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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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6 Dual-Modality Fluorescence Lifetime and Intravascular … 155
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Fluorescence measurements from en face frozen sections of human coronary arteries
and aorta were acquired with an Olympus BH-2 metallurgic bright-field microscope
and an argon ion laser (476 nm excitation) (Fitzmaurice et al. 1989). The fluorescence properties of collagen, elastin, lipid, and calcium allowed for normal arteries
and atherosclerotic arteries to be differentiated. Building on this work, Verbunt et al.
more carefully studied the fluorescence of lipid and calcium-rich plaques by analyzing ceroid deposits in these specimens (Verbunt et al. 1992). Ceroid, a type of
lipopigment, was found to have an autofluorescence spectrum that was wider and
red-shifted in comparison with both collagen and elastin. In 1994, a study was done
that showed autofluorescence spectra could distinguish fibrous, aneurysmal, and normal samples but not lipid and calcium-rich plaques. This work was performed on
samples of the abdominal aorta from cadavers and femoral artery from bypass surgeries with an He-Cd laser (442 nm excitation) (Papazoglou et al. 1994). In 2000, a
fluorescence spectroscopy study was performed in vivo to observe plaque disruption
in a rabbit model (Christov et al. 2000).
During the 1990s, the characteristics of plaque that indicate higher levels of risk
for causing heart attack were meticulously studied (Virmani et al. 2006). Subsequently, studies that focused on using fluorescence to assess features of plaque vulnerability were initiated. The first study to use fluorescence to look for a thin-capped
fibroatheroma was performed by Arakawa et al. in human femoral and coronary arteries obtained from cadavers (Arakawa et al. 2002). Autofluorescence was induced with
a He-Cd laser (excitation 325 nm); autofluorescence properties of collagen, elastin,
and lipid were compared to the measurements from the human tissue to determine
what fluorophores were fluorescing in the tissue samples. Plaques with lipid cores
had fluorescence spectra that were red-shifted and broader compared to normal tissue
and collagenous plaques. Lipid core fluorescence properties were similar to those of
oxidized low-density lipoprotein (oxLDL), indicating the presence of this molecule
in lipid cores. The fluorescence properties of fibrous plaques were similar to collagen
and those of normal artery were similar to elastin. A classification algorithm was able
to use the fluorescence spectra from these molecules (collagen, elastin, oxLDL) to
distinguish normal artery, lipid cores, atheroma, or pre-atheroma with 86% accuracy. This work also showed that fibrous cap thickness correlated well with spectral
collagen content (R = 0.65, P < 0.0001) (Arakawa et al. 2002).
Time-Resolved Fluorescence Spectroscopy and Imaging
Studies of Atherosclerotic Lesions
Point Measurements of Time-Resolved Fluorescence Spectroscopy
Single wavelength measurements Due to the increased ability of time-resolved
fluorescence spectroscopy (TRFS) to resolve fluorophores with overlapping fluorescence intensity spectra, these studies were used to determine if they could more
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accurately identify plaque composition than fluorescence intensity spectroscopy
alone. The TRFS point measurement technique involved for this work consisted of
exciting at a single wavelength and recording the time-resolved fluorescence decay of
the emitted light at a single wavelength band. Fluorescence emission intensity from
normal and atherosclerotic aorta was found to differ at 340 and 380 nm with 308 nm
ultraviolet laser excitation (Baraga et al. 1989). A binary classification scheme was
used to distinguish normal from the atherosclerotic aorta in 56 of 60 total cases by
using these wavelength bands that characterized the tryptophan content (340 nm)
and the elastin-to-collagen ratio (380 nm) (Baraga et al. 1990). Part of this study
also used a time-correlated single photon counting technique (TCSPC). With this
technique, fluorescence lifetime was shorter in the tryptophan region (340 nm) and
longer at the collagen/elastin region (380 nm) (Baraga et al. 1989). A frequencydoubled mode-locked and cavity-dumped continuous wave dye laser for picosecond
pulse generation at 320 nm was used by Andersson-Engels et al. with TCSPC to
acquire time-resolved signal from the human aorta samples in vitro. Both collagenous and calcified plaques exhibited longer fluorescence lifetimes than normal artery
at 400 and 480 nm (Andersson-Engels et al. 1990). Several studies by Maarek et al.
reported the spectrally resolved time-resolved fluorescence spectroscopy characterization of arterial wall constituents, including collagen, elastin, and lipid as well as
characterizing specific lesion types (Maarek et al. 1997, 1998; Marcu et al. 1998).
