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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3835_Библиотеки_им_академика_М_И_Перельмана
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176 Y. Li and Z. Chen
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Methods and Results
Integrated IVOCT/NIRS and IVOCT/NIRF Imaging Systems
OCT has superior spatial resolution and is a promising tool for imaging the
microstructure of coronary artery walls. However, it is insufficient for accurate characterization of atherosclerotic plaque because of an inability to supply a molecular
contrast that is a key factor for determining vulnerability. NIRF is able to provide
molecular contrast for the identification of inflammation reaction and lipid components using an endogenous or exogenous biomarker. Therefore, a dual-modality
IVOCT/NIRS (or IVOCT/NIRF) imaging system which can perform IVOCT and
NIRS (NIRF) simultaneously is capable of providing both microstructure and compositional information of biological tissue for better plaque characterization.
Integrated IVOCT/NIRS System
A dual-modality IVOCT/NIRS imaging system has been reported by Tearney’s group
(Fard et al. 2013). The system applies a single-swept light source (center wavelength:
1282 nm; bandwidth: ~106 nm; repetition rate: 100 kHz) to perform both IVOCT and
NIRS imaging. In addition, the utilization of a swept light source allows one to detect
the spectrum in the time domain using a single-pixel photoreceiver. The schematic of
the dual-modality IVOCT/NIRS is shown in Fig. 7.1. For IVOCT, the light from the
swept light source IVOCT is divided into two beams by a 90/10 optical power splitter.
The light with 10% power is delivered to the reference arm. Another one is delivered
to the sample arm and then goes through the core of a double-clad fiber (DCF)
coupler, rotary joint and dual-modality IVOCT/NIRS imaging probe to illuminate
the tissue. The function of the DCF coupler is to propagate the IVOCT light by a
single-mode core of DCF with low light loss and separate the IVOCT backscattered
light and NIRF diffuse light from the sample. The backscattered light from IVOCT
and backreflected light from the reference arm will generate interference through
a 50:50 fiber coupler. Then, the generated signal will be detected by a balanced
photodetector. For NIRS detection, the backscattered light is collected through the
inner cladding of the DCF and then detected by a photoreceiver.
The IVOCT-NIRS imaging probe consists of a single-mode fiber (SMF), multimode fiber (MMF), and DCF. The light propagates through the single-mode core
of the DCF, a power combiner, and then goes through a single-mode fiber to illuminate the tissue. For transmission and detection, OCT light always propagates in
the single-mode core. Regarding the NIRS, the backscattered light is collected by a
MMF. Then, the multimode light and single-mode light are combined into a DCF
through the power combiner. At the distal tip, both SMF and MMF are terminated
by two angle-cleaved ball lenses as shown in Fig. 7.2. In addition. This configuration
allows the light to penetrate the biological tissue deeper and make the NIRS detection in the diffuse regime possible. In order to perform cross-sectional imaging, the
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Fig. 7.1 Schematic of a dual-modality IVOCT and NIRS imaging system. OFDI: optical frequency
domain imaging; SMF: single-mode fiber; DCF: double-clad fiber; AOFS: acousto-optic frequency
shifter
Fig. 7.2 Schematic for IVOCT/NIRS imaging probe. SMF delivers and collects OCT backscattered
light to/from tissue and an MMF collects NIRS light. The two fibers are combined into the DCF
using a commercial power combiner
fibers and power combiner are housed in a cardiovascular drive shaft and stainless
steel tubing. A transparent plastic sheath is used to enclose the drive shaft and distal
optics.
Ex Vivo Studies
In order to demonstrate the capability of this dual-modality IVOCT/NIRS imaging system, human coronary arteries were imaged ex vivo. IVOCT and NIRS data
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Fig. 7.3 IVOCT/NIRS images of cadaver coronary artery ex vivo
sets were acquired simultaneously. The imaging was performed in water in order to
minimize the reflection from the tissue. Figure 7.3 shows two representative crosssectional IVOCT/NIRS images of human coronary artery obtained from ex vivo
imaging. The NIRS image (outer) shows the absorption spectrum versus wavelengths
for each A-line. Figure 7.3a shows a lesion indicated by the white arrow that has a
low OCT signal. The corresponding NIRS image also demonstrates a homogenous
flat absorption spectrum which indicates the low possibility of a high lipid concentration. In Fig. 7.3b, a lesion with a low OCT signal can be visualized, denoted by
the white arrow. According to reported studies (Fleming et al. 2013; Madder et al.
