Open-field handheld fluorescence imaging systems and methods

Description

FIELD OF THE INVENTION

The present disclosure relates generally to medical illumination and imaging. More specifically, the disclosure relates to illumination and imaging of a target material.

BACKGROUND OF THE INVENTION

Illumination is an important component of imaging systems such as, for example, broadband imaging systems with self-contained illumination. In many applications of imaging systems, such as in medical imaging and especially in fluorescence medical imaging, it may be challenging to achieve even, full field illumination of the imaging field of view, and also to provide a sufficient intensity of illumination to yield a sufficiently strong imaging signal. Matching the illumination profile to the imaging field of view is one method of conserving illumination power, while multiple illumination ports may be used to provide even illumination across the field of view. Existing illumination projection in imaging systems may feature anamorphic projection to match the imaging field of view, but typically only feature a single illumination port and are not configured for close working distances. Single port illumination systems result in substantial shadowed regions obscuring vision when illuminating complex topography such as, for example, human anatomical structures or other biological materials. Existing designs for open field surgical imaging and illumination devices may make use of multiple illumination ports to minimize shadowed regions, such as a ring light surrounding the imaging optics, but these designs waste excess illumination that falls outside of the field of view and fail to achieve even illumination of the field of view over a range of working distances.

SUMMARY OF THE INVENTION

According to some embodiments, an imaging device having an imaging field of view may include at least one illumination port configured to output light for illuminating a target; an imaging sensor to detect light traveling along an optical path to the imaging sensor; and a first movable window positioned upstream of the sensor with respect to a direction of travel of light along the optical path, wherein the first movable window is configured to move into the optical path in a deployed position for modifying light received from the target.

In any of these embodiments, the first movable window may be configured to rotate into the optical path in a deployed position.

In any of these embodiments, the first movable window may be configured to translate into the optical path in a deployed position.

In any of these embodiments, the first movable window may extend perpendicularly to an optical axis in the deployed position.

In any of these embodiments, the first movable window may be configured to pivot into the optical path in a deployed position.

In any of these embodiments, the first movable window may be configured to pivot about a first pivot axis extending perpendicularly to an optical axis.

In any of these embodiments, the first movable window may include a filter.

In any of these embodiments, the filter may be configured to filter out visible light.

In any of these embodiments, a second movable window may be positioned upstream of the imaging sensor with respect to the direction of travel of light along the optical path, wherein the second movable window is configured to move into the optical path in a deployed position for modifying light received from the target.

In any of these embodiments, the second movable window may be configured to pivot about a second pivot axis extending perpendicularly to an optical axis.

In any of these embodiments, the first movable window may be configured to pivot about a first pivot axis extending perpendicularly to the optical axis and the first pivot axis and the second pivot axis may be coplanar with a plane extending perpendicularly to the optical axis.

In any of these embodiments, the first movable window and the second movable window may be coupled to a linkage that is configured to simultaneously move the first and second pivoting windows.

In any of these embodiments, when the first movable window is in the deployed position, the second movable window may be moved out of the optical path in a stowed position.

In any of these embodiments, the image sensor may be translatable with respect to the first movable window.

In any of these embodiments, the first movable window may extend perpendicularly to an optical axis in the deployed position and the image sensor may be translatable along the optical axis.

Any of these embodiments may include a first illumination port and a second illumination port, wherein the first illumination port is configured to generate a first illumination distribution at the target, the second illumination port is configured to generate a second illumination distribution at the target, the second illumination port is spaced apart from the first illumination port, the first and second illumination distributions are simultaneously provided to the target and overlap at the target, and the illumination from the first and second ports is matched to a same aspect ratio and field of view coverage as the imaging field of view.

In any of these embodiments, the first and second illumination ports may be fixed with respect to each other.

In any of these embodiments, the at least one illumination port may be configured to output visible light and/or excitation light.

In any of these embodiments, the image sensor may be a single sensor that is configured to detect light from the target resulting from illumination by visible light and excitation light.

In any of these embodiments, the image sensor may comprise separate sensors configured to detect light from the target resulting from illumination by visible light separately from that resulting from illumination by excitation light.

Any of these embodiments may include a wavelength-dependent aperture upstream of the image sensor, wherein the wavelength-dependent aperture is configured to block visible light outside a central region.

Any of these embodiments may include one or more sensors for sensing an amount of light incident on the device.

Any of these embodiments may include a control system configured to adjust at least one image acquisition parameter based on output from the one or more sensors.

In any of these embodiments, the at least one image acquisition parameter may include an exposure duration, excitation illumination duration, excitation illumination power, or imaging sensor gain.

In any of these embodiments, at least one of the one or more sensors may be configured to sense visible light and near infrared light.

In any of these embodiments, at least one of the one or more sensors may be configured to sense near infrared light.

Any of these embodiments may include one or more drape sensors configured to detect a drape mounted to the device.

Any of these embodiments may include one or more light emitters for emitting light for detection by the one or more drape sensors.

In any of these embodiments, the one or more drape sensors may be configured to detect light emitted from the one or more light emitters after reflection of the emitted light off of one or more reflectors on the drape.

In any of these embodiments, the one or more reflectors may include a prism.

According to some embodiments, an imaging system may include an imaging device according to any one of the above embodiments, an illumination source for providing illumination to the imaging device, and a processor assembly for receiving imaging data generated by the imaging device.

According to some embodiments, a method for imaging a target may include illuminating the target with an illuminator of an imaging device; receiving light from the target at an imaging sensor of the imaging device in a first imaging mode, wherein at least some of the light received at the imaging sensor in the first imaging mode comprises wavelengths in a first band; switching to a second imaging mode; and while in the second imaging mode: blocking light of wavelengths outside of a second band received from the target from reaching the imaging sensor using a first movable filter of the imaging device, wherein at least some of the blocked light comprises wavelengths in the first band, and receiving light of wavelengths within the second band received from the target on the imaging sensor.

In any of these embodiments, the second band may include near infrared wavelengths.

In any of these embodiments, the first band may include visible light wavelengths.

In any of these embodiments, the method may include, while in the first imaging mode, sensing light levels at one or more light level sensors of the imaging device and adjusting one or more of image sensor signal gain, illumination pulse duration, image sensor exposure, and illumination power based on output of the one or more light level sensors.

In any of these embodiments, switching to the second imaging mode may include moving the first movable filter into an optical path along which light from the target travels to the imaging sensor.

In any of these embodiments, switching to the second imaging mode may include moving a clear window out of the optical path.

In any of these embodiments, switching to the second imaging mode may include moving a second movable filter out of the optical path.

In any of these embodiments, the first imaging mode may be switched to the second imaging mode in response to a user request.

In any of these embodiments, the user request may include a user input to the imaging device.

In any of these embodiments, the method may include, while in the second imaging mode, receiving a request from the user to switch to the first imaging mode; and in response to receiving the request from the user to switch to the first imaging mode, moving the movable filter out of the optical path.

In any of these embodiments, the method may include, while in the second imaging mode, sensing light levels at one or more light level sensors of the imaging device and adjusting one or more of image sensor signal gain, illumination pulse duration, image sensor exposure, and illumination power based on output of the one or more light level sensors; and in response to receiving the request from the user to switch to the first imaging mode, ceasing to adjust one or more of image sensor signal gain, illumination pulse duration, image sensor exposure, and illumination power based on output of the one or more light level sensors.

In any of these embodiments, the method may include detecting an object at least partially blocking an illumination beam of the illuminator, and in response to detecting the object, adjusting an illumination power of the illuminator.

According to some embodiments, a kit for imaging an object may include a fluorescence imaging agent and the device of any one of the above embodiments or the system of any one of the above embodiments.

According to some embodiments, a fluorescence imaging agent may include a fluorescence imaging agent for use with the device of any one of the above embodiments, the system of any one of the above embodiments, the method of any one of the above embodiments, or the kit of any one of the above embodiments.

In any of these embodiments, imaging an object may include imaging an object during blood flow imaging, tissue perfusion imaging, lymphatic imaging, or a combination thereof.

In any of these embodiments, blood flow imaging, tissue perfusion imaging, and/or lymphatic imaging may include blood flow imaging, tissue perfusion imaging, and/or lymphatic imaging during an invasive surgical procedure, a minimally invasive surgical procedure, or during a non-invasive surgical procedure.

In any of these embodiments, the invasive surgical procedure may include a cardiac-related surgical procedure or a reconstructive surgical procedure.

In any of these embodiments, the cardiac-related surgical procedure may include a cardiac coronary artery bypass graft (CABG) procedure.

In any of these embodiments, the CABG procedure may include on pump or off pump.

In any of these embodiments, the non-invasive surgical procedure may include a wound care procedure.

In any of these embodiments, the lymphatic imaging may include identification of a lymph node, lymph node drainage, lymphatic mapping, or a combination thereof.

In any of these embodiments, the lymphatic imaging may relate to the female reproductive system.

According to some embodiments, a system for imaging a target includes one or more processors; memory; and one or more programs, wherein the one or more programs are stored in the memory and configured to be executed by the one or more processors, the one or more programs including instructions for, within a period: activating an excitation light source to generate an excitation pulse to illuminate the target; receiving an ambient light intensity signal from a sensor during a portion of the period in which the excitation light source is not activated; exposing an image sensor for a fluorescent exposure time during the excitation pulse; receiving outputs from the image sensor; compensating for ambient light based on the ambient light intensity signal; and storing a resultant image in the memory.

In any of these embodiments, the one or more programs may include instructions for, within the period: activating a white light source to generate a white light pulse to illuminate the target such that the white light pulse does not overlap the excitation pulse; and exposing the image sensor for a visible exposure time during at least one white light pulse.

In any of these embodiments, the one or more programs may include instructions for exposing the image sensor for a background exposure time when the target is not illuminated.

In any of these embodiments, the one or more programs may include instructions for detecting a periodic frequency of the ambient light intensity.

In any of these embodiments, compensating for ambient light may include setting an image acquisition frame rate equal to a multiple or a factor of the periodic frequency prior to exposing the image sensor for the background exposure time and prior to exposing the image sensor for the fluorescent exposure time during the excitation pulse; and subtracting image sensor output received for the background exposure time from the image sensor output received for the fluorescence exposure time to form the resultant image.

In any of these embodiments, compensating for ambient light may include synthesizing or extracting, from one or more received ambient light intensity signals, a complete periodic cycle of ambient light intensity having the detected periodic frequency; extending the ambient light intensity periodic cycle to a time period corresponding to the fluorescence exposure time; calculating a first accumulated ambient light value corresponding to an area under the curve of ambient light intensity during a background exposure time; calculating a second accumulated ambient light value corresponding to an area under the curve of the ambient light intensity during the fluorescence exposure time; scaling the received image sensor output for the background exposure time and the received image sensor output for the fluorescence exposure time based on a ratio of the first and second accumulated ambient light values; and subtracting the scaled image sensor output for the background exposure time from the scaled image sensor output for the fluorescence exposure time to form the resultant image.

In any of these embodiments, the one or more programs may include instructions for receiving an ambient light intensity signal from the sensor during the background exposure time.

In any of these embodiments, the one or more programs may include instructions for extending the ambient light intensity periodic cycle to the time period corresponding to the fluorescence exposure time.

According to some embodiments, a method for imaging a target includes, at a system having one or more processors and memory, activating an excitation light source to generate an excitation pulse to illuminate the target; receiving an ambient light intensity signal from a sensor during a portion of the period in which the excitation light source is not activated; exposing an image sensor for a fluorescent exposure time during the excitation pulse; receiving outputs from the image sensor; compensating for ambient light based on the ambient light intensity signal; and storing a resultant image in the memory.

In any of these embodiments, the method may include, within the period, activating a white light source to generate a white light pulse to illuminate the target such that the white light pulse does not overlap the excitation pulse; and exposing the image sensor for a visible exposure time during at least one white light pulse.

In any of these embodiments, the method may include exposing the image sensor for a background exposure time when the target is not illuminated.

In any of these embodiments, the method may include detecting a periodic frequency of the ambient light intensity.

In any of these embodiments, the method may include receiving an ambient light intensity signal from the sensor during the background exposure time.

In any of these embodiments, the method may include extending the ambient light intensity periodic cycle to the time period corresponding to the fluorescence exposure time.

BRIEF DESCRIPTION OF THE DRAWINGS

Features will become apparent to those of ordinary skill in the art by describing in detail exemplary embodiments with reference to the attached drawings in which:

FIG. 1 illustrates a schematic view of a system for illumination and imaging according to an embodiment;

FIG. 2 illustrates a schematic view of an illumination module according to an embodiment;

FIGS. 3A and 3B illustrate a schematic side view and plan view, respectively, of an exemplary lens module in a steerable housing according to an embodiment;

FIG. 4A illustrates a schematic view of a linkage for synchronous focusing of the imaging system and steering of the illumination system according to embodiments;

FIGS. 4B and 4C illustrate a bottom view and a top view, respectively, of a linkage for synchronous focusing of the imaging system and steering of the illumination system according to embodiments;

FIGS. 5A and 5B illustrate bottom views of the linkage at a far working distance and a near working distance, respectively, according to an embodiment;

FIGS. 6A and 6B illustrate a perspective top view and a perspective bottom view of an illumination and imaging system according to an embodiment;

FIG. 7 illustrates an enclosure according to an embodiment;

FIGS. 8A and 8B illustrate perspective views of different exemplary positions in which the system may be used;

FIG. 9A illustrates a drape for use with the system according to an embodiment; FIGS. 9B to 9E illustrate perspective, front, top, and side views, respectively, of a drape lens and frame for use with the system according to an embodiment; FIG. 9F illustrates a drape lens and frame installed on an enclosure of the system, according to an embodiment; FIG. 9G illustrates a section view of the installed drape lens and frame on the enclosure of the system of FIG. 9F;

FIGS. 10A to 10D illustrate illumination distributions for different illumination configurations;

FIG. 11A illustrates a timing diagram for visible and excitation illumination and image sensor exposures according to an embodiment;

FIG. 11B illustrates a timing diagram for visible and excitation illumination and image sensor exposures according to an embodiment;

FIG. 11C illustrates a timing diagram for visible and excitation illumination and image sensor exposures according to an embodiment;

FIG. 11D illustrates a timing diagram for visible and excitation illumination and image sensor exposures according to an embodiment;

FIG. 11E illustrates a timing diagram for visible and excitation illumination, image sensor exposures and ambient light measurement according to an embodiment;

FIGS. 12A to 12C illustrate pixel layout and an interpolation scheme according to an embodiment;

FIGS. 13A to 13C illustrate diagrams of an embodiment of a display method output when a target reticle is placed over regions with no fluorescence intensity, high relative normalized fluorescence intensity, and moderate relative normalized fluorescence intensity, respectively;

FIG. 13D illustrates a diagram of an embodiment of a display method output that includes a signal time history plot of normalized fluorescence intensity values on the display;

FIG. 14 illustrates a recorded image of an anatomical fluorescence imaging phantom, featuring an embodiment of a display method output that displays normalized fluorescence intensity;

FIG. 15 illustrates an exemplary light source of an exemplary illumination source of the system for illumination shown in FIG. 1;

FIG. 16 illustrates an exemplary imaging module of the fluorescence imaging system in FIG. 1, the imaging module comprising a camera module;

FIG. 17A illustrates a perspective top view of an illumination and imaging system according to an embodiment;

FIG. 17B illustrates a schematic side view of a movable filter assembly for the illumination and imaging system of FIG. 17A, according to an embodiment;

FIGS. 17C to 17D illustrate an enclosure according to an embodiment;

FIG. 17E illustrates a sensor and light source arrangement in a forward portion of an enclosure according to an embodiment;

FIG. 18 illustrates a schematic diagram of components of an illumination and imaging system according to an embodiment; and

FIG. 19 illustrates a schematic diagram of a drape detection module according to an embodiment.

DETAILED DESCRIPTION OF THE INVENTION

Example embodiments will now be described more fully hereinafter with reference to the accompanying drawings; however, they may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey exemplary implementations to those skilled in the art. Various devices, systems, methods, processors, kits and imaging agents are described herein. Although at least two variations of the devices, systems, methods, processors, kits and imaging agents are described, other variations may include aspects of the devices, systems, methods, processors, kits and imaging agents described herein combined in any suitable manner having combinations of all or some of the aspects described.

Generally, corresponding or similar reference numbers will be used, when possible, throughout the drawings to refer to the same or corresponding parts.

Spatially relative terms, such as “beneath”, “below”, “lower”, “above”, “upper”, and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, elements described as “below” or “beneath” other elements or features would then be oriented “above” the other elements or features. Thus, the exemplary term “below” can encompass both an orientation of above and below. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.

FIG. 1 illustrates a schematic view of an illumination and imaging system 10 according to an embodiment. As may be seen therein, the system 10 may include an illumination module 11, an imaging module 13, and a video processor/illuminator (VPI) 14. The VPI 14 may include an illumination source 15 to provide illumination to the illumination module 11 and a processor assembly 16 to send control signals and to receive data about light detected by the imaging module 13 from a target 12 illuminated by light output by the illumination module 11. In one variation, the video processor/illuminator 14 may comprise a separately housed illumination source 15 and the processor assembly 16. In one variation, the video processor/illuminator 14 may comprise the processor assembly 16 while one or more illumination sources 15 are separately contained within the housing of the illumination module 11. The illumination source 15 may output light at different waveband regions, e.g., white (RGB) light, excitation light to induce fluorescence in the target 12, a combination thereof, and so forth, depending on characteristics to be examined and the material of the target 12. Light at different wavebands may be output by the illumination source 15 simultaneously, sequentially, or both. The illumination and imaging system 10 may be used, for example, to facilitate medical (e.g., surgical) decision making e.g., during a surgical procedure. The target 12 may be a topographically complex target, e.g., a biological material including tissue, an anatomical structure, other objects with contours and shapes resulting in shadowing when illuminated, and so forth. The VPI 14 may record, process, display, and so forth, the resulting images and associated information.

FIG. 2 illustrates a schematic perspective view of the illumination module 11 of FIG. 1 according to an embodiment. As may be seen therein, the illumination module 11 may include at least two illumination ports directing illumination from an illumination source 23, which may be included in the VPI box 14, to for example a rectangular target field 24. In some variations, the illumination source 23 may be located in a device housing along with the illumination module 11. Each illumination port is to provide illumination over the target field 24, such that the light overlaps, e.g., substantially or completely, at the target material 12 (shown in FIG. 1). More than two illumination ports may be used. The illumination distributions may be substantially similar and overlap (e.g., substantially or completely) at the target 12 to provide uniform illumination of the target 12. The use of at least two illumination ports facilitates reducing the effect of shadowing due to anatomical topography, and aids in providing uniform illumination over the target field 24. Directing illumination from the illumination module 11 to a rectangular target field 24 (which may have a configuration other than rectangular in other embodiments) allows matching the region of illumination to a rectangular imaging field of view (which may have a configuration other than rectangular in other embodiments), which aids in providing uniform illumination and may enhance efficiency of the illumination module by reducing extraneous illumination. Matching the illumination field to the imaging field of view also provides a useful indication of the location and extent of the anatomical region currently being imaged. In some variations, illumination from the illumination module 11 may be directed to provide uniform illumination of the target 12 without matching the region of illumination to a rectangular imaging field of view, and the rectangular target field 24 of FIG. 2 may be replaced by a non-rectangular target field.

In some embodiments, a light pipe may be used to achieve mixing of the illumination light in order to yield a uniform illumination profile. Mixing of the illumination light by a light pipe may remove the influence of the structure of the light source on the illumination profile, which could otherwise adversely affect uniformity of the illumination profile. For example, using a light pipe to mix the illumination light output from a fiber optic light guide may remove images of the structure of the individual optical fibers from the illumination profile. In some embodiments, a rectangular light pipe may be used to efficiently utilize illumination power while matching the illumination profile to a rectangular imaging field of view. In some embodiments, a light pipe material with a high index of refraction for both visible light and near infrared light, such as optical glass material N-SF11, may be used for high efficiency of illumination power transmission.

According to some embodiments, a rectangular light pipe with an aspect ratio matching the aspect ratio of the imaging field of view (e.g., both aspect ratios being 16:9) may be used in conjunction with rotationally symmetric illumination optic elements.

According to some embodiments, a rectangular light pipe with a different aspect ratio than the imaging field of view (e.g., a square light pipe along with a 16:9 imaging field of view aspect ratio) may be used in conjunction with cylindrical illumination optic elements. Cylindrical optic elements may be used to separately conform one or both dimensions of the rectangular illumination profile to match the aspect ratio of the imaging field of view.

Depending on the desired system requirements for range of working distance and illumination uniformity various approaches may be used for matching the illumination to overlap the imaging field of view. For example, applications which require a large range in working distances and high illumination uniformity may necessitate use of illumination optics and/or ports that are steered dynamically to adequately match the illumination to the imaging field of view, while applications with lower requirements may be served with fixed illumination optics and/or ports to match the illumination to the field of view.

In some embodiments, the direction of illumination is adjusted from multiple illumination ports in synchrony with adjustment of the field of view, in order to steer the field of illumination to maintain correspondence to the field of view.

In some embodiments, one or more illumination optic elements may be rotated by a driver in order to steer the illumination.

In some embodiments, one or more illumination optic elements may be translated perpendicular to the imaging optic axis by a driver in order to steer the illumination.

In some embodiments, one or more illumination optic elements may be configured to provide some distortion in the illumination profile, in order to account for distortion inherent to the accompanying imaging system.

In some embodiments, uniform illumination of the imaging field of view over a specified range of working distances may be achieved with a fixed location and orientation of the illumination optics. The offset distance of the illumination optics from the imaging optic axis may be configured, along with the orientation of the of the illumination optics, in order to optimize matching of the illumination profile to the imaging field of view at a working distance within the specified range of working distances while also maintaining substantial matching of the illumination profile to the imaging field of view at other working distances within the specified range.

As is illustrated in FIG. 2, each illumination port may include a lens module 20, a connecting cable 22 connected to the illumination light source 23, and a light pipe 21 adapting a high numerical aperture of the connecting cable 22 to a lower numerical aperture of the lens module 20. The lens module 20 may be steerable, as described in detail below. In some scenarios, acceptable performance may be achievable without steering. In other words, an illumination module, and imaging device having the same, that provides an illumination field having a rectangular form factor (or configuration other than rectangular) that matches the field of view of the imaging system using at least two illumination ports in which each port produces a gradient of illumination such that the sum illumination flux in the object plane is reasonably the same at each point in the illumination field, e.g., provides uniform illumination over the imaging field of view, alone may be sufficient.

In some variations in which the illumination light source 23 may be contained within a device housing along with illumination module 11, the connecting cable 22 from FIG. 2 may be replaced by one or more illumination light sources 23. In some variations, the connecting cable 22 and the light pipes 21 from FIG. 2 may be replaced by one or more illumination light sources 23. In some variations, the lens module 20 from FIG. 2 may contain the illumination light source 23. In some variations, separate variants of the lens module 20 from FIG. 2 may separately contain a white light source and a fluorescence excitation light source of the illumination light source 23. In one embodiment, three or more lens modules 20 may be arranged to comprise a ring of illumination ports, another functionally equivalent configuration of illumination ports, or another configuration including continuous or non-continuous distribution/arrangement of illumination ports, with each lens module 20 oriented to converge on and provide uniform illumination over the imaging field of view. In some variations, the three or more lens modules 20 comprising a ring of illumination ports may not necessarily constrain illumination to a rectangular field, and the rectangular target field 24 of FIG. 2 may be replaced by a non-rectangular target field, such as for example a circular/oval target field.

FIGS. 3A and 3B illustrate a side view and a plan view, respectively, of the lens module 20. The lens module 20 may include lenses mounted in a steerable lens housing 30. As used herein, a lens is any optical element having optical power, whether implemented by a refractive or diffractive element. Other elements not essential to understanding, such as a cover enclosing the lens module (see FIG. 2), are not shown for ease of illustration.

In the particular example shown herein, the lenses may include a pair of horizontal-axis cylindrical lenses 31-32 and a pair of vertical-axis cylindrical lenses 33-34. A prism element 35 is also shown which may align illumination light with the intended outgoing optical axis. In particular, the prism element 35 corrects for an angle introduced by the light pipe 21 for increased device compactness in accordance with an embodiment. The mounting design for each lens element 31-35 may allow for tuning of the magnification and focus of the illumination optical system. In accordance with this embodiment, the steerable lens housing 30 encloses and steers three of the cylindrical lenses 31, 33, 34 and the prism lens element 35, e.g., collectively as a group. This example of lenses is merely illustrative, and the lenses in the lens module 20 may be modified as appropriate.

In this particular embodiment, a base portion of the steerable housing 30 is pinned, e.g., using a pin 46 (see FIG. 6B) inserted into housing hole 37, about a pivot point 36, respectively to a fixed chassis frame 90 (see FIG. 6A) and a mechanical linkage 40 (see FIGS. 4A to 4C) described in detail below, while lens 32 is rigidly connected the chassis 90, i.e. not to the housing 30 (see FIG. 6B).

FIG. 4A illustrates a schematic view showing directions of motion provided by various components of the linkage 40. The linkage 40 may include a drive cam 41, illumination cams 45a, 45b (one for each illumination port), and an imaging cam 43. The drive cam 41 receives an input from a user (see FIG. 7), and translates that to synchronous motion of the lens module 20a, 20b, attached to a corresponding illumination cam 45a, 45b, via a respective housing 30 (see FIG. 3B) and a pin 46 (see FIG. 6B), and an imaging lens 51 and an imaging sensor 52 (see FIGS. 5A and 5B), attached to the imaging cam 43 via cam follower pins. Here, the imaging lens 51 is shown as a single field lens, but additional and/or alternative lenses for focusing light from the target 20 onto the imaging sensor 52 may be employed. Each port has its own associated illumination cam 45A or 45B, here shown as being to a left and right of an input window to receive light from the target 12. Here, drive cam 41 is shown as a plate with a front edge extending beyond the rear of the lens modules 20a, 20b, but the drive cam 41 need not be in the form of a plate and may instead comprise multiple surfaces to interface with and drive three or more lens modules, in which case the front edge of the drive cam 41 and the rear edges of illumination cams 45a, 45b may be set further to the rear in order to accommodate additional lens modules and corresponding illumination cams.

In particular, translation of the drive cam 41 may translate the imaging cam 43 along the x-axis, which, in turn, may result in the imaging cam 43 to translate the imaging lens 51 and the imaging sensor 52 along the z-axis, as well as translate the illumination cams 45a, 45b, which, in turn, simultaneously steer corresponding lens modules 20a, 20b about respective pivot points 36, such that steering of the lens modules 20a, 20b is synchronously performed with the position adjustment of the imaging lens 51 and the imaging sensor 52 to insure proper focus of light from the target onto the sensor 52. Alternatively, the imaging cam 43 may translate only the imaging lens 51 along the z-axis, or any other combination of imaging optical elements in order to insure proper focus of light from the target onto the sensor 52.