Multiple wavelength measurements Following the TRFS studies that interrogated single wavelength bands of emitted fluorescence light per measurement, newer
studies employed a technique that allowed for multiple bands of emitted fluorescence
to be temporally resolved. These newer studies could be faster and provide more
information than earlier TRFS studies. Human aortic samples were first studied with
this technique (94 samples, postmortem) (Maarek et al. 2000; Marcu et al. 2003).
Excitation was performed with a 337 nm nitrogen laser, and emission was collected
through silica fibers combined in a single probe. Wavelength selection occurred with
a scanning monochromator, a gated micro-channel plate photomultiplier was used
to measure the emission waveform, and sampling was performed with a digitizing oscilloscope. The intrinsic fluorescence decays were computed with a Laguerre
deconvolution method, from which the time-integrated fluorescence emission spectrum and fluorescence lifetime were derived. TRFS spectra from the aortic samples
varied with the progression of atherosclerosis–fluorescence intensity and average
lifetime. The substantial differences in time-resolved properties between clinically
relevant plaque compositions suggested that TRFS parameters could translate to
arterial disease diagnostic markers. TRFS was also found sensitive to macrophage
infiltration in plaques (Marcu et al. 2005) and the presence or absence of matrix metalloproteinases (Phipps et al. 2011). A TRFS study was also conducted in vivo in an
atherosclerotic rabbit model, demonstrating that TRFS could discriminate between
macrophage and collagen content in atherosclerotic plaques (Marcu et al. 2005).
A similar system as described above was also used to study time-resolved fluorescence emission of normal and atherosclerotic human coronary arteries (58 coronary
segments from 11 subjects, postmortem) (Marcu et al. 2001, 2003). Similar to the
study in the human aorta, this work showed parameters derived from time-resolved
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fluorescence spectra could be used to enhance discrimination between normal and
different grades (I, II, III, IV, Va, and Vb) of atherosclerotic lesions as defined by the
American Heart Association (AHA). Lipid-rich lesions were distinguishable from
other lesion types, particularly fibrous lesions and normal artery wall. The fluorescence emission of lipid-rich lesions matched that of lipid components and the
fluorescence emission of fibrous lesions matched that of collagen type I. This study
demonstrated that time-resolved spectra varied significantly between lipid-rich (more
unstable) and fibrous lesions (more stable), further validating the potential impact
TRFS could have if implemented intravascularly.
Fluorescence Lifetime Imaging Microscopy (FLIM) Studies
Fluorescence lifetime imaging microscopy (FLIM) allows for time-resolved spectra
to be acquired for an image versus a single point. An early fluorescence lifetime imaging microscopy (FLIM) system with 10 ps temporal resolution was introduced for
biomedical applications in 1998. The system acquired fluorescence lifetime images
to be acquired through excitation with a commercial Ti: Sapphire laser (415 nm), a
time-gated image intensifier, and an intensified CCD camera (Dowling et al. 1998).
Lifetime differences were found between elastin, collagen, and aorta samples. More
recent advances in FLIM technology revolutionized the potential of this technique
positive impact in clinically relevant biomedical applications (De Beule et al. 2007;
Munro et al. 2005).
In 2011, atherosclerotic aortas were studied with a FLIM system implemented in
a wide-field fiber bundle (Phipps et al. 2011). N = 11 human aorta samples (N =
48 locations) were imaged. A pulsed nitrogen laser was used for excitation (337 nm,
700 ps width), an imaging bundle with 10,000 optical fibers in a 0.6 mm outer diameter probe was used to collect fluorescence, and a fast-gated (up to 400 ps) intensified
CCD camera generated images. Two emission wavelength bands were detected,
F377: 377/50 nm and F460: 460/60 nm (center wavelength/bandwidth). This combination of wavelengths provided discrimination between intrinsic fluorophores related
to plaque vulnerability. Different tissue types were identified with average lifetime
and Laguerre deconvolution parameters (Jo et al. 2005). N = 4 distinct regions of
interest (ROIs): Lipid-rich (LR), collagen-rich (CR), elastin-rich (ER), and elastin
+ macrophage-rich (E + M) were identified based on histopathology from N = 81
regions of interest (ROIs) within the FLIM images. FLIM-derived parameters were
distinct in each group.
