Dual modality intravascular catheter system combining pulse-sampling fluorescence lifetime imaging and polarization-sensitive optical coherence tomography

Abstract

A dual modality catheter-based imaging system that is capable of simultaneously acquiring FLIm and PSOCT data is described. The system can acquire co-registered FLIm and PSOCT data in co-registration and birefringent phantoms and coronary artery specimens, and is compatible with a clinical setting, where it enables a comprehensive image-based assessment of plaque pathophysiology, leading to understanding of mechanisms underlying plaque formation and supporting the development of new therapies.

Description

DUAL MODALITY INTRAVASCULAR CATHETER SYSTEM COMBINING PULSE-SAMPLING FLUORESCENCE LIFETIME IMAGING AND POLARIZATION-SENSITIVE OPTICAL COHERENCE TOMOGRAPHYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. provisional patent application serial number 63 / 162,818 filed on January 26, 2024, incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under Grant Number R01 HL157712, awarded by the National Institutes of Health. The government has certain rights in the invention.NOTICE OF MATERIAL SUBJECT TO COPYRIGHT PROTECTION

[0003] A portion of the material in this patent document may be subject to copyright protection under the copyright laws of the United States and of other countries. The owner of the copyright rights has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the United States Patent and Trademark Office publicly available file or records but otherwise reserves all copyright rights whatsoever. The copyright owner does not hereby waive any of its rights to have this patent document maintained in secrecy, including without limitation its rights pursuant to 37 C. F. R. § 1 .14.BACKGROUND

[0004] 1. Technical Field

[0005] This technology pertains generally to fluorescence lifetime imaging microscopy techniques and more particularly to a dual modality intravascular catheter system that combines pulse-sampling fluorescence lifetime imagingand polarization-sensitive optical coherence tomography in an apparatus and techniques that use an optical rotary junction enabling bidirectional transmission of optical signals between a stationary and rotary fiber optics.

[0006] 2. Background

[0007] Worldwide, Coronary Artery Disease (CAD) remains the leading cause of death in humans. In its most severe form, plaque rupture or erosion leads to the formation of a thrombus that occludes a coronary artery branch, resulting in a myocardial infarction. Extensive research has identified common features of culprit plaques; for example, high plaque burden, a thin fibrous cap overlying a large lipid pool, and the presence of active inflammation. Plaque formation and evolution, however, are dynamic processes with a complex interplay of stabilizing phenomena, such as the recruitment of smooth muscle cells and the formation of a collagen-rich extracellular matrix (ECM), and destabilizing phenomena, such as the proliferation of macrophage foam cells (mFC) and accumulation of necrotic material. These features can only be investigated using imaging catheters that provide simultaneous assessment of morphology and composition.

[0008] Over the last decade, different combinations of imaging modalities providing morphological information (e.g., optical coherence tomography (OCT) and intravascular ultrasound (IVUS)) along with compositional information (e.g., fluorescence lifetime imaging (FLIm), near-infrared fluorescence (NIRF) and autofluorescence (NIRAF), near-infrared spectroscopy (NIRS)) have been developed. While such hybrid intracoronary imaging systems have shown the ability to assess key plaque features such as lipid accumulation, inflammation, oxidative stress, and endothelial permeability, new hybrid imaging modalities capable of comprehensive assessment of plaques features conducive to acute myocardial infarction are needed.

[0009] Ultraviolet excitation time-resolved fluorescence spectroscopy (TRFS) and its subsequent mesoscopic fluorescence lifetime imaging (FLIm) implementation have emerged as an approach for evaluating the biochemical composition of atherosclerotic lesions. FLIm imaging relies on the measurement of endogenous fluorescent molecule decay rates over multiplespectral bands associated with the emission of arterial vessels (e.g., collagen and crosslinks, elastin, lipid components, and ceroids). Earlier work conducted in ex-vivo human coronary arteries has demonstrated that a combination of FLIm-derived optical parameters can identify mFC accumulation and the presence of superficial calcification and newly formed ECM. Intravascular implementations, in combination with intravascular ultrasound (IVUS) and OCT, are a key step towards demonstrating the clinical utility of FLIm.

[0010] Intravascular OCT is an established technology and remains one of the the most used clinical research tools in interventional cardiology for evaluating new treatment modalities. It has played an important role in elucidating CAD- related pathobiological processes. Currently, it offers the highest spatial resolution for intravascular imaging, enables assessment of thin-fibrotic cap (associated with plaque rupture), and can elucidate aspects of plaque erosion.

[0011] The recent adaptation of PS-OCT to measure the polarization of the backscattered IR light has demonstrated the ability to measure depth-resolved birefringence and depolarization with standard intravascular imaging catheters; thus, enhancing OCT’s capabilities for plaque characterization. The PS-OCT high-resolution backscatter images enable the identification of smooth muscle cells, collagen, and cholesterol crystals via birefringence, as well as necrotic and lipid-rich regions via depolarization. PS-OCT, however, cannot directly measure tissue composition. As demonstrated in numerous studies, FLIm has the ability to detect compositional features associated with ECM composition, mFC infiltration and necrotic material.

[0012] Thus, a FLIm and PS-OCT combination could provide a system for retrieving complementary features and better stratify critical plaque pathobiology but also for cross-validating biochemical features. Cross- validation is of particular relevance for future clinical validation in patients because no ground truth information (e.g., histology) could be available to corroborate the intravascular imaging findings.

[0013] The engineering of intravascular systems that are able to perform imaging within coronary arteries presents several challenges. First, the device must have a low profile (<1 mm) and high flexibility to cross atheroscleroticlesions and maintain structural integrity and imaging performance (low non- uniform rotation distortion) when placed in tortuous anatomy. Second, a high imaging speed (typically 100 frames / second) is required to limit cardiac motion artifacts and ensure that a full imaging pullback (typically 80-100 mm) can be performed during the blood clearing period following a bolus flush lasting about 2 to 3 seconds.

[0014] Accordingly, there is a need for improved systems and methods for imaging that will address these challenges.BRIEF SUMMARY

[0015] The clinical management of coronary artery disease and the prevention of acute coronary syndromes requires accurate knowledge of the underlying atherosclerotic plaque pathobiology. Hybrid imaging modalities capable of comprehensive assessment of biochemical and morphological plaques features can address this need. An imaging apparatus and computational imaging techniques called light field tomographic imaging FLIm with Polarization-Sensitive Optical Coherence Tomography (FLIm-PSOCT) combined with an intravascular catheter system are provided.

[0016] According to one embodiment, the intravascular catheter system combining Fluorescence Lifetime Imaging (FLIm) with Polarization-Sensitive Optical Coherence Tomography (PSOCT) provides a multi-scale assessment of plaque structure and composition using high spatial resolution morphology from OCT, polarimetry-derived tissue microstructure, and biochemical composition from FLIm, without requiring any molecular contrast agent. This result was achieved with a low profile (2.7 Fr) double-clad fiber catheter and high speed (100 fps B-scan rate, 40 mm / s pullback speed) console. Successful implementation of the system required the development of a broad-band (UV-visible-IR), high return loss (47dB) rotary junction.

[0017] With the use of phantoms and coronary specimens ex vivo, it was demonstrated that the FLIm-PSOCT catheter system can simultaneously acquire co-registered FLIm data over four distinct spectral bands (380 / 20 nm, 400 / 20 nm, 452 / 45 nm, 540 / 45 nm) as well as PSOCT backscattered intensity, birefringence, and depolarization. The unique ability of the system tocollect complementary information from tissue (e.g., morphology, extracellular matrix composition, inflammation) with a device compatible with percutaneous coronary intervention offers new opportunities for cardiovascular research and clinical diagnosis.

[0018] According to another embodiment of the present disclosure, we describe an optical rotary junction that enables bidirectional transmission of optical signals between a stationary and rotary fiber optics. For typical implementations, focusing elements (refractive lens, gradient index lens) are integrated in both the rotary side and stationary side of the junction to collimate the beam exiting from one fiber and focus that beam into the opposite fiber.

[0019] A return signal, caused by back-reflection of the beam during its propagation in the rotary junction, can generate noise or artifacts when the rotary junction is used, for example, as part of an optical coherence tomography system. Therefore, achieving high return losses is often a key performance target. This is typically achieved by optical coatings and / or the use of index-matching fluid. Both coatings and optical matching fluids are only effective over a limited wavelength range and are therefore not suitable for broadband applications.

[0020] For certain applications, the insertion of additional optical elements in the optical path, such as dichroic mirrors, can be beneficial. In that case, a sealed design, required when using index matching fluid, is not suitable.

[0021] The system has been shown to dramatically increase the return loss without penalizing the coupling efficiency of the rotary junction, without need of any special optical coating or matching fluid, by adding a spacer in physical contact with the rotary fiber. This spacer ensures that the fresnel reflection generated at the optical interface between air and glass is generated away from the focal plane of the focusing element. With this design, only a very small amount of the back-reflected light is coupled into the stationary fiber, leading to a high return loss. Values of >47 dB were obtained with our rotary junction prototype, compared to approximately 14dB with a standard broadband implementation.