2013), a negative absorption slope in the near-infrared wavelengths (1200–1400 nm)
corresponds to lipid content. In Fig. 7.3b, a high absorption at a shorter wavelength
is shown in the NIRS images which suggests that the plaque in Fig. 7.3b contains
abundant lipids. The ex vivo imaging result shows the dual-modality imaging system
is capable of providing structural information and chemical contrast.
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Fig. 7.4 Overall design of the dual-modality NIRF/OCT imaging system. DM: dichroic mirror.
PMT: photomultiplier tubes
Integrated IVOCT/NIRF System
NIRF based on exogenous or endogenous biomarkers has demonstrated the capability of identifying vulnerable plaque. Integrated with IVOCT, dual-modality
IVOCT/NIRF has the capability to provide microstructure and molecular contrast
(Yoo et al. 2011;Lietal.2017b; Wang et al. 2015; Giovanni et al. 2016). Figure 7.4
illustrates the overall setup of the dual-modality IVOCT/NIRF imaging system. Typically, a dichroic mirror is utilized to combine the OCT and fluorescence laser beams
together. The combined beam is delivered to tissue through the imaging probe. For
the IVOCT system, the output light is split by a 90:10 coupler. The reference arm (low
energy) has a fixed delay. The sample arm (high energy) includes a rotary junction
and imaging probe for transmitting the light to the tissue. The backscattered light of
OCT comes back through the same path. Then, the collected light from the sample
arm and reference arm generates interference through a 50/50 coupler. The interference signal is detected by a balanced photodetector which is able to remove the
noise by subtracting the two optical input signals from each other. For NIRF imaging, a continuous laser is normally used to excite the biological tissue. The center
wavelength of the laser source depends on the absorption spectrum of an exogenous
or endogenous biomarker. For an endogenous biomarker, a 633-nm wavelength has
been demonstrated to be able to identify atherosclerosis plaque. For NIRF imaging
based on an exogenous biomarker, ICG is often used to target the lipid-rich inflamed
plaque so a 785-nm laser source which corresponds to the absorption peak of the
ICG is used as the excitation source. The emission light can be separated from the
excitation light by a dichroic mirror, then filtered by a bandpass filter, and detected
by photomultiplier tubes (PMT).
The IVOCT/NIRF imaging probe is similar to the typical IVOCT imaging probe,
as shown in Fig. 7.5. The difference is that a DCF is applied instead of a single-mode
fiber to propagate the illumination light. The combined light can be delivered to
tissue through the single-mode core of the DCF, and OCT backscattered light will
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Fig. 7.5 Schematic of the dual-modality IVOCT/NIRF imaging probe. a Ball-lens-based
IVOCT/NIRF imaging probe. b GRIN-lens-based IVOCT/NIRF imaging probe. GRIN: gradient
index. DCF: double-clad fiber
Fig. 7.6 Combined IVOCT/NIRF images of rabbit aorta. a IVOCT/NIRF cross-sectional image
along longitudinal direction. b Comparison of peak plaque target-to-background ratio (TBR) signals
in vivo between ICG-injected and saline-injected rabbits of aorta and iliac artery
return through the same path. Fluorescence emission light can be collected by the
inner cladding of the DCF.
Animal and Clinical Validation Studies
For the integrated IVOCT/NIRF imaging system, in vivo rabbit studies have been
reported by Lee et al. using an ICG-based integrated IVOCT/NIRF imaging system
(Lee et al. 2014). Figure 7.6 shows representative co-registered IVOCT and NIRF
images. In the IVOCT images, the microstructure of the coronary artery can be visualized clearly. From the NIRF images, the intensity corresponds to the compositional
data of coronary artery plaque. The high intensity represents the high possibility of the
existence of a lipid component. Figure 7.6b shows the plaque target-to-background
ratio (TBR) of four groups (Aorta-ICG, Aorta-Saline, Iliac-ICG, and Iliac-Saline).