Another FLIM investigation with a wide-field fiber bundle was used to study
ex vivo human coronary arteries and found discrimination between collagen-rich
plaques and normal (elastin-rich) artery (Thomas et al. 2010). However, this study
did not include lipid-rich plaques, and thus, the extensive comparison with TRFS
results could not be made.
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Wavelength-Multiplexed Fluorescence Lifetime Imaging (FLIm)
of Planar Samples
FLIM enables the acquisition of whole images of the field of view, but r elies on
bulky and stiff fiber bundles. Multispectral TRFS measurements can be performed
using a single fiber for excitation and collection, but the slow acquisition time is
prohibitive for the acquisition of images. Here, we present a fluorescence lifetime
imaging (FLIm) method that relies on a single fiber for excitation and collection and
is able to acquired data at high speed (Sun et al. 2011). This approach was initially
reported in 2008 (Sun et al. 2008) and allowed simultaneous acquisition and storage of fluorescence data from three wavelength bands in a few microseconds. When
coupled with a compact x-y-z 3D positioning stage, this system also allowed the
collection of point measurements from these wavelength bands in a fast-scanning
mode that could then be reconstructed to create fluorescence lifetime imaging (FLIm)
images (Sun et al. 2011). This scanning system was validated in ex vivo atherosclerotic aortas (Sun et al. 2011). Using the fast-scanning system, FLIm images were
created that demonstrated the distinction between plaque types. A similar system
has also been incorporated within optical coherence tomography (OCT) for arterial
imaging (Jo et al. 2015). We note here the difference between FLIM and FLIm. The
FLIm technique described here acquires multiple wavelengths of emitted fluorescence simultaneously through a single fiber in contrast to the FLIM technique that
acquires high-resolution images of the emitted fluorescence (microscopy) at a single
wavelength band per measurement. Moving forward, we will show how this single
fiber, high-speed technique has been further developed to allow for the technology
to be translated to an intravascular catheter.
Challenges for Implementing FLIm in an Intravascular
Catheter
This chapter will discuss the necessary qualities of a catheter-based FLIm system
and the challenges to achieving these specifications that include:
• Fast-scanning speed to account for the fact that blood will need to be flushed from
the field of view, which can only be done for short amounts of time for patient
safety
• Pairing with a morphologic imaging modality that will guide FLIm measurements
from within the coronary artery tree
• A flexible fiber that is able to reach the coronary arteries and acquire images from
tortuous vessels.
FLIm excitation and signal cover the near-UV to visible range. Over this wavelength
range, blood presents strong absorption, it is therefore necessary to displace blood
from the field of view during imaging. In a similar way to OCT, this can be achieved
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using a balloon located proximally to the imaging catheter field of view in combination of i njection of clear fluid, or bolus injection of clear fluid without occlusion.
In both cases, this restricts the imaging duration as blood flow interruption or fluid
injection duration need to be limited to a few seconds. A system able to acquire FLIM
images in vivo must therefore be able to measure locations with speeds in the kHz
range.
Coronary arteries, in particular when diseased, present a small cross section and
notable tortuosity.Successful navigation through lesions places a constraint on device
cross section and flexibility. Additionally, FLIm is not depth-resolved and only provides information down to 200 µm from the lumen surface. To provide navigational
information (lumen dimension, localization in the arterial tree) and structural and
anatomical information (plaque burden, presence of necrotic or calcified cores, etc.),
it needs to be combined with a morphological imaging technique such as IVUS.
While the biochemical information provided by FLIm is ideally complementing the
morphological information provided by IVUS, integration of FLIm with IVUS creates constraints for the design of the instrument. Namely, both FLIm and IVUS
elements need to be integrated into a low profile catheter, and the imaging section
needs to be both optically transparent in the near-UV to visible and present low sound
impedance in addition to being flexible.