[0022] Further aspects of the technology described herein will be brought outin the following portions of the specification, wherein the detailed description is for the purpose of fully disclosing preferred embodiments of the technology without placing limitations thereon.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The technology described herein will be more fully understood by reference to the following drawings which are for illustrative purposes only:

[0024] FIG. 1 is a diagram of a hybrid intravascular imaging system with FLIM and PSOCT engines located in a console and a multimodal motor drive unit (MDU), and an intravascular catheter shown schematically according to an embodiment of the technology of the technology.

[0025] FIG. 2 is a schematic diagram of a free-space fiber coupling between stationary OCT collimator and rotary catheter collimator (steering mirrors omitted for simplicity). This APC-to-APC junction provides the highest return loss but requires the catheter connector to be angled by 4 degrees to ensure efficient coupling. Consequently, this configuration is mechanically imbalanced and not suitable for high-speed rotation.

[0026] FIG. 3 is a schematic diagram of a free-space fiber coupling between stationary OCT collimator and rotary catheter collimator. This APC to PC rotary junction ensures that optical beam and catheter connector are concentric with the rotation axis, but the back reflection observed in the catheter proximal fiber facet leads to a low return loss of ~14 dB, negatively affecting the system sensitivity.

[0027] FIG. 4 is a schematic diagram of a free-space fiber coupling between stationary OCT collimator and rotary catheter collimator. The fiber receptacle of the rotary collimator used for the FLIm-PSOCT system presents an additional cylindrical “wedge” element with an 8-degree interface with the catheter APC connector, keeping the rotation assembly balanced. With this design, the back-reflection generated from the air / glass interface occurs on the proximal end of the wedge, far from the collimator’s focal plane, which ensures high return loss (44 dB). The APC interface between the distal face of the wedge and the catheter connector ensures that return losses remain high even if physical contact were to be lost due to wear or contamination of thatinterface. This design is suitable for simultaneous UV / Vis / NIR operation and does not require any index matching fluid.

[0028] FIG. 5 is a schematic cross-sectional view of a high return loss rotary junction according to an embodiment of the technology.

[0029] FIG. 6 is a plot of mean and standard deviation of the average lifetime from the stent phantom background.

[0030] FIG. 7 is a schematic diagram of rotary junction return power and corresponding OCT noise measurements with a no fiber-no wedge configuration (Configuration #1 ).

[0031] FIG. 8 is a schematic diagram of Configuration # 2, a UPC-no fiber configuration.

[0032] FIG. 9 is a schematic diagram of Configuration #3, a UPC-distal absorber-no wedge configuration.

[0033] FIG. 10 is a schematic diagram of Configuration #4, a no fiber-wedge configuration.

[0034] FIG. 11 is a schematic diagram of Configuration #5, an APC catheterwedge configuration.DETAILED DESCRIPTION

[0035] Referring more specifically to the drawings, for illustrative purposes, apparatus and methods for an intravascular catheter system combining Fluorescence Lifetime Imaging (FLIm) with Polarization-Sensitive Optical Coherence Tomography (PSOCT) are generally shown. Several embodiments of the technology are described generally in FIG. 1 to FIG. 11 to illustrate the characteristics and functionality of the apparatus and methods. It will be appreciated that the methods may vary as to the specific steps and sequence and the systems and apparatus may vary as to structural details without departing from the basic concepts as disclosed herein. The method steps are merely exemplary of the order that these steps may occur. The steps may occur in any order that is desired, such that it still performs the goals of the claimed technology.

[0036] Turning now to FIG. 1 , the basic structure of the FLIm-PSOCT apparatus 10 and imaging methods are generally illustrated schematically. Inthis embodiment of the hybrid catheter system, PSOCT module 34 and FLIm module engines 32, a multimodal motor drive unit (MDU) 22, and an intravascular catheter 12.

[0037] The primary diagnostic acquisition element of the system is FLIm-OCT imaging core 12 disposed at the distal end of an intravascular catheter structure. The imaging core of the catheter 12 has a micro-optic reflective surface 14, a fused silica ferule 16, a double-clad fiber (DCF) 18 that is enclosed in a and a 2-layer torque coil 20. The fused silica ferrule 16 improves reliability of the freeform micro-optic assembly by increasing the adhesive bond area, isolating the optics from forces that may be transferred by the torque coil 20, and preventing the micro-optics from contacting the sheath. An 8-degree angle at the interface with the micro-optics reduces the back-reflection of the optical adhesive interface.

[0038] The catheter is coupled to a motor drive unit (MDU) 22 by a rotary junction 24 that enables rotary and pullback actuation of the catheter, as well as coupling of FLIm and OCT optical beams into the catheter. In this embodiment, the optical coupling between PSOCT 32 and FLIm 34 engines and the catheter’s imaging core 12 is performed by a set of collimator lenses 28 for PSOCT, FLIm excitation, and FLIm collection and a set of dichroic mirrors 26 that are aligned with a rotary collimator of the rotary junction 24 of the MDU 22 and catheter imaging core 12.

[0039] In general, the FLIm 32 and PSOCT 34 engines are located in a console 30 that includes a display 40. The actuation (rotation, pullback) of the motor drive unit (MDU) is controlled by a FLIm engine 32. In one embodiment, the FLIm module uses a free-running pulsed diode-pumped solid-state laser fluorescence excitation light delivered to the MDU using a multimode fiber, a photodetector configured to detect fluorescence emission signals and a controller. In another embodiment, the photodetector utilizes a UV-enhanced avalanche photodiode with biasing circuitry able to vary detector gain between M=1 to >500 and a trans-impedance amplifier; and one or more synchronized high-speed digitizers configured to sample detector signals. The photodetector may also include one or more optical filters and dichroic mirrors so that the fluorescence emission signal can be spectrallyresolved and detected in different selected distinct spectral bands.

[0040] In one embodiment, the PSOCT module has a wavelength-swept laser, an OCT interferometer and a high-speed phase retarder synchronized with the swept laser and positioned between the laser and the OCT interferometer. A polarization modulator and polarization controller may be used to ensure a constant reference signal as well as detectors and a module controller in this embodiment.

[0041] In another embodiment, the MDU uses a first adjustable dichroic mirror that is configured to combine PSOCT and FLIm beams, a second adjustable dichroic mirror that is configured to combine FLIm excitation and emission pathways and a rotary collimator that is optically coupled with the imaging core of the catheter and optically aligned with the first and second adjustable dichroic mirrors. Actuators configured for rotary and pullback movement and a controller may also be used to enable the MDU to perform rotary and pullback actuation of the catheter and coupling of FLIm and OCT optical beams into the catheter.

[0042] In another embodiment, the rotary collimator has a housing with a bearing and rotating collimator shaft with an adjustable lens and fiber receptacle, an optical encoder mounted on the collimator shaft and a closed loop motion control with a motor and speed controller. The MDU receptacle may also include at least one lens configured to focus light on the spacer of the receptacle, so the lens focus is located at an opposite face of the spacer than the reflection.

[0043] Synchronization of FLIm data acquisition and PSOCT data acquisition is performed by the FLIm engine 32, where PSOCT A-line synchronization signals 36 and the rotation index of an MDU angular encoder are saved with a digitizer sharing a clock with the FLIm data acquisition.

[0044] Referring to FIG. 2, FIG. 3 and FIG. 4, to improve the PSOCT return loss of the catheter’s proximal end compared to the FLIm-OCT motor drive implementation, a 3-mm long fused silica wedge with an 8-degree facet was integrated into the rotary collimator’s fiber receptacle. This additional element ensured that the optical beam and fiber connector were concentric with the collimator’s rotation axis while providing separation between the location ofthe Fresnel reflection of the receptacle and the focal plane of the rotary collimator.

[0045] As shown schematically in FIG. 2, signals to and from the OCT engine are directed through the stationary OCT collimator (APC) 42 to produce a forward OCT optical beam 44 directed to the rotary collimator 48 with an APC connector 50 to the catheter. An angled physical contact (APC) optical coupling to APC junction provides the highest return loss but requires the catheter connector to be angled by 4 degrees to ensure efficient coupling. The catheter connection back reflection 46 is at an acute angle to the forward OCT optical beam 46 from the rotary collimator 48 and APC connector 50. It can be seen that this configuration is mechanically imbalanced and not suitable for high-speed rotations.

[0046] By comparison, the APC to PC rotary junction shown in FIG. 3 ensures that optical beam and catheter connector are concentric with the rotation axis, but the back reflection observed in the catheter proximal fiber facet leads to a low return loss of ~14 dB, negatively affecting the system sensitivity. In this configuration, the forward OCT optical beam from the stationary OCT collimator 52 is directed to the rotary collimator 54 and PC connector 56 and reflected back.