From the results, it can be seen that the ICG-injected group has higher TBR compared with the saline-injected group at the injured section, which demonstrates the
capability of this NIRF to identify the lesions from normal biological tissue.
Based on an endogenous biomarker, Ughi et al. have reported the first clinical
imaging of human coronary arteries in vivo using a dual-modality IVOCT and NIRF
imaging system in which IVOCT and NIRF data were obtained from 12 patients
with coronary artery disease (Ughi et al. 2016). Figure 7.7 shows representative
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Fig. 7.7 IVOCT/NIRF imaging of human coronary arteries. a Angiography. b NIRF image.
c Combined IVOCT/NIRF image of a diseased artery. d Enlarged IVOCT image. e Combined
IVOCT/NIRF image of a healthy artery. f 3D cutaway rendering
IVOCT and fluorescence images. In the IVOCT image, microstructure of the arterial
wall can be visualized. With respect to fluorescence imaging, it is excited by the
633-nm laser and can be used to further identify plaque types based on maximum
NIRF intensities. From Fig. 7.7c, the lipid lesions are marked, and the NIRF signal
is significantly high at one of these lesions. For a normal blood vessel (as is shown in
Fig. 7.7e), NIRF intensity is low and homogenous, which agrees with IVOCT image
results well. According to the maximum intensity change of the fluorescence signal,
IVOCT/NIRF imaging has the potential to differentiate plaque types. Figure 7.8
shows the maximum fluorescence intensity of different plaque types.
The ex vivo and in vivo imaging results verify that the dual-modality IVOCT
and NIRF system is able to provide microstructure and molecular contrast simultaneously which shows the potential for enhanced visualization, identification, and
quantification of tissue contents. However, for NIRS, basic spectra for chemical composition need to be further studied in order to extract the different compositions of
biological tissue. In addition, the mechanistic details with regard to ICG accumulation, such as factors determining its uptake by macrophages and binding to lipids,
still require further study.
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Fig. 7.8 Analysis of maximum NIRF plaque intensities for different plaque types
Integrated IVUS/NIRS and IVUS/NIRF Imaging Systems
NIRS/NIRF is a promising method for the identification of chemical components
of atherosclerotic plaque composition. IVUS imaging offers direct visualization of
the morphology of the arterial structures. Considering that both composition and
structure are highly associated with vulnerability of atherosclerotic plaque, a dualmodality imaging system combining NIRS or NIRF with IVUS is essential for accurate diagnosis in the clinic. Currently, a hybrid technology combining NIRS and
IVUS has been developed by InfraRedx Inc., TVC Imaging System
able to obtain structural and compositional data of coronary artery plaques simultaneously. In addition, a dual-modality imaging system which integrates IVUS and
NIRF together has been reported. This section will introduce combined NIRF/IVUS
and NIRS/IVUS imaging systems and discuss the corresponding imaging results.
TM
, which is
Integrated IVUS and NIRF System
The imaging system consisting of an NIRF system, IVUS system, and an imaging
probe is shown in Fig. 7.9. For the NIRF part, a DCF coupler is often applied to
propagate excitation light and collect the emission light. Alternatively, a free-space
optical path can also be used to separate the excitation light and emission light.
The center wavelength of the fluorescence laser is determined by the biomarker. For
transmission, the fluorescence light goes through the single-mode core of the DCF
from port A to port S, and the small diameter of the single-mode core contributes
to high fluence on the surface tissue which enables a high-efficiency excitation. The
emission light comes back from the first clad of the DCF and core (port S) to a
multimode fiber (port B) whose larger diameter and higher numeric number (NA)
enhance the capability of collecting emission light, filtered by a bandpass filter, and
then detected by a photomultiplier tube. For IVUS imaging, a Pulser/Receiver is used
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Fig. 7.9 Overall design of the dual-modality NIRF/IVUS imaging system. DCF: double-clad fiber.
PMT: photomultiplier tube
Fig. 7.10 Schematic of dual-modality NIRF/IVUS imaging probe. a Ball-lens-based NIRF/IVUS
imaging probe. b GRIN-lens-based NIRF/IVUS imaging probe. GRIN: gradient index
to generate and detect ultrasound signals. In order to obtain co-registered IVUS and
NIRF images, a trigger signal from the Pulser/Receiver is used to generate ultrasound
signals and synchronize the data acquisition of IVUS and NIRF signals.
Figure 7.10 is the schematic of a typical NIRF/IVUS imaging probe. Optical
components are similar to the IVOCT/NIRF imaging probe. In order to perform
ultrasound imaging, an ultrasound transducer is sequentially aligned with the optical
components.
In Vivo Animal Study
Abran et al. have imaged healthy and atherosclerosis rabbit aortas in vivo after
ICG injection using a combined IVUS/NIRF imaging system (Abran et al. 2015).
Figure 7.11 shows representative co-registered IVUS/NIRF images. Figures 7.11a–e
show co-registered images from an atherosclerosis rabbit in which the echogenicity and intimal thickening can be visualized. In addition, an enhanced intensity of
the NIRF signal can be found. Figure 7.11f shows co-registered images from a healthy
rabbit in which a typical layered structure and relatively low and homogenous NIRF
signal are demonstrated.
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Fig. 7.11 Integrated IVUS and NIRF images from rabbit aorta. a–e Cross-sectional IVUS/NIRF
images from cholesterol-enriched diet rabbit; f Cross-sectional IVUS/NIRF images from a regular
diet rabbit. The contour in the IVUS image represents the fluorescence signal intensity. Red arrows
show increased echogenicity in (a, e) and intimal thickening in (b, f)
Integrated IVUS and NIRS System
Figure 7.12 shows the commercial NIRS/IVUS imaging system. It consists of a
3.2-French rapid exchange catheter which is compatible with 6F-guiding catheters,
a pullback and rotation device, and a console that houses the scanning NIR laser,
computer and two monitors. For the NIRS/IVUS catheter, an optical fiber is applied
to deliver near-infrared light onto biological tissue and collect the backscattered light
in the form of an imaging spectrum. A single-element ultrasound transducer (center
frequency: 40 MHz; axial resolution: 100 µm) was applied for IVUS imaging. The
commercial NIRS/IVUS imaging system is able to perform imaging with a rotation
speed of 16 rps and pullback speed of 0.5 mm/s. Currently, an upgraded version
TM
of the TVC Catheter Imaging System
utilizes a new ultrasound transducer with
an extended bandwidth to generate IVUS images at frequencies between 30 and
70 MHz, which contributes to improved resolution and imaging depth.
Clinical Validation Studies
Several clinical studies using NIRS/IVUS have been reported. Figure 7.13 is a combined NIRS/IVUS in vivo image from a human subject. The outer ring image is a
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Fig. 7.12 Commercial NIRS/IVUS imaging system. a The console, which houses the scanning
NIR laser, computer and two monitors. b Pullback and rotation device. c NIRS/IVUS imaging
catheter. d Schematic of imaging catheter. e Photo of imaging catheter
near-infrared spectroscopy chemogram that indicates the location and intensity of
the lipid core with the probability of lipid content presence. The inner gray image
is a simultaneously acquired ultrasound image in which the structure of the entire
arterial wall can be visualized.
The combined NIRS/IVUS imaging system is able to obtain IVUS and NIRS
images simultaneously which provide both plaque composition and morphology
of the arterial wall. In addition, combined NIRS/IVUS has shown the potential to
provide improved LCP detection and fibroatheroma detection compared to either
IVUS or NIRS used alone (Brilakis and Banerjee 2015; Puri et al. 2015). In the
future, multiple ongoing clinical trials will hopefully validate this tool for vulnerable
plaque detection as well as treatment management.
Summary
Dual-modality imaging technologies, including IVOCT/NIRF, IVOCT/NIRS,
NIRF/IVUS, and NIRS/IVUS, are valuable tools that are able to provide both structure and molecular contrast for the characterization and quantification of cardiovascular tissue. Currently, IVOCT/NIRF and IVUS/NIRS have been applied in a
clinical trial and demonstrate improved capability of diagnosis of cardiovascular
disease. Such dual-modality technologies that combine structural and functional
imaging together will further improve the capability of diagnosis and managment
of cardiovascular diseases.
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