FLIm-IVUS Catheter System Instrumentation
The FLIm instrumentation dedicated to intracoronary imaging is composed of a multispectral high-speed time-domain fluorescence lifetime imaging system, integrated
with a clinical 40 MHz IVUS system. The design of the FLIm instrumentation as
well as its integration into a bimodal catheter system is described in the following
sections.
Principle of the High-Speed Fluorescence Lifetime Imaging
Instrumentation
The FLIm instrumentation (see Fig. 6.1) consists of a pulsed UV fiber laser (20 kHz,
80 ps pulses, Fianium, UK), a wavelength selection module (WSM) that directs
the laser light from the laser to the sample via the excitation/collection fiber optic.
Autofluorescence generated by the sample is then collected by the same fiber and
transmitted to the WSM where it is split into four different bands matched with the
emission wavelengths of fluorophores expected in diseased and healthy arteries.
Optical temporal multiplexing is performed by routing the signal from each band
through different optical delay lines (1, 10, 19, and 28 m). The 45 ns delay between
channels introduced by the fibers enables fluorescence contribution from each of
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Fig. 6.1 Fast FLIm principle of operation: A pulsed UV source delivers excitation light to the
vessel wall via a fiber optic channel (100–200 µm core silica fiber) integrated inside of the FLIm-
IVUS motor drive and catheter. Autofluorescent light generated by the arterial wall is collected
and transmitted via the same fiber and separated in four different wavelength bands. Temporal
multiplexing achieved by transmitting the contribution of each channel to the photodetector using
different length of fiber optic enables sampling of all four bands using a single channel 12.5 GS/s
digitizer. For each excitation pulse, full fluorescence decays over four different wavelengths are
acquired
the four spectral bands to be sent to a single multi-channel plate photomultiplier
(R3809U-50, Hamamatsu, Japan), without overlap of the signals. The electrical signal is amplified (C5594 Hamamatsu, Japan) and sampled using a high-speed digitizer
(12.5 GS/s, 3 GHz, 8-bit, 512 Mbytes, PXIe-5185, National Instruments, Austin, TX).
This detection method enables acquisition of fluorescence decay from multiple
wavelength bands from a single excitation pulse, therefore enabling much higher
acquisition speeds than alternative fluorescence lifetime methods (Stary et al. 1994).
Successful measurements of fluorescence decay using a pulse sampling technique
rely on a high enough number of photons reaching the photodetector following each
excitation pulse. Therefore, excitation pulse energy, throughput of the excitation and
collection optical paths, and width of each spectral band of the instrument need to
be optimized.
FLIm-IVUS Intravascular Catheter System
The FLIm system described above is ideally suited to the implementation of FLIm
in the intravascular setting since it is able to work at high speed and requires only
a single multimode fiber for fluorescence excitation and collection. Nevertheless,
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challenges to implement intravascular FLIm highlighted previously, coupled with
the high collection efficiency required for successful implementation of the pulse
sampling method lead to several engineering challenges. The design of a FLImIVUS catheter system suitable for in vivo interrogation of coronary arteries required
several design iterations until a configuration able to fulfill all requirements was
identified.
The first design, characterized by IVUS and FLIm channels arranged in a parallel
configuration, allowed for independent rotation of the ultrasonic and optical channels
(using independent motor drives) within an 8 Fr outer diameter catheter sheath (Bec
et al. 2012). No significant modification of the commercial IVUS system/catheter
was required. The ultrasound imaging core was still introduced in the original IVUS
sheath, while the FLIm fiber was housed in an acrylic tube. With this catheter, the
twin tube imaging section was enclosed in a compliant siloxane balloon that was
inflated with saline solution during imaging and displaced the blood from the field
of view. This catheter enabled the initial technical performance evaluations of the
rotational FLIm system and the first in vivo measurements in arterial vessels autofluorescence in pulsatile blood flow in swine peripheral arteries (Bec et al. 2014). In
this configuration, the scanning pullback length was limited to 6 mm.
This design was further refined in a subsequent design using a parallel/sequential
configuration (Design 2). It consisted of a catheter with a small cross-sectional profile
(3.2 Fr) relying on sequential scanning of the field of view by parallel independent
FLIm and IVUS imaging cores, advancing sequentially into a single sheath and imaging section (Ma et al. 2015) by a dedicated hardware and software interface. The use
of polymethylpentene (TPX med-18) for the imaging section provided both high
transparency and low autofluorescence in the near-UV-visible range, required for
FLIm operation, and low sound impedance, required for IVUS operation. Similarly
to Design 1, no significant modification of the commercial IVUS system/imaging
core was required. This catheter enabled us to demonstrate for the first time the
ability of our FLIm system to rapidly acquire spectrally resolved fluorescence lifetime data in helical scanning from tubular and tortuous structures (including ex vivo
porcine coronary arteries in intact hearts) (Ma et al. 2014). Moreover, this design
enabled the generation of experimental data from diseased human coronary arteries supporting the development of methods for IVUS image segmentation, FLIm
data acquisition under IVUS guidance, and methods/algorithms for plaque diagnosis
(Fatakdawala et al. 2015; Gorpas et al. 2015). However, in this configuration coregistration between FLIm and IVUS is only achieved in the absence of motion, and
thus, this was not suitable for in vivo use (Ma et al. 2015).
These limitations were addressed in the third design of the instrument, reported
in (Bec et al. 2017). It was built on the knowledge gained from the two earlier
designs and consisted of a catheter that fully integrated FLIm imaging capability
TM
into an existing clinical IVUS platform (iLab
Boston Scientific). A custom 3.7 Fr
monorail bimodal imaging catheter includes both a 40 MHz ultrasound transducer
and optical channel in tandem configuration (see Fig. 6.2). Additionally, the IVUS
motor drive was modified to accommodate an optical channel. Thus, both the 40 MHz
transducer and the fiberoptic are rotated by the same motor drive. This design enabled
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Fig. 6.2 Design 1 (Parallel): enabled co-registered FLIm-IVUS data acquisition in vivo in swine
peripheral arteries. Design 2 (Sequential): allowed for co-registered FLIm-IVUS data acquisition
in ex vivo excised human coronaries but co-registration is susceptible to motion artifacts. Design
3 (Integrated): FLIm and IVUS fully integrated into a single 3.7 Fr imaging core. With Boston
Scientific support, their IVUS motor drive (MDU5 PLUS) was modified to incorporate an optical
channel. This system was used for co-registered FLIm-IVUS data acquisition in vivo i n swine
coronary arteries as well as ex vivo diseased human coronary arteries
the acquisition of directly co-registered FLIm-IVUS data in a single pullback of the
catheter. With this system, 25,000 independent point spectroscopy measurements are
acquired in 5 s, using an 1800 rpm rotation speed, and 4 mm/s pullback speed. The
20 mm axial field of view can be increased by using higher pullback speeds, thus
increasing axial sampling. This novel catheter was found as being fully compatible
with in vivo coronary interventions (Bec et al. 2016).
Methods for Data Processing
FLIm data were processed using a Laguerre expansion technique (Upston et al. 2002)
due to the speed of this nonparametric technique and its ability to perform deconvolution without a priori information about the fluorescence emission. The acquired
waveform of each channel was fitted with a set of Laguerre functions convolved with
the instrument response function. The weights obtained from the fitting operation
were then applied to the original Laguerre basis functions (without IRF convolution)
to estimate the original fluorescence decay. The average fluorescence lifetime was
then derived from this decay. For each measurement, the average lifetime and fluorescence intensity were computed and maps were generated where the location of each
measurement corresponds to a distinct angular pullback location of the imaging core
of the catheter. IVUS data were also processed to identify the vessel lumen (Spite
and Serhan 2011) and to estimate the distance between catheter and vessel wall.
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The distance map was used to correct the FLIm intensity images from variations of
light excitation/collection due to changes in probe-to-wall distance (Angheloiu et al.
