2011 - Review MicroCT Ritman

BE13CH21-Ritman ARI 6 June 2011 17:57
ANNUAL
REVIEWS Further
Current Status of Developments
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Annu. Rev. Biomed. Eng. 2011.13:531-552. Downloaded from www.annualreviews.org
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Rochester, Minnesota 55905; email: elran@mayo.edu
by University of Regina on 05/22/13. For personal use only.
Annu. Rev. Biomed. Eng. 2011. 13:531–52 Keywords

The Annual Review of Biomedical Engineering is nano-CT, mini-CT, ex vivo, in vivo, X-ray phase, X-ray fluorescence
online at bioeng.annualreviews.org
This article’s doi: Abstract

10.1146/annurev-bioeng-071910-124717
Use of microscopic computed-tomography (micro-CT) scanning contin-
Copyright c 2011 by Annual Reviews. ues to grow in biomedical research. Laboratory-based micro-CT scanners,
All rights reserved
laboratory-based nano-CT scanners, and integrated micro-CT/SPECT and
1523-9829/11/0815-0531$20.00 micro-CT/PET scanners are now manufactured for “turn-key” operation by
a number of commercial vendors. In recent years a number of technical de-
velopments in X-ray sources and X-ray imaging arrays have broadened the
utility of micro-CT. Of particular interest are photon-counting and energy-
resolving detector arrays. These are being explored to maximize micro-CT
image grayscale dynamic range and to further increase image contrast by
utilizing the unique spectral attenuation characteristics of individual chemi-
cal elements. X-ray phase-shift images may increase contrast resolution and
reduce radiation exposure. Although radiation exposure is becoming a con-
cern with the drive for increased spatial and temporal resolution, especially
for longitudinal studies, gated scans and limited scan-data-set reconstruc-
tion algorithms show great potential for keeping radiation exposure to a
minimum.
531
Contents
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
2. MICRO-CT SCANNER COMPONENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
2.1. X-Ray Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
2.2. Flat-Panel X-Ray Detector Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
2.3. Algorithms to Complement Scanner Hardware Limitations . . . . . . . . . . . . . . . . . . . 536
2.4. Micro-CT Image Transport, Storage, Analysis, and Display . . . . . . . . . . . . . . . . . . 537
3. RATIONALE FOR USE OF SMALL-ANIMAL CT . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
3.1. Disease Detection and Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
3.2. Phenotype Characterization by Anatomic Structures
and Material Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
3.3. Physiological Spaces and Their Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538

3.4. Tissue Perfusion, Drainage, and Secretion: Molecular Transport. . . . . . . . . . . . . . 541
3.5. Need to Scan Entire Organ and Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
4. TYPES OF MICRO-CT APPROACHES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542
4.1. Attenuation-Based Scanning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542

4.2. Multienergy: K Absorption Edge Subtraction Scanning . . . . . . . . . . . . . . . . . . . . . . . 543
4.3. Fluorescence-Based Scanning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
4.4. Scatter-Based Scanning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
4.5. Phase-Contrast Scanning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
5. TECHNICAL ISSUES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
6. RADIATION EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
7. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
Micro-CT: X-ray
tomography with voxel
resolutions 50–1 μm 1. INTRODUCTION
X-ray phase shift: Microscopic computed tomography (micro-CT) was first developed in the early 1980s (1–3). In
the very small change
bench-top systems, the X-ray cone beam is used to magnify the X-ray beam. Thus, the development
in X-ray wavefront
arrival time due to of a cone-beam reconstruction algorithm by Feldkamp et al. (4) in the later 1980s greatly facilitated
passage through bench-top micro-CT.
matter CT is a three-dimensional (3D) X-ray imaging method that involves obtaining X-ray projection
Transaxial: normal to images at many angles of view around an axis through an object and then applying a tomographic
the direction of the reconstruction algorithm to generate a stack of thin tomographic images of contiguous transaxial
axis of rotation of the
slices through the object. The transaxial images are made up of voxels. A specimen is usually
CT scanner or of the
specimen scanned by rotating it around a vertical axis within a system comprising a stationary X-ray source
Voxel: a 3D picture
and an X-ray imaging array. Live animals are usually positioned horizontally and scanned by rotat-
element of a certain ing the X-ray source and its imaging array around an horizontal axis through the animal. Although
size and grayscale the term micro-CT is commonly used for CT scanners with submillimeter voxel resolution, today
information a more appropriate generic name is microscopic CT. As illustrated in Figure 1, there are three
Mini-CT: X-ray levels of microscopic CT based on their spatial resolutions: mini-CT, micro-CT, and nano-CT.
tomography with voxel Nonetheless, the term “micro-CT” will continue to be used as the generic name for these CT
resolutions 200–50 μm
scanners.
Nano-CT: X-ray The results from a Web of Science literature search demonstrate the increasing use of
tomography with voxel
resolutions 1–0.1 μm
micro-CT. The use of micro-CT has progressively increased from 1982 to the present with just
under 1000 publications in 2009. A PubMed search (within biology and the medical sciences)
532 Ritman
Whole animal Whole organ Basic functional unit Cells Organelles

105 μm 104 μm 102 μm 101 μm <100 μm
(Mouse) (Liver) (Liver lobule) (Hepatocytes) (Mitochondria)
Mini-CT Micro-CT Nano-CT