[0047] In contrast, the embodiment of FIG. 4 shows a stationary OCT collimator APC connection 58, which directs a forward OCT optical beam 60 from the stationary OCT collimator 52 to the rotary collimator 62 and APC connector 66. In this configuration, the fiber receptacle of the rotary collimator 62 used for the FLIm-PSOCT system presents an additional cylindrical “wedge” element with an 8-degree interface with the catheter APC connector 66, keeping the rotation assembly balanced. With this design, the back- reflection 64 generated from the air / glass interface occurs on the proximal end of the wedge, far from the collimator’s focal plane, which ensures high return loss (44 dB). The APC interface between the distal face of the wedge and the catheter connector ensures that return losses remain high even if physical contact were to be lost due to wear or contamination of that interface. This design is suitable for simultaneous UVA / is / NIR operation and does not require any index matching fluid.

[0048] Turning now to FIG. 5, one embodiment 70 of the wedge optic inside of a fiber optic rotary junction is illustrated. A shaft 72 is inserted in an air bearing block 74 and held in place using a retaining ring 76. A fiber receptacle composed of a flange 78, guide 80 and sleeve 82 is attached to the distal end of the shaft 72, such that the ferrule 84 of the fiber optic connector 86 is pressed against the optical wedge 88. The wedge 88 is held in place inside of the sleeve 82 by an axial stop 90. The focusing lens 92 is placed at a predetermined distance from the end face of the fiber optic ferrule 84 by way of a spacer 94 and adjustment shim 96 and is preloaded using a wave spring 98. Radial positioning of the focusing lens 92 is performed using four fine- thread adjustment ballpoint set screws 100. A circular groove 102 in the shaft 72 enables coupling with a rotary actuator by way of a round belt in this embodiment.

[0049] The combination of OCT and FLIm components leverages mature intravascular OCT technology and robust rotational FLIm instrumentation. Both modalities can be integrated using a single double-clad fiber with dimensions identical to regular single-mode fibers. While the FLIm-PSOCT catheter system provided here differs from standard OCT due to the addition of polarization modulation of the light directed to the tissue and polarization- diverse detection, the current implementation can achieve similar A-scan rates as a standard OCT system. Thus, the system has dimensions and characteristics similar to intravascular OCT systems currently used in patients. The system is capable of intraluminal imaging at 100 B-scans / s, over up to 80 mm pullback length, and at a speed of up to 40 mm / s, with an imaging section presenting a low profile (2.7 Fr). Fast framerate and pullback speeds are required because, in a clinical setting, FLIm and OCT acquisitions need to be completed during a bolus injection of fluid that clears the artery segment for a short duration of about 3 to 5 seconds. Because the characteristics of the FLIm-PSOCT catheter (device size, acquisition speed) are similar to intravascular OCT systems currently used in clinical settings, the device should integrate seamlessly with standard PCI procedures.

[0050] A key contributor to OCT performance is to minimize unwanted reflections throughout the optical path. Even if not pathlength-matched, thesecan lead to spurious interference effects that impact the noise floor and limit system sensitivity. In intraluminal FLIm-PSOCT, the main source of these unwanted reflections is in the rotary collimator.

[0051] The combination of polarization-diverse detection and the specific cavity length of the employed laser source made the current system more susceptible to these reflections. Fiber optic rotary junctions (FORJ) suitable for single-mode transmission over a narrow wavelength range are routinely used in telecom, robotics, and medical imaging. These implementations achieve high insertion and return losses by a combination of index matching fluid, antireflective coatings, low separation of rotary and stationary elements, and / or GRIN collimator to minimize the index mismatch at the optical interfaces. These standard solutions are not suitable for operation over extended wavelength ranges or when wavelength multiplexing is to be performed in the rotary junction’s gap. Therefore, intraluminal OCT systems operating at non-standard wavelength, or OCT in combination with FLIm or standard fluorescence relied on low return loss fiber optic rotary junctions.The effect of unwanted back-reflection from these low return loss junctions on system noise has not been specifically reported, so the exact effect on imaging performance is unclear. Although low insertion losses and high return losses have been achieved using lensless designs, reliability and stability are a concern, and this concept has not seen wide adoption.

[0052] In contrast, the FORJ of the system relies on a traditional lensed design, with the addition of a fused silica spacer placed in physical contact with the catheter fiber’s proximal facet. In this design, the air / glass interface encountered by the infrared beam generating the unwanted back-reflection is located at the proximal end of the spacer, rather than the fiber core itself. Because the back-reflection is generated out of the focal plane, it is rejected in a similar fashion to confocal microscopy, with the stationary OCT fiber core acting as the pinhole. Since only a small fraction of the light reflected at the interface is coupled back into the OCT single-mode fiber, a return loss of 43 dB was achieved. This is a significant improvement compared to the 14 dB return loss typically observed for low return loss designs.

[0053] The multi-APD FLIm system design utilized in the current dual-modalitysystem has been derived from a high-performance pulse-sampling-FLIm system designed for clinical research. The system offers high detection sensitivity (>3*104 V / W conversion gain), high lifetime measurement accuracy (< 200 ps standard deviation), and improved SNR (>50 dB) as a result of individual feedback gain adjustment for each spectral channel. The pulse-sampling lifetime measurement approach was chosen for intravascular application due to its high data acquisition speed compared to TCSPC which is the most commonly used method in fluorescence lifetime studies. For fiberbased systems, the pulse sampling approach was shown to have an imaging speed 25 times faster than traditional TCSPC making it well-suited for intravascular applications. Adjustment of the detector gain is critical to acquire high SNR FLIm data. Practically, the detector gain should be set to maximize signal intensity throughout a scan while ensuring that the detector output does not exceed the digitizer’s input range. However, real-time closed- loop control of the detector gains of each spectral channel, implemented in earlier FLIm systems designed for hand-held measurements to compensate for variations in probe-to-object distance and sample brightness, is not suitable for intravascular applications. This is due to the high pointmeasurement speed (30 kHz) and fast variations in signal intensity observed with a 100-rps catheter rotation speed.

[0054] Accordingly, the gain of the photodetector for each individual spectral band was fixed for each pullback, where the optimal gain was determined by manually adjusting the gain of each APD detector based on trial imaging runs. An alternative future solution is to optimize the gain based on the FLIm intensity histogram so that the number of FLIm pixels with good SNR is maximized.

[0055] FIG. 6 shows that the standard deviation of the average lifetime increases as the signal intensity and thus SNR decreases, but the average lifetime value remains very stable over the whole waveform intensity range. This result demonstrates the ability to extract accurate average lifetime values from waveforms of varying intensities.

[0056] As expected, the ability to retrieve accurate fluorescence lifetime is influenced by the object’s distance and tissue brightness. As distanceincreases, the fluorescence signal magnitude and SNR decrease, leading to a slight reduction in lifetime estimation accuracy, illustrated by the increase in lifetime standard deviation in both phantoms and artery specimens that were evaluated. Measurements in artery specimens also show a small but consistent reduction of average lifetime as the signal intensity decreases. Non-linearities in the FLIm system characteristics or artifacts due to data processing can be ruled out since the linearity of the system’s temporal response with intensity was confirmed and results from a cylindrical fluorescent phantom showed a variation of average lifetime of less than 50 ps over the whole intensity range as seen in FIG. 6. One possible explanation is that the relative amount of fluorescence emission of collagen and elastin, the main fluorophores present in a healthy vessel wall, may vary with excitation fluence, itself directly influenced by distance. Nevertheless, this change in lifetime related to intensity is unlikely to be observed in diseased vessels that typically present a small outer diameter due to stenosis.

[0057] The FLIm bands of the system were also adapted from earlier results to facilitate further investigation of the FLIm contrast. Based on earlier FLIm studies, the following fluorophores are expected to be detected in each spectral band as follows. Emissions from collagen, elastin, proteoglycans, and lipids (cholesterol, cholesteryl oleate, lipoproteins) are expected in the 390 / 40 nm band. Emissions from elastin, collagen, lipoproteins, and calcifications are expected in the 450 / 45 nm band.

[0058] Emissions from ceroids and structural proteins to a lesser extent are expected in the 540 / 50 nm band and extend into the 630 / 50 nm band with lower signal intensity. Investigation of the FLIm signature of human artery specimens has demonstrated that macrophage foam cell presence could be identified from their ceroid content with high sensitivity and specificity (AUC = 0.94) based on the signal from the 540 / 50 nm spectral band alone. On the other hand, the lifetime increased in the 390 / 40 nm band is associated with newly formed lesions, but it is unclear whether proteoglycans, Type III collagen, lipids, or other species present in these lesions are at the origin of this observed FLIm contrast. To support further investigation, the 390 / 40 band used in earlier systems from our group and other research groups in this fieldwas split into 380 / 20 and 400 / 20 bands to improve the spectral specificity and facilitate discrimination between these various constituents.