FIG. 4B illustrates a bottom view and FIG. 4C illustrates a top view of the linkage 40 according to an embodiment. The drive cam 41 may include two drive parts 41a and 41b, and, if steering is included, a third drive part 41c, all of which are shown here as being rigidly attached to form a rigid drive cam 41. Similarly, the imaging cam 43 may include two imaging parts 43a and 43b. The drive cam 41 receives the input from a user (via control surface 62) via the first drive part 41a and translates the imaging cam 43 via a cam follower pin in drive part 41b, resulting in the imaging cam part 43a translating the sensor 52 and the imaging cam part 43b translating the imaging lens 51. If steering is included in the linkage, the third drive part 41c simultaneously steers (rotates) the lens modules 20a, 20b using the pin 46 (see FIG. 6B) associated with each of the illumination cam parts 45a and 45b, by translating the illumination cam parts 45a and 45b. The pin 46 may be inserted through a through a slot 49 in each of the illumination cams 45a, 45b and the corresponding housing hole 37 in the lens modules 20a, 20b. The drive part 41c steers the lens modules 20a, 20b simultaneously such that they both still illuminate a same field of view as one another at the target field of view of the target 12.

FIGS. 5A and 5B illustrate bottom views of the linkage combined with the lens modules 20a, 20b, the imaging field lens 51, and the sensor 52, at a far working distance and a near working distance, respectively, according to an embodiment. As can be seen therein, the linkage 40 synchronizes steering of the illumination sources with focusing of the imaging system at two sample working distance illumination steering settings. FIGS. 5A-5B show the positions of lens modules 20a, 20b (rotated about the pivot pint 37) and the lens 51 and sensor 52 (translated along an optical axis 55 of the imaging system and along the x-axis) at two focus positions resulting from user input.

As illustrated in FIGS. 5A and 5B, each part that moves axially within the linkage mechanism 40 may be guided by two fixed rolling elements 47, and one spring-loaded rolling element 48, in order to reduce or minimize friction during motion. The linkage 40 also may include a drive cam input connection point 42.

FIGS. 6A and 6B illustrate a perspective top view and a perspective bottom top view of the device 10 in accordance with an embodiment. In FIGS. 6A and 6B, the illumination module 11 and the imaging module 13 are mounted on the chassis 90, the top portion of which is removed in for clarity. Also, a focus actuation mechanism 70 is illustrated, which translates motion from user input to motion of the drive cam 41 via the drive cam input connection point 42.

As can be seen in FIG. 6A, an optical axis 55 of the imaging module 13 runs through a center of the imaging module, with the lens modules 20a, 20b being arranged symmetrically relative to the imaging optical axis 55. The light to be imaged from the target 12 travels along the optical axis 55 to be incident on the lens 51 and sensor 52. A wavelength-dependent aperture 53 that includes a smaller central aperture that permits transmission of all visible and fluoresced light, e.g., near infrared (NIR) light, and a surrounding larger aperture that blocks visible light but permits transmission of fluoresced light, may be provided upstream of the lens 51.

Referring to FIGS. 6B and 4A-4B, the pin 46 connects the lens module 20, via the housing hole 37 in the housing 30, slot 49 of the linkage 40. Also, a pivot point pin 44 connects the lens module 20 to the chassis 90.

FIG. 7 illustrates an embodiment of an ergonomic enclosure 60 enclosing the illumination module 11 and the imaging module 13. The ergonomic enclosure 60 is designed to be held in different use-modes/configurations, for example, a pistol-style grip for forward imaging in a scanning-imaging orientation (FIG. 8A), and a vertical-orientation grip for use when imaging downward in an overhead imaging orientation (FIG. 8B). As may be seen in FIG. 7, the enclosure 60 includes a control surface 62, a grip detail 64, a window frame 68 and a nosepiece 66. The ergonomic enclosure 60 is connectable to the VPI box 14 via a light guide cable 67, through which the light is provided to the illumination ports 20a, 20b, and a data cable 65 that transmits power, sensor data, and any other (non-light) connections.

The control surface 62 includes focus buttons 63a (decreasing the working distance) and 63b (increasing the working distance) that control the linkage 40. Other buttons on the control surface 62 may be programmable and may be used for various other functions, e.g., excitation laser power on/off, display mode selection, white light imaging white balance, saving a screenshot, and so forth. Alternatively or additionally to the focus buttons, a proximity sensor may be provided on the enclosure and may be employed to automatically adjust the linkage 40.

As can be seen in FIG. 8A, when the enclosure 60 is held with the imaging window facing forward, the thumb rests on the control surface 62 while the other fingers on the operator's hand are wrapped loosely around the bottom of the grip detail 64. As can be seen in FIG. 8B, when the enclosure 60 is held with the imaging window facing downward, the grip detail 64 is between the thumb and index finger and the fingers are wrapped around to access the control buttons or switches on the control surface 62. The grip detail 64 is sculpted so as to provide for partial support of the device weight on the top of the wrist in the vertical-orientation grip, such that the enclosure 60 can hang loosely and without the need for a tight grip of the enclosure 60. Thus, the enclosure 60 may be operated by a single hand in multiple orientations. In various other embodiments, the enclosure 60 may be supported on a support (e.g., a movable support).

The window frame 68 (see also FIG. 9A), defines the different windows for the enclosure 60. In other words, the window frame 68 defines windows 68a and 68b, corresponding to the two lens modules 20a and 20b, as well as window 68c, which serves as an input window for light from the target to be incident on the sensor 52.

FIGS. 17A-D illustrate an imaging system 300 in accordance with one embodiment. Imaging system 300 may include one or more components of imaging system 10 of FIG. 1. For example, imaging system 300 may comprise illumination module 11 and imaging module 13 of system 10. System 300 may be used for or with any of the methods and processes described herein with respect to system 10.

As shown in FIG. 17A, which is a perspective top view, imaging system 300 includes two illumination ports 311, imaging module 313, and plate 302, each of which is mounted to a frame or chassis (not shown). The light to be imaged from target 12, which may include light from illumination ports 311 reflected by target 12 and/or fluorescent light emitted from target 12, travels along the optical axis 355, through plate 302 and into imaging module 313, which houses one or more imaging sensors. As described below, imaging module 313 may include movable filters for filtering light that enters the imaging module. In some embodiments, the imaging module 313 may include one or more wavelength-dependent apertures that includes a smaller central aperture that permits transmission of all visible and fluoresced light, e.g., NIR light, and a surrounding larger aperture that blocks visible light but permits transmission of fluoresced light.

Each illumination port 311 includes a lens module 320, a connecting cable 322 connected to the illumination light source 23, and a light pipe 321 adapting a high numerical aperture of the connecting cable 322 to a lower numerical aperture of the lens module 320. The lens modules 320 may provide illumination having a rectangular form factor that matches the field of view of the imaging system 300. Each illumination port 311 may produce a gradient of illumination such that the sum illumination flux in the object plane is reasonably the same at each point in the illumination field, e.g., providing uniform illumination over the imaging field of view. Lens modules 320 each include one or more lenses and/or prism elements for shaping and orienting illumination to meet application requirements. For example, since the two illumination ports 311 lie horizontally offset from the center of the optical axis 355 of the imaging system 300, prisms may be included in the lens modules 320 to direct the beams towards the center of the field of view. The degree of direction may be tailored to the specific application, or to a set of specific applications. For example, in some variations, the degree of direction is selected such that the beams overlap at a nominal imaging distance of 25 cm. In some variations, the horizontal offset of the illumination ports 311 and the degree of direction are selected such that the beams substantially overlap and substantially cover the field of view over a range of working distances, such as distances from 18-40 cm. In the embodiment illustrated in FIG. 17A, the illumination ports are fixed with respect to the frame. In other embodiments, the illumination ports are steerable, in accordance with the principles described above.

Imaging module 313 includes image sensor assembly 352, optics module 351, and movable filter assembly 330 aligned along an optical axis 355. The image sensor assembly 352, which includes an image sensor and may include one or more lenses, filters, or other optical components, is movable relative to the frame along the optical axis 355 via focus actuation assembly 370. Focus actuation assembly 370 includes lead nut 372 affixed to the housing of the image sensor assembly 352. The lead nut 372 is coupled to lead screw 374, which extends from focus motor 376. Focus motor 376 is fixed to the frame and can be actuated in forward and reverse directions to turn lead screw 374, which causes lead nut 372 to translate along the lead screw axis, moving image sensor assembly 352 forward and backward along the optical axis 355. Lead nut 372 and/or focus actuation assembly 370 may be mounted on shafts that slide within mountings on the frame, for example, using one or more linear ball bearings or bushings to restrain lateral and angular play. In some embodiments, the image sensor assembly 352 may comprise a single image sensor that is configured to detect light from the target resulting from illumination by visible light and excitation light. In other embodiments, the image sensor assembly 352 may comprise multiple image sensors for. For example, the image sensor assembly 352 may comprise separate image sensors configured to detect light from the target resulting from illumination by visible light separately from that resulting from illumination by excitation light.

A controller may be used to control movement of the image sensor assembly 352 for focusing, which may be based on user input. For example, system 300 may be provided with one or more controls such as buttons or touch screen controls to enable the user to adjust the focus. A user may actuate a focus control until the desired focus is achieved or may enter a value associated with a desired focus and the controller may actuate the image sensor assembly 352 until the desired focus is achieved. In some embodiments, a magnetic position sensor mounted on the housing of the image sensor assembly 352 detects the position of the image sensor assembly 352 for closed loop control of focus actuation assembly 370 by the controller. In some embodiments, the controller can use open loop control of focus actuation assembly 370, for example, by using a stepper motor.

Optics module 351, which is located forward of image sensor assembly 352, is fixed relative to the frame and may include one or more optical components (e.g., lenses, apertures, filters, etc.) for adjusting light traveling along the optical path before reaching the image sensor. For example, optics module 351 may include a wavelength-dependent aperture (e.g., similar to aperture 53 of FIG. 6A) that includes a smaller central aperture that permits transmission of all visible and fluoresced light, e.g., NIR light, and a surrounding larger aperture that blocks visible light but permits transmission of fluoresced light.

Movable filter assembly 330 is located forward (upstream with respect to the direction of travel of light from a target to the image sensor) of optics module 351 and includes first window 334a and second window 334b, each of which is housed in a bracket (first window bracket 332a and second window bracket 332b, respectively). First and second windows 334a, 334b can be alternately moved into and out of the optical path. In some embodiments, the first and second windows 334a, 334b can be alternately moved into and out of the optical path via linkage assembly 336, which is actuated by filter motor 338. In some variations, the first and/or second windows can be moved via any combination of motions including rotation (for example on a rotary wheel) and/or translation. One or both of the windows 334a, 334b can include filters for filtering light before it reaches the image sensor. By moving filters into and out of the optical path, imaging system 300 can be operated in different imaging modes. For example, in some embodiments, one of the windows (e.g., first window 334a) includes a filter for blocking visible light while the other window (e.g., second window 334b) includes a clear glass plate that does not block light. With the blocking filter in the optical path, the imaging system can be operated in a first mode and, with the clear glass in the optical path, the imaging system can be operated in a second mode. When switching modes, one window moves into the optical path while the other window moves out of the optical path. In some embodiments, a visible-light rejection filter which only transmits NIR light between 830-900 nm is included in a first window for a fluorescence-only imaging mode and an anti-reflective coated glass plate, which passes all light, is included in the second window for use in a second mode. The glass plate can ensure the same optical path length regardless of mode. In some variations, a controller of system 300 can control movable filter assembly 330 to change modes, for example, in response to a user input.

In the configuration illustrated in FIG. 17A, second window bracket 332b is in a deployed position such that second window 334b is positioned in the optical path and is oriented perpendicularly to the optical axis 355. By actuating filter motor 338, which actuates linkage assembly 336, the second window bracket 332b and second window 334b move out of the optical path by pivoting about a pivot axis that extends perpendicularly to optical axis 355. At the same time, first window bracket 332a and first window 334a move into the optical path by pivoting about a pivot axis that extends perpendicularly to optical axis 355. In some embodiments, the pivot axis of the first window bracket and the pivot axis of the second window bracket are vertically aligned and the first and second window brackets and window are symmetrical to provide matching optical path lengths regardless of mode.

Linkage assembly 336 is actuated by filter motor 338, which may be controlled by a controller of system 300. Filter motor 338 rotates filter lead screw 341, which moves filter lead nut 342 forward and rearward. Linkage 344 is pivotally connected on a first end to filter lead nut 342 and pivotally connected at a second end to slider 346a. A pivot link 348a is pivotally connected at one end to slider 346a and at the other end to first window bracket 332a. As illustrated in FIG. 17B, slider 346b and pivot link 348b (which are not shown in FIG. 17A) are provided below slider 346a and pivot link 348a for actuating second window bracket 332b.

Movable filter assembly 330 is schematically depicted in FIG. 17B. Filter motor 338, which is fixed relative to the frame, rotates the filter lead screw 341 clockwise and counterclockwise, causing filter lead nut 342 to translate forward and rearward along the filter lead screw axis. Translation of filter lead nut 342 causes translation of slider 346a via linkage 344. Translation of slider 346a causes translation of pivot link 348a. Pivot link 348a is pivotally connected to first window bracket 332a at a location off-center from the pivot connection 349a of first window bracket 332a to the frame. Therefore, movement of pivot link 348a causes rotation of first window bracket 332a. For example, from the configuration of FIG. 17B, translation of slider 346a forward (toward plate 302) causes first window bracket 332a to rotate 90 degrees out of the optical path.

Driving linkage 345 is pivotally connected at a first end to linkage 344, pinned to the frame at connection point 345a, and pivotally connected at a second end to slider 346b. Thus, translation of linkage 344 causes rotation of driving linkage 345, which translates slider 346b. Slider 346b is connected to second window bracket 332b via pivot link 348b, which is pivotally connected to second window bracket 332b at a location off-center from the pivot connection 349b of second window bracket 332b to the frame. Thus, translation of slider 346b causes rotation of second window bracket 332b. From the configuration of FIG. 17B, translation of slider 346b rearward (as slider 346a moves forward), causes second window bracket 332b to rotate 90 degrees into the optical path. One or more sensors may be included for sensing the position of one or more of the movable filter assembly 330 components for providing feedback to the controller for closed-loop control.

Plate 302 is a flat plate for sealing the housing and protecting the illumination and imaging optics. In some embodiments, plate 302 is a single plate of glass. One or more optical components such as a lens may be mounted between the glass plate and the movable filter assembly 330. In some variations, one or more sensors are positioned on the rear side of plate 302 to measure light incident on plate 302. One or more of these sensors may detect ambient light, light reflected from the target, light emitted by the target, and/or light reflected from non-target objects. In some embodiments, a drape detector is included to detect the presence of a drape. The drape detector may include, for example, an infrared emitter and a photodetector that detects infrared light reflected by a drape positioned on the imaging system.

FIGS. 17C-D illustrate an embodiment of an ergonomic enclosure 360 enclosing illumination ports 311 and imaging module 313, according to one variation. The ergonomic enclosure 360 is designed to be held in a pistol-style grip. The enclosure 360 may include a control surface 362, a grip 364, a window frame 368 and a nosepiece 366. The ergonomic enclosure 360 is connectable to the VPI box 14 via a light guide cable 367, through which the light is provided to illumination ports 311, and a data cable 365 that transmits power, sensor data, and any other (non-light) connections.

The control surface 362 includes focus buttons 363a and 363b that control the focus actuation assembly 370. Other buttons on the control surface 362 may be programmable and may be used for various other functions, e.g., excitation laser power on/off, display mode selection, white light imaging white balance, saving a screenshot, and so forth. Alternatively or additionally to the focus buttons, a proximity sensor may be provided on the enclosure and may be employed to automatically adjust the focus actuation assembly 370.

Enclosure 360 may be operated by a single hand in a pistol-grip style orientation. In various other embodiments, the enclosure 360 may be supported on a support (e.g., a movable support). In some embodiments, enclosure 360 may be used in concert with a drape, such as drape 80 of FIG. 9A or drape 390 of FIG. 9B.

In some embodiments, a window frame 368 is provided on the forward portion of enclosure 360 in front of plate 302. In other embodiments, the window frame 368 is provided on the forward portion of enclosure 360 behind plate 302, and plate 302 provides the outer surface of the enclosure. In other embodiments, no frame is provided and plate 302 provides the outer surface of the enclosure. Window frame 368 may include windows 368a and 368b, corresponding to the two lens modules 320, as well as window 368c, which serves as an input window for light from the target to be incident on the image sensor. Window frame 368 may also include one or more windows 369 for sensors provided behind plate 302.

FIG. 17E illustrates an embodiment of a sensor arrangement provided behind plate 302 on the forward portion of enclosure 360, according to one variation. In this embodiment, a central sensor group 391 comprising one or more sensors 392 is provided in order to detect reflected illumination light for input to an automatic gain control function, as described below. Also in this embodiment, peripheral sensor groups 393a and 393b, each comprising one or more sensors 394, are provided in order to detect reflected illumination light for purposes of proximity detection to the imaging target or to detect any objects near to the forward portion of the enclosure 360, as described below. The source of the illumination light for proximity detection may be either the main illumination beam or may be one or more dedicated emitters for proximity detection. Also in this embodiment, one or more sensors 387 and one or more light sources 386 are provided in order to detect the presence of an installed drape lens, as described below. Also in this embodiment, one or more sensors 395 may be provided in order to detect ambient room light intensity to facilitate correction of image intensity artifacts arising from pulsating room light components, as described herein.

The sensors 392 may be used to detect reflected light levels in order to provide input for an automatic gain control (AGC) function (see FIG. 18) that may be used to facilitate optimizing illumination and imaging parameters and providing a consistent and/or smoothly varying image brightness, even when varying the working distance. AGC may also be used to facilitate optimizing or maximizing the image signal to noise ratio, or to minimize the illumination intensity to facilitate minimizing photo-bleaching. For example, the AGC may be used to dynamically adjust image signal gain, illumination pulse duration, exposure, and/or illumination power. The reflected illumination light detected by the sensors 392 may include visible light and/or fluorescence excitation light, such as NIR light. In one embodiment, sensors 392 are sensitive to NIR light but not to visible light, such that ambient visible light and white light illumination do not contribute to the light level signal from sensors 392. In some variations, sensors 392 are comprised of photodiodes.

The reflected light level sensors 392 may be used as input to AGC in any imaging mode, including a white light imaging mode and/or a multiplexed combined white light and fluorescence imaging mode, and may be particularly important in a fluorescence-only imaging mode. When operating in a fluorescence-only imaging mode, for example with filter 334a blocking visible light from reaching the image sensor, no reflected white light luminance image is recorded, which could otherwise be used as an input to AGC, while the recorded fluorescence image necessarily excludes reflected fluorescence excitation light (which would otherwise overpower the fluorescence signal) through use of a notch filter in the imaging optics. Therefore, the sensors 392 may provide the only measure of reflected light. In one variation, the operation of AGC in a fluorescence-only imaging mode prioritizes maximizing the exposure duration and minimizing the gain.

In some embodiments, for which the sensors 392 are sensitive to the excitation light, the gain, excitation period (which may, for example, be the same as the image sensor exposure time) and instantaneous excitation power can be adjusted as follows in order to achieve a constant image brightness for a given fluorescence sample regardless of working distance. Based on the reflected excitation light E, as measured by sensors 392, the AGC may adjust the excitation period, T, instantaneous excitation power, P, and image sensor gain, G, such that E*T*G=K, where K is a constant based on the desired target brightness. The priorities of adjusting T, G and P can be optimized to minimize noise while limiting maximum exposure of tissue to excitation light.

In one embodiment, as shown in FIG. 17E, the sensors 392 are arranged such that their detection cones approximately cover the imaging field of view. For example, in this embodiment, a sensor group 391 is comprised of four sensors 392 arranged in a rectangular pattern surrounding the imaging port.

According to one embodiment, AGC operates by starting with settings for an initial gain g_o, initial exposure e_o, and initial illumination power p_o. User defined brightness parameters may prescribe target values, such as for example, a target peak brightness P_tand a target mean brightness M_t, as well as a choice of AGC mode to be based on the peak values, mean values, or a balanced combination of both peak and mean values.

During each image acquisition frame, a peak sensor brightness P_smay be calculated based on a peak signal from among sensors 392 during the acquisition duration, and a mean sensor brightness M_smay be calculated based on a mean of the signals from sensors 392 during the duration. An adjustment factor F is then calculated based on these values and used to calculate a target exposure value e_tand a target gain value g_t. For example, in peak mode F=P_t/P_s, in mean mode F=M_t/M_s, and in balanced mode F=(½)(P_t/P_s+M_t/M_s). In one variation, a balanced mode may be a weighted combination of sensor signal values, such as a weighted average of P_sand M_sas in F=(k1*P_s+k2*M_s), where k1 and k2 are constants. In one variation, the constants k1 and k2 may satisfy the constraints k1+k2=1 and 0<=k1 <=1. The target exposure is calculated as e_t=Fe_o, and the target gain is calculated as g_t=Fg_o.

According to an embodiment, AGC adjusts the exposure duration (and the corresponding excitation illumination duration) by a step equal to one-half of the value between the current exposure e_oand the target exposure e_t, such that the new exposure e₁=e_o+(e_t−e_o)/2. In this manner, the exposure cannot be increased above a maximum exposure e_maxor decreased below a minimum exposure emirs.

According to an embodiment, if the current exposure e_ois at the maximum exposure e_maxand the adjustment factor F is greater than unity, then AGC adjusts the gain to a new gain g₁=g_o+(g_t-g_o)/4. If the current gain is greater than unity and F is less than unity, then the gain is instead adjusted to a new gain g₁=g_o−(g_o−g_o(e_max/e_o))/4. Otherwise, the new gain instead remains unchanged as g₁=g_o.

According to an embodiment, the excitation power may be adjusted as a lowest adjustment priority.

Following each AGC cycle, the new values for exposure, gain, and power are treated as the current values for the next AGC cycle.

The sensors 394 may be used to detect reflected illumination light that is reflected off of objects entering into the periphery of the illumination beams and located near to the front of the enclosure 360. For example, detection of such near objects may be used to trigger switching to a reduced illumination power setting in order to reduce a possible safety risk from high illumination power being delivered to a nearby object. The reflected illumination light detected by sensors 394 may include visible light and/or fluorescence excitation light, such as NIR light. In one embodiment, sensors 394 are sensitive to NIR light but not to visible light, such that ambient visible light and white light illumination do not contribute to the detection signal from sensors 394. In some variations, sensors 394 are comprised of photodiodes or of time-of-flight sensors. In one variation, the sensors 394 are arranged such that they may detect objects entering the illumination beams which are not within the imaging field of view.

In some embodiments, a method for imaging a target includes illuminating the target with an illuminator of an imaging system, such as illumination ports 311 of imaging system 300, and receiving light from the target at an imaging sensor of the imaging system in an unrestricted imaging mode. In some embodiments the light received from the target include light reflected by the target and light emitted by the target. In some embodiments, the reflected light includes visible light and the emitted light includes fluorescent light from the target. The imaging mode is switched from the unrestricted imaging mode to a restricted imaging mode in which light of wavelengths outside of a desired wavelength band or bands is blocked from reaching the imaging sensor. The light is blocked using a movable filter of the imaging device. The light that is passed by the filter is received by the imaging sensor. The imaging mode can be switched back to the unrestricted imaging mode in which the filter is moved out of the optical path so that it no longer blocks light in the optical path.

For example, system 300 can be operated in an unrestricted imaging mode in which first window 334a is in a deployed position in the optical path. First window 334a may include a clear plate that permits all light to pass through it. In this unrestricted imaging mode, the image sensor may receive all or most of the light that reaches first window 334a. System 300 can be switched to a restricted imaging mode in which the first window 334a is in a stowed position out of the optical path and the second window 334b is in a deployed position in the optical path, according to the principles described above. The second window 334b may include a filter that filters out light that is not in a desired wavelength band or set of wavelength bands. For example, the filter may filter out all visible light but pass infrared light (e.g., NIR light). Thus, during the restricted imaging mode, the imaging sensor provides imaging data of only the light passed by the filter.

System 300 may be switched to the restricted imaging mode in response to a request that may be received from a user (e.g., via actuation of one or more buttons on the control surface 362) or that may be received from an external control system. Although the above description refers to restricted and unrestricted modes, the same principles can be used to switch between two restricted modes (i.e., some light is blocked in both modes). For example, the system can switch between two restricted imaging modes by including a first filter configured to block a first wavelength band or set of wavelength bands and a second filter, different from the first, that is configured to block a different wavelength band or set of wavelength bands from the first.

In some embodiments, the automatic gain control process described above can be started upon switching to the restricted imaging mode and may be stopped upon switching to the unrestricted imaging mode (e.g., AGC can be automatically started and stopped by a controller of the system 300). In other embodiments, AGC is performed during both the restricted and unrestricted imaging modes.

As illustrated in FIG. 9A, the enclosure 60 of FIG. 7 may be used in concert with a drape 80. The drape 80 may be a surgical drape suitable for use during a surgical procedure. The drape includes drape material 81, a drape lens 82, a drape window frame 83 surrounding the drape lens, and an interlock interface 84 that is integral with the drape window frame 83. The drape material 81 is to envelope the device in the enclosure 60, as well as to cover anything else as required. The drape window frame 83 may follow a shape of the enclosure nosepiece 66 such that the drape window frame 83 may be inserted therein without obstructing the windows 68a to 68c. The drape 80 is designed to minimize reflections and imaging ghosting by ensuring the drape lens 82 is flush, e.g., to within 0.5 mm, with the imaging and illumination window frame 68. The drape 80 may use the interlock interface 84, which may fit over a ridge on the inner surface of the enclosure nosepiece 66, to be secured flush thereto. In one variation, the interlock interface 84 may fit into a recess on the inner surface of the enclosure nosepiece 66.

One or more interlock interfaces 84 may be used on the inner or outer surface of the enclosure nosepiece 66, in order to ensure a secure and close fit of the drape lens 82 against the window frame 68. In the particular embodiment shown, two interfaces 84, here one on the top and one on the bottom of the drape window frame 83 to engage with an inner surface of the enclosure nosepiece 66, are used.

According to some variations, feedback may be provided to the user to indicate when the drape lens has been installed correctly onto the enclosure nosepiece. In one variation, a raised ridge around at least a portion of the drape window frame may provide tactile and/or aural feedback when pushed over one or more detent features on the interior surface of the enclosure nosepiece. In another variation, a raised ridge around at least a portion of the drape window frame may provide tactile and/or aural feedback when pushed over one or more detent features on the exterior surface of the enclosure nosepiece. In another variation, one or more interlock interfaces may provide tactile and/or aural feedback when pushed into place to engage with an inner surface of the enclosure nosepiece. In another variation, one or more interlock interfaces may provide tactile and/or aural feedback when pushed into place to engage with an outer surface of the enclosure nosepiece. Additionally or alternatively, a drape detection module, as described below, may provide feedback to indicate when the drape lens has been installed correctly.

According to an embodiment, the drape may be symmetrical such that it may be rotated by 180 degrees about its central axis (e.g., the axis aligned with the imaging optical axis) and may be installed correctly onto the enclosure nosepiece both before and after such a rotation.

The drape lens material may comprise a transparent polymer material such as, for example, polymethyl methacrylate (PMMA), polycarbonate, polyvinyl chloride, or polyethylene terephthalate glycol-modified. In one embodiment, the drape lens material may be chosen based in part on having a relatively low refractive index and high light transmission in the visible and NIR bands compared to other candidate materials, so as to minimize artifacts caused by reflections at the drape lens and to maximise illumination and imaging transmission. For example, the drape lens material, such as PMMA, may have an index of refraction of less than about 1.5 and light transmission greater than about 92% in the visible and NIR bands. The drape lens and/or the drape window frame may be manufactured by injection molding.

In one variation, the drape lens may be coated with an anti-reflection coating to reduce imaging and illumination artifacts from reflection at the window.

FIGS. 9B-G illustrate an embodiment of a drape 390 comprising drape lens 380 and drape window frame 381 to be used in combination with drape material (not shown), such as drape material 81 (see FIG. 9A), to cover the enclosure 360 of FIG. 17C-D. The drape 390 may be a surgical drape suitable for use during a surgical procedure. The drape includes drape material (not shown), a drape lens 380, a drape window frame 381 surrounding the drape lens, an interlock interface 384 that is integral with the drape window frame 381, and a reflective feature 388. The drape material is to envelope the device in the enclosure 360, as well as to cover anything else as required. The drape window frame 381 may follow a shape of a forward portion of the enclosure 360 such that the drape window frame 381 may be inserted thereon. The drape 390 is designed to minimize reflections and imaging ghosting by ensuring the drape lens 380 is flush, e.g., to within 0.5 mm, with the front surface of the enclosure 360, such as plate 302 of FIGS. 17A-B. The drape 390 may use the interlock interface 384, which may fit into over a ridge 383 on the inner surface of the front portion of the enclosure 360, to be secured flush thereto.

In one embodiment, a drape detection module may be provided to detect the installation of the drape lens onto the enclosure nosepiece. For example, the drape detection module may use any combination of one or more ultrasonic sensor, inductive sensor, capacitive sensor, optical sensor, light emitter, radio frequency identification chip and antenna, hall effect sensor, proximity sensor, or electrical contacts in order to detect the installation of the drape lens onto the enclosure. In one embodiment, a drape detection light source 386 (see FIG. 17E), such as an LED, may be used to transmit light that is detected by a corresponding sensor 387, such as a photodiode, only when reflected off of an installed drape lens. For example, according to an embodiment, the light source 386 may have a narrow emission wavelength band centered around about 905 nm and the sensor 387 may have a narrow wavelength detection band that includes wavelengths of about 905 nm. In one embodiment, the light source 386 and the sensor 387 are located near the forward portion of the enclosure 360 behind the plate 302. In one embodiment, as shown in FIG. 9C, a reflective feature 388 is located on the drape lens 380 in a position aligned with the light source 386 and the sensor 387, such that light from the light source 386 is reflected off of one or more interfaces of the reflective feature 388 and onto the sensor 387. For example, according to one embodiment of a drape detection module 385 as shown in FIG. 19, the reflective feature 388 may comprise a triangular prism protruding from the surface of the drape lens 380, which may reflect detection light 389 from light source 386 onto sensor 387. For example, the reflective feature 388 may reflect detection light 389 using total internal reflection. In one variation, the output from the sensor 387 may be fed to a transimpedance amplifier in order to amplify the drape detection signal. In one variation, the light source 386 and the sensor 387 may be located on the enclosure nosepiece. In one variation, the intensity of the reflected light signal detected at the sensor 387 may be used as feedback to assess and adjust the installation positioning of the drape lens 380, in order to minimize artifacts caused by misalignment of the drape lens. In one variation, detection of the installation of the drape lens 380 as indicated by the drape detection module 385 may trigger automatic adjustment of illumination and/or imaging parameters or automated changes to the image processing performed by the processor assembly. For example, the imaging and illumination system may be calibrated and/or configured to correct for distortion, attenuation, or other effects on illumination and/or imaging caused by the installation of the drape lens 380.

According to an embodiment, the process for installation of the drape onto the enclosure includes unpacking the drape, installing the drape lens onto the enclosure nosepiece by pushing the drape lens into place until an audible and/or tactile click is sensed by the user (indicating the interlock interfaces have engaged with the corresponding ridges in the enclosure nosepiece), rolling the drape bag back over the camera, and securing as needed the drape bag at the front and rear of the enclosure and along the enclosure cables. To remove the drape from the enclosure, the clips on the drape interlock interfaces may be pressed inwards in order to disengage from the ridges and then pulled away from the enclosure. In accordance with the above processes, both the installation and removal of the drape lens may be performed with one hand in contact with the drape lens.

FIGS. 10A to 10C illustrate typical illumination distributions (fill) relative to a rectangular imaging field of view (outline) for an illumination ring (FIG. 10A), a pair of fixed anamorphic projection illumination sources (FIG. 10B), a pair of steered anamorphic projection illumination sources in accordance with an embodiment (FIG. 10C), and a steered illumination ring (FIG. 10D) at working distances of 10 cm (left column), 15 cm (center column), and 20 cm (right column). FIG. 10A illustrates use of a ring of illumination ports to minimize shadowing, but does not match illumination to the imaging field of view and may not provide even illumination at all working distances (e.g. varied distributions in accordance with distance). FIG. 10D illustrates use of a steered ring of three or more illumination ports to facilitate minimizing shadowing and providing even illumination when changing working distance in accordance with an embodiment, but does not constrain illumination to the imaging field of view. FIG. 10B illustrates anamorphic projection from two illumination sources (using, e.g., an illumination lens arrangement featuring cylindrical lenses or an engineered diffuser) that are fixed, thus they are well calibrated for even illumination that matches the imaging field of view at a fixed working distance, e.g., 15 cm, but not as even or well matched at other distances, whether smaller or greater. As noted above, such illumination is often acceptable on its own. FIG. 10C illustrates the ability to better maintain even illumination and constrain illumination to the field of view by steering illumination when changing the working distance (and imaging focus) in accordance with an embodiment.

As noted above, the illumination used may include both white light and fluorescence excitation illumination, e.g., from a laser, to excite NIR light from the target. However, ambient light may interfere with the light from the target.

FIG. 11A illustrates a timing diagram for white light (RGB) and fluorescence excitation (Laser) illumination, and visible (VIS) and NIR fluorescence (FL) imaging sensor exposures configured to allow ambient room light subtraction from the fluorescence signal with a single sensor. As used herein, a white pulse will indicate that the white light (RGB) is illuminating the target and an excitation pulse will indicate that the laser is illuminating the target.

Exposures of even (Exp 1) and odd (Exp 2) sensor pixel rows are shown interleaved with differing exposure times to facilitate isolation of an estimate of the ambient room light signal component. Such an interleaved exposure read-out mode is offered on some imaging sensors, such as the ‘High Dynamic Range Interleaved Read-out’ mode offered on the CMOSIS CMV2000 sensor.

Pulsing the white light illumination at 80 Hz brings the frequency of the flashing light above that which is perceptible by the human eye or which may trigger epileptic seizures. The visible light image exposure may be longer than, e.g., twice, the RGB illumination to ensure overlap between the 60 Hz exposure frame rate and the 80 Hz RGB illumination pulse. Extra ambient light captured during the visible exposure may be ignored, due to the much greater intensity of the RGB illumination pulse and signal from the target 12.

By setting the NIR fluorescence image exposure times Exp 1 and Exp 2 to acquire for one-half frame and one quarter frame periods, respectively, while running the excitation laser only in the last one quarter of every third frame, the even rows (Exp 1) record one-half frame of ambient room light in addition to one quarter frame of NIR fluorescence, while the odd rows (Exp 2) record one quarter frame of ambient room light plus one quarter frame of NIR fluorescence. Performing these fractional exposures within each visible or NIR fluorescence frame minimizes motion artifacts which would otherwise be caused by inserting additional exposure frames into the frame sequence for the purpose of ambient room light subtraction.

With such an acquisition design, an estimate of the ambient room light contribution to the image signals can be isolated by subtracting the Exp 2 sensor rows of the NIR fluorescence image from the Exp 1 sensor rows (interpolated to match Exp 2 pixel positions), yielding an estimate of one quarter frame of ambient room light signal. The estimate of one quarter frame of ambient room light signal can then be subtracted from the Exp 2 sensor rows of the NIR fluorescence image to yield an estimate of the NIR fluorescence signal with the one quarter frame of ambient room light removed. The control of the illumination and the exposure may be performed by the VPI box 14.

In one embodiment, the above room light subtraction method may be altered in order to accommodate use of a Bayer-pattern color sensor. FIG. 12A illustrates a Bayer pattern arrangement of colored sensor pixels, wherein the even sensor rows and odd sensor rows have different filter arrangements (e.g., no red pixels in the even sensor rows and no blue pixels in the odd sensor rows), so the ambient light recorded on even rows will not be a good estimate of what reached the odd rows over the same period. However, every row does include green pixel signals, which are also sensitive to NIR fluorescence. Using only the green pixels, and performing a two-dimensional interpolation from the green pixel signals to the other pixel locations can yield an estimate of the ambient light signal component, and thus also of the NIR fluorescence or visible light components for the NIR and visible light images, respectively.

In order to calculate the NIR signal value at a given location, calculate the Exp 1 (even row) and Exp 2 (odd row) green pixel values near that location, with one or both of those values needing to be interpolated. FIG. 12B demonstrates an example wherein at a red pixel location, the best estimate of the Exp 1 (even row) green value is the average of the immediately neighboring green values above and below, while the best estimate of the Exp 2 (odd row) green value is the average of the immediately neighboring green values to the left and right.

The following mathematical example serves to illustrate an embodiment of the ambient room light subtraction method. If A=ambient light incident in one quarter frame period, and F=fluorescence incident in one quarter frame period, then:

Exp 1=2A+F
Exp 2=A+F

Solving for F yields:

F=2*Exp 2−Exp 1

In the particular example illustrated in FIG. 11A, a period for the sensing is three frames, the white light pulse and the excitation pulse have a same duration or width, but different frequencies, the visible light is sensed during two frames, e.g., the first two frames, and the fluorescence is sensed for during one frame, e.g., the third or final frame, for two different exposure times. As shown therein, the visible exposure time may be twice the duration of the white light pulse, a first fluorescent exposure times may be equal to the duration of the excitation pulse, and a second fluorescent exposure time may be pulse longer, e.g., twice, than the excitation pulse. Further, the visible exposure may have a different frequency than the white light pulse, e.g., visible exposure does not occur with every white light pulse, while the fluorescent exposure may have a same frequency as the excitation pulse.

Alternative timing and exposure diagrams are discussed below, in which a sensor having rows that are all active for a common exposure duration may be used while still compensating for ambient light using a single sensor. For example, background light may be directly detected by the sensor when the target is not illuminated. Other variations on pulsing, exposing, and sensing may be apparent to those of skill in the art.

FIG. 11B illustrates an alternative timing diagram for white light (RGB) and fluorescence excitation (Laser) illumination, and visible (VIS) and NIR fluorescence (FL) imaging sensor exposures configured to allow ambient room light subtraction from the fluorescence signal with a single sensor. Exposures for visible light and for fluorescence are shown in sequence along with an exposure to capture the background (BG) image signal due to ambient light. The white light illumination may be pulsed at 80 Hz as described above. The fluorescence excitation illumination may be pulsed at 20 Hz and the pulse duration or width may be increased, e.g., up to double the white light pulse duration, to enable a longer corresponding fluorescence exposure. If using an imaging sensor with a global shutter, each sensor exposure must terminate with the read-out period at the end of an imaging frame. An exposure to capture the ambient light background image signal may be performed at the end portion of a frame in the absence of any pulsed white light or excitation light. In the case of acquiring video at a frame rate of 60 Hz, as shown in the example in FIG. 11B, a white light illumination pulse width of one quarter frame duration may be used, along with a one quarter frame duration visible light exposure occurring in frames when the end of a white light illumination pulse is aligned with the end of the frame.

A scaled image signal recorded during one or more background exposures can be subtracted from each fluorescence exposure image to remove the contribution of ambient light from the fluorescence image. For example, the image signal from a one quarter frame duration background exposure may be scaled up by two times and subtracted from a subsequent image signal from a one-half frame duration fluorescence exposure. As another example, a one quarter frame duration background exposure image signal prior to a one-half frame duration fluorescence exposure image signal, and a second one quarter frame background image signal subsequent to the fluorescence exposure, may both be subtracted from the fluorescence image signal. Scaling of the image signals from a first and a second background exposure can include interpolation of pixel values from the first exposure time point and the second exposure time point to estimate pixel values corresponding to an intermediate time point.

Use of an imaging sensor with high speed read-out that enables higher video frame acquisition rates may allow for additional exposure periods to be allocated within an illumination and exposure timing scheme for a given white light pulse frequency. For example, maintaining an 80 Hz white light illumination pulse as above and using a sensor with a higher video frame acquisition rate such as 120 Hz may allow additional white light, ambient background, or fluorescence exposures within a given time period, compared to when using a slower video frame acquisition rate such as 60 Hz.

In the particular example illustrated in FIG. 11B, a period for the sensing is three frames, the excitation pulse has twice the width of the white light pulse, the visible light is sensed during one frame, e.g., the first frame, the background light is sensed during one frame, e.g., the second frame, and the fluorescence is sensed during one frame, e.g., the third or final frame. Here, a visible exposure time may be equal to the duration of the white light pulse, the background exposure time may be equal to the duration of the white light pulse, and the fluorescence exposure time may be equal to the duration of the excitation pulse. Further, the visible exposure may have a different frequency than the white light pulse, e.g., visible exposure does not occur with every white light pulse, while the fluorescent exposure may have a same frequency as the excitation pulse. Finally, the background exposure may occur only once within the period.

FIG. 11C illustrates an alternative timing diagram for white light (RGB) and fluorescence excitation (Laser) illumination, and visible (VIS) and NIR fluorescence (FL) imaging sensor exposures configured to allow ambient room light subtraction from the fluorescence signal with a single sensor with a 120 Hz video frame acquisition rate. A white light pulse frequency of 80 Hz is used, and a white light illumination pulse width of one-half frame duration may be used, along with a one-half frame duration visible light exposure occurring in frames when the end of a white light illumination pulse is aligned with the end of the frame. The fluorescence excitation illumination is shown pulsed at 40 Hz with a pulse duration of one frame, to enable a higher frequency of corresponding fluorescence exposures. An exposure to capture the ambient light background image signal may be performed at the end portion of a frame in the absence of any pulsed white light or excitation light, such as an exposure of one-half frame duration occurring in the frame between a fluorescence exposure and a successive white light exposure as shown in this example embodiment.

In the particular example illustrated in FIG. 11C, a period for the sensing is three frames, the excitation pulse has twice the width of the white light pulse, the visible light is sensed during one frame, e.g., the second frame, the background light is sensed during one frame, e.g., the first frame, and the fluorescence is sensed during one frame, e.g., the third or final frame. Here, a visible exposure time may be equal to the duration of the white light pulse, the background exposure time may be equal to the duration of the white light pulse, and the fluorescence exposure time may be equal to the duration of the excitation pulse. Further, the visible exposure may have a different frequency than the white light pulse, e.g., visible exposure does not occur with every white light pulse, while the fluorescent exposure may have a same frequency as the excitation pulse. Finally, the background exposure may occur only once within the period.

Depending on the intensity of the fluorescence excitation light used, there may be safety considerations limiting the duration and frequency of excitation light pulses. One approach to reduce the excitation light intensity applied is to reduce the duration of the excitation light pulses and the corresponding fluorescence exposures. Additionally or alternatively, the frequency of excitation light pulses (and corresponding fluorescence exposures) may be reduced, and the read-out periods which could otherwise be used for fluorescence exposures may instead be used for background exposures to improve measurement of the ambient light.

FIG. 11D illustrates an alternative timing diagram for white light (RGB) and fluorescence excitation (Laser) illumination, and visible (VIS) and NIR fluorescence (FL) imaging sensor exposures configured to allow ambient room light subtraction from the fluorescence signal with a single sensor with a 120 Hz video frame acquisition rate. A white light pulse frequency of 80 Hz is used, and a white light illumination pulse width of one-half frame duration may be used, along with a one-half frame duration visible light exposure occurring in frames when the end of a white light illumination pulse is aligned with the end of the frame. The fluorescence excitation illumination is shown pulsed at 20 Hz with a pulse duration of one frame. An exposure to capture the ambient light background image signal may be performed at the end portion of a frame in the absence of any pulsed white light or excitation light, such as a background exposure of one-half frame duration occurring in the frame between a fluorescence exposure and a successive first white light exposure, and a first background exposure of one frame duration and a second background exposure of one-half frame duration both occurring in the frames between the first white light exposure and a successive second white light exposure, as shown in this example embodiment.

In the particular example illustrated in FIG. 11D, a period for the sensing is six frames, the excitation pulse has twice the width of the white light pulse, the visible light is sensed during two frames, e.g., the second and fifth frames, the background light is sensed during three frames, e.g., the first, third, and fourth frames, and the fluorescence is sensed for during one frame, e.g., the sixth or final frame. Here, a visible exposure time may be equal to the duration of the white light pulse, the background exposure time may be equal to or twice the duration of the white light pulse, and the fluorescence exposure time may be equal to the duration of the excitation pulse. Further, the visible exposure may have a different frequency than the white light pulse, e.g., visible exposure does not occur with every white light pulse, e.g., only twice within the period, while the fluorescence exposure may have a same frequency as the excitation pulse. Finally, the background exposure may occur three times within the period for a total duration equal to four times the duration of the white light pulse.

In some use environments for an open field imaging device, such as the device according to the various embodiments described herein, the ambient room lighting may comprise light that is pulsating, or periodic, rather than continuous. Such pulsating light components may, for example, be due to the interaction between some room light sources and an AC frequency of their power source. For example, incandescent lights, some LED lights, some fluorescent lights including fluorescent lights with low frequency ballasts, or arc lamps may emit pulsating light when connected to common 50 Hz or 60 Hz AC mains power or other AC power sources. The presence of pulsating light components in the background light signal may introduce distracting image intensity artifacts during acquisition of sequential images, due to sequential exposures receiving different accumulated light intensity contributions from the pulsating light components in the background light, therefore it may be useful to correct acquired images to reduce or remove such artifacts. Such correction may be useful both with or without also using a room light subtraction technique, and may include one or more exemplary techniques such as: detecting the AC frequency of the power source for the pulsating light components; modifying the image acquisition frame rate; modifying the exposure durations for fluorescence and/or background light exposures; measuring the pulsating light intensity during a period in which the device illumination is turned off; synthesizing a complete periodic cycle of the pulsating light intensity; identifying the portion of the periodic cycle of the pulsating light intensity coinciding with the fluorescence and/or background light exposures; calculating a fluorescence accumulated ambient light value, FL_acc, corresponding to the accumulated ambient light intensity during a fluorescence exposure; calculating a background accumulated ambient light value, BG_acc, corresponding to the accumulated ambient light intensity during a background exposure; and scaling the image intensity of a fluorescence image or a background image based on a ratio of the respective accumulated light values, FL_accand BG_acc, and, subtracting the background image from the fluorescence image to output a resultant image.

In some embodiments, the AC frequency, F_AC, of the power source for a pulsating light component of the ambient room lighting may be retrieved from the device memory, for example due to a user setting a known frequency value during device calibration in a use environment, or may be detected based on measurements by the imaging device. For example, one or more sensors 395 (see FIG. 17E) may be used to measure the ambient light intensity during one or more periods when the device white light illumination is turned off and the fluorescence excitation illumination is turned off. In one embodiment, the one or more sensors 395 may be photodiodes and may have similar responsivity to the sensor used for fluorescence imaging, such as responsivity to visible and NIR light, with input cones approximating the field of view of the imaging device. As another example, in one variation in which an image sensor responsive only to NIR light, or an image sensor with separate filters provided forward of the image sensor that block visible or other non-NIR light from reaching the sensor, is used for fluorescence imaging, the one or more sensors 395 may be photodiodes with responsivity only to NIR light.

The periods of measurement by sensors 395 should be of sufficient duration and number such that they capture, in combination of successive measurement periods captured over, at maximum, about the time between successive fluorescence exposures, portions of the pulsating ambient light intensity constituting a complete periodic cycle, and such that there is at least partial overlap of cycle coverage for successive measurement periods in order to assist with synthesizing the periodic cycle of the pulsating ambient light, which may constrain the lower limit of frequencies F_ACwhich may be supported. However, frequency values for F_ACthat are below 30 Hz may not be practical for use with room lighting as they may induce noticeable and distracting visible light flicker in general use. The frequency of the pulsating light intensity is typically twice that of the corresponding value of F_AC, since room light sources typically have equivalent response for each of the positive and negative voltage halves of an AC cycle.

FIG. 11E illustrates an exemplary timing diagram for white light (RGB) and fluorescence excitation (Laser) illumination, periods of ambient light measurement by sensors 395, and visible (VIS) and fluorescence (FL) imaging sensor exposures configured to allow ambient room light subtraction from the fluorescence signal and correction for pulsatile ambient light intensity with a single sensor, according to an embodiment. In this embodiment, the frequency of fluorescence excitation illumination and corresponding fluorescence exposures is 20 Hz, the frequency of white light illumination is 80 Hz, and ambient light measurement periods are all those periods in which both the white light illumination and fluorescence excitation illumination are turned off. The timing scheme shown may allow for pulsating ambient light intensity signals corresponding to all practical frequency values for F_ACof 30 Hz or greater to be detected based on measurements within the time between successive fluorescence exposures, by capturing, in combination of multiple measurement periods, portions of the pulsating ambient light intensity constituting a complete periodic cycle, with at least partial overlap of cycle coverage for the multiple measurement periods. While a simplified pulsatile ambient light intensity profile with a frequency of 120 Hz, corresponding to a F_ACof 60 Hz, is shown here for reference, the pulsatile ambient light correction technique as described herein may be used for any arbitrary pulsatile, or periodic, ambient light intensity profile. As seen here, the sample pulsatile ambient light intensity profile would yield different contributions of accumulated ambient light intensity for a fluorescence exposure and a background exposure, wherein those differences are not accounted for simply by a difference in exposure duration, because of those exposures capturing different portions of the pulsatile ambient light intensity profile. Other pulsatile ambient light intensity profiles, such as those with a frequency that is not a multiple or a factor of the fluorescence exposure frequency, may generally also yield different contributions of accumulated ambient light intensity from one fluorescence exposure to the next.

In some embodiments, a minimum sampling rate within each measurement period for sensors 395 may be set to at least four times the quotient of the anticipated maximum frequency F_ACand the measurement period duty cycle in order to allow accurate synthesis of a complete pulsating ambient light intensity cycle with periodic frequency twice that of F_AC. In some variations, a higher sensor sampling rate may be used to provide more measurement points in partial overlap regions and/or to support higher possible F_ACvalues. For example, as shown in FIG. 11E, with a measurement period duty cycle of 50%, a sensor sampling rate of at least 480 Hz may be used within the ambient light intensity measurement periods to support frequency values for F_ACof up to 60 Hz and corresponding pulsatile ambient light intensity frequencies of up to 120 Hz. Partial overlap of cycle coverage allows comparison of measurements taken from multiple measurement periods in order to detect the frequency F_AC(or the corresponding frequency of the pulsatile ambient light intensity), for example by calculating the frequency F_AC(or the corresponding frequency of the pulsatile ambient light intensity) corresponding with the best temporal alignment, such as by minimizing a measure of average error between corresponding measurement points in candidate temporal alignments, of the portions of the periodic cycle captured by the multiple measurement periods. Arranging the portions of the periodic cycle captured by the multiple measurement periods according to the best temporal alignment may then yield the synthesis of a complete periodic cycle of duration 1/(2F_AC). In some variations, a complete periodic cycle may be extracted directly from a single measurement period which is longer in duration than the complete periodic cycle. Synthesis or extraction of the complete periodic cycle permits extending/extrapolating the pulsatile ambient light signal beyond periods in which measurement by the sensors 395 was performed.

In some embodiments, the imaging device image acquisition frame rate may be set to match the known or detected AC frequency, or a multiple thereof, of the power source for a pulsating light component of the ambient room lighting such that equivalent contributions from the pulsating light component are present in each fluorescence exposure of a given duration. To accommodate such a setting of the image acquisition frame rate, corresponding scaling may be performed of the frequency of a pulsed white light source, the frequency of a pulsed fluorescence excitation light source, and the frequencies of image exposures. In embodiments also using a room light subtraction technique that includes taking a background light exposure, exposure durations for the background light exposure and the fluorescence light exposure may be set to be equal such that equivalent contributions from the pulsating light component are present in both exposures.

In some embodiments using a room light subtraction technique that includes taking a background light exposure, a background exposure image intensity and/or a fluorescence exposure image intensity may be scaled based on measurements of the pulsating room light intensity, in order that the scaled image intensities correspond to equivalent contributions from the pulsating room light. After measuring the pulsating light intensity and synthesizing a complete periodic cycle of the pulsating light intensity, as described herein, identification of the portion of the periodic cycle of the pulsating light intensity coinciding with a fluorescence exposure and a background light exposure may be performed by repeating/extrapolating the periodic cycle as necessary to find the portion that coincided with the time spanned by each respective exposure. Calculating a fluorescence accumulated ambient light value, FL_acc, corresponding to the accumulated ambient light intensity during a fluorescence exposure may then be performed by calculating the area under the curve marked by the portion of the periodic cycle of pulsating light intensity for that exposure, and calculating a background accumulated ambient light value, BG_acc, corresponding to the accumulated ambient light intensity during a background exposure may be performed by calculating the area under the curve for the portion of the periodic pulsating light intensity coinciding with that exposure. Scaling the image intensity of a fluorescence image or a background image may then be performed based on a ratio of the respective accumulated light values, FL_accand BG_acc, in order to normalize the scaled images such that they reflect equivalent contributions of accumulated ambient light. Subsequent to scaling, the scaled background image may be subtracted from the scaled fluorescence image to yield a corrected fluorescence image that removes the ambient light signal and includes correction for pulsatile ambient light contributions. In one embodiment, one or the other of the fluorescence image or the background image is scaled by a factor of 1.

In embodiments where room light subtraction is not employed, the fluorescence exposure image intensity may be scaled based on measurements of the pulsating room light intensity, in order to facilitate reducing image intensity artifacts resulting from the pulsating room light. For example, the scaling may be performed based on a ratio of measured intensities for successive fluorescence images.

To improve performance of ambient room light compensation methods described herein, a wavelength-dependent aperture (e.g., element 55 in FIG. 6A) may be used that includes a smaller central aperture that permits transmission of all visible and NIR light, and a surrounding larger aperture that blocks visible light but permits transmission of NIR light. Use of such a wavelength-dependent aperture allows a larger proportion of NIR signal to be collected relative to the visible light signal, which improves performance of the image signal subtraction for estimation and removal of the ambient room light component. A wavelength-dependent aperture may also feature a third, larger aperture, surrounding the other smaller apertures, that blocks both visible and NIR light. As an example, a wavelength-dependent aperture may comprise a film aperture, wherein a film (e.g., a plastic or glass film) of material that blocks transmission of visible light but permits transmission of NIR light has a central opening (e.g., a hole) that permits transmission of both visible and NIR light. Such a film aperture may comprise material that blocks transmission of visible light through reflection and/or material that blocks transmission of visible light through absorption. As another example, a wavelength-dependent aperture may comprise a dichroic aperture which is formed by masked thin-film deposition on a single substrate, wherein a thin-film that permits transmission of visible and NIR light is deposited on a smaller central aperture, and a second thin-film that blocks transmission of visible light but permits transmission of NIR light is deposited on a surrounding larger aperture. The respective aperture sizes of the smaller central aperture and the surrounding larger aperture of a wavelength-dependent aperture may be set in order to make the depth of field for visible light and for NIR light appear substantially similar when imaged by the imaging system. One or more wavelength-dependent filters may be placed in different positions throughout the device, where rejection of the visible and passage of the NIR signal may be optimized. For example, such a wavelength-dependent filter may be positioned just before the lens 51. As another example, one or more wavelength-dependent filters may be placed in a pupil plane of the imaging lens.

It may be useful, e.g., to facilitate comparison of the fluorescence signal of different regions, to display a target reticle around a region within the imaged field of view, and to calculate and display the normalized fluorescence intensity within that region. Normalization of the measured fluorescence intensity values may allow for meaningful comparison of multiple images and corresponding values. To correct for the variation of measured fluorescence intensity with working distance (e.g., distance of the imaging system to the imaged anatomy), normalized fluorescence intensity values may be based on a ratio between the measured fluorescence intensity values and a reflected light value within the target reticle region.

A numerical representation of the normalized fluorescence intensity value within the target reticle region may be displayed on or near the image frame, to facilitate comparing values when aiming the target reticle at different locations on the imaged anatomy. For example, the numerical representation may be the mean value of the normalized fluorescence intensity values for all of the image pixels in the target reticle region.

Additionally or alternatively, a time history plot of the numerical representation of the normalized fluorescence intensity value within the target reticle region may be displayed on or near the image frame, to facilitate comparing values when aiming the target reticle at different locations on the imaged anatomy or at the same location over a series of time points. Such a time history plot may further assist the user in assessing the fluorescence profile in the imaged tissue surface by scanning across the anatomy region of interest and viewing the relative normalized fluorescence intensity profile plot.

FIG. 13A illustrates a diagram of a sample display output from an embodiment of the display method, wherein the target reticle 125 is positioned over a region of no fluorescence intensity 122 on the imaged anatomy 120, and the numerical representation of the fluorescence intensity 126 is displayed near the target reticle 125. FIG. 13B illustrates a diagram of another sample display output, wherein the target reticle 125 is positioned over a region of high relative normalized fluorescence intensity 124, and showing a corresponding numerical representation 126 of relatively high fluorescence intensity. FIG. 13C illustrates a diagram of another sample display output, wherein the target reticle 125 is positioned over a region of moderate relative normalized fluorescence intensity 124, and showing a corresponding numerical representation 126 of relatively moderate fluorescence intensity. FIG. 13D illustrates a diagram of a sample display output, wherein the target reticle 125 is positioned over a region of moderate relative normalized fluorescence intensity 124, and showing a time history plot 128 of the numerical representation of normalized fluorescence intensity that would be consistent with sequential imaging of regions of zero, high, and moderate relative normalized fluorescence intensity. Alternatively or additionally to displaying the numerical representation and/or historical plot on the target, a display region associated with the target reticle, e.g., on the device itself or some other display, may display this information.

FIG. 14 illustrates a recorded image of an anatomical fluorescence imaging phantom, featuring an embodiment of a display method output that displays normalized fluorescence intensity. In particular, a target 110 is illuminated by excitation light in accordance with an embodiment and a target reticle 115 is positioned over a region of fluorescence intensity 112. A numerical representation of the target reticle 115 is displayed in a region 116 associated with the target reticle 115. A time history plot 118 of the numerical representation of normalized fluorescence intensity due to imaging of different positions of the reticle 115 may be displayed.

Normalization of the measured fluorescence intensity values may additionally or alternatively be performed on a pixel basis for an entire acquired fluorescence image or series of images, which may facilitate providing a consistent and/or smoothly varying image brightness, even when varying the working distance. To correct for the variation of measured fluorescence intensity with working distance (e.g., distance of the imaging system to the imaged anatomy), normalized fluorescence intensity values for each pixel in an acquired fluorescence image may be based on a ratio between the measured fluorescence intensity value of that pixel and a reflected light value or component of a reflected light value for the same pixel in an acquired reflected light image. In one embodiment, the reflected light image used for such normalization is a white light image formed from reflection of visible white light illumination. For example, in embodiments in which a color image sensor is used to acquire the reflected light image, an overall luminance value, or a combination of one or more color channel intensities detected for each pixel from the color image sensor may be used.

Such a display method and/or technique for normalization of the measured intensity values, as any one of those described herein, may be useful for a variety of fluorescence imaging systems, including an endoscopic or laparoscopic fluorescence imaging system, an open field fluorescence imaging system, or a combination thereof. Such normalization and display of the fluorescence intensity values can allow useful quantitative comparisons of relative fluorescence intensity between image data from various time points within an imaging session. Combined with appropriate standardized fluorescent agent administration and imaging protocols, and standardized calibration of imaging devices, such normalization and display of the fluorescence intensity values can further allow useful quantitative comparisons of relative fluorescence intensity between image data from different imaging sessions.

EXAMPLES

A Fluorescence Medical Imaging System for Acquisition of Image Data

In some embodiments, a system (also referred in some embodiments as a device) for illumination and imaging of a subject may be used with or as a component of a medical imaging system such as, for example, a fluorescence medical imaging system for acquiring fluorescence medical image data. An example of such a fluorescence medical imaging system is the fluorescence imaging system 10 schematically illustrated in FIG. 1. In this embodiment, the fluorescence imaging system 10 is configured to acquire a time series of fluorescence signal intensity data (e.g., images, video) capturing the transit of a fluorescence imaging agent through the tissue.

The fluorescence imaging system 10 (FIG. 1) comprises an illumination source 15 and illumination module 11 to illuminate the tissue of the subject to induce fluorescence emission from a fluorescence imaging agent 17 in the tissue of the subject (e.g., in blood), an imaging module 13 configured to acquire the time series of fluorescence images from the fluorescence emission, and a processor assembly 16 configured to utilize the acquired time series of fluorescence images (fluorescence signal intensity data) according to the various embodiments described herein.

In various embodiments, the illumination source 15 (FIG. 1) comprises, for example, a light source 200 (FIG. 15) comprising a fluorescence excitation source configured to generate an excitation light having a suitable intensity and a suitable wavelength for exciting the fluorescence imaging agent 17. The light source 200 in FIG. 15 comprises a laser diode 202 (e.g., which may comprise, for example, one or more fiber-coupled diode lasers) configured to provide excitation light to excite the fluorescence imaging agent 17 (not shown). Examples of other sources of the excitation light which may be used in various embodiments include one or more LEDs, arc lamps, or other illuminant technologies of sufficient intensity and appropriate wavelength to excite the fluorescence imaging agent 17 in the tissue (e.g., in blood). For example, excitation of the fluorescence imaging agent 17 in blood, wherein the fluorescence imaging agent 17 is a fluorescent dye with near infra-red excitation characteristics, may be performed using one or more 793 nm, conduction-cooled, single bar, fiber-coupled laser diode modules from DILAS Diode Laser Co, Germany.

In various embodiments, the light output from the light source 200 in FIG. 15 may be projected through an optical element (e.g., one or more optical elements) to shape and guide the output being used to illuminate the tissue area of interest. The shaping optics may consist of one or more lenses, light guides, and/or diffractive elements so as to ensure a flat field over substantially the entire field of view of the imaging module 13. In particular embodiments, the fluorescence excitation source is selected to emit at a wavelength close to the absorption maximum of the fluorescence imaging agent 17 (e.g., ICG). For example, referring to the embodiment of the light source 200 in FIG. 15, the output 204 from the laser diode 202 is passed through one or more focusing lenses 206, and then through a homogenizing light pipe 208 such as, for example, light pipes commonly available from Newport Corporation, USA. Finally, the light is passed through an optical diffractive element 214 (e.g., one or more optical diffusers) such as, for example, ground glass diffractive elements also available from Newport Corporation, USA. Power to the laser diode 202 itself is provided by, for example, a high-current laser driver such as those available from Lumina Power Inc. USA. The laser may optionally be operated in a pulsed mode during the image acquisition process. In this embodiment, an optical sensor such as a solid state photodiode 212 is incorporated into the light source 200 and samples the illumination intensity produced by the light source 200 via scattered or diffuse reflections from the various optical elements. In various embodiments, additional illumination sources may be used to provide guidance when aligning and positioning the module over the area of interest. In various embodiments, at least one of the components of light source 200 depicted in FIG. 15 may be components comprising the illumination source 15 and/or comprising the illumination module 11.

Referring back to FIG. 1, in various embodiments, the imaging module 13 may be a component of, for example, the fluorescence imaging system 10 configured to acquire the time series of fluorescence images (e.g., video) from the fluorescence emission from the fluorescence imaging agent 17. Referring to FIG. 16, there is shown an exemplary embodiment of an imaging module 13 comprising a camera module 250. As is shown in FIG. 16, the camera module 250 acquires images of the fluorescence emission 252 from the fluorescence imaging agent 17 in the tissue (e.g., in blood) (not shown) by using a system of imaging optics (e.g., front element 254, rejection filter 256, dichroic 260 and rear element 262) to collect and focus the fluorescence emission onto an image sensor assembly 264 comprising at least one 2D solid state image sensor. A rejection filter 256 may be, for example, a notch filter used to reject a band of wavelengths corresponding to the excitation light. A dichroic 260 may be, for example, a dichroic mirror used to selectively pass one subset of the incoming light wavelength spectrum and redirect remaining wavelengths off of the optical path for rejection or towards a separate image sensor. The solid state image sensor may be a charge coupled device (CCD), a CMOS sensor, a CID or similar 2D sensor technology. The charge that results from the optical signal transduced by the image sensor assembly 264 is converted to an electrical video signal, which includes both digital and analog video signals, by the appropriate read-out and amplification electronics in the camera module 250.

According to some embodiments, excitation wavelength of about 800 nm+/−10 nm and emission wavelengths of >820 nm are used along with NIR compatible optics for ICG fluorescence imaging. A skilled person will appreciate that other excitation and emission wavelengths may be used for other imaging agents.

Referring back to FIG. 1, in various embodiments, the processor assembly 16 comprises, for example,

- a processor module (not shown) configured to perform various processing operations, including executing instructions stored on computer-readable medium, wherein the instructions cause one or more of the systems described herein to execute the methods and techniques described herein, and
- a data storage module (not shown) to record and store the data from the operations, as well as to store, in some embodiments, instructions executable by the processor module to implement the methods and techniques disclosed herein.

In various embodiments, the processor module comprises any computer or computing means such as, for example, a tablet, laptop, desktop, networked computer, or dedicated standalone microprocessor. Inputs are taken, for example, from the image sensor 264 of the camera module 250 shown in FIG. 16, from the solid state photodiode in the light source 200 in FIG. 15, and from any external control hardware such as a footswitch or remote-control. Output is provided to the laser diode driver, and optical alignment aids. In various embodiments, the processor assembly 16 (FIG. 1) may have a data storage module with the capability to save the time series of input data (e.g., image data) to a tangible non-transitory computer readable medium such as, for example, internal memory (e.g. a hard disk or flash memory), so as to enable recording and processing of data. In various embodiments, the processor module may have an internal clock to enable control of the various elements and ensure correct timing of illumination and sensor shutters. In various other embodiments, the processor module may also provide user input and graphical display of outputs. The fluorescence imaging system may optionally be configured with a video display (not shown) to display the images as they are being acquired or played back after recording, or further to visualize the data generated at various stages of the method as was described above.

In operation, and with continuing reference to the exemplary embodiments in FIGS. 1, 15 and 16, the subject is in a position for imaging where the anatomical area of interest of the subject is located beneath both the illumination module 11 and the imaging module 13 such that a substantially uniform field of illumination is produced across substantially the entire area of interest. In various embodiments, prior to the administration of the fluorescence imaging agent 17 to the subject, an image may be acquired of the area of interest for the purposes of background deduction. For example, in order to do this, the operator of the fluorescence imaging system 10 in FIG. 1 may initiate the acquisition of the time series of fluorescence images (e.g., video) by depressing a remote switch or foot-control, or via a keyboard (not shown) connected to the processor assembly 16. As a result, the illumination source 15 is turned on and the processor assembly 16 begins recording the fluorescence image data provided by the image acquisition assembly 13. In lieu of the pulsed mode discussed above, it will be understood that, in some embodiments, the illumination source 15 can comprise an emission source which is continuously on during the image acquisition sequence. When operating in the pulsed mode of the embodiment, the image sensor 264 in the camera module 250 (FIG. 16) is synchronized to collect fluorescence emission following the laser pulse produced by the diode laser 202 in the light source 200 (FIG. 15). In this way, maximum fluorescence emission intensity is recorded, and signal-to-noise ratio is optimized. In this embodiment, the fluorescence imaging agent 17 is administered to the subject and delivered to the area of interest via arterial flow. Acquisition of the time series of fluorescence images is initiated, for example, shortly after administration of the fluorescence imaging agent 17, and the time series of fluorescence images from substantially the entire area of interest are acquired throughout the ingress of the fluorescence imaging agent 17. The fluorescence emission from the region of interest is collected by the collection optics of the camera module 250. Residual ambient and reflected excitation light is attenuated by subsequent optical elements (e.g., optical element 256 in FIG. 16 which may be a filter) in the camera module 250 so that the fluorescence emission can be acquired by the image sensor assembly 264 with minimal interference by light from other sources.

In various embodiments, the processor is in communication with the imaging system or is a component of the imaging system. The program code or other computer-readable instructions, according to the various embodiments, can be written and/or stored in any appropriate programming language and delivered to the processor in various forms, including, for example, but not limited to information permanently stored on non-writeable storage media (e.g., read-only memory devices such as ROMs or CD-ROM disks), information alterably stored on writeable storage media (e.g., hard drives), information conveyed to the processor via transitory mediums (e.g., signals), information conveyed to the processor through communication media, such as a local area network, a public network such as the Internet, or any type of media suitable for storing electronic instruction. In various embodiments, the tangible non-transitory computer readable medium comprises all computer-readable media. In some embodiments, computer-readable instructions for performing one or more of the methods or techniques discussed herein may be stored solely on non-transitory computer readable media.

In some embodiments, the illumination and imaging system may be a component of a medical imaging system such as the fluorescence medical imaging system 10, which acquires medical image data. In embodiments where the illumination and imaging system is a component of the imaging system, such as the fluorescence imaging system described above, the light source, illumination module, imaging module and the processor of the medical imaging system may function as the camera assembly and the processor of the illumination and imaging system. A skilled person will appreciate that imaging systems other than fluorescence imaging systems may be employed for use with illumination and/or imaging systems such as those described herein, depending on the type of imaging being performed.

Example Imaging Agents for Use in Generating Image Data

According to some embodiments, in fluorescence medical imaging applications, the imaging agent is a fluorescence imaging agent such as, for example, indocyanine green (ICG) dye. ICG, when administered to the subject, binds with blood proteins and circulates with the blood in the tissue. The fluorescence imaging agent (e.g., ICG) may be administered to the subject as a bolus injection (e.g., into a vein or an artery) in a concentration suitable for imaging such that the bolus circulates in the vasculature and traverses the microvasculature. In other embodiments in which multiple fluorescence imaging agents are used, such agents may be administered simultaneously, e.g. in a single bolus, or sequentially in separate boluses. In some embodiments, the fluorescence imaging agent may be administered by a catheter. In certain embodiments, the fluorescence imaging agent may be administered less than an hour in advance of performing the measurement of signal intensity arising from the fluorescence imaging agent. For example, the fluorescence imaging agent may be administered to the subject less than 30 minutes in advance of the measurement. In yet other embodiments, the fluorescence imaging agent may be administered at least 30 seconds in advance of performing the measurement. In still other embodiments, the fluorescence imaging agent may be administered contemporaneously with performing the measurement.

According to some embodiments, the fluorescence imaging agent may be administered in various concentrations to achieve a desired circulating concentration in the blood. For example, in embodiments where the fluorescence imaging agent is ICG, it may be administered at a concentration of about 2.5 mg/mL to achieve a circulating concentration of about 5 μM to about 10 μM in blood. In various embodiments, the upper concentration limit for the administration of the fluorescence imaging agent is the concentration at which the fluorescence imaging agent becomes clinically toxic in circulating blood, and the lower concentration limit is the instrumental limit for acquiring the signal intensity data arising from the fluorescence imaging agent circulating with blood to detect the fluorescence imaging agent. In various other embodiments, the upper concentration limit for the administration of the fluorescence imaging agent is the concentration at which the fluorescence imaging agent becomes self-quenching. For example, the circulating concentration of ICG may range from about 2 μM to about 10 mM. Thus, in one aspect, the method comprises the step of administration of the imaging agent (e.g., a fluorescence imaging agent) to the subject and acquisition of the signal intensity data (e.g., video) prior to processing the signal intensity data according to the various embodiments. In another aspect, the method excludes any step of administering the imaging agent to the subject.

According to some embodiments, a suitable fluorescence imaging agent for use in fluorescence imaging applications to generate fluorescence image data is an imaging agent which can circulate with the blood (e.g., a fluorescence dye which can circulate with, for example, a component of the blood such as lipoproteins or serum plasma in the blood) and transit vasculature of the tissue (i.e., large vessels and microvasculature), and from which a signal intensity arises when the imaging agent is exposed to appropriate light energy (e.g., excitation light energy, or absorption light energy). In various embodiments, the fluorescence imaging agent comprises a fluorescence dye, an analogue thereof, a derivative thereof, or a combination of these. A fluorescence dye includes any non-toxic fluorescence dye. In certain embodiments, the fluorescence dye optimally emits fluorescence in the near-infrared spectrum. In certain embodiments, the fluorescence dye is or comprises a tricarbocyanine dye. In certain embodiments, the fluorescence dye is or comprises indocyanine green (ICG), methylene blue, or a combination thereof. In other embodiments, the fluorescence dye is or comprises fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde, fluorescamine, rose Bengal, trypan blue, fluoro-gold, or a combination thereof, excitable using excitation light wavelengths appropriate to each dye. In some embodiments, an analogue or a derivative of the fluorescence dye may be used. For example, a fluorescence dye analog or a derivative includes a fluorescence dye that has been chemically modified, but still retains its ability to fluoresce when exposed to light energy of an appropriate wavelength.

In various embodiments, the fluorescence imaging agent may be provided as a lyophilized powder, solid, or liquid. In certain embodiments, the fluorescence imaging agent may be provided in a vial (e.g., a sterile vial), which may permit reconstitution to a suitable concentration by administering a sterile fluid with a sterile syringe. Reconstitution may be performed using any appropriate carrier or diluent. For example, the fluorescence imaging agent may be reconstituted with an aqueous diluent immediately before administration. In various embodiments, any diluent or carrier which will maintain the fluorescence imaging agent in solution may be used. As an example, ICG may be reconstituted with water. In some embodiments, once the fluorescence imaging agent is reconstituted, it may be mixed with additional diluents and carriers. In some embodiments, the fluorescence imaging agent may be conjugated to another molecule, such as a protein, a peptide, an amino acid, a synthetic polymer, or a sugar, for example to enhance solubility, stability, imaging properties, or a combination thereof. Additional buffering agents may optionally be added including Tris, HCl, NaOH, phosphate buffer, and/or HEPES.

A person of skill in the art will appreciate that, although a fluorescence imaging agent was described above in detail, other imaging agents may be used in connection with the systems, methods, and techniques described herein, depending on the optical imaging modality.

In some variations, the fluorescence imaging agent used in combination with the methods, systems and kits described herein may be used for blood flow imaging, tissue perfusion imaging, lymphatic imaging, or a combination thereof, which may performed during an invasive surgical procedure, a minimally invasive surgical procedure, a non-invasive surgical procedure, or a combination thereof. Examples of invasive surgical procedure which may involve blood flow and tissue perfusion include a cardiac-related surgical procedure (e.g., CABG on pump or off pump) or a reconstructive surgical procedure. An example of a non-invasive or minimally invasive procedure includes wound (e.g., chronic wound such as for example pressure ulcers) treatment and/or management. In this regard, for example, a change in the wound over time, such as a change in wound dimensions (e.g., diameter, area), or a change in tissue perfusion in the wound and/or around the peri-wound, may be tracked over time with the application of the methods and systems. Examples of lymphatic imaging include identification of one or more lymph nodes, lymph node drainage, lymphatic mapping, or a combination thereof. In some variations such lymphatic imaging may relate to the female reproductive system (e.g., uterus, cervix, vulva).

In variations relating to cardiac applications or any vascular applications, the imaging agent(s) (e.g., ICG alone or in combination with another imaging agent) may be injected intravenously. For example, the imaging agent may be injected intravenously through the central venous line, bypass pump and/or cardioplegia line and/or other vasculature to flow and/or perfuse the coronary vasculature, microvasculature and/or grafts. ICG may be administered as a dilute ICG/blood/saline solution down the grafted vessel or other vasculature such that the final concentration of ICG in the coronary artery or other vasculature depending on application is approximately the same or lower as would result from injection of about 2.5 mg (i.e., 1 ml of 2.5 mg/ml) into the central line or the bypass pump. The ICG may be prepared by dissolving, for example, 25 mg of the solid in 10 ml sterile aqueous solvent, which may be provided with the ICG by the manufacturer. One milliliter of the ICG solution may be mixed with 500 ml of sterile saline (e.g., by injecting 1 ml of ICG into a 500 ml bag of saline). Thirty milliliters of the dilute ICG/saline solution may be added to 10 ml of the subject's blood, which may be obtained in an aseptic manner from the central arterial line or the bypass pump. ICG in blood binds to plasma proteins and facilitates preventing leakage out of the blood vessels. Mixing of ICG with blood may be performed using standard sterile techniques within the sterile surgical field. Ten ml of the ICG/saline/blood mixture may be administered for each graft. Rather than administering ICG by injection through the wall of the graft using a needle, ICG may be administered by means of a syringe attached to the (open) proximal end of the graft. When the graft is harvested surgeons routinely attach an adaptor to the proximal end of the graft so that they can attach a saline filled syringe, seal off the distal end of the graft and inject saline down the graft, pressurizing the graft and thus assessing the integrity of the conduit (with respect to leaks, side branches etc.) prior to performing the first anastomosis. In other variations, the methods, dosages or a combination thereof as described herein in connection with cardiac imaging may be used in any vascular and/or tissue perfusion imaging applications.

Lymphatic mapping is an important part of effective surgical staging for cancers that spread through the lymphatic system (e.g., breast, gastric, gynecological cancers). Excision of multiple nodes from a particular node basin can lead to serious complications, including acute or chronic lymphedema, paresthesia, and/or seroma formation, when in fact, if the sentinel node is negative for metastasis, the surrounding nodes will most likely also be negative. Identification of the tumor draining lymph nodes (LN) has become an important step for staging cancers that spread through the lymphatic system in breast cancer surgery for example. LN mapping involves the use of dyes and/or radiotracers to identify the LNs either for biopsy or resection and subsequent pathological assessment for metastasis. The goal of lymphadenectomy at the time of surgical staging is to identify and remove the LNs that are at high risk for local spread of the cancer. Sentinel lymph node (SLN) mapping has emerged as an effective surgical strategy in the treatment of breast cancer. It is generally based on the concept that metastasis (spread of cancer to the axillary LNs), if present, should be located in the SLN, which is defined in the art as the first LN or group of nodes to which cancer cells are most likely to spread from a primary tumor. If the SLN is negative for metastasis, then the surrounding secondary and tertiary LN should also be negative. The primary benefit of SLN mapping is to reduce the number of subjects who receive traditional partial or complete lymphadenectomy and thus reduce the number of subjects who suffer from the associated morbidities such as lymphedema and lymphocysts.

The current standard of care for SLN mapping involves injection of a tracer that identifies the lymphatic drainage pathway from the primary tumor. The tracers used may be radioisotopes (e.g. Technetium-99 or Tc-99m) for intraoperative localization with a gamma probe. The radioactive tracer technique (known as scintigraphy) is limited to hospitals with access to radioisotopes require involvement of a nuclear physician and does not provide real-time visual guidance. A colored dye, isosulfan blue, has also been used, however this dye cannot be seen through skin and fatty tissue. In addition, blue staining results in tattooing of the breast lasting several months, skin necrosis can occur with subdermal injections, and allergic reactions with rare anaphylaxis have also been reported. Severe anaphylactic reactions have occurred after injection of isosulfan blue (approximately 2% of patients). Manifestations include respiratory distress, shock, angioedema, urticarial and pruritus. Reactions are more likely to occur in subjects with a history of bronchial asthma, or subjects with allergies or drug reactions to triphenylmethane dyes. Isosulfan blue is known to interfere with measurements of oxygen saturation by pulse oximetry and methemoglobin by gas analyzer. The use of isosulfan blue may result in transient or long-term (tattooing) blue coloration.

In contrast, fluorescence imaging in accordance with the various embodiments for use in SLN visualization, mapping, facilitates direct real-time visual identification of a LN and/or the afferent lymphatic channel intraoperatively, facilitates high-resolution optical guidance in real-time through skin and fatty tissue, visualization of blood flow, tissue perfusion or a combination thereof.

In some variations, visualization, classification or both of lymph nodes during fluorescence imaging may be based on imaging of one or more imaging agents, which may be further based on visualization and/or classification with a gamma probe (e.g., Technetium Tc-99m is a clear, colorless aqueous solution and is typically injected into the periareolar area as per standard care), another conventionally used colored imaging agent (isosulfan blue), and/or other assessment such as, for example, histology. The breast of a subject may be injected, for example, twice with about 1% isosulfan blue (for comparison purposes) and twice with an ICG solution having a concentration of about 2.5 mg/ml. The injection of isosulfan blue may precede the injection of ICG or vice versa. For example, using a TB syringe and a 30 G needle, the subject under anesthesia may be injected with 0.4 ml (0.2 ml at each site) of isosulfan blue in the periareolar area of the breast. For the right breast, the subject may be injected at 12 and 9 o'clock positions and for the left breast at 12 and 3 o'clock positions. The total dose of intradermal injection of isosulfan blue into each breast may be about 4.0 mg (0.4 ml of 1% solution: 10 mg/ml). In another exemplary variation, the subject may receive an ICG injection first followed by isosulfan blue (for comparison). One 25 mg vial of ICG may be reconstituted with 10 ml sterile water for injection to yield a 2.5 mg/ml solution immediately prior to ICG administration. Using a TB syringe and a 30 G needle, for example, the subject may be injected with about 0.1 ml of ICG (0.05 ml at each site) in the periareolar area of the breast (for the right breast, the injection may be performed at 12 and 9 o'clock positions and for the left breast at 12 and 3 o'clock positions). The total dose of intradermal injection of ICG into each breast may be about 0.25 mg (0.1 ml of 2.5 mg/ml solution) per breast. ICG may be injected, for example, at a rate of 5 to 10 seconds per injection. When ICG is injected intradermally, the protein binding properties of ICG cause it to be rapidly taken up by the lymph and moved through the conducting vessels to the LN. In some variations, the ICG may be provided in the form of a sterile lyophilized powder containing 25 mg ICG with no more than 5% sodium iodide. The ICG may be packaged with aqueous solvent consisting of sterile water for injection, which is used to reconstitute the ICG. In some variations the ICG dose (mg) in breast cancer sentinel lymphatic mapping may range from about 0.5 mg to about 10 mg depending on the route of administration. In some variations, the ICG does may be about 0.6 mg to about 0.75 mg, about 0.75 mg to about 5 mg, about 5 mg to about 10 mg. The route of administration may be for example subdermal, intradermal (e.g., into the periareolar region), subareolar, skin overlaying the tumor, intradermal in the areola closest to tumor, subdermal into areola, intradermal above the tumor, periareolar over the whole breast, or a combination thereof. The NIR fluorescent positive LNs (e.g., using ICG) may be represented as a black and white NIR fluorescence image(s) for example and/or as a full or partial color (white light) image, full or partial desaturated white light image, an enhanced colored image, an overlay (e.g., fluorescence with any other image), a composite image (e.g., fluorescence incorporated into another image) which may have various colors, various levels of desaturation or various ranges of a color to highlight/visualize certain features of interest. Processing of the images may be further performed for further visualization and/or other analysis (e.g., quantification). The lymph nodes and lymphatic vessels may be visualized (e.g., intraoperatively, in real time) using fluorescence imaging systems and methods according to the various embodiments for ICG and SLNs alone or in combination with a gamma probe (Tc-99m) according to American Society of Breast Surgeons (ASBrS) practice guidelines for SLN biopsy in breast cancer patients. Fluorescence imaging for LNs may begin from the site of injection by tracing the lymphatic channels leading to the LNs in the axilla. Once the visual images of LNs are identified, LN mapping and identification of LNs may be done through incised skin, LN mapping may be performed until ICG visualized nodes are identified. For comparison, mapping with isosulfan blue may be performed until ‘blue’ nodes are identified. LNs identified with ICG alone or in combination with another imaging technique (e.g., isosulfan blue, and/or Tc-99m) may be labeled to be excised. Subject may have various stages of breast cancer (e.g., IA, IB, IIA).

In some variations, such as for example, in gynecological cancers (e.g., uterine, endometrial, vulvar and cervical malignancies), ICG may be administered interstitially for the visualization of lymph nodes, lymphatic channels, or a combination thereof. When injected interstitially, the protein binding properties of ICG cause it to be rapidly taken up by the lymph and moved through the conducting vessels to the SLN. ICG may be provided for injection in the form of a sterile lyophilized powder containing 25 mg ICG (e.g., 25 mg/vial) with no more than 5.0% sodium iodide. ICG may be then reconstituted with commercially available water (sterile) for injection prior to use. According to an embodiment, a vial containing 25 mg ICG may be reconstituted in 20 ml of water for injection, resulting in a 1.25 mg/ml solution. A total of 4 ml of this 1.25 mg/ml solution is to be injected into a subject (4×1 ml injections) for a total dose of ICG of 5 mg per subject. The cervix may also be injected four (4) times with a 1 ml solution of 1% isosulfan blue 10 mg/ml (for comparison purposes) for a total dose of 40 mg. The injection may be performed while the subject is under anesthesia in the operating room. In some variations the ICG dose (mg) in gynecological cancer sentinel lymph node detection and/or mapping may range from about 0.1 mg to about 5 mg depending on the route of administration. In some variations, the ICG does may be about 0.1 mg to about 0.75 mg, about 0.75 mg to about 1.5 mg, about 1.5 mg to about 2.5 mg, about 2.5 mg to about 5 mg. The route of administration may be for example cervical injection, vulva peritumoral injection, hysteroscopic endometrial injection, or a combination thereof. In order to minimize the spillage of isosulfan blue or ICG interfering with the mapping procedure when LNs are to be excised, mapping may be performed on a hemi-pelvis, and mapping with both isosulfan blue and ICG may be performed prior to the excision of any LNs. LN mapping for Clinical Stage I endometrial cancer may be performed according to the NCCN Guidelines for Uterine Neoplasms, SLN Algorithm for Surgical Staging of Endometrial Cancer; and SLN mapping for Clinical Stage I cervical cancer may be performed according to the NCCN Guidelines for Cervical Neoplasms, Surgical/SLN Mapping Algorithm for Early-Stage Cervical Cancer. Identification of LNs may thus be based on ICG fluorescence imaging alone or in combination or co-administration with for a colorimetric dye (isosulfan blue) and/or radiotracer.

Visualization of lymph nodes may be qualitative and/or quantitative. Such visualization may comprise, for example, lymph node detection, detection rate, anatomic distribution of lymph nodes. Visualization of lymph nodes according to the various embodiments may be used alone or in combination with other variables (e.g., vital signs, height, weight, demographics, surgical predictive factors, relevant medical history and underlying conditions, histological visualization and/or assessment, Tc-99m visualization and/or assessment, concomitant medications). Follow-up visits may occur on the date of discharge, and subsequent dates (e.g., one month).

Lymph fluid comprises high levels of protein, thus ICG can bind to endogenous proteins when entering the lymphatic system. Fluorescence imaging (e.g., ICG imaging) for lymphatic mapping when used in accordance with the methods and systems described herein offers the following example advantages: high-signal to background ratio (or tumor to background ratio) as NIR does not generate significant autofluorescence, real-time visualization feature for lymphatic mapping, tissue definition (i.e., structural visualization), rapid excretion and elimination after entering the vascular system, and avoidance of non-ionizing radiation. Furthermore, NIR imaging has superior tissue penetration (approximately 5 to 10 millimeters of tissue) to that of visible light (1 to 3 mm of tissue). The use of ICG for example also facilitates visualization through the peritoneum overlying the para-aortic nodes. Although tissue fluorescence can be observed with NIR light for extended periods, it cannot be seen with visible light and consequently does not impact pathologic evaluation or processing of the LN. Also, florescence is easier to detect intra-operatively than blue staining (isosulfan blue) of lymph nodes. In other variations, the methods, dosages or a combination thereof as described herein in connection with lymphatic imaging may be used in any vascular and/or tissue perfusion imaging applications.

Tissue perfusion relates to the microcirculatory flow of blood per unit tissue volume in which oxygen and nutrients are provided to and waste is removed from the capillary bed of the tissue being perfused. Tissue perfusion is a phenomenon related to but also distinct from blood flow in vessels. Quantified blood flow through blood vessels may be expressed in terms that define flow (i.e., volume/time), or that define speed (i.e., distance/time). Tissue blood perfusion defines movement of blood through micro-vasculature, such as arterioles, capillaries, or venules, within a tissue volume. Quantified tissue blood perfusion may be expressed in terms of blood flow through tissue volume, namely, that of blood volume/time/tissue volume (or tissue mass). Perfusion is associated with nutritive blood vessels (e.g., micro-vessels known as capillaries) that comprise the vessels associated with exchange of metabolites between blood and tissue, rather than larger-diameter non-nutritive vessels. In some embodiments, quantification of a target tissue may include calculating or determining a parameter or an amount related to the target tissue, such as a rate, size volume, time, distance/time, and/or volume/time, and/or an amount of change as it relates to any one or more of the preceding parameters or amounts. However, compared to blood movement through the larger diameter blood vessels, blood movement through individual capillaries can be highly erratic, principally due to vasomotion, wherein spontaneous oscillation in blood vessel tone manifests as pulsation in erythrocyte movement.

By way of summation and review, one or more embodiments may accommodate varied working distances while providing a flat illumination field and matching an illumination field to a target imaging field, thus allowing accurate quantitative imaging applications. An imaging element that focuses light from a target onto a sensor may be moved in synchrony with steering of the illumination field. Additionally or alternatively, a drape may be used that insures a close fit between a drape lens and a window frame of the device. Additionally or alternatively, one or more embodiments may allow ambient light to be subtracted from light to be imaged using a single sensor and controlled timing of illumination and exposure or detection. Additionally or alternatively, one or more embodiments may allow the display of a normalized fluorescence intensity measured within a target reticle region of an image frame.

In contrast, when illumination and imaging devices do not conform illumination to the target imaging field of view or provide a flat, i.e., even or substantially uniform, illumination field, illumination and image quality may suffer. An uneven illumination field can cause distracting and inaccurate imaging artifacts, especially for hand held imaging devices and when used at varied working distances, while excess light outside the imaging field of view reduces device efficiency and can distract the user when positioning the device.

The methods and processes described herein may be performed by code or instructions to be executed by a computer, processor, manager, or controller, or in hardware or other circuitry. Because the algorithms that form the basis of the methods (or operations of the computer, processor, or controller) are described in detail, the code or instructions for implementing the operations of the method embodiments may transform the computer, processor, or controller into a special-purpose processor for performing the methods described herein.

Also, another embodiment may include a computer-readable medium, e.g., a non-transitory computer-readable medium, for storing the code or instructions described above. The computer-readable medium may be a volatile or non-volatile memory or other storage device, which may be removably or fixedly coupled to the computer, processor, or controller which is to execute the code or instructions for performing the method embodiments described herein.

One or more embodiments are directed to an illumination module for use in an imaging system having an imaging field of view for imaging a target, the illumination module including a first illumination port to output a first light beam having a first illumination distribution at the target to illuminate the target and a second illumination port to output a second light beam having a second illumination distribution at the target to illuminate the target. The second illumination distribution may be substantially similar to the first illumination distribution at the target, the second illumination port being spaced apart from the first illumination port, the first and second illumination distributions being simultaneously provided to the target and overlapping at the target, wherein the illumination from the first and second ports is matched to a same aspect ratio and field of view coverage as the imaging field of view.

Light from the first and second illumination ports may respectively overlap to provide uniform illumination over a target field of view.

The illumination module may include a steering driver to simultaneously steer the first and second illumination ports through different fields of view.

Each of the first and second illumination ports may include a lens module having at least one fixed lens, a steerable housing, and at least one lens mounted in the steerable housing, the steerable housing being in communication with the steering driver.

The illumination module may include an enclosure, the enclosure housing the first and second illumination ports and the steering driver.

The enclosure may be a hand held enclosure and may include a control surface including activation devices to control the steering driver.

Each of the first and second illumination distributions may be a rectangular illumination distribution.

Each of the first and second illumination ports may include a lens module having two pairs of cylindrical lenses.

The first and second illumination ports may be symmetrically offset from a long dimension midline of the rectangular illumination distribution.

One or more embodiments are directed to an imaging device having an imaging field of view, the imaging device including a first illumination port to output first light having a first illumination distribution at a target to illuminate the target, a second illumination port to output second light having a second illumination distribution at the target to illuminate the target, the second illumination distribution being substantially similar to the first illumination distribution at the target, the second illumination port being spaced apart from the first illumination port, the first and second illumination distributions being simultaneously provided to the target and overlapping at the target, wherein the illumination from the first and second ports is matched to a same aspect ratio and field of view coverage as the imaging field of view, and a sensor to detect light from the target.

The imaging device may include an enclosure, the enclosure housing the first and second illumination ports, and the sensor.

The imaging device may include a steering driver to simultaneously steer the first and second illumination ports through different fields of view.

The imaging device may include an imaging element to focus light onto the sensor, wherein the steering driver is to move the imaging element in synchrony with steering of the first and second illumination ports.

The steering driver may be in the enclosure and the enclosure may include a control surface including activation devices to control the steering driver.

The enclosure may have a hand held enclosure having a form factor that allows a single hand to control the control surface and illumination of the target from multiple orientations.

The imaging device may include an illumination source to output light to the first and second illumination ports, the illumination source being outside the enclosure.

The illumination source may output visible light and/or excitation light to the first and second illumination ports.

The sensor may be a single sensor that is to detect light from the target resulting from illumination by visible light and excitation light.

The imaging device may include a wavelength-dependent aperture upstream of the sensor, the wavelength-dependent aperture to block visible light outside a central region.

The imaging device may include a video processor box, the video processor box being outside the enclosure.

The illumination source may be integral with the video processor box.

One or more embodiments are directed to a method of examining a target, the method including simultaneously illuminating the target with a first light output having a first illumination distribution at the target and with a second light output having a second illumination distribution at the target, the second illumination distribution being substantially similar to the first illumination distribution, the first and second illumination distributions overlapping at the target, wherein the illumination on the target is matched to the same aspect ratio and field of view coverage as an imaging field of view.

The method may include simultaneously steering the first and second light outputs through different fields of view.

The method may include receiving light from the target and focusing light onto a sensor using an imaging element, the imaging element being moved in synchrony with simultaneous steering of the first and second light outputs.

One or more embodiments are directed to a drape for use with an imaging device, the drape including a barrier material enveloping the imaging device, a drape window frame defining an opening in the barrier material, a drape lens in the opening in the barrier material, and an interface integral with the drape window frame to secure the drape lens to a window frame of the imaging device.

The drape may be insertable into the window frame of the imaging device.

The interface may include two clamps integrated symmetrically on respective opposing sides of the drape window frame.

The two clamps are on a top and a bottom of the drape window frame.

One or more embodiments are directed to a processor to image a target, the processor to, within a period, turn on an excitation light source to generate an excitation pulse to illuminate the target, turn on a white light source to generate a white pulse to illuminate the target such that the white pulse does not overlap the excitation pulse and the white pulse is generated at least twice within the period, expose an image sensor for a fluorescent exposure time during the excitation pulse, expose the image sensor for a visible exposure time during at least one white pulse, detect outputs from the image sensor, compensate for ambient light, and output a resultant image.

To compensate for ambient light, the processor may expose a first set of sensor pixel rows of the image sensor for a fraction of the fluorescent exposure time for a first set of sensor pixel rows; and expose a second set of sensor pixel rows of the image sensor for all of the fluorescent exposure time, the first and second sets to detect at least one different color from the other.

The fraction may be ½.

The processor may determine the fluorescent signal F using the following equation:

F=2*Exp 2−Exp 1,

where Exp 1 is a signal output during the fraction of fluorescent exposure time and Exp 2 is a signal output during all of the fluorescent exposure time.

The fraction of the exposure time may equal a width of the excitation pulse.

The visible exposure time may be longer than a width of the at least one white pulse.

The visible exposure time may be for one white pulse within the period.

The visible exposure time may be for two white pulses within the period.

To compensate for ambient light, the processor may expose the image sensor for a background exposure time when target is not illuminated at least once within the period.

One or more embodiments are directed a method for imaging a target, within a period, the method including generating an excitation pulse to illuminate the target, generating a white pulse to illuminate the target such that the white pulse does not overlap the excitation pulse and the white pulse is generated at least twice within the period, exposing an image sensor for a fluorescent exposure time during the excitation pulse, exposing the image sensor for a visible exposure time during at least one white pulse, detecting outputs from the image sensor, compensating for ambient light, and outputting a resultant image.

Compensating for ambient light may include exposing a first set of sensor pixel rows of the image sensor for a fraction of the fluorescent exposure time and exposing a second set of sensor pixel rows of the image sensor for all of the fluorescent exposure time, the first and second sets to detect at least one different color from the other.

Compensating for ambient light may include exposing the image sensor for a background exposure time when target is not illuminated at least once within the period.

Generating the excitation pulse may include providing uniform, anamorphic illumination to the target.

Providing uniform, anamorphic illumination to the target includes overlapping illumination from at least two illumination ports.

One or more embodiments are directed to a method of displaying fluorescence intensity in an image, the method including displaying a target reticle covering a region of the image, calculating a normalized fluorescence intensity within the target reticle, and displaying the normalized fluorescence intensity in a display region associated with the target.

The display region may be projected onto the target.

The normalized fluorescence intensity may include a single numerical value and/or a historical plot of normalized fluorescence intensities.

One or more embodiments are directed to a kit, including an illumination module including at least two illumination ports spaced apart from one another, first and second illumination distributions to being simultaneously provided to a target and to overlap at the target, and an imaging module including a sensor to detect light from the target.

The kit may include an enclosure to enclose the illumination module and the imaging module.

One or more embodiments are directed to a fluorescence imaging agent for use in the imaging device and methods as described herein. In one or more embodiments, the use may comprise blood flow imaging, tissue perfusion imaging, lymphatic imaging, or a combination thereof, which may occur during an invasive surgical procedure, a minimally invasive surgical procedure, a non-invasive surgical procedure, or a combination thereof. The fluorescence agent may be included in the kit described herein.

In one or more embodiments, the invasive surgical procedure may comprise a cardiac-related surgical procedure or a reconstructive surgical procedure. The cardiac-related surgical procedure may comprise a cardiac coronary artery bypass graft (CABG) procedure which may be on pump and/or off pump.

In one or more embodiments, the minimally invasive or the non-invasive surgical procedure may comprise a wound care procedure.

In one or more embodiments, the lymphatic imaging may comprise identification of a lymph node, lymph node drainage, lymphatic mapping, or a combination thereof. The lymphatic imaging may relate to the female reproductive system.

Example embodiments have been disclosed herein, and although specific terms are employed, they are used and are to be interpreted in a generic and descriptive sense only and not for purpose of limitation. In some instances, as would be apparent to one of ordinary skill in the art as of the filing of the present application, features, characteristics, and/or elements described in connection with a particular embodiment may be used singly or in combination with features, characteristics, and/or elements described in connection with other embodiments unless otherwise specifically indicated. Accordingly, it will be understood by those of skill in the art that various changes in form and details may be made without departing from the spirit and scope of the present invention as set forth in the following.

While the present disclosure has been illustrated and described in connection with various embodiments shown and described in detail, it is not intended to be limited to the details shown, since various modifications and structural changes may be made without departing in any way from the scope of the present disclosure. Various modifications of form, arrangement of components, steps, details and order of operations of the embodiments illustrated, as well as other embodiments of the disclosure may be made without departing in any way from the scope of the present disclosure, and will be apparent to a person of skill in the art upon reference to this description. It is therefore contemplated that the appended claims will cover such modifications and embodiments as they fall within the true scope of the disclosure. For the purpose of clarity and a concise description, features are described herein as part of the same or separate embodiments, however, it will be appreciated that the scope of the disclosure includes embodiments having combinations of all or some of the features described. For the terms “for example” and “such as,” and grammatical equivalences thereof, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise. As used herein, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

Claims

1. An imaging device having an imaging field of view, the imaging device comprising: at least one illumination port configured to output light for illuminating a target;an imaging sensor assembly to detect light traveling along an optical axis from a light receiving portion of the imaging device to the imaging sensor assembly, the optical axis extending in a first direction; anda first movable window positioned upstream of the sensor with respect to a direction of travel of light along the optical axis, wherein the first movable window is configured to move into a path of the optical axis in a deployed position for modifying light received from the target, the first movable window moving into the path of the optical axis by pivoting about a first pivot axis that extends in a second direction that is perpendicular to the first direction.
2. The imaging device of claim 1, wherein the first movable window is configured to rotate into the optical path in the deployed position.
3. The imaging device of claim 1, wherein the first movable window is configured to translate into the optical path in the deployed position.
4. The imaging device of claim 1, wherein the first movable window extends perpendicularly to the optical axis in the deployed position.
5. The imaging device of claim 1, wherein the first movable window comprises a filter.
6. The imaging device of claim 5, wherein the filter is configured to filter out visible light.
7. The imaging device of claim 1, comprising a second movable window positioned upstream of the imaging sensor assembly with respect to the direction of travel of light along the optical axis, wherein the second movable window is configured to move into the path of the optical axis in a deployed position for modifying light received from the target.
8. The imaging device of claim 7, wherein the second movable window is configured to pivot about a second pivot axis that extends in the second direction perpendicular to the first direction.
9. The imaging device of claim 8, wherein the first pivot axis and the second pivot axis are coplanar with a plane extending perpendicularly to the optical axis.
10. The imaging device of claim 7, wherein the first movable window and the second movable window are coupled to a linkage that is configured to simultaneously move the first and second pivoting windows.
11. The imaging device of claim 7, wherein, when the first movable window is in the deployed position, the second movable window is moved out of the path of the optical axis in a stowed position.
12. The imaging device of claim 1, wherein the image sensor assembly is translatable with respect to the first movable window.
13. The imaging device of claim 12, wherein the first movable window extends perpendicularly to the optical axis in the deployed position and the image sensor assembly is translatable along the optical axis.
14. The imaging device of claim 1, comprising a first illumination port and a second illumination port, wherein the first illumination port is configured to generate a first illumination distribution at the target, the second illumination port is configured to generate a second illumination distribution at the target, the second illumination port is spaced apart from the first illumination port, the first and second illumination distributions are simultaneously provided to the target and overlap at the target, and the illumination from the first and second ports is matched to a same aspect ratio and field of view coverage as the imaging field of view.
15. The imaging device of claim 14, wherein the first and second illumination ports are fixed with respect to each other.
16. The imaging device of claim 1, wherein the at least one illumination port is configured to output at least one of visible light and excitation light.
17. The imaging device of claim 16, wherein the image sensor assembly is a single sensor that is configured to detect light from the target resulting from illumination by visible light and excitation light.
18. The imaging device of claim 17, comprising a wavelength-dependent aperture upstream of the image sensor, wherein the wavelength-dependent aperture is configured to block visible light outside a central region.
19. The imaging device of claim 1, comprising one or more sensors for sensing an amount of light incident on the device.
20. The imaging device of claim 19, comprising a control system configured to adjust at least one image acquisition parameter based on output from the one or more sensors.
21. The imaging device of claim 20, wherein the at least one image acquisition parameter comprises an exposure duration, excitation illumination duration, excitation illumination power, or imaging sensor gain.
22. The imaging device of claim 19, wherein at least one of the one or more sensors is configured to sense visible light and near infrared light.
23. The imaging device of claim 19, wherein at least one of the one or more sensors is configured to sense near infrared light.
24. The imaging device of claim 1, comprising one or more drape sensors configured to detect a drape mounted to the device.
25. The imaging device of claim 24, comprising one or more light emitters for emitting light for detection by the one or more drape sensors.
26. The imaging device of claim 25, wherein the one or more drape sensors are configured to detect light emitted from the one or more light emitters after reflection of the emitted light off of one or more reflectors on the drape.
27. The imaging device of claim 26, wherein the one or more reflectors comprise a prism.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No. 15/591,909, filed May 10, 2017, which claims priority to U.S. Provisional Application No. 62/457,690, filed Feb. 10, 2017, the entire contents of each of which are hereby incorporated by reference herein.

US Referenced Citations (806)

Number	Name	Date	Kind
1290744	Hollander	Jan 1919	A
D62892	Dinkelspiel	Aug 1923	S
2453336	Orser	Nov 1948	A
2857523	Corso	Oct 1958	A
3215029	Woodcock	Nov 1965	A
3582178	Boughton et al.	Jun 1971	A
3671098	Rotter	Jun 1972	A
3749494	Hodges	Jul 1973	A
3762801	Baker	Oct 1973	A
3790248	Kellow	Feb 1974	A
3931593	Marshall	Jan 1976	A
3970373	Pledger	Jul 1976	A
3971068	Gerhardt et al.	Jul 1976	A
4037866	Price	Jul 1977	A
4066330	Jones	Jan 1978	A
4109647	Stern et al.	Aug 1978	A
4115812	Akatsu	Sep 1978	A
4149190	Wessler et al.	Apr 1979	A
4158504	de Ponteves et al.	Jun 1979	A
4162405	Chance et al.	Jul 1979	A
4200801	Schuresko	Apr 1980	A
4260217	Traeger et al.	Apr 1981	A
4263916	Brooks et al.	Apr 1981	A
4318395	Tawara	Mar 1982	A
4355325	Nakamura et al.	Oct 1982	A
4378571	Handy	Mar 1983	A
4394199	Barnhard, IV et al.	Jul 1983	A
4449535	Renault	May 1984	A
4471766	Terayama	Sep 1984	A
4473841	Murakoshi et al.	Sep 1984	A
4532918	Wheeler	Aug 1985	A
4541438	Parker et al.	Sep 1985	A
4556057	Hiruma et al.	Dec 1985	A
4575632	Lange	Mar 1986	A
4597630	Brandstetter et al.	Jul 1986	A
4611888	Prenovitz et al.	Sep 1986	A
4619249	Landry	Oct 1986	A
4638365	Kato	Jan 1987	A
4656508	Yokota	Apr 1987	A
4660982	Okada	Apr 1987	A
4688905	Okamura	Aug 1987	A
4717952	Kohayakawa et al.	Jan 1988	A
4718417	Kittrell et al.	Jan 1988	A
4719508	Sasaki et al.	Jan 1988	A
4742388	Cooper et al.	May 1988	A
4768513	Suzuki	Sep 1988	A
4773097	Suzaki et al.	Sep 1988	A
4774568	Matsuo	Sep 1988	A
4786813	Svanberg et al.	Nov 1988	A
4799104	Hosoya et al.	Jan 1989	A
4805597	Iwakoshi	Feb 1989	A
4806005	Schneider et al.	Feb 1989	A
4815848	Hadeishi	Mar 1989	A
4821117	Sekiguchi	Apr 1989	A
4827908	Matsuo	May 1989	A
4837625	Douziech et al.	Jun 1989	A
4852579	Gilstad et al.	Aug 1989	A
4852985	Fujihara et al.	Aug 1989	A
4856495	Tohjoh et al.	Aug 1989	A
4858001	Milbank et al.	Aug 1989	A
4860731	Matsuura	Aug 1989	A
4867137	Takahashi	Sep 1989	A
4868647	Uehara et al.	Sep 1989	A
4885634	Yabe	Dec 1989	A
4895145	Joffe et al.	Jan 1990	A
4900934	Peeters et al.	Feb 1990	A
4930516	Alfano et al.	Jun 1990	A
4930883	Salzman	Jun 1990	A
4938205	Nudelman	Jun 1990	A
4951135	Sasagawa et al.	Aug 1990	A
4953539	Nakamura et al.	Sep 1990	A
4954897	Ejima et al.	Sep 1990	A
4957114	Zeng et al.	Sep 1990	A
4974936	Ams et al.	Dec 1990	A
4993404	Lane	Feb 1991	A
4995396	Inaba et al.	Feb 1991	A
4995398	Turnidge	Feb 1991	A
4998972	Chin et al.	Mar 1991	A
5001556	Nakamura et al.	Mar 1991	A
5003977	Suzuki et al.	Apr 1991	A
5007408	Ieoka	Apr 1991	A
5028128	Onuki	Jul 1991	A
5034888	Uehara et al.	Jul 1991	A
5041852	Misawa et al.	Aug 1991	A
5042494	Alfano	Aug 1991	A
5071417	Sinofsky	Dec 1991	A
5078150	Hara et al.	Jan 1992	A
5090400	Saito	Feb 1992	A
5091652	Mathies et al.	Feb 1992	A
5115137	Andersson-Engels et al.	May 1992	A
5115308	Onuki	May 1992	A
5117466	Buican et al.	May 1992	A
5121220	Nakamoto	Jun 1992	A
5125404	Kittrell et al.	Jun 1992	A
5128803	Sprafke	Jul 1992	A
5131398	Alfano et al.	Jul 1992	A
5132837	Kitajima	Jul 1992	A
5134662	Bacus et al.	Jul 1992	A
5150292	Hoffmann et al.	Sep 1992	A
5159398	Maekewa et al.	Oct 1992	A
5165079	Schulz-Hennig	Nov 1992	A
5178616	Uemiya et al.	Jan 1993	A
5196928	Karasawa et al.	Mar 1993	A
5205280	Dennison, Jr. et al.	Apr 1993	A
5208651	Buican	May 1993	A
5212593	Williamson	May 1993	A
5214503	Chiu et al.	May 1993	A
5225883	Carter et al.	Jul 1993	A
5255087	Nakamura et al.	Oct 1993	A
5278642	Danna et al.	Jan 1994	A
5279298	Flower	Jan 1994	A
5282082	Espie et al.	Jan 1994	A
5295017	Brown	Mar 1994	A
RE34622	Ledley	May 1994	E
D346921	Stallsmith	May 1994	S
5318023	Vari et al.	Jun 1994	A
5318024	Kittrell et al.	Jun 1994	A
5318869	Hashimoto et al.	Jun 1994	A
5340592	Goodrich, Jr. et al.	Aug 1994	A
5361769	Nilsson	Nov 1994	A
5365057	Morley et al.	Nov 1994	A
5371355	Wodecki	Dec 1994	A
5375603	Feiler	Dec 1994	A
5377676	Vari et al.	Jan 1995	A
5377686	O'Rourke et al.	Jan 1995	A
5379756	Pileski et al.	Jan 1995	A
5394199	Flower	Feb 1995	A
5408263	Kikuchi et al.	Apr 1995	A
5410363	Capen et al.	Apr 1995	A
5419323	Kittrell et al.	May 1995	A
5420628	Poulsen et al.	May 1995	A
5421337	Richards-Kortum et al.	Jun 1995	A
5421339	Ramanujam et al.	Jun 1995	A
5424841	Van Gelder et al.	Jun 1995	A
5426530	Copenhaver et al.	Jun 1995	A
5430476	Häfele et al.	Jul 1995	A
5437274	Khoobehi et al.	Aug 1995	A
5438989	Hochman et al.	Aug 1995	A
D362435	Charych et al.	Sep 1995	S
D362465	Gallenmore	Sep 1995	S
5453448	Narciso, Jr.	Sep 1995	A
5465718	Hochman et al.	Nov 1995	A
5481401	Kita et al.	Jan 1996	A
5485203	Nakamura et al.	Jan 1996	A
5490015	Umeyama et al.	Feb 1996	A
5491343	Brooker	Feb 1996	A
5496369	Howard, III	Mar 1996	A
5507287	Palcic et al.	Apr 1996	A
5514127	Shanks	May 1996	A
5515449	Tsuruoka et al.	May 1996	A
5519534	Smith et al.	May 1996	A
5535052	Jörgens	Jul 1996	A
5536236	Yabe et al.	Jul 1996	A
5557451	Copenhaver et al.	Sep 1996	A
5576013	Williams et al.	Nov 1996	A
5582168	Samuels et al.	Dec 1996	A
5585846	Kim	Dec 1996	A
5590660	MacAulay et al.	Jan 1997	A
5596654	Tanaka	Jan 1997	A
5623930	Wright et al.	Apr 1997	A
5627907	Gur et al.	May 1997	A
5630782	Adair	May 1997	A
5646680	Yajima	Jul 1997	A
5647368	Zeng et al.	Jul 1997	A
5647840	D'Amelio et al.	Jul 1997	A
5656498	Iijima et al.	Aug 1997	A
5662644	Swor	Sep 1997	A
5664574	Chance	Sep 1997	A
5667472	Finn et al.	Sep 1997	A
5673701	Chance	Oct 1997	A
5677724	Takizawa et al.	Oct 1997	A
5682567	Spruck et al.	Oct 1997	A
5689241	Clarke, Sr. et al.	Nov 1997	A
5689354	Orino	Nov 1997	A
5695049	Bauman	Dec 1997	A
5697373	Richards-Kortum et al.	Dec 1997	A
5699798	Hochman et al.	Dec 1997	A
5707986	Miller et al.	Jan 1998	A
5713364	DeBaryshe et al.	Feb 1998	A
5729382	Morita et al.	Mar 1998	A
5732707	Widder et al.	Mar 1998	A
5741648	Hemstreet, III et al.	Apr 1998	A
5743266	Levene et al.	Apr 1998	A
5749830	Kaneko et al.	May 1998	A
5756541	Strong et al.	May 1998	A
5769792	Palcic et al.	Jun 1998	A
5772355	Ross et al.	Jun 1998	A
5772580	Utsui et al.	Jun 1998	A
5785965	Pratt et al.	Jul 1998	A
5803914	Ryals et al.	Sep 1998	A
5827190	Palcic et al.	Oct 1998	A
5833617	Hayashi	Nov 1998	A
5838001	Minakuchi et al.	Nov 1998	A
5840017	Furuswaba et al.	Nov 1998	A
5845639	Hochman et al.	Dec 1998	A
5851181	Talmor	Dec 1998	A
5852498	Youvan et al.	Dec 1998	A
5865754	Sevick-Muraca et al.	Feb 1999	A
5879621	Faries, Jr. et al.	Mar 1999	A
5891016	Utsui et al.	Apr 1999	A
5897269	Ross et al.	Apr 1999	A
5910510	Strong et al.	Jun 1999	A
5919616	Aurelian et al.	Jul 1999	A
5927284	Borst et al.	Jul 1999	A
5935942	Zeimer	Aug 1999	A
5951980	Collen	Sep 1999	A
5956435	Buzug et al.	Sep 1999	A
5965356	Aurelian et al.	Oct 1999	A
5971918	Zanger	Oct 1999	A
5973315	Saldana et al.	Oct 1999	A
5984861	Crowley	Nov 1999	A
5986271	Lazarev et al.	Nov 1999	A
5986642	Ueda et al.	Nov 1999	A
5990996	Sharp	Nov 1999	A
5999240	Sharp et al.	Dec 1999	A
5999841	Aoyagi et al.	Dec 1999	A
6002137	Hayashi	Dec 1999	A
6004263	Nakaichi et al.	Dec 1999	A
6008889	Zeng et al.	Dec 1999	A
6013265	Aurelian	Jan 2000	A
6021344	Lui et al.	Feb 2000	A
6028323	Liu	Feb 2000	A
6028622	Suzuki	Feb 2000	A
6030339	Tatsuno et al.	Feb 2000	A
6032070	Flock et al.	Feb 2000	A
6054131	Aurelian	Apr 2000	A
6059719	Yamamoto et al.	May 2000	A
6059720	Furusawa et al.	May 2000	A
6061591	Freitag et al.	May 2000	A
6069689	Zeng et al.	May 2000	A
6070096	Hayashi	May 2000	A
6074627	Dean et al.	Jun 2000	A
6081612	Gutkowicz-Krusin et al.	Jun 2000	A
6093149	Guracar et al.	Jul 2000	A
6095982	Richards-Kortum et al.	Aug 2000	A
6099466	Sano et al.	Aug 2000	A
6110106	MacKinnon et al.	Aug 2000	A
6120435	Eino	Sep 2000	A
6122042	Wunderman et al.	Sep 2000	A
6140314	Zeimer	Oct 2000	A
6147705	Krauter et al.	Nov 2000	A
6148227	Wagnières et al.	Nov 2000	A
6149671	Nordquist et al.	Nov 2000	A
6161035	Furusawa	Dec 2000	A
6162242	Peyman	Dec 2000	A
6178340	Svetliza	Jan 2001	B1
6179421	Pang	Jan 2001	B1
6181414	Raz et al.	Jan 2001	B1
6186628	Van de Velde	Feb 2001	B1
6192267	Scherninski et al.	Feb 2001	B1
6196226	Hochman et al.	Mar 2001	B1
6207168	Aurelian	Mar 2001	B1
6211953	Niino et al.	Apr 2001	B1
6212425	Irion et al.	Apr 2001	B1
6217848	Achilefu et al.	Apr 2001	B1
6223069	Pfeiffer et al.	Apr 2001	B1
6226126	Conemac	May 2001	B1
6233480	Hochman et al.	May 2001	B1
6241672	Hochman et al.	Jun 2001	B1
6246901	Benaron	Jun 2001	B1
6248727	Zeimer	Jun 2001	B1
6258576	Richards-Kortum et al.	Jul 2001	B1
6263227	Boggett et al.	Jul 2001	B1
D446524	Bontly et al.	Aug 2001	S
6272374	Flock et al.	Aug 2001	B1
6280378	Kazuhiro et al.	Aug 2001	B1
6280386	Alfano et al.	Aug 2001	B1
6293911	Imasizumi et al.	Sep 2001	B1
6315712	Rovegno	Nov 2001	B1
6319273	Cheen et al.	Nov 2001	B1
6331703	Yarnall et al.	Dec 2001	B1
6332092	Deckert et al.	Dec 2001	B1
6335429	Cai et al.	Jan 2002	B1
6351663	Flower et al.	Feb 2002	B1
6351667	Godie	Feb 2002	B1
6353750	Kimura et al.	Mar 2002	B1
6364829	Fulghum	Apr 2002	B1
6364831	Crowley	Apr 2002	B1
6377842	Pogue et al.	Apr 2002	B1
D456809	Schieffers	May 2002	S
6399354	Knipe et al.	Jun 2002	B1
6419628	Rudischhauser et al.	Jul 2002	B1
6422994	Kaneko et al.	Jul 2002	B1
6440950	Zeimer	Aug 2002	B1
6443976	Flower et al.	Sep 2002	B1
6447443	Keogh et al.	Sep 2002	B1
6462770	Cline et al.	Oct 2002	B1
6485413	Boppart et al.	Nov 2002	B1
6498945	Alfheim et al.	Dec 2002	B1
6510338	Irion et al.	Jan 2003	B1
6526213	Ilenda et al.	Feb 2003	B1
6529239	Dyck et al.	Mar 2003	B1
6529768	Hakamata	Mar 2003	B1
6537211	Wang et al.	Mar 2003	B1
6544102	Schäfer et al.	Apr 2003	B2
6544183	Thorn Leeson et al.	Apr 2003	B2
6566641	Suda	May 2003	B1
6571119	Hayashi	May 2003	B2
6577884	Boas	Jun 2003	B1
6596996	Stone et al.	Jul 2003	B1
6603552	Cline et al.	Aug 2003	B1
6621917	Vilser	Sep 2003	B1
6631286	Pfeiffer et al.	Oct 2003	B2
6639664	Haan et al.	Oct 2003	B2
6652452	Seifert et al.	Nov 2003	B1
D483668	Le Roux	Dec 2003	S
6671540	Hochman	Dec 2003	B1
6750971	Overbeck et al.	Jun 2004	B2
6757554	Rubinstein et al.	Jun 2004	B2
6772003	Kaneko et al.	Aug 2004	B2
6773392	Kikuchi et al.	Aug 2004	B2
6786865	Dhindsa	Sep 2004	B2
6804549	Hayashi	Oct 2004	B2
6821245	Cline et al.	Nov 2004	B2
6821946	Goldspink et al.	Nov 2004	B2
6826424	Zeng et al.	Nov 2004	B1
6840933	Pang et al.	Jan 2005	B1
6853857	Pfeiffer et al.	Feb 2005	B2
6882366	Kijima et al.	Apr 2005	B1
6898458	Zeng et al.	May 2005	B2
6899675	Cline et al.	May 2005	B2
6915154	Docherty et al.	Jul 2005	B1
6922583	Perelman et al.	Jul 2005	B1
6936043	Peyman	Aug 2005	B2
6944493	Alam et al.	Sep 2005	B2
6958862	Joseph	Oct 2005	B1
6960165	Ueno et al.	Nov 2005	B2
7043291	Sendai	May 2006	B2
D524985	Lukan et al.	Jul 2006	S
D524987	Lukan et al.	Jul 2006	S
7113817	Winchester, Jr. et al.	Sep 2006	B1
7150552	Weidel	Dec 2006	B2
7179222	Imaizumi et al.	Feb 2007	B2
7235045	Wang et al.	Jun 2007	B2
7236815	Richards-Kortum et al.	Jun 2007	B2
7253894	Zeng et al.	Aug 2007	B2
7268878	Wolf	Sep 2007	B2
7317554	Ueda et al.	Jan 2008	B2
7324674	Ozawa et al.	Jan 2008	B2
7333270	Pochapsky et al.	Feb 2008	B1
7341557	Cline et al.	Mar 2008	B2
D567649	Borkowski et al.	Apr 2008	S
7364574	Flower	Apr 2008	B2
7381400	Woltering	Jun 2008	B2
7385772	Forkey et al.	Jun 2008	B2
7400753	Seino et al.	Jul 2008	B2
7400755	West et al.	Jul 2008	B2
7420151	Fengler et al.	Sep 2008	B2
7474906	Rubinstein et al.	Jan 2009	B2
7479990	Imaizumi et al.	Jan 2009	B2
7482318	Aurelian et al.	Jan 2009	B2
7581191	Rice et al.	Aug 2009	B2
D599799	Di Bari et al.	Sep 2009	S
D603408	Fitch	Nov 2009	S
D606544	Di Bari et al.	Dec 2009	S
7697975	Zeng	Apr 2010	B2
7704206	Suzuki et al.	Apr 2010	B2
7722534	Cline et al.	May 2010	B2
7729750	Tromberg et al.	Jun 2010	B2
7774048	Nakaoka et al.	Aug 2010	B2
7777191	Olcott et al.	Aug 2010	B2
7798955	Ishihara et al.	Sep 2010	B2
7811229	Sugimoto	Oct 2010	B2
7881777	Docherty et al.	Feb 2011	B2
7885438	Uppaluri et al.	Feb 2011	B2
7928352	Toda	Apr 2011	B2
D646315	Orf	Oct 2011	S
8035067	Toda	Oct 2011	B2
8036437	Arditi et al.	Oct 2011	B2
8068899	Llewellyn	Nov 2011	B2
8073224	Strobel et al.	Dec 2011	B2
D653811	BenZion	Feb 2012	S
8140147	Maynard et al.	Mar 2012	B2
8144958	Nahm et al.	Mar 2012	B2
8185176	Mangat et al.	May 2012	B2
8194981	Suzuki	Jun 2012	B2
8285015	Demos	Oct 2012	B2
8285353	Choi et al.	Oct 2012	B2
8294757	Yu	Oct 2012	B2
8294977	Kirkby	Oct 2012	B2
8337400	Mizuyoshi	Dec 2012	B2
8361775	Flower	Jan 2013	B2
D677258	Mistkawi	Mar 2013	S
8406860	Dvorsky et al.	Mar 2013	B2
8408269	Fengler et al.	Apr 2013	B2
8408772	Li	Apr 2013	B2
D682277	Tasselli et al.	May 2013	S
8448867	Liu et al.	May 2013	B2
8473035	Frangioni	Jun 2013	B2
8480579	Serov et al.	Jul 2013	B2
8498695	Westwick et al.	Jul 2013	B2
8521260	Grinvald et al.	Aug 2013	B2
8538107	Röttger	Sep 2013	B2
D692004	Man	Oct 2013	S
D692576	Steinman et al.	Oct 2013	S
D692892	Mistkawi	Nov 2013	S
D693802	Wikel	Nov 2013	S
8630698	Fengler et al.	Jan 2014	B2
8647605	Mangat et al.	Feb 2014	B2
8718747	Bjornerud et al.	May 2014	B2
8721532	Takei et al.	May 2014	B2
8725225	Golijanin et al.	May 2014	B2
8736748	Takita	May 2014	B2
8759243	Coffy et al.	Jun 2014	B2
8773756	Tesar et al.	Jul 2014	B2
8788021	Flusberg	Jul 2014	B1
8790253	Sunagawa et al.	Jul 2014	B2
8796699	So et al.	Aug 2014	B2
8830339	Velarde et al.	Sep 2014	B2
8849380	Patwardhan	Sep 2014	B2
8892190	Docherty et al.	Nov 2014	B2
D719574	Alegiani et al.	Dec 2014	S
8929974	Hauger et al.	Jan 2015	B2
8961403	Cline et al.	Feb 2015	B2
8965488	Dvorsky et al.	Feb 2015	B2
D723563	Alegiani	Mar 2015	S
8979301	Moore	Mar 2015	B2
D726186	Jenkins et al.	Apr 2015	S
9054262	Lewis et al.	Jun 2015	B2
D734339	Zhou et al.	Jul 2015	S
9082922	Ban et al.	Jul 2015	B2
9089601	Golijanin et al.	Jul 2015	B2
9125552	Dunki-Jacobs et al.	Sep 2015	B2
9129366	Nahm et al.	Sep 2015	B2
9143746	Westwick et al.	Sep 2015	B2
D742509	Anderson	Nov 2015	S
9173554	Fengler et al.	Nov 2015	B2
9241636	Koizumi et al.	Jan 2016	B2
D749598	Ray et al.	Feb 2016	S
RE45916	Golijanin et al.	Mar 2016	E
9282305	Kikuchi	Mar 2016	B2
9294691	Ooki	Mar 2016	B2
9295392	Douplik et al.	Mar 2016	B2
9351644	Nahm et al.	May 2016	B2
9357931	Nahm et al.	Jun 2016	B2
9386909	Fengler et al.	Jul 2016	B2
D764565	Tekunoff et al.	Aug 2016	S
9407838	Butte et al.	Aug 2016	B2
9421280	Mangat et al.	Aug 2016	B2
9435496	Moore	Sep 2016	B2
9451903	Feinberg	Sep 2016	B2
9472597	Mohseni	Oct 2016	B2
9554738	Gulati et al.	Jan 2017	B1
9577012	Ooki	Feb 2017	B2
D782901	Richter	Apr 2017	S
9610021	Dvorsky et al.	Apr 2017	B2
9642532	Fengler et al.	May 2017	B2
D791137	Wang et al.	Jul 2017	S
9814378	Moore	Nov 2017	B2
9816930	Moriyama et al.	Nov 2017	B2
D815928	Rummel et al.	Apr 2018	S
9936887	Dvorsky et al.	Apr 2018	B2
D826234	Zhou et al.	Aug 2018	S
10041042	Flower	Aug 2018	B2
D834583	Janzen et al.	Nov 2018	S
10134815	So et al.	Nov 2018	B2
D835284	Barker et al.	Dec 2018	S
D835285	Barker et al.	Dec 2018	S
10219742	Dvorsky et al.	Mar 2019	B2
10231624	Mangat et al.	Mar 2019	B2
10265419	Golijanin	Apr 2019	B2
10278585	Ferguson, Jr. et al.	May 2019	B2
10285603	Flower	May 2019	B2
10356334	Moore et al.	Jul 2019	B2
10694151	Westwick et al.	Jun 2020	B2
10694152	Westwick et al.	Jun 2020	B2
11025867	Westwick et al.	Jun 2021	B2
11298024	Fengler et al.	Apr 2022	B2
20010016679	Futatsugi et al.	Aug 2001	A1
20010028458	Xiao	Oct 2001	A1
20010049473	Hayashi	Dec 2001	A1
20020007123	Balas	Jan 2002	A1
20020013937	Ostanevich et al.	Jan 2002	A1
20020016533	Marchitto et al.	Feb 2002	A1
20020021355	Utsui et al.	Feb 2002	A1
20020025541	Nelson et al.	Feb 2002	A1
20020035330	Cline et al.	Mar 2002	A1
20020038120	Duhaylongsod et al.	Mar 2002	A1
20020049389	Abreu	Apr 2002	A1
20020076480	Hsieh et al.	Jun 2002	A1
20020099279	Pfeiffer et al.	Jul 2002	A1
20020099295	Gil et al.	Jul 2002	A1
20020138008	Tsujita et al.	Sep 2002	A1
20020143243	Geordakoudi et al.	Oct 2002	A1
20020146369	Goldenberg	Oct 2002	A1
20020148902	Schlieffers	Oct 2002	A1
20020155619	Kurihara et al.	Oct 2002	A1
20020156380	Feld et al.	Oct 2002	A1
20020161282	Fulghum	Oct 2002	A1
20020161283	Sendai	Oct 2002	A1
20020161284	Tanaka	Oct 2002	A1
20020168096	Hakamata et al.	Nov 2002	A1
20020175993	Ueno et al.	Nov 2002	A1
20020177778	Averback et al.	Nov 2002	A1
20020181752	Wallo et al.	Dec 2002	A1
20020183621	Pfeiffer et al.	Dec 2002	A1
20020186478	Watanabe et al.	Dec 2002	A1
20020196335	Ozawa	Dec 2002	A1
20030001951	Tsujita et al.	Jan 2003	A1
20030002036	Haan et al.	Jan 2003	A1
20030032885	Rubinstein et al.	Feb 2003	A1
20030042493	Kazakevich	Mar 2003	A1
20030050543	Hartmann	Mar 2003	A1
20030060718	Alam et al.	Mar 2003	A1
20030060722	Pfeiffer et al.	Mar 2003	A1
20030063398	Abe et al.	Apr 2003	A1
20030064025	Yang et al.	Apr 2003	A1
20030080193	Ryan et al.	May 2003	A1
20030093064	Peyman	May 2003	A1
20030093065	Peyman	May 2003	A1
20030117491	Avni et al.	Jun 2003	A1
20030127609	El-Hage et al.	Jul 2003	A1
20030135092	Cline et al.	Jul 2003	A1
20030139667	Hewko et al.	Jul 2003	A1
20030153811	Muckner	Aug 2003	A1
20030156252	Morris et al.	Aug 2003	A1
20030158470	Wolters et al.	Aug 2003	A1
20030187349	Kaneko et al.	Oct 2003	A1
20030191368	Wang	Oct 2003	A1
20030216626	Tsujita et al.	Nov 2003	A1
20030229270	Suzuki et al.	Dec 2003	A1
20030232016	Heinrich	Dec 2003	A1
20030236458	Hochman	Dec 2003	A1
20040002660	Mielekamp	Jan 2004	A1
20040006276	Demos et al.	Jan 2004	A1
20040010183	Dhindsa	Jan 2004	A1
20040020990	Haven et al.	Feb 2004	A1
20040021859	Cunningham	Feb 2004	A1
20040037454	Ozawa et al.	Feb 2004	A1
20040044275	Hakamata	Mar 2004	A1
20040046865	Ueno et al.	Mar 2004	A1
20040066961	Spreeuwers et al.	Apr 2004	A1
20040077952	Rafter et al.	Apr 2004	A1
20040109231	Haisch et al.	Jun 2004	A1
20040133073	Berci et al.	Jul 2004	A1
20040134990	Fitch et al.	Jul 2004	A1
20040143162	Krattiger et al.	Jul 2004	A1
20040148141	Tsujita et al.	Jul 2004	A1
20040149998	Henson et al.	Aug 2004	A1
20040156124	Okada	Aug 2004	A1
20040156782	Alam et al.	Aug 2004	A1
20040162489	Richards-Kortum et al.	Aug 2004	A1
20040171827	Peng et al.	Sep 2004	A1
20040174495	Levine	Sep 2004	A1
20040186351	Imaizumi et al.	Sep 2004	A1
20040218115	Kawana et al.	Nov 2004	A1
20040225222	Zeng et al.	Nov 2004	A1
20040245350	Zeng	Dec 2004	A1
20040263643	Imaizumi et al.	Dec 2004	A1
20050011954	Hennick et al.	Jan 2005	A1
20050019744	Bertuglia	Jan 2005	A1
20050020891	Rubinstein et al.	Jan 2005	A1
20050027166	Matsumoto et al.	Feb 2005	A1
20050033145	Graham et al.	Feb 2005	A1
20050051723	Neagle	Mar 2005	A1
20050065432	Kimura	Mar 2005	A1
20050069525	Mikael	Mar 2005	A1
20050088763	Weaver et al.	Apr 2005	A1
20050089866	Hinuma et al.	Apr 2005	A1
20050096505	Imaizumi et al.	May 2005	A1
20050107380	Nimmo et al.	May 2005	A1
20050140270	Henson et al.	Jun 2005	A1
20050142556	Hoon et al.	Jun 2005	A1
20050143627	Cline et al.	Jun 2005	A1
20050154319	Cline et al.	Jul 2005	A1
20050171440	Maki et al.	Aug 2005	A1
20050182291	Hirata	Aug 2005	A1
20050182321	Frangioni	Aug 2005	A1
20050182327	Petty et al.	Aug 2005	A1
20050182431	Hausen et al.	Aug 2005	A1
20050182434	Docherty et al.	Aug 2005	A1
20050187477	Serov et al.	Aug 2005	A1
20050197583	Chance	Sep 2005	A1
20050203421	Zeng et al.	Sep 2005	A1
20050225656	Ihama	Oct 2005	A1
20050254008	Ferguson et al.	Nov 2005	A1
20050256373	Bar-Or et al.	Nov 2005	A1
20050259318	Armstrong	Nov 2005	A1
20050273011	Hattery et al.	Dec 2005	A1
20050280783	Yamasaki et al.	Dec 2005	A1
20050288593	Geordakoudi et al.	Dec 2005	A1
20060002141	Ouderkirk et al.	Jan 2006	A1
20060004292	Beylin	Jan 2006	A1
20060011853	Spartiotis et al.	Jan 2006	A1
20060013768	Woltering	Jan 2006	A1
20060017913	Kawamata et al.	Jan 2006	A1
20060079750	Fauci et al.	Apr 2006	A1
20060089554	Ishihara et al.	Apr 2006	A1
20060094109	Trainer	May 2006	A1
20060108509	Frangioni et al.	May 2006	A1
20060118742	Levenson et al.	Jun 2006	A1
20060146322	Komachi et al.	Jul 2006	A1
20060147897	Grinvald et al.	Jul 2006	A1
20060149133	Sugimoto et al.	Jul 2006	A1
20060155166	Takahashi et al.	Jul 2006	A1
20060211915	Takeuchi et al.	Sep 2006	A1
20060215406	Thrailkill	Sep 2006	A1
20060217594	Ferguson	Sep 2006	A1
20060239921	Mangat et al.	Oct 2006	A1
20060241496	Fengler et al.	Oct 2006	A1
20060241499	Irion et al.	Oct 2006	A1
20060247537	Matsumoto	Nov 2006	A1
20060250696	McGuire	Nov 2006	A1
20060256451	Schaack	Nov 2006	A1
20060258910	Stefanchik et al.	Nov 2006	A1
20070041195	Chen	Feb 2007	A1
20070091634	Sakurada	Apr 2007	A1
20070121099	Matsumoto et al.	May 2007	A1
20070122344	Golijanin	May 2007	A1
20070122345	Golijanin	May 2007	A1
20070152161	Olcott et al.	Jul 2007	A1
20070177152	Tearney et al.	Aug 2007	A1
20070203413	Frangioni	Aug 2007	A1
20070213593	Nakaoka	Sep 2007	A1
20070229309	Tomita et al.	Oct 2007	A1
20070254276	Deutsch et al.	Nov 2007	A1
20070276236	Jong	Nov 2007	A1
20080007733	Marks et al.	Jan 2008	A1
20080015446	Mahmood et al.	Jan 2008	A1
20080021274	Bayer et al.	Jan 2008	A1
20080024868	Okamura	Jan 2008	A1
20080025918	Frangioni et al.	Jan 2008	A1
20080027280	Fengler et al.	Jan 2008	A1
20080039697	Morishita	Feb 2008	A1
20080044073	Bernhardt et al.	Feb 2008	A1
20080064925	Gill et al.	Mar 2008	A1
20080074752	Chaves et al.	Mar 2008	A1
20080081990	Berenfeld et al.	Apr 2008	A1
20080161744	Golijanin et al.	Jul 2008	A1
20080177140	Cline et al.	Jul 2008	A1
20080188728	Neumann et al.	Aug 2008	A1
20080208006	Farr	Aug 2008	A1
20080217411	Ledwith et al.	Sep 2008	A1
20080221421	Choi et al.	Sep 2008	A1
20080221648	Flower	Sep 2008	A1
20080239070	Westwick et al.	Oct 2008	A1
20080246920	Buczek et al.	Oct 2008	A1
20080319309	Bredno et al.	Dec 2008	A1
20090005693	Brauner et al.	Jan 2009	A1
20090012361	MacKinnon et al.	Jan 2009	A1
20090021739	Tsujita et al.	Jan 2009	A1
20090036734	Dunki-Jacobs et al.	Feb 2009	A1
20090040754	Brukilacchio et al.	Feb 2009	A1
20090042179	Peltie et al.	Feb 2009	A1
20090048516	Yoshikawa et al.	Feb 2009	A1
20090052185	Toriyama et al.	Feb 2009	A1
20090054788	Hauger et al.	Feb 2009	A1
20090112097	Kato et al.	Apr 2009	A1
20090114799	Maeda	May 2009	A1
20090114803	Yamaguchi	May 2009	A1
20090118623	Serov et al.	May 2009	A1
20090122135	Matsui	May 2009	A1
20090122152	Yamaguchi et al.	May 2009	A1
20090124854	Yamaguchi et al.	May 2009	A1
20090137902	Frangioni et al.	May 2009	A1
20090153797	Allon et al.	Jun 2009	A1
20090181339	Liang et al.	Jul 2009	A1
20090201577	LaPlante et al.	Aug 2009	A1
20090218405	Joseph et al.	Sep 2009	A1
20090236541	Lommes et al.	Sep 2009	A1
20090252682	Hillman	Oct 2009	A1
20090285762	Flower	Nov 2009	A1
20090290149	Roth	Nov 2009	A1
20090297004	Baumgart	Dec 2009	A1
20100016669	Takaoka et al.	Jan 2010	A1
20100022898	Rubinstein et al.	Jan 2010	A1
20100036217	Choi et al.	Feb 2010	A1
20100041999	Schuhrke et al.	Feb 2010	A1
20100061604	Nahm et al.	Mar 2010	A1
20100065641	Liu et al.	Mar 2010	A1
20100069759	Schuhrke et al.	Mar 2010	A1
20100080757	Haaga et al.	Apr 2010	A1
20100087741	Douplik et al.	Apr 2010	A1
20100094136	Nakaoka et al.	Apr 2010	A1
20100099961	Hubner et al.	Apr 2010	A1
20100110168	Avni et al.	May 2010	A1
20100110393	Chen et al.	May 2010	A1
20100111361	Tan et al.	May 2010	A1
20100121146	Sugimoto	May 2010	A1
20100125164	LaBombard	May 2010	A1
20100155487	Liu et al.	Jun 2010	A1
20100157039	Sugai	Jun 2010	A1
20100168588	Matsumoto et al.	Jul 2010	A1
20100198010	Cline et al.	Aug 2010	A1
20100206731	Lau	Aug 2010	A1
20100208487	Li	Aug 2010	A1
20100222673	Mangat et al.	Sep 2010	A1
20100277817	Durell	Nov 2010	A1
20100286529	Carroll et al.	Nov 2010	A1
20100308116	Sani et al.	Dec 2010	A1
20110001061	Ishihara	Jan 2011	A1
20110013002	Thompson et al.	Jan 2011	A1
20110019992	Orf	Jan 2011	A1
20110032350	Kikuchi et al.	Feb 2011	A1
20110063427	Fengler et al.	Mar 2011	A1
20110071403	Sevick-Muraca	Mar 2011	A1
20110073658	Vassura et al.	Mar 2011	A1
20110098685	Flower	Apr 2011	A1
20110158914	Yamada et al.	Jun 2011	A1
20110235017	Iwasaki	Sep 2011	A1
20110244506	Sutter et al.	Oct 2011	A1
20110270092	Kang et al.	Nov 2011	A1
20110279679	Samuel et al.	Nov 2011	A1
20110290889	Tamburini et al.	Dec 2011	A1
20110306877	Dvorsky et al.	Dec 2011	A1
20110309275	Azimi et al.	Dec 2011	A1
20120006897	Barkan et al.	Jan 2012	A1
20120013773	Yoshino et al.	Jan 2012	A1
20120026325	Bunker	Feb 2012	A1
20120044462	Kaji	Feb 2012	A1
20120078093	Flower	Mar 2012	A1
20120252699	Jaffrey et al.	Apr 2012	A1
20120150046	Watson et al.	Jun 2012	A1
20120165627	Yamamoto	Jun 2012	A1
20120165662	Nahm et al.	Jun 2012	A1
20120256002	O'Donnell et al.	Oct 2012	A1
20120271176	Moghaddam et al.	Oct 2012	A1
20120292530	Ono et al.	Nov 2012	A1
20120319645	O'Donnell et al.	Dec 2012	A1
20120323118	Gopalakrishna et al.	Dec 2012	A1
20130008964	Hawley et al.	Jan 2013	A1
20130035569	Heanue et al.	Feb 2013	A1
20130203082	Gonda et al.	Aug 2013	A1
20130203083	Connors et al.	Aug 2013	A1
20130230866	Miyashita et al.	Sep 2013	A1
20130237762	Fengler et al.	Sep 2013	A1
20130245456	Ferguson, Jr. et al.	Sep 2013	A1
20130286176	Westwick et al.	Oct 2013	A1
20130296715	Lasser et al.	Nov 2013	A1
20130342674	Dixon	Dec 2013	A1
20130345560	Ferguson, Jr. et al.	Dec 2013	A1
20140071328	Miesak	Mar 2014	A1
20140078378	Demers et al.	Mar 2014	A1
20140099007	Sarkar et al.	Apr 2014	A1
20140111652	So et al.	Apr 2014	A1
20140139893	Sugiyama et al.	May 2014	A1
20140184769	Ishihara et al.	Jul 2014	A1
20140186351	Britta et al.	Jul 2014	A1
20140187967	Wood et al.	Jul 2014	A1
20140192258	Yang et al.	Jul 2014	A1
20140194687	Fengler et al.	Jul 2014	A1
20140217284	So et al.	Aug 2014	A1
20140254909	Carmi et al.	Sep 2014	A1
20140261456	Malackowski et al.	Sep 2014	A1
20140264025	Mohseni	Sep 2014	A1
20140308656	Flower	Oct 2014	A1
20140316262	Havens	Oct 2014	A1
20140371583	Flower	Dec 2014	A1
20150008390	Lewis et al.	Jan 2015	A1
20150018690	Kang et al.	Jan 2015	A1
20150083932	Rizo et al.	Mar 2015	A1
20150112192	Docherty et al.	Apr 2015	A1
20150112193	Docherty et al.	Apr 2015	A1
20150164396	Acharya et al.	Jun 2015	A1
20150182137	Flower et al.	Jul 2015	A1
20150184811	Moore	Jul 2015	A1
20150196208	Dvorsky et al.	Jul 2015	A1
20150230698	Cline et al.	Aug 2015	A1
20150230710	Nahm et al.	Aug 2015	A1
20150230715	Nahm et al.	Aug 2015	A1
20150248758	Pautot	Sep 2015	A1
20150320296	Morita	Nov 2015	A1
20150341551	Perrin et al.	Nov 2015	A1
20150381909	Butte	Dec 2015	A1
20160035104	Bigioi et al.	Feb 2016	A1
20160038027	Brzozowski et al.	Feb 2016	A1
20160041098	Hirawake et al.	Feb 2016	A1
20160044253	Dainty et al.	Feb 2016	A1
20160097716	Gulati et al.	Apr 2016	A1
20160100763	Fengler et al.	Apr 2016	A1
20160173802	Matsuo et al.	Jun 2016	A1
20160199515	Flower	Jul 2016	A1
20160245750	Jiang	Aug 2016	A1
20160249019	Westwick et al.	Aug 2016	A1
20160253800	Gurevich et al.	Sep 2016	A1
20160360956	Moore	Dec 2016	A1
20160371834	Watanabe et al.	Dec 2016	A1
20170039710	Minai et al.	Feb 2017	A1
20170064257	Westwick et al.	Mar 2017	A1
20170064258	Westwick et al.	Mar 2017	A1
20170084024	Gurevich	Mar 2017	A1
20170142314	Moore	May 2017	A1
20170167980	Dimitriadis et al.	Jun 2017	A1
20170196527	Kokubun	Jul 2017	A1
20170209050	Fengler et al.	Jul 2017	A1
20170245766	Flower et al.	Aug 2017	A1
20170245803	Ahmed	Aug 2017	A1
20170273567	Fengler et al.	Sep 2017	A1
20170303800	Flower et al.	Oct 2017	A1
20170307355	Seitz et al.	Oct 2017	A1
20170354392	Fengler et al.	Dec 2017	A1
20180020933	Dvorsky et al.	Jan 2018	A1
20180104362	Golijanin et al.	Apr 2018	A1
20180120230	Moriyama et al.	May 2018	A1
20180220907	Dvorsky et al.	Aug 2018	A1
20180234603	Moore et al.	Aug 2018	A1
20180369426	Flower et al.	Dec 2018	A1
20190297245	Moore et al.	Sep 2019	A1
20190374106	Ferguson et al.	Dec 2019	A1
20190388565	Golijanin	Dec 2019	A1
20200154019	Murrat et al.	May 2020	A1
20210166806	Fengler et al.	Jun 2021	A1
20210274131	Westwick et al.	Sep 2021	A1
20210307613	Fengler et al.	Oct 2021	A1
20230031797	Fengler et al.	Feb 2023	A1
20240029869	Fengler et al.	Jan 2024	A1

Foreign Referenced Citations (285)

Number	Date	Country
409451	Aug 2002	AT
2212257	Aug 1996	CA
2413033	Mar 2000	CA
2711560	Jul 2009	CA
2913692	Jan 2015	CA
1049781	Mar 1991	CN
2076516	May 1991	CN
1200174	Nov 1998	CN
1399528	Feb 2003	CN
101264014	Sep 2008	CN
101451953	Jun 2009	CN
101726980	Jun 2010	CN
101828139	Sep 2010	CN
102026668	Apr 2011	CN
201974160	Sep 2011	CN
102257510	Nov 2011	CN
102288589	Dec 2011	CN
102405212	Apr 2012	CN
102436648	May 2012	CN
103608662	Feb 2014	CN
105658138	Jun 2016	CN
3906860	Sep 1989	DE
19535114	Mar 1996	DE
19608027	Sep 1996	DE
10028233	Jan 2002	DE
10120980	Nov 2002	DE
69727220	Dec 2004	DE
102005044531	Mar 2007	DE
0091805	Oct 1983	EP
0215772	Mar 1987	EP
0512965	Nov 1992	EP
0672379	Sep 1995	EP
0774865	May 1997	EP
0792618	Sep 1997	EP
0807402	Nov 1997	EP
0826335	Mar 1998	EP
0671706	Jun 1999	EP
1374755	Jan 2004	EP
1 496 690	Jan 2005	EP
1677097	Jul 2006	EP
1761171	Mar 2007	EP
1874181	Jan 2008	EP
1883337	Feb 2008	EP
2051603	Apr 2009	EP
2859837	Apr 2015	EP
2 988 654	Jun 2020	EP
2671405	Jul 1992	FR
2944104	Oct 2010	FR
2203831	Oct 1988	GB
S52-34584	Mar 1977	JP
S58-222331	Dec 1983	JP
S59-069721	Apr 1984	JP
S59-070903	Apr 1984	JP
S60-246733	Dec 1985	JP
S61-159936	Jul 1986	JP
H01-135349	May 1989	JP
H01-236879	Sep 1989	JP
02-200237	Aug 1990	JP
03-97439	Apr 1991	JP
03-97441	Apr 1991	JP
03-97442	Apr 1991	JP
H03-115958	May 1991	JP
04-297236	Oct 1992	JP
05-115435	May 1993	JP
H05-264232	Oct 1993	JP
H06-007353	Jan 1994	JP
06-125911	May 1994	JP
06-335451	Dec 1994	JP
H07-043303	Feb 1995	JP
07-065154	Mar 1995	JP
07-079955	Mar 1995	JP
H07-155285	Jun 1995	JP
H07-155286	Jun 1995	JP
H07-155290	Jun 1995	JP
H07-155291	Jun 1995	JP
H07-155292	Jun 1995	JP
07-222712	Aug 1995	JP
H07-204156	Aug 1995	JP
H07-222712	Aug 1995	JP
H07-222723	Aug 1995	JP
H07-250804	Oct 1995	JP
H07-250812	Oct 1995	JP
H07-327913	Dec 1995	JP
08-024227	Jan 1996	JP
H08-126605	May 1996	JP
08-140928	Jun 1996	JP
08-140929	Jun 1996	JP
H08-224208	Sep 1996	JP
H08-224209	Sep 1996	JP
H08-224210	Sep 1996	JP
H08-224240	Sep 1996	JP
H08-252218	Oct 1996	JP
H09-19408	Jan 1997	JP
09-066023	Mar 1997	JP
09-070384	Mar 1997	JP
H09-120033	May 1997	JP
H09-305845	Nov 1997	JP
H09-308609	Dec 1997	JP
H09-309845	Dec 1997	JP
H10-14926	Jan 1998	JP
H10-500479	Jan 1998	JP
H10-503480	Mar 1998	JP
H10-085222	Apr 1998	JP
H10-104070	Apr 1998	JP
H10-127563	May 1998	JP
H10-151104	Jun 1998	JP
H10-506440	Jun 1998	JP
H10-506550	Jun 1998	JP
10-225427	Aug 1998	JP
H10-201700	Aug 1998	JP
H10-201707	Aug 1998	JP
H10-225426	Aug 1998	JP
H10-243915	Sep 1998	JP
H10-243920	Sep 1998	JP
H10-308114	Nov 1998	JP
H10-309281	Nov 1998	JP
H10-309282	Nov 1998	JP
H10-321005	Dec 1998	JP
H10-328129	Dec 1998	JP
H11-47079	Feb 1999	JP
11-089789	Apr 1999	JP
H11-104059	Apr 1999	JP
H11-104060	Apr 1999	JP
H11-104061	Apr 1999	JP
H11-104070	Apr 1999	JP
H11-113839	Apr 1999	JP
H11-137517	May 1999	JP
H11-155812	Jun 1999	JP
H11-509748	Aug 1999	JP
H11-244220	Sep 1999	JP
H11-332819	Dec 1999	JP
2000-504968	Apr 2000	JP
2000-245693	Sep 2000	JP
2000-354583	Dec 2000	JP
2001-78205	Mar 2001	JP
2001-198079	Jul 2001	JP
2001-518241	Oct 2001	JP
2002-000560	Jan 2002	JP
2002-049302	Feb 2002	JP
2002-219129	Aug 2002	JP
2002-244122	Aug 2002	JP
2003-045210	Feb 2003	JP
2003-510121	Mar 2003	JP
2003-144401	May 2003	JP
2003-187226	Jul 2003	JP
2003-329589	Nov 2003	JP
2004-024611	Jan 2004	JP
2004-094043	Mar 2004	JP
2004-163902	Jun 2004	JP
2004-520105	Jul 2004	JP
2004-247156	Sep 2004	JP
2004-528917	Sep 2004	JP
2004-289545	Oct 2004	JP
2004-292722	Oct 2004	JP
2004-325200	Nov 2004	JP
2005-010315	Jan 2005	JP
2005-058618	Mar 2005	JP
2005-058619	Mar 2005	JP
2005-058620	Mar 2005	JP
2005-080819	Mar 2005	JP
2005-081079	Mar 2005	JP
2005-149996	Jun 2005	JP
2005-292404	Oct 2005	JP
2005-326777	Nov 2005	JP
2006-003103	Jan 2006	JP
2006-503620	Feb 2006	JP
2006-61376	Mar 2006	JP
2006-073767	Mar 2006	JP
2006-087764	Apr 2006	JP
2006-192280	Jul 2006	JP
2006-525494	Nov 2006	JP
2006-326153	Dec 2006	JP
2007-021006	Feb 2007	JP
2007-029453	Feb 2007	JP
2007-072392	Mar 2007	JP
3896176	Mar 2007	JP
2007-089840	Apr 2007	JP
2008-023113	Feb 2008	JP
2008-525126	Jul 2008	JP
2008-220926	Sep 2008	JP
2008-535600	Sep 2008	JP
2008-231113	Oct 2008	JP
2009-095683	May 2009	JP
2009-519082	May 2009	JP
2009-259703	Nov 2009	JP
2009-291554	Dec 2009	JP
2010-505582	Feb 2010	JP
2010-107751	May 2010	JP
2010-117442	May 2010	JP
2010-521267	Jun 2010	JP
2010-524194	Jul 2010	JP
2011-500921	Jan 2011	JP
2011-509768	Mar 2011	JP
2011-072424	Apr 2011	JP
2011-110272	Jun 2011	JP
2011-519589	Jul 2011	JP
2011-169819	Sep 2011	JP
2011-528918	Dec 2011	JP
5231625	Jul 2013	JP
2014-123941	Jul 2014	JP
2015-16332	Jan 2015	JP
5859578	Feb 2016	JP
5918532	May 2016	JP
2016-521612	Jul 2016	JP
90-0005434	Jul 1990	KR
2002-0064287	Aug 2002	KR
2288633	Dec 2006	RU
99592	Nov 2010	RU
WO-198602730	May 1986	WO
WO-199010219	Sep 1990	WO
WO-199012536	Nov 1990	WO
WO-199304648	Mar 1993	WO
WO-199325141	Dec 1993	WO
WO-199412092	Jun 1994	WO
WO-199413191	Jun 1994	WO
WO-199500171	Jan 1995	WO
WO-199526673	Oct 1995	WO
WO-199609435	Mar 1996	WO
WO-199609792	Apr 1996	WO
WO-199618415	Jun 1996	WO
WO-199623524	Aug 1996	WO
WO-199639925	Dec 1996	WO
WO-199708538	Mar 1997	WO
WO-199824360	Jun 1998	WO
WO-199830144	Jul 1998	WO
WO-199846122	Oct 1998	WO
WO-199900053	Jan 1999	WO
WO-199901749	Jan 1999	WO
WO-199947940	Sep 1999	WO
WO-199953832	Oct 1999	WO
WO-200042910	Jul 2000	WO
WO-200047107	Aug 2000	WO
WO-200054652	Sep 2000	WO
WO-200108552	Feb 2001	WO
WO-200117561	Mar 2001	WO
WO-200122870	Apr 2001	WO
WO-200139764	Jun 2001	WO
WO-200169244	Sep 2001	WO
WO-200180734	Nov 2001	WO
WO-200182786	Nov 2001	WO
WO-2002007587	Jan 2002	WO
WO-200250518	Jun 2002	WO
WO-2002061390	Aug 2002	WO
WO-2003006658	Jan 2003	WO
WO-2003059159	Jul 2003	WO
WO-2003059159	Jul 2003	WO
WO-2004006963	Jan 2004	WO
WO-2004052195	Jun 2004	WO
WO-2005026319	Mar 2005	WO
WO-2005034747	Apr 2005	WO
WO-2005036143	Apr 2005	WO
WO-2005079238	Sep 2005	WO
WO-2006111836	Oct 2006	WO
WO-2006111909	Oct 2006	WO
WO-2006116634	Nov 2006	WO
WO-2006116847	Nov 2006	WO
WO-2006119349	Nov 2006	WO
WO-2006121631	Nov 2006	WO
WO-2006121631	Nov 2006	WO
WO-2006123742	Nov 2006	WO
WO-2007028032	Mar 2007	WO
WO-2007081707	Jul 2007	WO
WO-2008011722	Jan 2008	WO
WO-2008039968	Apr 2008	WO
WO-2008044822	Apr 2008	WO
WO-2008070269	Jun 2008	WO
WO-2008070269	Jun 2008	WO
WO-2008071240	Jun 2008	WO
WO-2008087869	Jul 2008	WO
WO-2009033021	Mar 2009	WO
WO-2009046985	Apr 2009	WO
WO-2009046985	Apr 2009	WO
WO-2009048660	Apr 2009	WO
WO-2009092162	Jul 2009	WO
WO-2009127972	Oct 2009	WO
WO-2012038824	Mar 2012	WO
WO-2012096878	Jul 2012	WO
WO-2013160279	Oct 2013	WO
WO-2013190391	Dec 2013	WO
WO-2014066906	May 2014	WO
WO-2014176375	Oct 2014	WO
WO-2015001427	Jan 2015	WO
WO-2013002350	Feb 2015	WO
WO-2015164774	Oct 2015	WO
WO-2016055837	Apr 2016	WO

Non-Patent Literature Citations (769)

Entry
US 6,692,429 B1, 02/2004, Imaizumi et al. (withdrawn)
Akintunde, A. et al. (Oct.-Nov. 1992). “Quadruple Labeling of Brain-Stem Neurons: A Multiple Retrograde Fluorescent Tracer Study of Axonal Collateralization,” Journal of Neuroscience Methods 45(1-2):15-22.
Alander, J.T. et al. (Jan. 1, 2012). “A Review of Indocyanine Green Fluorescent Imaging in Surgery,” International Journal of Biomedical Imaging 2012:1-26, article ID 940585.
Alfano et al. (Oct. 1987). “Fluorescence Spectra from Cancerous and Normal Human Breast and Lung Tissues,” IEEE Journal of Quantum Electronics QE-23(10):1806-1811.
Alm, A. et al. (Jan. 1, 1973). “Ocular and Optic Nerve Blood Flow at Normal and Increased Intraocular Pressures in Monkeys (Macaca irus): A Study with Radioactively Labelled Microspheres Including Flow Determinations in Brain and Some Other Tissues,” Experimental Eye Research 15(1):15-29.
Alonso-Burgos, A. et al.(2006). “Preoperative planning of deep inferior epigastric artery perforator flap reconstruction with multi-slice-CT angiography: imaging findings and initial experience,” Journal of Plastic, Reconstructive & Aesthetic Surgery 59:585-593.
Alvarez, F. J. et al. (Apr. 1996). “Behaviour of Isolated Rat and Human Red Blood Cells Upon Hypotonic-Dialysis Encapsulation of Carbonic Anhydrase And Dextran,” Biotechnology and Applied Biochemistry 23(2): 173-179.
Ancalmo, N. et al. (1997). “Minimally invasive coronary artery bypass surgery: really minimal?” Ann. Thorac. Surg. 64:928-929.
Andersson-Engels, S. et al. (1991). “Fluorescence Characteristics of Atherosclorotic Plaque and Malignant Tumors,” in Optical Methods for Tumor Treatment and Early Diagnosis: Mechanisms and Techniques, T. J. Dougherty (Ed.), The Society of Photo-optical Instrumentation Engineers (SPIE) 1426:31-43, fourteen pages.
Andersson-Engels, S. et al. (Mar. 1989). “Tissue Diagnostics Using Laser-Induced Fluorescence,” Berichte der Bunsengesellschaft für physikalische Chemie 93(3):335-342.
Angelov, D.N. et al. (Apr. 1999). “Contralateral Trigeminal Nerve Lesion Reduces Polyneuronal Muscle Innervation after Facial Nerve Repair in Rats,” European Journal of Neuroscience 11(4):1369-1378.
Annese, V. et al. (2005). “Erthrocytes-Mediated Delivery of Dexamethasone in Steroid-Dependent IBD Patients—a Pilot Uncontrolled Study,” American Journal of Gastroenterology 100:1370-1375.
Argus-50/CA, Inter cellular CA2+ (calcium ion) Image Analysis system (Feb. 1992). “Observation and 2-dimensional analysis of Ca2+ concentration distribution. Fura-2 and Indo-1 compatible. Ca2+ concentrations are calculated from the fluorescence ratio,” pp. 1-10.
Australian Notice of Acceptance for Patent Application dated Sep. 17, 2018 for Australian Patent Application No. 2015327665, filed on Mar. 23, 2017, three pages.
Australian Notice of Acceptance for Patent Application dated Jul. 3, 2019 for Australian Patent Application No. 2014408488, filed on Mar. 31, 2017, three pages.
Australian Notice of Acceptance for Patent Application dated Jun. 26, 2019 for Patent Application No. 2016351730 filed on Nov. 10, 2016, three pages.
Australian Office Action dated Jun. 26, 2018 for Australian Patent Application No. 2014408488, filed on Mar. 31, 2017, nine pages.
Australian Office Action dated Jun. 28, 2018 for Australian Patent Application No. 2016351730 filed on Nov. 10, 2016, five pages.
Australian Office Action dated May 10, 2019 for Australian Patent Application No. 2016351730 filed on Nov. 10, 2016, ten pages.
Author Unknown. (Jun. 4, 2008). “Invitrogen,” Material Safety Data Sheet, p. 1-4.
Awano, T. et al. (Jun. 2010). “Intraoperative EC-IC Bypass Blood Flow Assessment with Indocyanine Green Angiography in Moyamoya and Non-moyamoya Ischemic Stroke,” World Neurosurg. 73(6):668-674.
Azuma, R. et al. (2008, presented in part Jun. 2007). “Detection of Skin Perforators by Indocyanine Green Fluorescence Nearly Infrared Angiography,” PRS Journal 122(4):1062-1067.
Balacumarswami, L. et al. (Aug. 2004). “Does Off-Pump Total Arterial Grafting Increase the Incidence of Intraoperative Graft Failure?,” The Journal of Thoracic and Cardiovascular Surgery 128(2):238-244.
Barton, J.K. et al. (1999) “Simultaneous irradiation and imaging of blood vessels during pulsed laser delivery,” Lasers in Surgery and Medicine 24(3):236-243.
Bassingthwaighte, J.B. et al. (Apr. 1974). “Organ Blood Flow, Wash-in, Washout, and Clearance of Nutrients and Metabolites,” Mayo Clin. Proc. 49(4):248-255.
Batliwala, H. et al. (Apr. 15, 1995). “Methane-Induced Haemolysis of Human Erythrocytes,” Biochemical J. 307(2):433-438.
Baumgartner, R. et al. (1987). “Section V—In vivo Localization and Photodynamic Therapy: A Fluorescence Imaging Device for Endoscopic Detection of Early Stage Cancer—Instrumental and Experimental Studies,” Photochemistry and Photobiology 46(5):759-763.
Baumgartner, R. et al. (Jan. 1, 1990). “A Fluorescence Imaging Device for Endoscopic Detection of Early Stage Cancer Instumental and Experimental Studies,” Photochemistry and Photobiology 46:513-517.
Bek, T. (1999). “Diabetic Maculopathy Caused by Disturbances in Retinal Vasomotion: A New Hypothesis,” Acta Ophthalmologica Scandinavica 77:376-380.
Benson, R.C. et al. (1978). “Fluorescence Properties of Indocyanine Green as Related to Angiography,” Phys. Med. Biol. 23(1):159-163.
Bhunchet, E. et al. (Apr. 2002). “Fluorescein Electronic Endoscopy: A Novel Method for Detection of Early Stage Gastric Cancer Not Evident to Routine Endoscopy,” Gastrointestinal Endoscopy 55(4):562-571.
Black's Medical Dictionary, “Perfusion,” 42nd Edition (2009), two pages.
Boer, F. et al. (1994). “Effect of Ventilation on First-Pass Pulmonary Retention of Alfentaril and Sufentanil in Patients Undergoing Coronary Artery Surgery,” British Journal Anesthesia 73:458-463.
Boldt, .J. et al. (Feb. 1990). “Lung management during cardiopulmonary bypass: influence on extravascular lung water,” Journal of Cardiothoracic Anesthesia 4(1):73-79.
Boldt, J. et al. (1991). “Does the technique of cardiopulmonary bypass affect lung water content?” European Journal of Cardio-Thoracic Surgery 5:22-26.
Brazilian Office Action dated Aug. 5, 2019, for Patent Application No. BR112013022997-7, filed Mar. 8, 2012, 4 pages.
Brazilian Office Action dated Mar. 16, 2020 for Patent Application No. 112013022997-7, filed Mar. 8, 2012, six pages.
Brazilian Office Action dated May 14, 2019 for Brazilian Application No. PI 0907272-1, filed on Oct. 14, 2010, five pages.
Bütter, A. et al. (May 2005). “Melanoma in Children and the Use of Sentinel Lymph Node Biopsy,” Journal of Pediatric Surgery 40(5):797-800.
C2741, Compact High Performance video camera for industrial applications with Built-in contrast enhancement circuit, Jun. 1998, six pages.
Canada Health. (1997). “Coronary Bypass Surgery and Angioplasty, 1982-1995, Heart Disease and Stroke in Canada,” Canada Health, located at <http:/www.hc-sc.gc.ca/hpb>, eighty two pages.
Canadian Notice of Allowance dated Oct. 29, 2019, for Patent Application No. 2998920, filed Nov. 10, 2016, one page.
Canadian Notice of Allowance dated Jan. 4, 2018 for Canadian Application No. 2,750,760, filed on Jul. 25, 2008, one page.
Canadian Notice of Allowance dated Sep. 27, 2017 for Canadian Application No. 2,811,847, filed on Mar. 20, 2013, one page.
Canadian Office Action dated Dec. 11, 2019, for Patent Application No. 2,963,450, filed Oct. 9, 2014, 3 pages.
Canadian Office Action dated Nov. 18, 2019, for Patent Application No. 2,914,778, filed Jun. 20, 2013, 4 pages.
Canadian Office Action dated Dec. 12, 2018 for CA Application No. 2,963,987 filed on Mar. 27, 2017, four pages.
Canadian Office Action dated Dec. 28, 2018 for CA Application No. 2,963,450 filed on Apr. 3, 2017, four pages.
Canadian Office Action dated Feb. 1, 2017 for Canadian Patent Application No. 171282, filed on Oct. 27, 2016, two pages.
Canadian Office Action dated Feb. 13, 2018 for CA Application No. 2,963,450 filed on Apr. 3, 2017, three pages.
Canadian Office Action dated Feb. 19, 2019 for CA Patent Application No. 2,998,920 filed on Mar. 16, 2018, four pages.
Canadian Office Action dated Feb. 27, 2017 for Canadian Application No. 2,750,760, filed on Jul. 25, 2011, three pages.
Canadian Office Action dated Feb. 28, 2018 for CA Application No. 2,963,987 filed on Mar. 27, 2017, five pages.
Canadian Office Action dated Jan. 19, 2017 for Canadian Application No. 2,914,778 filed on Dec. 8, 2015, four pages.
Canadian Office Action dated Mar. 16, 2016 for CA Application No. 2,750,760 filed on Jan. 23, 2009, five pages.
Canadian Office Action dated May 28, 2019 for Canadian Application No. 3,011,310, filed on Jul. 11, 2018, four pages.
Canadian Office Action dated Nov. 28, 2017 for Canadian Application No. 2,914,778 filed on Dec. 8, 2015, six pages.
Canadian Office Action dated Nov. 28, 2018 for CA Application No. 2,750,760 filed on Jan. 23, 2009, three pages.
Canadian Office Action dated Nov. 5, 2019, for Canadian Patent Application No. 3027592, filed on Jun. 14, 2017, four pages.
Canadian Office Action dated Oct. 25, 2016 for Canadian Patent Application No. 2,811,847, filed on Sep. 20, 2011, three pages.
Canadian Office Action dated Sep. 30, 2015 for CA Application No. 2,811,847, filed on Sep. 20, 2011, four pages.
Chinese Notice of Allowance dated Jan. 13, 2020, for Patent Application No. 2017- 10785223.7, filed Mar. 8, 2012, six pages.
Chinese Notice of Allowance dated Jun. 19, 2017 for Chinese Patent Application No. 201280022284.3, filed on Nov. 7, 2013, four pages.
Chinese Office Action dated Jul. 3, 2012, issued in counterpart Chinese Application No. 200980123414.0, eight pages.
Chinese Office Action dated Nov. 22, 2019, for Patent Application No. 201480083915.1, filed Oct. 9, 2014, seventeen pages (including English translation).
Chinese Office Action dated Apr. 6, 2017 for Chinese Application No. 201510214021.8, filed on May 14, 2009, fifteen pages.
Chinese Office Action dated Apr. 17, 2019 for Chinese Application No. 201510214021.8, filed on May 14, 2009, sixteen pages.
Chinese Office Action dated Apr. 26, 2019 for CN Application No. 201580064648.8 filed on May 26, 2017, twenty six pages.
Chinese Office Action dated Aug. 8, 2016 for Chinese Application No. 201180057244.8 filed on Sep. 20, 2011, eighteen pages.
Chinese Office Action dated Dec. 19, 2017 for Chinese Application No. 201180057244.8 filed on Sep. 20, 2011, eleven pages.
Chinese Office Action dated Feb. 8, 2018 for Chinese Application No. 201510214021.8, filed on May 14, 2009, seventeen pages.
Chinese Office Action dated Jul. 29, 2016 for Chinese Patent Application No. 2012800222843 filed on Mar. 8, 2012, eight pages.
Chinese Office Action dated Mar. 13, 2017 for Chinese Application No. 201180057244.8 filed on Sep. 20, 2011, twenty pages.
Chinese Office Action dated Mar. 14, 2017 for Chinese Patent Application No. 201280022284.3, filed on Nov. 7, 2013, seven pages.
Chinese Office Action dated May 23, 2013, issued in counterpart Chinese Application No. 200980123414.0, nineteen pages.
Chinese Office Action dated Nov. 12, 2015 for Chinese Patent Application No. 201180057244.8, filed on Sep. 20, 2010, five pages.
Chinese Office Action dated Nov. 24, 2015 for Chinese Patent Application No. 2012800222843 filed on Mar. 8, 2012, sixteen pages.
Chinese Office Action dated Sep. 26, 2018 for Chinese Patent Application No. 2018092001857100, filed on Sep. 4, 2017, nineteen pages.
Chinese Office Action dated Sep. 27, 2018 for Chinese Application No. 201510214021.8, filed on May 14, 2009, seventeen pages.
Chinese Office Action, Notification to Pay Restoration Fee for Unity, dated Apr. 7, 2020, for Patent Application No. 2016800660600, filed Nov. 10, 2016, 2 pages.
Coffey, J.H. et al. (1984). “Evaluation of Visual Acuity During Laser Photoradiation Therapy of Cancer,” Lasers in Surgery and Medicine 4(1):65-71.
Conley, M.P. et al. (Oct. 2004). “Anterograde Transport of Peptide-Conjugated Fluorescent Beads in the Squid Giant Axom Identifies a Zip-Code for Synapse,” Biological Bulletin 207(2):164, one page.
Costa, R.A. et al. (Oct. 2001). “Photodynamic Therapy with Indocyanine Green for Occult Subfoveal Choroidal Neovascularization Caused by Age-Related Macular Degeneration,” Curr. Eye Res. 23(4):274-275.
Cothren, R.M. et al. (Mar. 1990). “Gastrointestinal Tissue Diagnosis by Laser-Induced Fluorescence Spectroscopy at Endoscopy,” Gastrointestinal Endoscopy 36(2):105-111.
Dail, W.G. et al. (Oct. 1999). “Multiple Vasodilator Pathways from the Pelvic Plexus to the Penis of the Rat,” International Journal of Impotence Research 11(5):277-285.
Dan, A.G. et al. (Nov. 2004). “1% Lymphazurin vs 10% Fluorescein for Sentinel Node Mapping in Colorectal Tumors,” Arch Surg. 139(11):1180-1184.
Daniels, G. et al. (Apr. 2007). “Towards Universal Red Blood Cell,” Nature Biotechnology 25(4): 427-428.
Dawson, J.B. et al. (Jul. 1980). “A Theoretical and Experimental Study of Light Absorption and Scattering by In Vivo Skin,” Phys. Med. Biol. 25(4):695-709.
De Flora, A. (Sep. 1986). “Encapsulation of Adriamycin in human erythrocytes,” Proc. Natl. Acad. Sci., USA 83(18):7029-7033.
Decision to Grant a Patent dated Jun. 29, 2020, directed to JP Application No. 2018-516161; 6 pages [w/English translation].
Decision to Grant dated Jul. 18, 2019, directed to EP Application No. 09819758.5; 2 pages.
Declaration of Brian Wilson dated Aug. 22, 2017 for Inter Partes Review No. IPR2017-01426, twelve pages, [Exhibit 2002].
Definition of “Expose,” Excerpt of Merriam Webster's Medical Desk Dictionary (1993), four pages, [Exhibit 2004].
Definition of “Graft,” Excerpt of Stedman's Medical Dictionary for the Health Professions and Nursing; 6th Ed. (2008), three pages, [Exhibit 2003].
De-Grand, A.M. et al. (Dec. 2003). “An Operational Near Infrared Fluorescence Imaging System Prototype for Large Animal Surgery,” Technology in Cancer Research & Treatment 2(6):1-10.
Deloach, J.R. (ed.) et al. (1985). Red Blood Cells as Carriers for Drugs. A Method for Disseminating Chemotherapeutics, Hormones, Enzymes and Other Therapeutic Agents via the Circulatory System, Karger, Basel, CH, pp. v-vii, (Table of Contents), seven pages.
Deloach, J.R. (Jun. 1983). “Encapsulation of Exogenous Agents in Erythrocytes and the Circulating Survival of Carrier Erythrocytes,” Journal of Applied Biochemistry 5(3):149-157.
Demos (May/Jun. 2004). “Near-Infrared Autofluorescence Imaging for Detection of Cancer,” Journal of Biomedical Optics 9(3):587-592.
Desai, N.D. et al. (Oct. 18, 2005, e-published on Sep. 28, 2005) “Improving the Quality of Coronary Bypass Surgery with Intraoperative Angiography,” Journal of the American College of Cardiology 46(8):1521-1525.
Detter, C. et al. (Aug. 28, 2007). “Fluorescent Cardiac Imaging: A Novel Intraoperative Method for Quantitative Assessment of Myocardial Perfusion During Graded Coronary Artery Stenosis,” Circulation 116(9):1007-1014.
Detter, C. et al. (Jun. 2002). “Near-Infrared Fluorescence Coronary Angiography: A New Noninvasive Technology for Intraoperative Graft Patency Control.” The Heart Surgery Forum #2001-6973 5(4):364-369.
Dietz, F.B. et al. (Feb. 2003). “Indocyanine Green: Evidence of Neurotoxicity in Spinal Root Axons,” Anesthesiology 98(2):516-520.
Digital CCD Microscopy (date unknown). Chapter 14, pp. 259-282.
Dougherty, T.J. et al. (1990). “Cutaneous Phototoxic Occurrences in Patients Receiving Photofrin,” Lasers in Surgery and Medicine 10(5):485-488.
Draijer, M.J. et al. (Jun. 17-19, 2007). “Laser Doppler Perfusion Imaging with a High-Speed CMOS-Camera,” in Novel Optical Instrumentation for Biomedical Applications III, C. Depeursinge, ed., Proceedings of SPIE-OSA Biomedical Optics (Optical Society of America, 2007), SPIE-OSA, 6631:0N1-0N7, eight pages.
Dünne, A. et al. (Nov. 2001). “Value of Sentinel lymphonodectomy in Head and Neck Cancer Patients without Evidence of Lymphogenic Metastatic Disease,” Auris Nasus Larynx 28(4):339-344.
Ekstrand, M.I. et al. (Feb. 14, 2008). “The Alpha-Herpesviruses: Molecular Pathfinders in Nervous System Circuits,” Trends in Molecular Medicine, Elsevier Current Trends 14(3):134-140.
Emery R.W. et al. (Aug. 1996). “Revascularization Using Angioplasty and Minimally Invasive Techniques Documented by Thermal Imaging,” The Annals of Thoracic Surgery 62(2):591-593.
Enquist, L.W. et al. (2002). “Directional Spread of an aα-Herpesvirus in the Nervous System,” Veterinary Microbiology 86:5-16.
Eren, S. et al. (Dec. 1995). “Assessment of Microcirculation of an Axial Skin Flap Using Indocyanine Green Fluorescence Angiography,” Plast. Reconstr. Surg. 96(7):1636-1649. [Exhibit 1008].
European Decision in Opposition Proceeding Revoking (Jun. 10, 2010). European Patent No. 1 143 852, thirty pages.
European Decision of European Patent Office Technical Board of Appeal Revoking Counterpart Patent No. 1143852, dated Oct. 23, 2013. [Exhibit-1009].
European Extended Search Report dated Jan. 14, 2020, for Patent Application No. 17812362.6, filed Jun. 14, 2017, 8 pages.
European Extended Search Report dated May 7, 2019, for Patent Application No. 16863277.6, filed Nov. 10, 2016, seven pages.
European Extended Search Report dated Oct. 16, 2019, for Patent Application No. 17743524.5, filed Jan. 26, 2017, four pages.
European Notice of Allowance dated Apr. 21, 2017 for EP Application No. 09732993.2, filed on Nov. 8, 2010, two pages.
European Notice of Allowance dated Dec. 1, 2017 for European patent Application No. 09739980.2, filed on Nov. 30, 2010, seven pages.
European Notice of Allowance dated Feb. 28, 2018 for EP Patent Application No. 12754208.2 filed Oct. 4, 2013, six pages.
European Notice of Allowance dated Jul. 12, 2018 for EP Patent Application No. 12754208.2 filed Oct. 4, 2013, two pages.
European Notice of Allowance dated Jul. 16, 2019 for EP Application No. 18166591.0, filed on May 1, 2009, eight pages.
European Notice of Allowance dated Jun. 22, 2017 for EP Patent Application No. 08706262.6 filed on Aug. 21, 2009, two pages.
European Notice of Allowance dated Mar. 15, 2018 for EP Application No. 09739980.2 filed on Nov. 30, 2010, two pages.
European Notice of Allowance dated Mar. 18, 2019 for EP Patent Application No. 09819758.5, filed on May 4, 2011, seven pages.
European Notice of Allowance dated Mar. 6, 2018 for EP Patent Application No. 13180297.7 filed Aug. 13, 2013, seven pages.
European Notice of Allowance dated May 25, 2018 for EP Patent Application No. 13180297.7 filed Aug. 13, 2013, two pages.
European Notice of Allowance dated Nov. 21, 2017 for European Patent Application No. 15160177.0, filed on Aug. 11, 2000, seven pages.
European Notice of Allowance dated Nov. 25, 2016 for EP Patent Application No. 08706262.6 filed on Aug. 21, 2009, eight pages.
European Notice of Allowance dated Oct. 21, 2015 for EP Application No. 11 826 475.3, filed on Sep. 20, 2010, eight pages.
European Notice of Allowance dated Oct. 29, 2015 for EP Application No. 09 704 642.9, filed on Jan. 25, 2008, two pages.
European Notice of Allowance dated Sep. 26, 2019, for Patent Application No. 16163909.1, filed Jan. 25, 2008,.
European Office Action dated Nov. 11, 2019, for Patent Application No. 13806313.6 filed Jun. 20, 2013, seven pages.
European Office Action dated Apr. 6, 2018 for EP Application No. 15188378.2 filed on Oct. 5, 2015, four pages.
European Office Action dated Apr. 13, 2017, for EP Patent Application No. 12754208.2 filed on Oct. 4, 2013, five pages.
European Office Action dated Apr. 6, 2017, for EP Patent Application No. 09819758.5, filed on May 4, 2011, five pages.
European Office Action dated Aug. 31, 2017 for EP Application No. 09739980.2 filed on Nov. 30, 2010, four pages.
European Office Action dated Dec. 3, 2015 for EP Patent Application No. 08706262.6 filed on Jan. 23, 2008, fifteen pages.
European Office Action dated Jan. 23, 2017 for EP Patent Application No. 16186321.2 filed on Aug. 30, 2016, two pages.
European Office Action dated Mar. 9, 2016 for European Patent Application No. 09739980.2 filed on May 1, 2009, five pages.
European Office Action dated Mar. 27, 2015 for EP Application No. 09 732 993.2, filed on Apr. 14, 2008, six pages.
European Office Action dated May 15, 2014 in EP Application No. 09732993.2 , one page.
European Office Action dated May 27, 2016 for EP Application No. 15160177.0 filed on Aug. 11, 2000, five pages.
European Office Action dated May 28, 2018 for EP Application No. 16183434.6 filed on Aug. 9, 2016, four pages.
European Office Action dated Nov. 14, 2016 in EP Application No. 16163909.1, two pages.
European Office Action dated Nov. 19, 2015 for EP Patent Application No. 07 785 001.4, filed on Jul. 30, 2007, four pages.
European Office Action dated Nov. 3, 2015 for EP Patent Application No. 12754208.2 filed Oct. 4, 2013, four pages.
European Office Action dated Sep. 21, 2017 for European Application No. 16163909.1 filed on Apr. 5, 2016, three pages.
European Office Action dated Sep. 29, 2015, for EP Patent Application No. 09721252.6 filed Mar. 18, 2009; five pages.
European Opposition of European Patent No. EP1143852 lodged by Hamamatsu Photonics, Inc., Jul. 30, 2008.
European Search Report dated Apr. 28, 2014 for EP Application No. 09 732 993.2, filed on Apr. 14, 2008, eight pages.
European Search Report dated Dec. 16, 2010 for European Application No. 10186218.3 filed on Aug. 11, 2000, seven pages.
European Search Report dated Dec. 21, 2016 for EP Patent Application No. 16186321.2 filed on Aug. 30, 2016, nine pages.
European Search Report dated Feb. 18, 2019 for EP Patent Application No. 18178620.3 filed on Jun. 19, 2018, eight pages.
European Search Report dated Feb. 22, 2012 for EP Application No. 09 704 642.9, filed on Jan. 25, 2008, fifteen pages.
European Search Report dated Jan. 10, 2018 for EP Application No. 17171383.7 filed on May 16, 2017, eleven pages.
European Search Report dated Jan. 24, 2012 for EP Patent Application No. 07785001.4 filed on Jul. 30, 2007, seven pages.
European Search Report dated Jan. 28, 2014 for EP Application No. 11 826 475.3, filed on Sep. 20, 2010, six pages.
European Search Report dated Jul. 6, 2004 for EP Application No. 00955472.6 filed on Aug. 11, 2000, five pages.
European Search Report dated Jul. 16, 2018 for EP Application No. 15846111.1, filed on Apr. 25, 2017, thirteen pages.
European Search Report dated Jul. 17, 2014 for EP Patent Application No. 09721252.6 filed Mar. 18, 2009, eleven pages.
European Search Report dated Jun. 6, 2018 for EP Application No. 18166591.0 filed on Apr. 10, 2018, six pages.
European Search Report dated Jun. 11, 2014 for European Application No. 13178642.8, filed on May 1, 2009, five pages.
European Search Report dated Jun. 28, 2016 for European Application No. 16163909.1 filed on Apr. 5, 2016, six pages.
European Search Report dated May 23, 2018 for EP Application No. 14903635.2 filed on May 2, 2017, nine pages.
European Search Report dated Oct. 1, 2014 for EP Patent Application No. 12754208.2 filed on Mar. 8, 2012, five pages.
European Search Report dated Oct. 14, 2015 for EP Application No. 13806313.6 filed on Jun. 20, 2013, nine pages.
European Search Report dated Oct. 9, 2013, for European Patent Application No. 06721854.5, filed on May 4, 2005, seven pages.
European Search Report dated Sep. 16, 2016 for EP Application No. 16183434.6 filed on Aug. 9, 2016, ten pages.
European Search Report dated Sep. 20, 2013 for EP Patent Application No. 08706262.6 filed on Jan. 23, 2008, five pages.
European Summons to attend oral proceedings pursuant to Rule 115(1) EPC mailed Nov. 28, 2019, for EP Patent application No. 15188378.2, filed Jan. 23, 2009, seven pages.
European Summons to attend Oral Proceedings pursuant to Rule 115(1) EPC issued on Apr. 25, 2016 for European patent application No. 09732993.2, filed on Apr. 14, 2009, 5 pages.
European Summons to attend Oral Proceedings pursuant to Rule 115(1) EPC mailed on Dec. 16, 2016 for European patent application No. 15160177.0, filed on Aug. 11, 2000, seven pages.
European Summons to Attend the Oral Proceedings mailed on May 31, 2019 for European Application No. 16163909.1 filed on Apr. 5, 2016, two pages.
European Summons to Attend the Oral Proceedings mailed on Oct. 24, 2018 for European Application No. 16163909.1 filed on Apr. 5, 2016, four pages.
Extended European Search Report dated Oct. 14, 2020, directed to EP Application No. 17895908.6; 8 pages.
Falk, T. et al. (Apr. 15, 2001). “A Herpes Simplex Viral Vector Expressing Green Fluorescent Protein can be Used to Visualize Morphological Changes in High-density Neuronal Culture,” Electronic Journal of Biotechnology 4(1):34-45.
Fengler et al., U.S. Advisory Action dated Dec. 20, 2019, directed to U.S. Appl. No. 15/416,876; 5 pages.
Fengler et al., U.S. Advisory Action dated Nov. 2, 2020, directed to U.S. Appl. No. 15/416,876; 5 pages.
Fengler et al., U.S. Notice of Allowance and Fee(s) Due dated Aug. 18, 2020, directed to U.S. Appl. No. 15/623,100; 7 pages.
Fengler et al., U.S. Office Action dated Jul. 15, 2020, directed to U.S. Appl. No. 15/416,876; 20 pages.
Flower, R. et al. (Apr.-Jun. 1999). “Effects of free and liposome-encapsulated hemoglobin on choroidal vascular plexus blood flow, using the rabbit eye as a model system,” European Journal of Ophthalmology 9(2):103-114.
Flower, R.W. (1992). “Choroidal Angiography Today and Tomorrow,” Retina 12(3):189-190.
Flower, R.W. (Apr. 2000). “Experimental Studies of Indocyanine Green Dye-Enhanced Photocoagulation of Choroidal Neovascularization Feeder Vessels,” American Journal of Ophthalmology 129(4):501-512.
Flower, R.W. (Aug. 2002). “Optimizing Treatment of Choroidal Neovascularization Feeder Vessels Associated with Age-Related Macular Degeneration,” American Journal of Ophthalmology 134(2):228-239.
Flower, R.W. (Dec. 1973). “Injection Technique for Indocyanine Green and Sodium Fluorescein Dye Angiography of the Eye,” Investigative Opthamology 12(12):881-895.
Flower, R.W. (Sep. 1, 1994). “Does Preinjection Binding of Indocyanine Green to Serum Actually Improve Angiograms?,” Arch Ophthalmol. 112(9):1137-1139.
Flower, R.W. et al. (Aug. 1977). “Quantification of Indicator Dye Concentration in Ocular Blood Vessels,” Exp. Eye Res. 25(2):103-111.
Flower, R.W. et al. (Dec. 1, 2008, e-published Aug. 15, 2008). “Observation of Erythrocyte Dynamics in the Retinal Capillaries and Choriocapillaris Using ICG-Loaded Erythrocyte Ghost Cells,” Investigative Ophthalmology, & Visual Science 49(12):5510-5516.
Flower, R.W. et al. (Mar. 26, 2008-Mar. 29, 2008). “Observation of Erythrocyte Dynamics in the Retinal Capillaries and Choriocapillaris Using ICG-Loaded Erythrocyte Ghost Cells,” Annual Meeting of the Macula Society, Abstract No. XP002535355, Palm Beach, FL, USA, fourteen pages, (Schedule of the Meeting only).
Forrester et al. (Nov. 1, 2002). “Comparison of Laser Speckle and Laser Doppler Perfusion Imaging: Measurement in Human Skin and Rabbit Articular Tissue,” Medical and Biological Engineering and Computing 40(6):687-697.
Frangioni, J.V. (Oct. 2003). “In Vivo Near-Infrared Fluorescence Imaging,” Current Opinion in Chemical Biology 7(5):626-634.
Frenzel H. et al. (Apr. 18, 2008). “In Vivo Perfusion Analysis of Normal and Dysplastic Ears and its Implication on Total Auricular Reconstruction,” Journal of Plastic, Reconstructive and Aesthetic Surgery 61(Supplement1):S21-S28.
Fritzsch, B. et al. (Aug. 1991).“Sequential Double Labeling With Different Fluorescent Dyes Coupled to Dextran Amines as a Tool to Estimate the Accuracy of Tracer Application and of Regeneration,” Journal of Neuroscience Methods 39(1):9-17.
Gagnon, A.R. et al. (2006). “Deep and Superficial Inferior Epigastric Artery Perforator Flaps,” Cirugia Plástica Ibero-Latinoamericana 32(4):7-13.
Gardner, T.J. (1993). “Coronary Artery Disease and Ventricular Aneurysms,” in Surgery, Scientific Principles and Practice, Greenfield, L.J. (ed.) et al., J.B. Lippincott Co., Philadelphia, PA, pp. 1391-1411, twenty three pages.
Garrett, W.T. et al. (Jul. 8, 1991). “Fluoro-Gold's Toxicity makes it Inferior to True Blue for Long-Term Studies of Dorsal Root Ganglion Neurons and Motoneurons,” Neuroscience Letters 128(1):137-139.
Geddes, C. D. et al. (2003, e-published on Mar. 20, 2003). “Metal-Enhanced Fluorescence (MEF) Due to Silver Colloids on a Planar Surface: Potential Applications of Indocyanine Green to in Vivo Imaging,” Journal Of Physical Chemistry A 107(18):3443-3449.
Georgakoudi, I. et al. (2003). “Quantitative Characterization of Biological Tissue Using Optical Spectroscopy,” in Chapter 31 of Biomedical Photonics Handbook, Tuan Vo-Dinh (ed.), CRC Press, New York, thirty three pages.
Georgakoudi, I. et al. (Apr. 2005). “Characterization of Dysplastic Tissue Morphology and Biochemistry in Barrett's Esophagus using Diffuse Reflectance and Light Scattering Spectroscopy,” Techniques in Gastrointestinal Endoscopy 7(2):100-105.
Gipponi, M. et al. (Mar. 1, 2004). “New Fields of Application of the Sentinel Lymph Node Biopsy in the Pathologic Staging of Solid Neoplasms: Review of Literature and Surgical Perspectives,” Journal of Surgical Oncology 85(3):171-179.
Giunta, R.E. et al. (Jul. 2005). “Prediction of Flap Necrosis with Laser Induced Indocyanine Green Fluorescence in a Rat Model,” British Journal of Plastic Surgery 58(5):695-701.
Giunta, R.E. et al. (Jun. 2000). “The Value of Preoperative Doppler Sonography for Planning Free Perforator Flaps,” Plastic and Reconstructive Surgery 105(7):2381-2386.
Glossary, Nature, downloaded from the internet <http://www.nature.com/nrg/journal/v4/nl0/glossary/nrgl 183_glossary.html>> HTML on Jun. 30, 2014, three pages.
Glover, J.C. et al. (Nov. 1986). “Fluorescent Dextran-Amines Used as Axonal Tracers in the Nervous System of the Chicken Embryo,” Journal of Neuroscience Methods 18(3):243-254.
Goldstein, J.A. et al. (Dec. 1998). “Intraoperative Angiography to Assess Graft Patency After Minimally Invasive Coronary Bypass,” Ann. Thorac. Surg. 66(6):1978-1982. [Exhibit 1007].
Gothoskar A.V. (Mar. 2004). “Resealed Erythrocytes: A Review,” Pharmaceutical Technology pp. 140, 142, 144, 146, 148, 150, 152 and 154-158, twelve pages.
Granzow, J.W. et al. (Jul. 2007). “Breast Reconstruction with Perforator Flaps” