• Iodine has higher attenuation difference, compared to bone. • Scanning allows the computer to process bone and iodine content on images differently.

Routine Use of Dual-energy CT for Material Differentiation• Creation of 3D vascular images ("Direct Angio") by easy removal of bony structures• Plaque analysis (calcified vs. soft plaques)• Lung perfusion• Virtual unenhanced scan (creation of unenhanced scan from enhanced images by deleting iodine content from the images)• Calculi characterization (uric acid vs. others)

http://www.dsct.com/index.php/clinical-applications-dual-energy-ct/

Use the spectral properties of iodine to differentiate it from other dense materials in the dataset (similar to magnetic resonance angiography (MRA)).

With Dual Energy CT, it is possible to identify bone by its spectral behavior and to erase it from an angiogram. Then, the iodine in the vessels remains the only dense material in the dataset and a MIP can be calculated from a CT angiogram to closely resemble an MRA.

Additionally, it is possible to detect those voxels that contain both calcium and iodine and add them back to the dataset.

Calcified plaques of atherosclerotic vessels can thereby be switched on and off in the dataset to visualize both the residual lumen and the plaque distribution.

Dual Energy in Angiography