[0059] Accordingly, the intravascular FLIm-PSOCT catheter system can provide morphology, microstructure, and biochemical composition information of a subject. The ability to acquire robust FLIm data as well as birefringence and depolarization via a DCF imaging catheter was confirmed in phantoms and artery specimens. This intravascular imaging platform is a promising tool for the investigation of inflammatory activity, where the high FLIm sensitivity and specificity, combined with depth resolution provided by OCT may prove valuable to ensure better quantification. Additionally, the system’s improved FLIm spectral specificity in the 370 nm to 410 nm range, combined with the ability of PSOCT to provide information about collagen presence in the ECM may improve the understanding of the specific lesion components that are identified by FLIm.

[0060] The technology described herein may be better understood with reference to the accompanying examples, which are intended for purposes of illustration only and should not be construed as in any sense limiting the scope of the technology described herein as defined in the claims appended hereto.

[0061] Example 1

[0062] In order to demonstrate the functionality of the apparatus and methods, a dual FLIm-PSOCT catheter imaging system was assembled that was able to simultaneously acquire tomographic structure, depth-resolved birefringence and cumulative depolarization, and surface fluorescence lifetime measurements over four distinct spectral bands from the luminal surface.

[0063] The system, as shown in FIG. 1 , was assembled with an intravascular catheter, a motor drive unit (MDU), and integrated FLIm-PSOCT sub-systems and display within a console. The imaging catheter was composed of a double-clad fiber (SM-9 / 105 / 125-20A, Nufern, CT, United States), enclosed in a 500-pm outer diameter torque coil (Asahi Intecc, Aishi, Japan), terminated at the proximal end with a stainless-steel shaft and an SC / APC connector. OCT is performed via the DCF’s core whereas the inner cladding is used to transmit both fluorescence excitation and fluorescence emission. The distalend of the catheter consisted of an angle-polished fused silica spacer and freeform reflective optic with a working distance of ~1.2 mm. The catheter sheath was terminated by a 2.7 Fr (0.92 mm) outer diameter transparent polymethylpentene imaging window (Mitsui Chemicals, Tokyo, Japan). The sheath was flushed with saline solution before use.

[0064] The MDU enabled rotary and pullback actuation of the catheter, as well as coupling of FLIm and OCT optical beams into the catheter. As shown in FIG. 1 , an optical coupling between PSOCT and FLIm engines and the catheter’s imaging core was performed using individual stationary collimators for PSOCT, FLIm excitation, and FLIm collection, aligned with a rotary collimator to which the catheter imaging core was connected. A first adjustable dichroic mirror (F735-Di02-25x36, Semrock, NY, United States) was used to combine PSOCT and FLIm beams, whereas a second adjustable dichroic mirror (Di01 -R355, Semrock, NY, United States) was used to combine FLIm excitation and emission pathway.

[0065] The rotary collimator was composed of a stationary air bearing (OAV0500IB, NJ, United States), a custom rotating shaft housing an adjustable lens and custom fiber receptacle, combined with a closed loop motion control itself composed of a brushless motor (EC-max 22, Maxon motors, Sachseln, Switzerland), optical encoder mounted on the collimator shaft (US Digital, Vancouver, WA, United States), and speed controller (ESCON 24 / 2, Maxon Motors, Sachseln, Switzerland). The index channel of the optical encoder was acquired by a dedicated digitizer card to enable accurate reconstruction of FLIm and PSOCT B-scans.

[0066] A polarization-modulated, fiber-based frequency domain PS-OCT setup derived from a 1310 nm swept-source OCT system (Soleron, NH, USA) was used. The PS-OCT engine consisted of a wavelength-swept laser (HSL- 200-50LC, Santec Corp., Japan) with a center wavelength of 1310 nm, a wavelength scanning range of 105 nm, and an A-line acquisition rate of 50 kHz. This results in a full width at half maximum of the intensity point spread function, i.e. , the squared norm of the reconstructed tomogram of a single reflector, of about 9 pm in tissue, assuming a refractive index of 1 .34. The system utilized a polarization modulation scheme, in which the sourcepolarization state was alternated for consecutive A-lines to illuminate the sample with polarization states located orthogonal to each other on the Poincare sphere. This was achieved using a customized fiber-based highspeed phase retarder (Boston Applied Technologies, United States) synchronized with the swept-source laser and positioned between the laser source and the OCT interferometer.

[0067] To ensure a constant reference signal, the modulated polarization states were adjusted with a polarization controller, following the polarization modulator but still before splitting into sample and reference arms, to project equally onto the linear polarizer in the reference arm input to the polarization- diverse receiver. The output of the dual balanced detectors (PDB410C, Thorlabs Inc, USA) was digitized at 200MS / S (ATS9352, AlazarTech, Pointe- Claire, Canada). A 50 MHz acousto-optic frequency shifter in the reference arm resolved depth degeneracy leading to a full imaging depth of 13.2 mm in air.

[0068] The FLIm instrumentation was based on a pulse sampling technique, where the entire fluorescence decay was obtained for each excitation pulse. An instrumental setup developed for clinical validation of FLIm in intraoperative settings was adapted to intravascular use. Specifically, fluorescence excitation light was provided by a free-running pulsed 355-nm diode-pumped solid-state laser (30 kHz repetition rate, 2-pJ pulse energy, SNV-60P-100, TEEM photonics, France) and delivered to the MDU using a 50-pm core multimode fiber (FG050UGA, Thorlabs, NJ). The fluorescence emission signal was spectrally resolved and detected in four distinct spectral bands using a set of filters and dichroic (380 / 20 nm, 400 / 20 nm, 452 / 45 nm, 540 / 50 nm) and individual photodetector modules (APD430A2-SP1 , Thorlabs, NJ, United States). Each module was composed of a UV-enhanced avalanche photodiode, biasing circuitry able to vary the detector gain between M=1 to >500, and a trans-impedance amplifier. Sampling of the detector signals is performed at 6.25 GS / s by two synchronized high-speed digitizers (Nl PXIe-5185, National Instruments, TX). To improve SNR, a moving average of five lifetime values was used.

[0069] The bi-modal catheter’s small diameter of 2.7 Fr (1 .65 m length) assured compatibility with intravascular interrogation of coronary arteries. The MDU enabled a catheter rotation of 100 rps and a pullback length of 100 mm at up to 40 mm / s pullback speed, values similar to clinical OCT for which blood displacement during imaging is achieved with a bolus flush. The OCT engine located in the console contained a polarization-modulated light source with a sweep rate of 50 kHz that enables 500 OCT A-lines per rotation. Polarization information is obtained by alternating the polarization state for each A-line, combined with polarization-diverse balanced detection, yielding 250 pairs of polarization-resolved measurements used to extract birefringence and depolarization information. The FLIm engine, also located in the console, contained a 32 kHz repetition rate 355-nm laser, leading to 320-point measurements per OCT B-scan. FLIm detection is achieved by individual avalanche photodiode detectors for each of the four spectral bands of the instrument (380 / 20 nm, 400 / 20 nm, 452 / 45 nm, 540 / 45 nm) allowing independent control of the detector gain for each spectral channel, thus enabling optimization of SNR for each individual channel.

[0070] Example 2

[0071] A potential performance limitation in FLIm / OCT multimodal systems stemming from the crosstalk between inner cladding modes and the fundamental core mode of the catheter’s double-clad fiber (DCF) feature was evaluated. DCFs may introduce image artifacts due to the crosstalk between inner cladding modes and the fundamental core mode occurring at different coupling interfaces. Such crosstalk is expected to generate a ghost image, whose location is determined by the length of the DCF, the core and index cladding differences, and the inner cladding modal distribution, and thus appears distributed along the imaging depth, with minimum and maximum locations determined by the following equations:where 0maxis the maximum incidence angle of a ray guided in the inner cladding. Using the parameters of the DCF (see Table 2), AZmin=-4.62 mm, whereas Zmax= 18.37 mm, with light guided in the lowest order claddingmode being propagated faster than the core mode, and light propagated in the highest order cladding mode being propagated slower.

[0072] This effect was evaluated and compared with results obtained from a standard OCT catheter relying on an SMF fiber. It was observed that DCF artifacts that are due to the propagation of the backscattered OCT signal in the inner cladding of the DCF are generated by the system’s interfaces as well as objects within the field of view. In both cases, most of the artifact appears at a shorter path length determined by the length of the DCF and the core and inner cladding optical group refractive indices. Therefore, DCF artifacts generated by the light back-reflected at the exit surface of the imaging core are not expected to overlap with the signal measured from tissue, for example.

[0073] The adoption of an open sheath catheter design, where the inner cavity of the catheter is flushed with fluid, further reduces the exit surface artifact. Indeed, the index of water is closer to the index of fused silica used for the device’s distal end, so a fluid-filled sheath leads to a reduction of the back- reflected power at this interface. In that configuration, it was observed that the noise of the system is actually inferior to what was obtained with the reference SMF catheter.