Figure 1
Small rodents are of the order of 10 cm in size, their organs are 1 cm, and their tissue basic functional units (BFU) are a nominal
100 μm in diameter. Cells are of the order of 5–10 μm in diameter. The three levels of microscopic-CT can image the entire
animal/organ, BFU, or cell as a single volume image, respectively.
in that year indicates that 58% of the publications involved bone, 16% vasculature, and 26%
other applications. These numbers only approximate the actual number of publications because
the Web of Science and Compendex databases mainly cover engineering and physical sciences.
The search terms used also affect the “capture” of relevant publications (5). The wide range
of applications of micro-CT is well conveyed in the most recent biannual SPIE Conference
Proceedings, Developments in X-Ray Tomography (6). Utilization and availability of small-animal
CT systems have evolved from custom-made scanners to commercially available scanners
designed for in vivo imaging of skeletal and soft tissues. Numerous reviews of the development
and applications of micro-CT have been published (7–10).
Since the review published in the Annual Review of Biomedical Engineering in 2004 (9), several
advances in the range and repertoire can be summarized as follows:
1. lab-based nano-CT, which is made possible by very small X-ray focal spots and/or zone-plate
focusing of the X-ray beam;
2. availability of high-spatial-resolution spectral X-ray detection, which provides photon counts
along with each photon’s energy (this capability essentially duplicates imaging that was
possible only with tunable monochromatic X-ray);
3. development of nanoparticle-based contrast agents that can be targeted to specific cells; and
4. development of tomographic reconstruction algorithms that (a) reduce the need for radiation
exposure and/or speed up the scanning procedure owing to the need for reduced numbers
of angles of view per scan and (b) reduce the need for X-ray detector arrays to cover the
entire transaxial extent of the body.
These developments are discussed in more detail below.
The increased utilization of commercially available micro-CT scanners by academic biomed-
ical investigators is reflected in the number of grant applications submitted to the National Insti-
tutes of Health (personal communication, Dr. M. Tingle). In 2009, there were 70 submissions.
There are now at least a dozen commercial vendors of a variety of micro-CT scanners for imag-
ing specimens and/or live small animals. Many of these commercially available, laboratory-based
scanners have imaging characteristics that match synchrotron-based micro-CT capabilities, espe-
cially in terms of submicrometer voxel resolutions (i.e., nano-CT) (11). The commercial vendors
include the major clinical and nonclinical X-ray companies as well as companies devoted solely
www.annualreviews.org • Microscopic Computed Tomography 533

to micro-CT. Nonetheless, the more than one dozen synchrotrons around the world still provide
micro-CT capabilities. The advantage of these systems is their very narrow bandwidth, tunable,
monochromatic X-ray with essentially parallel X-ray beams with sufficiently high flux to allow
rapid scanning as well as convenient in-depth exploration of specialty X-ray imaging modalities
such as fluorescence, phase contrast, and short-exposure time scans.
The scanner imaging characteristics of the commercially available scanners vary consider-
ably. Depending on the particular characteristics of the scanner (particularly the various available
software and hardware accessories included), its cost ranges from approximately $300,000 to
$500,000. Because manufacturers and the scanner characteristics change fairly frequently, they
are not detailed in this review. However, when comparing scanners, researchers should ensure
they are comparing “apples to apples,” i.e., CT image resolutions should be expressed as modula-
tion transfer function values at, for instance, 10% contrast modulation (rather than just voxel size)
at a given X-ray beam peak voltage and metal filter type and thickness. An example of the issues
involved, especially as they relate to specific applications of the scanners, is presented in the work
by Lee et al. (12).
A number of commercially marketed micro-CT scanners are now available for in vivo small-
animal imaging. Nonetheless, the different functional characteristics of these scanners and the
different imaging needs of the potential purchaser need to be carefully matched. Similarly, be-
cause some scanners have a range of operational characteristics, whereas others are more suitable
for “turn-key” operation, an investigator needs to consider the positives and negatives of the
operational flexibility of a scanner.
In micro-CT of intact small animals, CT images are scaled such that the number of voxels
per organ are similar to that obtained in human CT images. As small animals have higher heart
and respiratory rates than humans do (mouse heart rates can be as high as 600 beats per minute
and respiratory rates 100 breaths per minute), scanning of the thorax involves scans that provide
incremental scan data acquired over a number of sequential heart and/or respiratory cycles, so-
called gated scanning. Hence, even though the scan data used in a gated-scan acquisition may be
from a very brief time interval (e.g., 50 ms) at a selected phase of the cardiac or respiratory cycle,
the total scan duration may occur over 10 or more minutes. To provide CT image signal-to-noise
ratio (SNR) comparable to clinical CT scanners, the X-ray exposure of the animal or specimen
should be increased by an amount proportional to at least the inverse of the voxel volume (13–15).
As the radiation may affect the pathophysiology of interest in, for instance, angiogenesis or cancer
(7), a voxel size less than (50 μm)3 could result in excessive radiation exposure in living animals if
repeated scans are involved, such as could be the case in longitudinal studies.
Micro-CT at <(50 μm)3 voxel resolution is suitable for scanning isolated organs from small
animals or tissue biopsies from larger animals or for a once-only scan of intact small animals. For
isolated specimens, for which higher resolution is often desired, the scanner generally operates at
lower X-ray photon energy that is matched to the diameter of the specimen (16) so as to optimize
the CT image SNR. In the quest to reduce scan duration, higher X-ray photon energies are used
because of the reduced attenuation of the X-ray beam resulting in increased photon counts in the
projected images; however, this process comes at the cost of reduced X-ray image contrast.
2. MICRO-CT SCANNER COMPONENTS

The technologies used in micro-CT scanners are basically identical but differ in detail depending
on the emphasis on CT image quality and resolution as well as the size of 3D volume that can be
imaged in a given time duration. As increased magnification generally results in a smaller volume
534 Ritman
being imaged for a given detector size, the imaging of larger volumes at high magnification requires
increased array sizes or abutment of smaller arrays.
Partial-volume
effect: the grayscale
2.1. X-Ray Sources
value of a voxel is
X-ray sources vary widely in terms of their X-ray output, focal-spot size, etc., all of which set limits altered depending on
on the micro-CT image quality. Conventional rotating-anode X-ray sources have the potential the proportion of
materials (of different
problem of slight focal-spot “wobble,” so that even small focal spots become, in effect, larger,
X-ray-attenuation
and the nonuniformity of a focal-spot emission distribution can result in unequal resolution in coefficients) “within” a
the vertical and horizontal directions and even false resolution (17). The recently available carbon voxel’s location
nanotube field-emission X-ray sources are quite interesting (18) especially as these can be pulsed
so that stroboscopic X-ray imaging can be performed to achieve very brief, gated acquisition,
scan durations. Another approach that is under investigation involves use of a laser to generate
high-intensity pulsed X-ray (19).
2.2. Flat-Panel X-Ray Detector Technology