2011). This step enables quantification of the amount of fluorescence emitted in each
location. For each channel, intensity ratio maps were created by normalizing each
pixel of the intensity images of each channel by the summed intensities of the same
pixel across all four channels. Intensity-weighted lifetime maps were then created
where colors represent lifetime values, while brightness represents the amount of
fluorescence. Spectral ratio weighted lifetime maps, where color represents lifetime
while brightness represents spectral contribution, were created. This representation
contains both time-resolved and spectral information and is independent of changes
in excitation/collection efficiency as they are inherently ratiometric. Finally, fluorescence lifetime information was projected on the vessel surface recovered from IVUS
to generate 3D renderings of the fluorescence lifetime maps.
FLIm-IVUS Imaging of In Vivo Swine Coronary Arteries
The ability of the catheter system to access tortuous anatomy, flush blood from the
imaged location, image varioussized vessels, recover the signal with sufficient signalto-noise ratio, and discriminate targets based on lifetime and spectral information
was tested in 60–70 kg swine, which present morphology similar to humans.
Flushing was performed through the catheter guide using a power injector for
precise control of the injection parameters. 10% LMD solution (Dextran 40) with
5% glucose was used as a flushing medium. This solution, evaluated for human use
as an alternative to iodinated contrast for OCT flushing (Ozaki et al. 2012; Frick et al.
2014), is well suited to FLIm imaging due to its high transparency in the near-UV,
low toxicity, and high viscosity. Flushing flows between 2 and 10 cc/s were evaluated.
It was observed that flow above 4 cc/s was sufficient to provide adequate clearing.
The ability of the system to recover lifetime information from the vessel wall
in vivo was demonstrated by imaging a healthy section of coronary, expected to have
a homogeneous composition, and computing the average lifetime (Bec et al. 2017). In
spite of large variations of the amount of signal collected for different regions of the
field of view, a low standard deviation was obtained (5.19 ± 0.12 ns). Subsequently,
a stent with fluorescent markers was placed and imaged. Both spectral and temporal
information enabled easy identification of the marker locations, as demonstrated
in Fig. 6.3. Finally, the ability to recover lifetime measurements was evaluated in
larger vessels (5 mm diameter). In that case, an increase in standard deviation of the
measured lifetime was observed compared to smaller vessels, but the correct lifetime
was still retrieved (5.14 ± 0.33 ns).
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Fig. 6.3 View of large animal surgical facility at UC Davis (top left): Boston Scientific IVUS
interface provides real-time IVUS display and enables identification of areas of interest for bimodal
imaging. A commercial Medrad
deliver 10% LMD (dextran 40) in 5% dextrose solution required to displace blood during bimodal
acquisition (4–6 cc/s, 8 s). Close-up of stent deployed in coronary vessels: Fluorescent painted
sections on stent struts were used to provide contrast in healthy pig coronary arteries. Bimodal
B-scans (from one in vivo image cross section) showing easily differentiated fluorescence signal
from painted section of stent and artery wall fluorescence between painted section. Full spectral
and average lifetime data: 20 mm section imaged in 5 s. Both spectral and lifetime data sets enable
straightforward identification of two marker sets from arterial wall (Bec et al. 2014)
®
Ava n taTMfluid management system (power injector) is used to
FLIm-IVUS Imaging of Ex Vivo Human Coronary Arteries
To image ex vivo human samples, coronary arteries are imaged in circulating heated
(37 °C) PBS using the FLIm-IVUS catheter system. IVUS and FLIm data sets are
co-registered by shared time stamps during acquisition. IVUS data are processed
twofold: (1) RF data are used to extract spectral parameters such as integrated
backscatter and energy norm, and (2) gray-scale images are segmented to extract
lumen and media boundaries. FLIm data are deconvolved using Laguerre-based
techniques (Liu et al. 2012;Suetal.2016) and for each spectral channel, inte-
grated intensity, average lifetime, and Laguerre coefficients are computed. FLIm and
IVUS data are then jointly displayed (3D rendering, cross and longitudinal sections)
and registered with histology sections. Axial registration is achieved using pullback
position information and angular registration is achieved using IVUS morphology
(lumen shape, presence of calcifications). Classification groups are chosen based on
histologic analysis: normal intima, fibrous cap, macrophage infiltration, and lipid
core/extracellular lipid, as determined by H&E, Movat’s pentachrome and CD68
citeRN192, RN32.
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