[0074] DCF artifacts generated by objects in the field of view were also evaluated by imaging a target of a 0.5 mm sheet of acrylonitrile butadiene styrene (ABS). This material was chosen because it generates a signal intensity of approximately 30 dB, which is more realistic than the strong reflection obtained from a mirror, but higher than what is typically observed from the artery specimen (approximately 20 dB) and thus represents a worstcase condition. The DCF artifact induced by the object has a maximum intensity of approximately 10 dB. As with the exit surface artifact, this maximum is located proximal to the object by about 4 mm and therefore will not overlap with any other object in the field of view.

[0075] Specifically, the OCT background was measured for the FLIm-PSOCT DCF imaging core in air, in water and for a reference single-mode commercial OCT catheter imaging core. The delay was set to maximize the sensitivity where tissue is expected to be present during use. Sharp reflections from thefiber to distal optics were visible for the DCF probe, reflection from the distal optics exit face was clearly visible for all probes. A DCF artifact caused by the inner-cladding propagation of light backscattered at the exit surface was observed when the DCF core was evaluated in air. The maximum distance between exit surface and DCF artifact of 4.2 mm was consistent with what was expected from the catheter length and core and inner cladding mismatch.

[0076] When tested in water, the reflection from the distal optics exit surface was reduced by approximately 10 dB and the associated DCF artifact was suppressed. In that configuration, the background of the FLIm-PSOCT DCF imaging core is better than what is obtained from a clinical imaging core that relies on a single-mode fiber. Imaging of the 0.5-mm thick ABS sheet demonstrates that both probes lead to similar sensitivities. The DCF artifact caused by the sample starts 4.2 mm closer than the object. It leads to 2-4 dB additional noise in the imaging region compared to the SMF probe. Images of background and test object indicated that despite the presence of DCF artifacts, the DCF probe provides images comparable to the reference SMF probe.

[0077] Most of the ghost images were located at a shorter pathlength with respect to the distal optics exit surface, with a maximum path difference of approximately 4.2 mm, in good agreement with the expected location computed from Eq. 1 . The portion of the ghost image located deeper than the surface at the origin of the ghost image had an amplitude of only 2 dB to 4 dB. These findings were consistent with the expectation that only the lower modes of the inner cladding are likely to be coupled back into the single-mode core of the stationary fiber. None of these DCF-induced artifacts seemed to create specific issues with birefringence and depolarization measurements, as the images obtained from the birefringence phantom were in close agreement with images acquired with the reference PSOCT system. Birefringence values observed from artery specimens are also consistent with contrast expected from healthy vessels.

[0078] Example 3

[0079] The performance of the rotary design and performance was also evaluated. The hybrid rotary junction consists of three stationary collimatorsfor OCT, FLIm excitation and FLIm emission light, respectively, coupled with a rotary collimator to which the catheter imaging core is interfaced as shown in the system of FIG. 1 . The use of individual stationary collimators enabled the compensation of the chromatic focal shift observed in the shared rotary collimator lens over the 355 nm to1370 nm spectral range required for FLIm and OCT operation. The addition of a 3-mm long fused silica spacer, angle- polished to match the 8-degree facet of APC connectors and integrated into the catheter connector receptacle enables suppression of the reflection from the proximal catheter facet. This configuration leads to an approximately 800- fold reduction of the reflected optical power originating from the rotary junction compared to the reference design with an UPC-connectorized catheter (from 287 pW to 0.35 pW), corresponding to a 29 dB increase of the return loss. This return power value is close to the return power observed without any catheter present and leads to an identical baseline noise in the OCT image.

[0080] The different rotary conjunction configurations for return power and noise measurements are shown in FIG. 7 through FIG. 11 and Table 1. These schematic diagrams depict rotary junction return power and corresponding OCT noise measurements for APC, UPC, UPC with distal absorber, wedge APC, demonstrating that the wedge design leads to a return power and corresponding image noise on par with the value observed without any optical interface after the rotary junction’s focusing lens.

[0081] The configuration designated #1 and shown in FIG. 7 (no wedge and catheter removed) is the reference configuration with no return signal from the catheter. The configuration #2 (no wedge, UPC patch cord) shown in FIG. 8 shows back-reflections originating from the proximal UP and distal UPC interfaces. In the configuration #3 (no wedge, UPC patch cord with “black hole”), shown in FIG. 9, the back-reflection originating from the proximal UPC connector alone due to the index-matched absorber (“black hole”) on the distal fiber facet can be seen.

[0082] In FIG. 10, the configuration designated #4 (wedge, no connector) shows that the back-reflection on the proximal facet of the wedge is minimally coupled back into the OCT fiber and the back-reflection of the distal wedge facet is directed off-axis due to the 8 degrees polish. In the configuration #5(wedge, APC connector) shown in FIG. 11 , the back-reflection on the proximal facet of the wedge is minimally coupled back into the OCT fiber, back- reflection on the distal facet of the wedge is prevented by the physical contact with the APC connector fiber facet. This result was achieved without adversely impacting the single-mode coupling efficiency of >70%. It was observed that the axial preload of the catheter connector ensures a physical contact that extends beyond the double-clad fiber facet, ensuring that no additional Fresnel losses are incurred by the insertion of this element in the optical path.

[0083] Example 4

[0084] To demonstrate the functionality of the image reconstruction, OCT backscattered intensity, tissue birefringence and degree of polarization were evaluated. The fluorescence decay parameters from each FLIm point measurement were retrieved using a constrained least-square deconvolution with Laguerre expansion (CLSD-LE) method (J. Liu, Y. Sun, J. Qi, and L. Marcu, 'A novel method for fast and robust estimation of fluorescence decay dynamics using constrained least-squares deconvolution with Laguerre expansion," Phys Med Biol 57, 843 (2012). This approach provided average lifetime values for each spectral band and captures more complex decay dynamics from a mixture of fluorophores, as expected from atherosclerotic lesions.

[0085] Computationally, this method is also more time-efficient than the multiexponential approaches. En-face images were obtained by combining FLIm point measurements obtained between consecutive timestamps as part of the same 360-degree rotation. Detailed investigation of the FLIm average lifetime variation with signal intensity in phantom and arteries was performed by binning FLIm measurements based on signal intensity and computing the mean and standard deviation of the averaged lifetime for each intensity bin.

[0086] For reconstruction of the OCT backscattered intensity, tissue birefringence and degree of polarization, conventional structural OCT and PS- OCT images were obtained simultaneously from the raw datasets offline. Birefringence is the unitless ratio of retardation per propagation distance. Itcorresponds to the difference in refractive indices (An) experienced by light polarized parallel and orthogonal to the fibrillary tissue components.

[0087] Depth-resolved tissue birefringence was reconstructed using spectral binning to mitigate artifacts caused by polarization mode dispersion originating from the fiber optic components of the imaging system. The spectral binning algorithm employed bins of 1 / 5th of the original spectral bandwidth and a lateral (circumferential) Gaussian filter for averaging Stokes vectors with a full width at half maximum (FWHM) corresponding to a catheter rotation angle of 8.64° (6 A-lines per input polarization state). Birefringence was retrieved by computing the retardance <p between adjacent depth-pixels and converted to birefringence with An = (pAc / (4irAz), where Ac is the center wavelength in air, and Az = 4.81 pm the axial separation between adjacent pixels in a medium with refractive index n = 1.34. Areas of high depolarization, which precluded the reconstruction of meaningful birefringence, were omitted from the visualization maps.

[0088] Depolarization corresponds to a randomization of the detected polarization states within the small neighborhood around each pixel defined by the Gaussian filtering of Stokes vectors. It is expressed as the ratio of the depolarized signal to the total intensity. Depolarization (D) was computed as the complement to 1 of the degree of polarization. Depolarization is always in the range of 0 (completely polarized) to 1 (completely random and depolarized). All processing steps were implemented in Matlab 2022a (Mathworks Inc., Natick, Massachusetts) with an Intel Core i9-12900k processor, 64 GB of RAM and GPU acceleration (RTX 3090, Nvidia).

[0089] To merge the color-mapped birefringence and reflectance image with the gray scale reflection image in regions of high depolarization, the birefringence color image was weighted with w = [1 / 2— erf{(D-2 / 3) / 0.08}], where erf is the error function. The gray-scale image was scaled with the complementary weight 1-w, and then the two images were added. The final rendering visualized the tissue structure, enhanced with the tissue birefringence mapped to color, and indirectly specifies regions of high depolarization in grayscale.

[0090] Synchronization of FLIm and OCT is an important aspect of the process to ensure proper co-registration of the multimodal data. Both FLIm and PSOCT light sources are free-running and if a fixed number of measurements per B-scan are used, drifts in the FLIm laser repetition rate or OCT sweep rate could lead to loss of co-registration. Thus, OCT and FLIm measurements for each B-scan were determined based on timestamps obtained from the rotary collimator’s angular encoder index channel, corresponding to the start of each consecutive catheter rotation.

[0091] PSOCT data was acquired with a digitizer that did not share the same clock as the FLIm and rotation index digitizer. This limitation, however, was addressed by acquiring the OCT digitizer’s synchronization output with the same digitizer card as the rotation index, thus providing shared timestamps across both modalities. Structural OCT, tissue birefringence, and depolarization were computed and displayed. For each FLIm spectral band, hybrid FLIm-OCT B-scans were generated by color-coding each OCT A-line by the average lifetime value at that angular location.

[0092] For the phantom and specimen imaging, FLIm-OCT co-registration was evaluated in a 3-mm inner diameter tubular fluorescent acrylic phantom where a stent was placed to provide clearly identifiable features. Birefringence evaluation was performed using a custom phantom consisting of birefringent (polymer) positioned in a 3D-printed structure. DCF artifacts observed in the OCT image were characterized using a 0.5-mm thick ABS (Acrylonitrile Butadiene Styrene) sheet.

[0093] Imaging of coronary artery vessels was performed using a healthy swine heart obtained from the UC Davis meat lab, a federally inspected meat processing plant. The segment used for imaging consisted of the left ostium, left main and left anterior descending artery. A 0.014” guidewire was placed in the artery to guide the imaging catheter and removed prior to imaging to allow full visualization of the vessel without guidewire shadow. Before and during imaging, the healthy swine coronary artery was kept in saline solution.

[0094] Example 5

[0095] The performance of the system and imaging methods was assessed with phantoms. The FLIM-PSOCT co-registration accuracy was evaluated ina phantom consisting of a stent placed in a fluorescent acrylic tube. The stent struts were clearly visible in the OCT maximum intensity projection and the strut shadows were clearly seen in the en-face FLIm intensity images. The FLIm and OCT processes are inherently spatially co-registered as both FLIm and OCT beams are concentric, and the accurate overlap of FLIm and OCT images demonstrated proper synchronization of both imaging modalities.

[0096] The process was illustrated with a stent deployed in a fluorescent acrylic tubular phantom that provided both FLIm and OCT contrast. Binary masks were generated for FLIm and OCT and combined to demonstrate registration. Both modalities were shown to be spatially registered since the FLIm and OCT optical beams are concentric, but synchronization of both subsystems was required to achieve accurate co-registration, as demonstrated in the overlap en face images. Imaging of the birefringence phantom was performed for the FLIm-PSOCT hybrid system and a reference PSOCT system. Both systems were able to characterize the layered birefringence of the polymer sheets. The FLIm and OCT strut masks were obtained by performing intensity normalization across each angular position and applying a fixed threshold.

[0097] The performance of the current hybrid system relative to a reference PSOCT intravascular imaging system was evaluated with a phantom consisting of a birefringent film of stretched scattering polycarbonate held in place by a 3D printed holder. As expected, the DCF used for the construction of the hybrid catheter presented crosstalk between the cladding and core modes that locally increased the noise floor at characteristic pathlength positions within the OCT image compared to a PSOCT-only reference system. While the DCF artifacts are apparent in the structural OCT signal, they had less impact on the reconstruction of birefringence and depolarization images. The strong birefringence of the polycarbonate film was clearly revealed, contrasting with the lower birefringence of the supporting material. Depolarization increased for more oblique imaging angles, both in the multimodal and in the reference system.

[0098] Example 6

[0099] An assessment of the performance of the system and methods wasperformed on a pig coronary artery ex vivo. The performance of the hybrid system in artery specimens was important to ensure that FLIm and PSOCT parameters can be extracted from samples with optical properties (fluorescence, absorption, scattering, birefringence, depolarization, attenuation) that are similar to the target application.

[0100] Acquired en face maps of peak fluorescence intensity and average lifetime demonstrate that consistent average lifetime values can be successfully extracted despite large variations of signal intensity.

[0101] Cross-sections in two areas of the vessel, side branches, large vessel diameter were evaluated. The FLIm average lifetime encoded B-scans demonstrated uniform lifetime values. The OCT backscatter intensity image demonstrated clear visualization of arterial morphological structure (media, adventitia, and perivascular tissue), with a penetration depth of at least 1 mm.

[0102] In young healthy animals, the intima typically consists of a single layer of endothelial cells, which thickness is less than the axial resolution of OCT and is therefore not visible. High birefringence associated with high smooth muscle cell content is observed in the media. As expected, the demarcation between media and adventitia based on birefringence is less clear when the optical beam is crossing the media at a shallow angle. In that configuration, the muscle fibers are more closely aligned with the beam and thus birefringence is reduced. The depolarization was uniform and low due to the absence of lipid pools in healthy vessels.

[0103] Displays of mean and standard deviation of average lifetimes for the 380 nm, 400 nm and 450 nm spectral bands showed a reduction of average lifetime as the wavelength increases. This finding was consistent with a relative increase in elastin-to-collagen fluorescence contribution at longer wavelength. For each spectral band and intensity level, we also report a low standard deviation of the measured lifetime (~0.1 ns to 0.2 ns), which increases with decreasing intensity.

[0104] A modest but very consistent reduction of the average lifetime with decreasing signal intensity was also observed. The strong smooth muscle cell content in the media generates high birefringence in conditions where the optical beam is normal to the vessel wall. As expected, the demarcationbetween media and adventitia based on birefringence is less clear when the optical beam crosses the media at a shallow angle. Specifically, in that configuration, the optic axis of the birefringent tissue is more closely aligned with the beam directly and thus less birefringence is detected.

[0105] As expected from healthy coronary arteries, the depolarization is low and uniformly distributed across the artery cross-section. The en-face average lifetime FLIm maps demonstrated a predominant emission in the 380-nm, 400-nm, and 450-nm bands, as expected from healthy vessels, with uniform average lifetime and intensity ratio (380 / 20 nm band lifetime: 6.021 +- 0.130 ns, 400 / 20 nm band lifetime: 5.891 +- 0.157 ns, 452 / 45 nm band lifetime: 5.766 +- 0.124 ns, 540 / 45 nm band lifetime: 4.803 ns +- 0.248 ns).

[0106] Embodiments of the technology of this disclosure may be described herein with reference to flowchart illustrations of methods and systems according to embodiments of the technology. Embodiments of the technology of this disclosure may also be described with reference to procedures, algorithms, steps, operations, formulae, or other computational depictions, which may be included within the flowchart illustrations or otherwise described herein. It will be appreciated that any of the foregoing may also be implemented as computer program instructions. In this regard, each block or step of a flowchart, and combinations of blocks (and / or steps) in a flowchart, as well as any procedure, algorithm, step, operation, formula, or computational depiction can be implemented by various means, such as hardware, firmware, and / or software including one or more computer program instructions embodied in computer-readable program code. As will be appreciated, any such computer program instructions may be executed by one or more computer processors, including without limitation a general purpose computer or special purpose computer, or other programmable processing apparatus to produce a machine, such that the computer program instructions which execute on the computer processor(s) or other programmable processing apparatus create means for implementing the function(s) specified.

[0107] Accordingly, blocks of the flowcharts, and procedures, algorithms, steps, operations, formulae, or computational depictions described hereinsupport combinations of means for performing the specified function(s), combinations of steps for performing the specified function(s), and computer program instructions, such as embodied in computer-readable program code logic means, for performing the specified function(s). It will also be understood that each block of the flowchart illustrations, as well as any procedures, algorithms, steps, operations, formulae, or computational depictions and combinations thereof described herein, can be implemented by special purpose hardware-based computer systems which perform the specified function(s) or step(s), or combinations of special purpose hardware and computer-readable program code.

[0108] Furthermore, these computer program instructions, such as embodied in computer-readable program code, may also be stored in one or more computer-readable memory or memory devices that can direct a computer processor or other programmable processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory or memory devices produce an article of manufacture including instruction means which implement the function specified in the block(s) of the flowchart(s). The computer program instructions may also be executed by a computer processor or other programmable processing apparatus to cause a series of operational steps to be performed on the computer processor or other programmable processing apparatus to produce a computer- implemented process such that the instructions which execute on the computer processor or other programmable processing apparatus provide steps for implementing the functions specified in the block(s) of the flowchart(s), procedure (s) algorithm(s), step(s), operation(s), formula(e), or computational depiction(s).

[0109] It will further be appreciated that the terms "programming" or "program executable" as used herein refer to one or more instructions that can be executed by one or more computer processors to perform one or more functions as described herein. The instructions can be embodied in software, in firmware, or in a combination of software and firmware. The instructions can be stored locally to the device in non-transitory media, or can be stored remotely such as on a server, or all or a portion of the instructions can bestored locally and remotely. Instructions stored remotely can be downloaded (pushed) to the device by user initiation, or automatically based on one or more factors.

[0110] It will further be appreciated that as used herein, the terms controller, microcontroller, processor, microprocessor, hardware processor, computer processor, central processing unit (CPU), and computer are used synonymously to denote a device capable of executing the instructions and communicating with input / output interfaces and / or peripheral devices, and that the terms controller, microcontroller, processor, microprocessor, hardware processor, computer processor, CPU, and computer are intended to encompass single or multiple devices, single core and multicore devices, and variations thereof.

[0111] From the description herein, it will be appreciated that the present disclosure encompasses multiple implementations of the technology which include, but are not limited to, the following:

[0112] A hybrid intravascular imaging system, comprising: (a) a Fluorescence Lifetime Imaging (FLIm) module configured to excite and detect fluorescence;(b) a Polarization-Sensitive Optical Coherence Tomography (PSOCT) module configured to produce 2D and 3D images with micrometer scale resolution; (c) a multimodal motor drive unit (MDU) operably coupled to the FLIm and PSCOT modules, the MDU configured to simultaneously acquire coregistered FLIm data and PSOCT backscattered intensity, birefringence, and depolarization data; (d) an intravascular catheter optically coupled to the MDU with an optical coupling comprising: (i) a receptacle configured to receive an APC optical fiber connector of the catheter, the connector having an 8-degree pre-angled facet; and (ii) a fused silica spacer mounted in a MDU receptacle, the spacer oriented along a central axis of the APC optical fiber connector when received within the receptacle, the spacer angle-polished to match an 8- degree facet of an APC coupling.

[0113] The system of any preceding or following implementation, wherein the intravascular catheter further comprises a double clad fiber and a torque coil surrounding the fiber.

[0114] The system of any preceding or following implementation furthercomprising a display.

[0115] The system of any preceding or following implementation, wherein the FLIm module comprises: a free-running pulsed diode-pumped solid-state laser fluorescence excitation light delivered to the MDU using a multimode fiber; a photodetector configured to detect fluorescence emission signals; and a controller.

[0116] The system of any preceding or following implementation, wherein the photodetector comprises: a UV-enhanced avalanche photodiode; biasing circuitry able to vary detector gain between M=1 to >500; a trans-impedance amplifier; and one or more synchronized high-speed digitizers configured to sample detector signals.

[0117] The system of any preceding or following implementation, wherein the photodetector further comprises: one or more optical filters; and one or more dichroic mirrors; wherein a fluorescence emission signal can be spectrally resolved and detected in a plurality of selected distinct spectral bands.

[0118] The system of any preceding or following implementation, wherein synchronization of FLIm data acquisition and PSOCT data acquisition is performed by the FLIm module, wherein a PSOCT A-line synchronization signal and a rotation index of an MDU angular encoder are saved with a digitizer sharing a clock with the FLIm data acquisition.

[0119] The system of any preceding or following implementation, wherein the PSOCT module comprises: a wavelength-swept laser; an OCT interferometer; a high-speed phase retarder synchronized with the swept laser and positioned between the laser and the OCT interferometer; a polarization modulator and polarization controller to ensure a constant reference signal; detectors; and a module controller.

[0120] The system of any preceding or following implementation, wherein the MDU comprises: a first adjustable dichroic mirror configured to combine PSOCT and FLIm beams; a second adjustable dichroic mirror configured to combine FLIm excitation and emission pathways; a rotary collimator optically coupled with an imaging core of the catheter, the rotary collimator optically aligned with the first and second adjustable dichroic mirrors; actuators configured for rotary and pullback movement; and a controller; wherein theMDU enables rotary and pullback actuation of the catheter and coupling of FLIm and OCT optical beams into the catheter.

[0121] The system of any preceding or following implementation, wherein the rotary collimator comprises: a housing with a bearing and rotating collimator shaft with an adjustable lens and fiber receptacle; an optical encoder mounted on the collimator shaft; and a closed loop motion control with a motor and speed controller.

[0122] The system of any preceding or following implementation, the MDU receptacle further comprising at least one lens configured to focus light on the spacer of the receptacle, wherein the lens focus is located at an opposite face of the spacer than a reflection.

[0123] The system of any preceding or following implementation, further comprising a system controller operably coupled to the PSOCT module, FLIm module, MDU and catheter, the system controller configured to control data acquisition and processing.

[0124] The system of any preceding or following implementation, further comprising a processor configured to receive input from the PSOCT module, FLIm module, MDU and catheter; and a non-transitory memory storing instructions executable by the processor wherein the instructions, when executed by the processor, perform steps comprising simultaneously acquiring co-registered FLIm data and PSOCT backscattered intensity, birefringence, and depolarization data of a subject and analyzing the acquired data to produce an image.

[0125] The system of any preceding or following implementation, wherein the instructions when executed by the processor further perform steps comprising: simultaneously acquiring co-registered FLIm data and PSOCT backscattered intensity, birefringence, and depolarization data of a target; analyzing acquired data to assess plaque structure and composition of the target; forming an image of the target; displaying the formed image on a display; and recording the formed images.

[0126] A reflection suppressive angled physical contact (APC) optical coupling, comprising: a receptacle configured to receive an APC optical fiber connector having an 8-degree pre-angled facet; and a fused silica spacermounted in the receptacle, the spacer oriented along a central axis of the APC optical fiber connector when received within the receptacle, the spacer angle-polished to match an 8-degree facet of an APC coupling; wherein a back-reflections within the optical fibers are suppressed.

[0127] The coupling of any preceding or following implementation, the receptacle further comprising at least one lens configured to focus light on the spacer of the receptacle, wherein the lens focus is located at an opposite face of the spacer than a reflection.

[0128] An optical rotary junction apparatus, the apparatus comprising: stationary fiber optics; rotary fiber optics; a rotary collimator that enables bidirectional transmission of optical signals between a stationary and rotary fiber optics; and an optical coupling configured to mate with an APC catheter connector, the coupling having a cylindrical spacer with a polished 8-degree angled interface; wherein back-reflection of a beam during its propagation in the rotary junction is suppressed.

[0129] The apparatus of any preceding or following implementation, further comprising focusing elements integrated in both a rotary side and a stationary side of the junction to collimate the beam exiting from one fiber and focus that beam into an opposite fiber.

[0130] The apparatus of any preceding or following implementation, wherein the focusing elements are selected from the group consisting of a refractive lens and a gradient index lens.

[0131] The apparatus of any preceding or following implementation, further comprising actuators configured for rotary and pullback movement of the rotary collimator; and a controller.

[0132] A method for multi-scale assessment of plaque structure and composition, the method comprising: simultaneously acquiring co-registered FLIm data and PSOCT backscattered intensity, birefringence, and depolarization data from a subject; and analyzing acquired data to assess plaque structure and composition of the subject.

[0133] As used herein, the term "implementation" is intended to include, without limitation, embodiments, examples, or other forms of practicing the technology described herein.

[0134] As used herein, the singular terms "a," "an," and "the" may include plural referents unless the context clearly dictates otherwise. Reference to an object in the singular is not intended to mean "one and only one" unless explicitly so stated, but rather "one or more."

[0135] Phrasing constructs, such as “A, B and / or C”, within the present disclosure describe where either A, B, or C can be present, or any combination of items A, B and C. Phrasing constructs indicating, such as “at least one of” followed by listing a group of elements, indicates that at least one of these groups of elements is present, which includes any possible combination of the listed elements as applicable.

[0136] References in this disclosure referring to “an embodiment”, “at least one embodiment” or similar embodiment wording indicates that a particular feature, structure, or characteristic described in connection with a described embodiment is included in at least one embodiment of the present disclosure. Thus, these various embodiment phrases are not necessarily all referring to the same embodiment, or to a specific embodiment which differs from all the other embodiments being described. The embodiment phrasing should be construed to mean that the particular features, structures, or characteristics of a given embodiment may be combined in any suitable manner in one or more embodiments of the disclosed apparatus, system, or method.

[0137] As used herein, the term "set" refers to a collection of one or more objects. Thus, for example, a set of objects can include a single object or multiple objects.

[0138] Relational terms such as first and second, top and bottom, upper and lower, left and right, and the like, may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions.

[0139] The terms "comprises," "comprising," "has", "having," "includes", "including," "contains", "containing" or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, apparatus, or system, that comprises, has, includes, or contains a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article,apparatus, or system. An element proceeded by "comprises . . . a", "has . . . a", "includes . . . a", "contains . . . a" does not, without more constraints, preclude the existence of additional identical elements in the process, method, article, apparatus, or system, that comprises, has, includes, contains the element.

[0140] As used herein, the terms "approximately", "approximate", "substantially", "substantial", "essentially", and "about", or any other version thereof, are used to describe and account for small variations. When used in conjunction with an event or circumstance, the terms can refer to instances in which the event or circumstance occurs precisely as well as instances in which the event or circumstance occurs to a close approximation. When used in conjunction with a numerical value, the terms can refer to a range of variation of less than or equal to ± 10% of that numerical value, such as less than or equal to ±5%, less than or equal to ± 4%, less than or equal to ±3%, less than or equal to ± 2%, less than or equal to ± 1 %, less than or equal to ± 0.5%, less than or equal to ± 0.1 %, or less than or equal to ± 0.05%. For example, "substantially" aligned can refer to a range of angular variation of less than or equal to ± 10°, such as less than or equal to ± 5°, less than or equal to ± 4°, less than or equal to ± 3°, less than or equal to ± 2°, less than or equal to ± 1 °, less than or equal to ± 0.5°, less than or equal to ± 0.1 °, or less than or equal to ± 0.05°.