Flat-panel detector arrays are now incorporated in several micro-CT scanners (for a comparison
of X-ray detector systems, see Reference 20). They have a number of advantages such as their large
area that allows scanning of rats and even rabbits. They can also be downloaded with sufficient
speed such that rapid CT scans can be performed, an important aspect for scanning live animals.
Given this imaging capability, these scans can be used in soft-tissue imaging (21) and skeletal
imaging of rats (22). Although the detector pixels in these arrays are relatively large (100–200 μm
on a side), the resulting CT voxels are still small enough to have minimal partial volume effects
when soft tissues are imaged. However, when bone structure and degree of mineralization at bone
surfaces are of interest, partial volume effects become more problematic. Hence, X-ray image
magnification by a factor of 3 or more is needed to reduce voxel size. This process involves placing
the X-ray focal spot close to the subject relative to the subject-to-detector array distance. As a
result, smaller volumes are imaged, making flat-panel detector arrays, which can be quite large in
area, more desirable.
An exciting development in micro-CT is that photon counting and spectral X-ray imaging
can now be performed at high spatial resolution relative to the spectral imaging approaches used
in many radionuclide imaging systems. X-ray detectors can be classified as energy-integrating
detectors or photon-counting detectors. Energy-integrating detectors are used in today’s CT
scanners. In these detectors, the electrical signals from all the X-ray interactions over a certain
sampling period are added together, yielding a signal that is proportional to the overall energy
deposited by all the photons in the X-ray spectrum. In this process, information regarding each
individual photon energy is lost. By contrast, photon-counting detectors record the signal from
each individual X-ray photon, including the energy deposited by each photon. Photon-counting
detectors have a number of advantages over energy-integrating detectors: They fundamentally
have a higher SNR because they eliminate electronic noise (23). They can also assign a more
optimal, energy-dependent weighting factor to each detected photon to further improve the SNR
(24). In energy-integrating detectors, photons are weighted according to their energy; therefore,
the low-energy photons receive a lower weighting relative to the high-energy photons, despite
the fact that they carry more information regarding material contrast (25). For the low X-ray
energies up to 40 keV, the optimal weighting factor is approximately 1/E3 (E = X-ray photon
energy), independent of material and thickness, due to the strong photo-electric effect in this en-
ergy range (26). Improvement of the SNR for photon-counting detectors is 10%–30% relative to

integrating detectors when the weighting factor is equal to 1 for all energies, but it increases to
20%–90% when optimal weighting factors are used (27) as a result of the lower photon energy
associated with Compton scatter. This effect underlies the need to increase the monochromatic
X-ray photon energy with the increase of X-ray path length through a specimen (28). An ad-
ditional SNR improvement is possible by the complete or partial rejection of scattered radia-
tion (29). Spectral-discriminating detectors can provide valuable information about the elemental
composition (30, 31).
One commercially available detector array (32) is available for a broad range of applications
that involve X-ray photon energies below approximately 20 keV and has pixel size of (172 μm)2
and an array of 83.8 × 3.5 mm2 . It will cope with 2 × 106 photon/second/pixel. Another imaging
array is based on a family of pixel-detector readout chips originally derived from the RD19 collab-
oration at CERN for high-energy physics experiments (33). The Medipix1 has a pixel dimension
of (170 μm)2 and each pixel contains approximately 400 transistors, which were implemented in a
1-μm CMOS process. The Medipix2 (34) has a pixel dimension of (55 μm)2 . A 0.25-μm CMOS
process was used in the development with approximately 500 transistors per pixel. The perfor-
mance of the Medipix2 imaging system is largely limited by charge sharing among neighboring
pixels, which distorts the energy spectrum seen by each individual pixel (35). This effect in-
creases with decreasing detector pixel size. Medipix3 was developed to overcome this limitation. A
0.13-μm CMOS process with eight metal layers was used to manufacture the chip. Using a sum-
ming circuit at the corner of each pixel, researchers can analyze the charge deposited in four
neighboring pixels, thus eliminating the spectral distortion generated by charge sharing. The
readout pixels provide eight energy thresholds for spectroscopic imaging. The Medipix chip al-
lows for the use of different detection materials, such as Si, GaAs, or CdTe. The appropriateness
of the detection materials depends on the incoming X-ray energy range. For X-ray energy up to
60 keV, GaAs (Z = 31, 33) is most appropriate (36). For X-ray energies up to 100 keV, CdTe
(Z = 48, 52) is a better choice (37). Because of its highly efficient and low noise readout, high-
spatial resolution, and energy-resolving capability, Medipix has been used in various imaging
fields, including high-resolution radiography and μCT (36–39). The maximum count rate of this
system is approximately 108 photon/mm2 /s.
2.3. Algorithms to Complement Scanner Hardware Limitations

Several algorithms have recently been developed to mitigate or even largely overcome limitations
resulting from limited-scan data sets such as number and/or range of angles of view (40). In
addition, there are now algorithms that use a priori knowledge about the scanning sequence,
taking image data from other, but similar, images in a scan sequence to boost the SNR of any
one image in a sequence (41). This approach has potential for reducing the radiation exposure by
overcoming the image noise due to reduced photon flux, which is needed to keep total radiation
exposure within desirable limits when a sequence of CT scans is required. Another approach is to
use interior reconstruction (42), an improvement on local tomography developed almost 20 years
ago (43). A conventional approach involves extending the X-ray-transmission intensity profiles to
the assumed outer surface of the object (44) or by using some of the profile data from a lower
magnification scan (45).
CT image ring artifacts can be caused by a number of instrument deficiencies. Several methods
can overcome, or at least greatly reduce, the rings. One method is to move the detector array
in measured steps at each angle of view, which effectively blurs out the ring-causing impact of
defective detector pixels or image blemishes (46). Another problem is that the detector array does
not fully cover the entire transaxial extent of the object or body of a small animal. This occurs
536 Ritman
especially when the X-ray focal spot is brought closer to the object to increase magnification of
the X-ray image. This results in loss of accuracy of the CT values as well as a bright ring artifact
at the edge of the imaged region within the object or body. Off-center scanning, which effectively
Volume image: a 3D
almost doubles the transaxial diameter that can be fully scanned, is one method to overcome this image made up of a 3D
problem (47), although only 180◦ of angle of view is now available. array of contiguous
voxels
2.4. Micro-CT Image Transport, Storage, Analysis, and Display