[0141] Additionally, amounts, ratios, and other numerical values may sometimes be presented herein in a range format. It is to be understood that such range format is used for convenience and brevity and should be understood flexibly to include numerical values explicitly specified as limits of a range, but also to include all individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly specified. For example, a ratio in the range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual ratios such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, and so forth.

[0142] The term "coupled" as used herein is defined as connected, althoughnot necessarily directly and not necessarily mechanically. A device or structure that is "configured" in a certain way is configured in at least that way but may also be configured in ways that are not listed.

[0143] Benefits, advantages, solutions to problems, and any element(s) that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as a critical, required, or essential feature or element of the technology described herein or any or all the claims.

[0144] In addition, in the foregoing disclosure various features may be grouped together in various embodiments for the purpose of streamlining the disclosure. This method of disclosure is not to be interpreted as reflecting an intention that the claimed embodiments require more features than are expressly recited in each claim. Inventive subject matter can lie in less than all features of a single disclosed embodiment.

[0145] The abstract of the disclosure is provided to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims.

[0146] It will be appreciated that the practice of some jurisdictions may require deletion of one or more portions of the disclosure after the application is filed. Accordingly, the reader should consult the application as filed for the original content of the disclosure. Any deletion of content of the disclosure should not be construed as a disclaimer, forfeiture, or dedication to the public of any subject matter of the application as originally filed.

[0147] All text in a drawing figure is hereby incorporated into the disclosure and is to be treated as part of the written description of the drawing figure.

[0148] The following claims are hereby incorporated into the disclosure, with each claim standing on its own as a separately claimed subject matter.

[0149] Although the description herein contains many details, these should not be construed as limiting the scope of the disclosure, but as merely providing illustrations of some of the presently preferred embodiments. Therefore, it will be appreciated that the scope of the disclosure fully encompasses other embodiments which may become obvious to those skilled in the art.

[0150] All structural and functional equivalents to the elements of thedisclosed embodiments that are known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the present claims. Furthermore, no element, component, or method step in the present disclosure is intended to be dedicated to the public regardless of whether the element, component, or method step is explicitly recited in the claims. No claim element herein is to be construed as a "means plus function" element unless the element is expressly recited using the phrase "means for". No claim element herein is to be construed as a "step plus function" element unless the element is expressly recited using the phrase "step for".Table 1Rotary junction return power and corresponding OCT noise measurements for APC, UPC, UPC with distal absorber, wedge APC, demonstrating that the wedge design leads to a return power and corresponding image noise on par with the value observed without any optical interface after the rotary junction’s focusing lens.Table 2Double-clad Fiber characteristics. The inner cladding consists of pure silica. The core and outer cladding indices were computed based on the core and inner cladding reported numerical apertures.

Claims

CLAIMSWhat is claimed is:1 . A hybrid intravascular imaging system, comprising:(a) a Fluorescence Lifetime Imaging (FLIm) module configured to excite and detect fluorescence;(b) a Polarization-Sensitive Optical Coherence Tomography (PSOCT) module configured to produce 2D and 3D images with micrometer scale resolution;(c) a multimodal motor drive unit (MDU) operably coupled to the FLIm and PSCOT modules, said MDU configured to simultaneously acquire co-registered FLIm data and PSOCT backscattered intensity, birefringence, and depolarization data;(d) an intravascular catheter optically coupled to the MDU with an optical coupling comprising:(i) a receptacle configured to receive an APC optical fiber connector of the catheter, said connector having an 8-degree pre-angled facet; and(ii) a fused silica spacer mounted in a MDU receptacle, the spacer oriented along a central axis of the APC optical fiber connector when received within the receptacle, the spacer angle-polished to match an 8-degree facet of an APC coupling.

2. The system of claim 1 , the intravascular catheter further comprising: a double clad fiber; and a torque coil surrounding the fiber.

3. The system of claim 1 , the system further comprising a display.

4. The system of claim 1 , wherein the FLIm module comprises:(a) a free-running pulsed diode-pumped solid-state laser fluorescence excitation light delivered to the MDU using a multimode fiber;(b) a photodetector configured to detect fluorescence emission signals; and(c) a controller.

5. The system of claim 4, wherein the photodetector comprises:(a) a UV-enhanced avalanche photodiode;(b) biasing circuitry able to vary detector gain between M=1 to >500;(c) a trans-impedance amplifier; and(d) one or more synchronized high-speed digitizers configured to sample detector signals.

6. The system of claim 4, wherein the photodetector further comprises:(a) one or more optical filters; and(b) one or more dichroic mirrors;(c) wherein a fluorescence emission signal can be spectrally resolved and detected in a plurality of selected distinct spectral bands.

7. The system of claim 1 , wherein synchronization of FLIm data acquisition and PSOCT data acquisition is performed by the FLIm module, wherein a PSOCT A-line synchronization signal and a rotation index of an MDU angular encoder are saved with a digitizer sharing a clock with the FLIm data acquisition.

8. The system of claim 4, wherein the PSOCT module comprises:(a) a wavelength-swept laser;(b) an OCT interferometer;(c) a high-speed phase retarder synchronized with the swept laser and positioned between the laser and the OCT interferometer;(d) a polarization modulator and polarization controller to ensure a constant reference signal;(e) detectors; and(f) a module controller.

9. The system of claim 1 , wherein the MDU comprises:(a) a first adjustable dichroic mirror configured to combine PSOCT and FLIm beams;(b) a second adjustable dichroic mirror configured to combine FLIm excitation and emission pathways;(c) a rotary collimator optically coupled with an imaging core of the catheter, the rotary collimator optically aligned with the first and second adjustable dichroic mirrors;(d) actuators configured for rotary and pullback movement; and(e) a controller;(f) wherein the MDU enables rotary and pullback actuation of the catheter and coupling of FLIm and OCT optical beams into the catheter.

10. The system of claim 9, wherein the rotary collimator comprises:(a) a housing with a bearing and rotating collimator shaft with an adjustable lens and fiber receptacle;(b) an optical encoder mounted on the collimator shaft; and(c) a closed loop motion control with a motor and speed controller.11 . The system of claim 1 , said MDU receptacle further comprising at least one lens configured to focus light on the spacer of the receptacle, wherein the lens focus is located at an opposite face of the spacer than a reflection.

12. The system of claim 1 , said system further comprising a system controller operably coupled to the PSOCT module, FLIm module, MDU and catheter, said system controller configured to control data acquisition and processing.

13. The system of claim 12, said system further comprising: a processor configured to receive input from the PSOCT module, FLIm module, MDU and catheter; and a non-transitory memory storing instructions executable by the processor; wherein said instructions, when executed by the processor, perform steps comprising:simultaneously acquiring co-registered FLIm data and PSOCT backscattered intensity, birefringence, and depolarization data of a subject; and analyzing the acquired data to produce an image.

14. The system of claim 13, wherein said instructions when executed by the processor further perform steps comprising: simultaneously acquiring co-registered FLIm data and PSOCT backscattered intensity, birefringence, and depolarization data of a target; analyzing acquired data to assess plaque structure and composition of the target; forming an image of the target; displaying the image on a display; and recording the formed images.

15. A reflection suppressive angled physical contact (APC) optical coupling, comprising:(a) a receptacle configured to receive an APC optical fiber connector having an 8-degree pre-angled facet; and(b) a fused silica spacer mounted in the receptacle, the spacer oriented along a central axis of the APC optical fiber connector when received within the receptacle, the spacer angle-polished to match an 8-degree facet of an APC coupling;(c) wherein a back-reflections within the optical fibers are suppressed.

16. The coupling of claim 15, said receptacle further comprising at least one lens configured to focus light on the spacer of the receptacle, wherein the lens focus is located at an opposite face of the spacer than a reflection.

17. An optical rotary junction apparatus, the apparatus comprising:(a) stationary fiber optics;(b) rotary fiber optics;(c) a rotary collimator that enables bidirectional transmission of optical signals between a stationary and rotary fiber optics; and(d) an optical coupling configured to mate with an APC catheter connector, said coupling having a cylindrical spacer with a polished 8-degree angled interface;(e) wherein back-reflection of a beam during its propagation in the rotary junction is suppressed.

18. The apparatus of claim 17, further comprising focusing elements integrated in both a rotary side and a stationary side of the junction to collimate the beam exiting from one fiber and focus that beam into an opposite fiber.

19. The apparatus of claim 18, wherein the focusing elements are selected from the group consisting of a refractive lens and a gradient index lens.

20. The apparatus of claim 17, further comprising: actuators configured for rotary and pullback movement of the rotary collimator; and a controller.21 . A method for multi-scale assessment of plaque structure and composition, the method comprising:(a) simultaneously acquiring co-registered FLIm data and PSOCT backscattered intensity, birefringence, and depolarization data with the system of Claim 1 of a subject; and(b) analyzing acquired data to assess plaque structure and composition of the subject.

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