The 3D volume images generated with microscopic tomography range between 5003 voxels and
20003 voxels. Each voxel has at least 8–16 bits of grayscale information; therefore, the data load
for each 3D image is immense. Hence, image storage, transfer, display, and analysis are major
issues. Although many investigators have developed their own image display/analysis programs,
commercially available programs include Amira (48), Analyze (49), and open-source programs
such as Drishti (50) and Image J (51), which perform these tasks. Special application software
packages can focus on specific organs [e.g., VIDA (52)] or can be specific-task based, such as ITK
(53), which specializes in image segmentation and registration.
3. RATIONALE FOR USE OF SMALL-ANIMAL CT

Small-animal CT has been used primarily to provide 3D images of anatomic structures. Although
less frequently, small-animal CT is also used to measure function of organ motion and/or of
dynamic distribution of contrast agent within the vascular tree. Some uses of small-animal CT in
biology are described below.
3.1. Disease Detection and Monitoring

As illustrated in Figure 2, scanning live animals is particularly useful to detect the onset of
disease (especially cancer) or to monitor the progression of that disease (55–57). Early detection of
cancer and its subsequent growth, regression, or metastasis can be used to evaluate new diagnostic
or therapeutic approaches. Detection and identification of certain cancers can be achieved with
antibodies targeted to some aspect of the tumor cells that are labeled with radiopaque nanoparticles
(58).
3 weeks 4 weeks 5 weeks
5.0
5 0 mm
Figure 2
Serial hepatobiliary contrast-enhanced micro-CT scans reveal progression of liver metastasis over time in a
mouse; arrows highlight tumors. Shown at 3 weeks (left), 4 weeks (middle), and 5 weeks (right). Reproduced
with permission from Reference 54.

E10.5 E11.5 E13.5 E15.5 E17.5 P0

a b c d e f
VR
g h i j k l
MIP
m n o p q r
MPR
200 µm 200 µm 200 µm 1 mm 1 mm 1 mm

Figure 3
Visualization of mouse development by micro-CT. Three viewing modes are used to generate micro-CT
images of mouse embryos at increasing stages of development (E10.5–E17.5). Also shown is a neonate at
postnatal day 0 (P0) (skin removed): volume rendering (VR) windowed to show external features to allow for
accurate staging (a–f ); maximum intensity projection (MIP) images show that blood is most intensely
stained, allowing delineation of many vascular structures ( g–l ); representative sagittal sections generated by
multiplanar reformatting (MPR) show differential staining of soft issues in all stages except E10.5 (m–r). By
E11.5, even structures such as somites (arrows in panel n) can be delineated. Reproduced with permission
from Reference 67.
3.2. Phenotype Characterization by Anatomic Structures

and Material Composition
Phenotype characterization generally involves measurement of organ dimensions (e.g., of airways
or volumes of lung, heart wall, or chambers) (59, 60), bone mineralization (61, 62), microar-
chitecture of the cancellous bone and cortical bone thickness (63), blood vessel lumen diameter
and branching geometry (64–66), or tumor size and impact on its surrounding tissues (e.g., bone
erosion or compression of adjacent blood vessels). Such measurements change in response to mat-
uration and/or disease or as a result of exposure to various pharmacological agents, environmental
conditions, or radiation. These dimensions and local CT grayscales can be measured directly from
the 3D CT image data, thereby representing the main application of small-animal CT imaging
to date. Figure 3 illustrates the use of micro-CT to provide anatomic information in fetuses
at progressive stages of maturation and immediately after birth. In this case, the soft tissue was
differentially opacified with iodine impregnation, but osmium tetroxide may also be used (68).
3.3. Physiological Spaces and Their Contents

For cardiovascular and respiratory imaging, motion needs to be accounted for to prevent blur-
ring. Additionally, if the function conveyed by that motion is of interest, then special scanners
and/or modes of scanner operation are needed. This information can be acquired either by post
scan selection of the appropriate phase of the motion (but this approach involves more radiation
exposure than needed) or prospectively “gated” scans, which involve triggering the scanner only
538 Ritman
a b
5 mm
Figure 4
Retrospectively gated cardiac micro-CT applied to the study of ventricular remodeling post myocardial
infarction in C57B16 mice. Coronal long-axis (top) and short-axis (bottom) images are shown of a mouse heart
(a) prior to and (b) 4 weeks following myocardial infarction induced by ligation of the left anterior
descending coronary artery. The arrows indicate the infarcted region near the apex of the left ventricle.
Four-dimensional images were acquired in 50 s with isotropic voxel spacing of 15 μm, using a low-dose
injection of Fenestra VC. Images courtesy of Sarah Detombe, Robarts Research Institute, University of
Western Ontario. Reproduced with permission from Reference 10.
when the desired phase of the cyclic motion is detected [via ECG for the heart or movement of
the thoracic cage (see Figure 4) or airway pressure] (69–73).
In addition to entire organs, imaging may also be of “macroscopic” physiological spaces such
as the airways (Figure 5), intravascular lumens (Figure 6), and the lumens of ducts (e.g., renal
tubules, ureters, bowel, bladder, and bile ducts, which tend to vary with time or pathophysiological
conditions) as well as less well-defined microscopic spaces such as the extravascular space between
the vessel endothelium and the parenchymal cells. The extravascular space swells with edema or
with deposition of pathological proteins (such as occurs in amyloidosis) or lipids (such as occurs in
atherosclerosis). These spaces can be detected and thereby delineated using contrast agents, which
selectively accumulate (or avoid) those spaces. To highlight a vascular tree, iodinated-molecule
solutions are used, and bile and renal ducts can be opacified via intravascular injection of contrast
agents that are selectively excreted by the liver or kidney, respectively. Very transient labeling of
those spaces can still be scanned despite the relatively slow micro-CT scans, if incremental scans
acquired from repeated contrast injections (76), use of long-duration contrast agent concentration
in the blood stream (77), or snap-freezing of the tissue of interest for subsequent cryostatic scanning
(78) are used to acquire the needed scan data. The volume of these spaces can be computed from
the increase in CT values of those spaces (79–82).
Figure 7 illustrates how the CT image data obtained in a sequence of rapid sequential CT
images can be used to generate contrast dilution curves in tissue during the passage of a transient

a b
5 mm
Figure 5
Minimum-intensity projection images of the same mouse taken at end expiration (a) and inspiration (b). The
airways are larger in the inspiration case, although there is some motion blurring because the image
acquisition occurred while the lungs filled and emptied, corresponding to the whole inspiratory phase. The
dark round objects in the bottom right of each panel are gas bubbles in the stomach and intestines.
Reproduced with permission from Reference 74.
bolus of intravascular contrast agent. As the bolus passes through the organ within several seconds,
the scan has to be accelerated by reducing the number of angles of view or reducing the exposure
time in each angle of view. Both methods result in poorer SNR of the CT image. This figure
shows that this loss of SNR in any one CT image can be reduced by use of CT image data in the
entire sequence of CT images (83).
a
b
C1 c
d
100 µm
Figure 6
Hierarchical investigation of vascular architecture. (a) Intact mouse brain vasculature scanned at medium resolution (16-μm voxel size)
using a desktop μCT system. (b) Z-buffer slice of the section marked red in panel a, revealing the frontal cortex. The orange square
labeled “C1” denotes a region of interest that was measured using SRμCT. (c) Z-buffer slice of SRμCT high-resolution data visualizing
intracerebral arteries and the capillary network. The latter is not visualized in the medium resolution data (b) but provides essential
structural characteristics of the vasculature, as, for example, the microinfarct marked by the orange rectangle. (d ) Surface rendering of
the infarct region marked in panel c suitable for detailed and high-quality three-dimensional analysis. Reproduced with permission from
Reference 75.
540 Ritman
500
Filtered back projection
PICCS full average prior
400 PICCS selected prior length 7
PICCS selected prior length 3
300
200
Δ HU
100
–100
–200
0 10 20 30 40 50 60
Time (s)
Figure 7
Illustrates the impact of prior image constrained compressed sensing (PICCS) application to a sequence of
computed-tomography images during the passage of a bolus of intravascular contrast agent through a “tissue
bed” within a test phantom. Note the wide variations in the contrast dilution curve generated from the usual
filtered back projection reconstruction sequence. This variation is due to poor signal-to-noise ratio (resulting
from the need to complete each scan before adequate scan data can be collected). Reproduced with
permission from Reference 83.
3.4. Tissue Perfusion, Drainage, and Secretion: Molecular Transport

Tissue perfusion is classically estimated from the spatial density of radiolabeled microspheres
that have lodged in the tissue microvasculature. This has been extended to the use of fluorescent
microspheres or microspheres that can be identified by their neutron-induced X-ray fluorescence.
These approaches involve cutting the specimens into small pieces (e.g., up to 1 cm3 ) for processing.
If those microspheres can be detected by micro-CT, then tissue perfusion can be assessed within
intact specimens (e.g., in situ rodent organs) because the spatial-distribution density is proportional
to the regional perfusion (84).
3.5. Need to Scan Entire Organ and Resolution

The volume that needs to be scanned is determined by several, sometimes conflicting, needs. Thus,
we would need to scan an entire organ if we are looking for a focal lesion such as early cancer.
By contrast, at high voxel resolution, it may not be practically possible to scan an entire organ at
that resolution owing to, for instance, limits on the X-ray detection-system resolution and size.
To estimate organ volume, relatively large voxel sizes can be tolerated, e.g., a (2 cm)3 heart needs
approximately 4000 voxels of (30 μm)3 if uncertainty better than 1% is desired). However, if a
200-μm-diameter basic functional unit (the smallest accumulation of diverse cells that behave like
the organ in which they are found, e.g., an hepatic lobule or a Haversian canal-centered osteome) is
of interest, then voxel resolutions of better than (100 μm)3 will be needed to enable unambiguous

detection of the unit, but a (3 μm)3 voxel would be needed if the volume of the basic functional
unit is to be estimated within 10%.
Reproducibility of CT scans is an important issue especially if longitudinal studies are involved.
Factors that affect reproducibility are scanner conditions (e.g., kVp, X-ray filtration, number of
angles of view, magnification, etc.) as well as voxel size. The smaller the voxel is, the less partial-
volume effect is present, especially at the interfaces with large contrast differentials (85) on micro-
CT grayscale and structural dimension data in longitudinal studies. Even with some variation
in scan parameters, the variation of measured dimensions of high-contrast structures such as
trabeculae is less than 4%.
With the generation of high-voxel resolution, large-volume scan data, and subsequent 3D-
image data sets (i.e., a large number of voxels) (86, 87), two problems resulted. One problem is the
transfer and storage of these huge data sets within a reasonable time period at a reasonable cost.
The other problem is a function of the display and analysis of those images. Although via Moore’s
Law hardware improvements may eventually overcome today’s data-handling problems, these
very improvements reintroduce the problems by producing increasingly larger data sets. Hence,
image-compression methodologies will always play an important role. For instance, compression
of computed tomography projection samples reduces hardware costs in terms of bandwidth and
memory requirements. Along this line is Prism CTTM , a low-complexity, CT-optimized, com-
pression algorithm that achieves up to 2.75:1 lossless compression (88). Prism CT decompression
operates at 100,000,000 samples per second using one core of a dual-core Xeon CPU. Wegner
et al. (89) describe a methodology to evaluate the effects of lossy compression on image quality to
achieve even higher compression ratios. They compared the image quality of five images created
from Prism CT-compressed projection data at a variety of compression ratios up to 4:1 using dif-
ferent image statistics. At 2:1 compression, the images had a pixel difference of ±1 HU compared
with the original image. For higher compression ratios, the difference images contained either
white-noise artifacts or noise levels that seem to affect some viewers more than others.
4. TYPES OF MICRO-CT APPROACHES

The above considerations apply to most current uses of small-animal CT. These applications
provided only minimal information about specific atomic content and essentially none about
molecular content. There are, however, other aspects of X-ray/matter interaction that can be
used to discriminate and quantitate concentration of specific atoms as well as of some chemical
bonds, i.e., a more direct aspect of molecular characteristics.
4.1. Attenuation-Based Scanning

Attenuation-based scanning is the basis for the most common and most technically straightforward
mode of CT scanning. The basic mechanism is the generation of a shadowgraph that is quantitated
by measuring the reduction in local X-ray intensity using the Beer-Lambert law, I = Io · e−μx ,
where I is the detected X-ray intensity at a detector pixel after passing through an object of
thickness x, Io is the incident X-ray intensity at the same pixel, and μ is the attenuation coefficient
of the specimen’s material. The attenuation coefficient (usually expressed as “/cm” of matter
traversed) decreases exponentially with increasing X-ray photon energy up to an energy of up
to approximately 50 keV due to the photo-electric effect (proportional to Z3 /E3 , where Z is the
atomic number and E is the X-ray photon energy). Beyond 50 keV, μ decreases slowly with
photon energy as a result of the Compton effect (largely independent of Z and falls slowly with
increasing E).
542 Ritman
The X-ray beam should be monochromatic if beam hardening is to be avoided. This is readily
achievable with a synchrotron (90, 91) using a diffraction crystal that can select those X-ray photons
within a ±50-eV energy range. This can also be achieved in part by filtering the X-ray beam by
using a layer of aluminum that preferentially removes the lower-energy photons. However, if the
Kα emission of the anode is to be used as the primary source (e.g., 17.5 keV for a molybdenum
anode), then a suitably matched filter with a K-edge absorption energy slightly greater than the
Kα energy would also selectively reduce the photons with energy greater than the Kα energy
(92) (e.g., 18 keV for a zirconium filter that matches the Kα of molybdenum). This approach is
effective, but for the bench-top X-ray source, it results in a greatly diminished X-ray flux and
hence requires long scan periods, which are generally incompatible with in vivo scanning.
4.2. Multienergy: K Absorption Edge Subtraction Scanning

At 10 keV, tissues of different density (e.g., fat, muscle, and bone) show considerable differences in
attenuation coefficients (3.1/cm, 5.6/cm, and 54/cm, respectively) and can be distinguished from
each other by their attenuation coefficient alone. However, the attenuation coefficient can change
dramatically at the K-edge of elements in the tissue. For instance, the attenuation coefficient of
iodine increases from 6.55/cm to 35.8/cm when the photon energy increases by a mere electron
volt around 33.1694 keV. Unfortunately, none of the common elements that occur naturally in
the tissues of the body (e.g., Na, K, Ca, P, etc.) have K-edges at sufficiently high kiloelectronvolt
photon energy that can be used to image isolated mouse organs, much less intact mice. In such
cases, given the very low photon energies (i.e., <10 keV), the attenuation of the X-ray is so
large (i.e., only 0.5% of photons pass through 1 cm of water, equal to the thickness of a mouse
abdomen) that useful images cannot be generated at acceptable radiation exposure levels. Use of
heavy elements with K-edge photon energies are useful for this imaging approach. Examples of
in vivo use include the following: xenon gas to study lung ventilation (Figure 8) as well as iodine
attached to sugar-like molecules injected into the blood stream to evaluate vascular anatomy or
detect heavy-metal contamination in tissues, such as lead accumulation in bone (94).
Conventional X-ray sources, which produce broad-spectrum bremsstrahlung suitable selection
of the anode material for its characteristic Kα emission of the material, combined with a thin-
metal foil filter, which has an absorption K-edge just above the Kα photon energy, can reduce
the spectral bandwidth to 30% or less. If an energy-discriminating detector is used, then photons
with energies of interest can be selected from the X-ray image data (Figure 9) (95–99).
4.3. Fluorescence-Based Scanning

Elements that are irradiated with X rays also fluoresce with X-ray photons that have an energy
characteristic of that element. Although this so-called Kα emission also has low energy for most
biological elements (e.g., Na 1 keV, P 2 keV, K 3.3 keV), this approach is particularly useful for
detection of heavy-metal contamination such as lead deposited in bone. This approach can have
several source/detector configurations (100), but all detect the fluorescent X rays at an angle to the
illuminating beam. Thus, the regular transmission image can also be recorded during this scan.
4.4. Scatter-Based Scanning

Coherent scatter of X rays has the same photon energy as the illuminating X ray and incoherent
scatter has less energy than the illuminating beam. These two scattering mechanisms distribute
their photons over different solid angles relative to the illuminating beam. The angular distribution

b
μL s–1
0.08
c
Heart 0.06
0.04
0.02
Vena cava 0
Figure 8
A dual energy subtraction computed-tomography image of a rabbit lung obtained during inhalation of xenon
gas (K-edge 34.56 keV). Note the bright left and right bronchi and the less-bright parenchymal signal of the
xenon in the alveoli. Reproduced with permission from Reference 93.
a b c
Iodine in right heart and
33 keV lung vessels
Barium in bronchi (lungs)
37.4 keV
Calcium in bones
10 mm 10 mm
Figures 9
(a) Computed-tomography (CT) image of a transaxial cross section of a mouse thorax. The bronchial tree had barium sulfate infused
and the pulmonary artery had an iodine-based contrast injected. These different materials and the skeletal bone cannot be distinguished
unambiguously on the basis of their CT grayscale values. (b) The use of principal component analysis by virtue of the ability to extract
the different X-ray photon energy components from the bremsstrahlung X-ray exposure allowed identification and quantitation of the
three elements by virtue of their different attenuation-to-photon energy relationships (c) (95).
544 Ritman
of coherent X-ray scatter intensity is characteristic for different materials, especially for polymeric
molecules such as collagen by virtue of the repetitive nature of the chemical bonds that have
lengths of the order of an X-ray wavelength. The scanner arrangement and subsequent processing
X-ray scatter: the
of the detected signals is very similar to that of the fluorescence approach. The angle-dependent X-ray detectable at an
pattern of coherent X-ray scatter is wavelength dependent and is expressed as q = (1/λ)sin(θ/2), angle to an X-ray beam
where λ is the X-ray photon wavelength and θ is the angle between the illuminating X-ray beam passing through matter
and the scatter direction. This pattern, described by q(θ), is called the momentum transfer profile.
This profile generally generated by observing the scatter over a range of angles θ. However,
bremsstrahlung X-ray beams plus an energy-discriminating detector array can be used to reduce
(or even eliminate) the need for multiple angles of view because q can also be represented by
q = (E/12.3)sin (θ/2), where θ is fixed so that the range in photon energy E (keV) provided by the
breakdown of the broad X-ray spectrum into a number of energy “bins” provides the equivalent
of the range of angles (101).
Collagen or protein, which contain strings of repetitive chemical bonds, differ distinctly in their
scattering characteristics. Different collagen types differ in their X-ray scattering characteristics,
such as occurs when the collagen is malformed in cancerous tissues, though all can be detected
(102). This is perhaps the most promising aspect of X-ray imaging with respect to the ability to
detect and discriminate a variety of molecules directly with X-ray imaging.
4.5. Phase-Contrast Scanning

Similar to the way light functions, X rays are refracted by matter, resulting in slight deviations of
the X-ray beam from its initial straight-line trajectory. However, the refractive index of X rays in
water is very small, 7.4 × 10−7 . Nonetheless, the phase-shift component (δ) of the refractive index
is orders of magnitude greater than the attenuation component (β) of the compound refractive
√
index n: n = 1 – δ – i.β, where i = −1. At 17.5 keV, there is a 180◦ phase shift caused by 50 μm
of tissue, whereas the change in intensity of an X-ray beam due to attenuation caused by 50 μm of
water is only 0.25%. The phase shift is proportional to mass density for most biological materials,
except when there is a high proportion of hydrogen present, which has almost double the effect
on phase owing to its unique electron charge to Z ratio.
Phase shift cannot be measured directly with imaging systems because the frequency of approx-
imately 1018 /second is much too fast. However, phase shift can be detected much more readily
by virtue of interference patterns that can be generated by several means. This can be achieved
by four methods. An early demonstration of this approach (103) involved use of a parallel beam
of narrow-bandwidth monochromatic X ray that is split into a reference beam that bypasses the
specimen so that the interference pattern generated by mixing the reference beam and the beam
passing through the specimen can be used to generate a map of the line integrals of phase shift at
each angle of view. This method is very effective but would be technically very difficult to scale up
for intact animals or large-tissue specimens. Another method involves using a Bragg diffraction
crystal, which is used to differentiate the very slight angle between the refracted and transmit-
ted X-ray beam (104). This also requires a parallel beam of very-narrow-bandwidth X rays and
involves rotating (rocking) the analyzer crystal over a range of angles to generate the multiple
images of X-ray intensities at each angle of view around the specimen and for each pixel at that
angle of view around the specimen. Nonparallel X-ray beam provides the most practical method,
and the one that most readily can accommodate a broad spectrum, as it involves use of multiple
venetian blind-like gratings (for instance, consisting of micrometer-wide layers of gold on silicon)
placed between the source and specimen (to convert the full area beam into a series of parallel
linear sources) and between the specimen and the detector array (to analyze the transmitted X-ray

BE13CH21-Ritman
Annu. Rev. Biomed. Eng. 2011.13:531-552. Downloaded from www.annualreviews.org ARI 6 June 2011 17:57
1 mm
Figure 10
Phase-contrast X-ray computed-tomography image of a rat kidney obtained at 35 keV. Whole structures of
the renal cortex, medulla, and pelvis were observed (114). Reproduced with permission.
image). The slight deflection of the X-rays due to the refraction in the specimen can be quantita-
tively detected by moving the analyzer grating across the image in steps that are fractions of the
interval between adjacent slats in the source grid, similar to the function of a vernier micrometer
(105–114). Figure 10 is an example of the high contrast that is achievable with this methodology.
5. TECHNICAL ISSUES
Keeping the X-ray source/detector system stationary (which is always the case if the X-ray source is
a synchrotron) and rotating the specimen make possible for the heavy components of the scanner
to be rigidly and accurately positioned with great precision. This works very well for isolated,
inert specimens; however, it generally requires a vertical (rather than horizontal) rotation of the
specimen, as this minimizes the gravity-induced movement or distortion of the specimen, relative
to its axis of rotation. In the living animal, the internal organs cannot be secured with sufficient
rigidly to prevent motion as the animal is rotated about a horizontal axis. Although rotation of a
living animal about a vertical axis minimizes this problem, maintenance of a vertical position over
an extended period of time is not physiologically possible and may interfere with cardiopulmonary
function.
Rotation of the X-ray source/detector system about a horizontal axis ensures that the animal
is on its physiological horizontal position, thus preventing distortion with angle of view. This
arrangement requires that the generally heavy source/detector components rotate so that deviation
from the ideal trajectory about the axis of rotation is smaller than the detector pixel size. The
duration of a complete scan depends on the X-ray flux that can be generated by the X-ray source,
as this governs the duration required to generate a projection image of sufficient quality (i.e.,
signal-to-noise versus motion blurring) to be used for tomographic imaging and to a lesser extent
the speed with which the necessary X-ray detection information can be recorded and transferred
to an off-scanner memory. These factors vary greatly depending on the specific X-ray modality
used to generate the tomographic image data. A novel X-ray-source methodology utilized a pulsed
X-ray source based on field emission from carbon nanotubes (115) and has been used to reduce
gated-scan temporal resolution down to 15 ms.
546 Ritman
6. RADIATION EXPOSURE
X-ray exposure results in direct disruption of chemical bonds and generates super radicals, which in
turn damage nearby molecules. Among those structures, DNA is of particular concern, as damage
there affects cell reproduction and control. The impact of radiation on tissues has been studied
for many years. Unfortunately, the main measure of impact was the mortality rate rather than
nonfatal consequences such as changes in the immune system or development of cancer. From
those studies, it is clear that the magnitude of any one exposure, the frequency of those exposures,
and the photon energy of the exposures all have an impact on the severity of the reaction to the
radiation as well as the rate and degree of recovery (116–118).
In micro-CT, the radiation exposure to the subject increases with the fourth power of the voxel-
side dimension if the image noise is to remain unchanged. Consequently, higher spatial resolution
corresponds with higher radiation exposure. The LD50/30 dose (following which 50% of animals
die within 30 days) for small animals is somewhat less than 8 Gray. A scan-generating (65 μm)3
voxel would involve 5 Gray exposure, tolerable in a terminal study, but not in the first of several
sequential scans of the same animal in a longitudinal study. A study specifically adding micro-CT
indicated that a 60-s scan at 15 mAs results in 14–20-mGy exposure, which is probably below the
threshold for affecting tumor growth (119). Using thermolucent detectors placed within the body
of mice, Willekens et al. (120) showed that for scans with a decreasing number of angles of view
(166 down to 21 around 180◦ ), the radiation exposure reduced from a mean of 5.5 mGy mAs−1 to
0.76 mGy mAs−1 in proportion to the number of angles of view used in the scan. However, the
contrast-to-noise ratio of the CT images decreased from 0.9 to 0.6 if 83-μm voxels were used and
reduced from 2.0 to 1.2 if 166-μm voxels were used. Kim et al. (121) clearly demonstrated that
synchrotron radiation can acutely cause tissue damage. The complex interplay between the rate
and amount of tissue exposure make assessment of the potential impact of the micro-CT scans
difficult to summarize. Hence, simulations are often used to provide a reasonable indication of the
relative magnitudes of the radiation exposures (122).
7. CONCLUSIONS
Micro-CT, in all its forms, has become a powerful instrument in biomedical research. Ongoing
improvement of image resolution and image contrast are likely to continue in the foreseeable fu-
ture. A major strength of small-animal CT is that it provides clinically relevant image information
of pathophysiology, at a scale equivalent to that of clinical CT scan resolution. Micro-CT can pro-
vide image data at resolutions much higher than achievable with clinical scanners such that deeper
insights into pathophysiological processes can be expected. Another strength of small-animal CT
is that it provides a test bed for development and evaluation of novel, clinically applicable, X-ray
imaging approaches.
DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
Dr. Ritman’s micro-CT work was supported in part by grant number EB000305 from the National
Institutes of Health.

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Current Status of Developments and Applications of Micro-CT
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Annu. Rev. Biomed. Eng. 2011. 13:531–52 Keywords

This article’s doi: Abstract

3.3. Physiological Spaces and Their Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538

4.1. Attenuation-Based Scanning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542

Whole animal Whole organ Basic functional unit Cells Organelles

Mini-CT Micro-CT Nano-CT

www.annualreviews.org • Microscopic Computed Tomography 533

2. MICRO-CT SCANNER COMPONENTS

high-intensity pulsed X-ray (19).

2.2. Flat-Panel X-Ray Detector Technology

www.annualreviews.org • Microscopic Computed Tomography 535

2.3. Algorithms to Complement Scanner Hardware Limitations

2.4. Micro-CT Image Transport, Storage, Analysis, and Display

3. RATIONALE FOR USE OF SMALL-ANIMAL CT

3.1. Disease Detection and Monitoring

3 weeks 4 weeks 5 weeks

www.annualreviews.org • Microscopic Computed Tomography 537

E10.5 E11.5 E13.5 E15.5 E17.5 P0

200 µm 200 µm 200 µm 1 mm 1 mm 1 mm

3.2. Phenotype Characterization by Anatomic Structures

3.3. Physiological Spaces and Their Contents

www.annualreviews.org • Microscopic Computed Tomography 539

3.4. Tissue Perfusion, Drainage, and Secretion: Molecular Transport

3.5. Need to Scan Entire Organ and Resolution

www.annualreviews.org • Microscopic Computed Tomography 541

4. TYPES OF MICRO-CT APPROACHES

4.1. Attenuation-Based Scanning

4.2. Multienergy: K Absorption Edge Subtraction Scanning

4.3. Fluorescence-Based Scanning

4.4. Scatter-Based Scanning

www.annualreviews.org • Microscopic Computed Tomography 543

detect and discriminate a variety of molecules directly with X-ray imaging.

4.5. Phase-Contrast Scanning

www.annualreviews.org • Microscopic Computed Tomography 545

www.annualreviews.org • Microscopic Computed Tomography 547

www.annualreviews.org • Microscopic Computed Tomography 549

histomorphometric indices of turnover. Bone 37(1):1–9

microspheres. Phys. Med. Biol. 51:N9–16

www.annualreviews.org • Microscopic Computed Tomography 551

Whole-Organ Tissue Engineering: Decellularization and

The Role of Body-on-a-Chip Devices in Drug and Toxicity Studies

Vision-Based Navigation in Image-Guided Interventions

Monika Zwerger, Chin Yee Ho, and Jan Lammerding p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 397

Nonthrombogenic Approaches to Cardiovascular Bioengineering

Cumulative Index of Contributing Authors, Volumes 4–13 p p p p p p p p p p p p p p p p p p p p p p p p p p p p 553

An online log of corrections to Annual Review of Biomedical Engineering articles may be

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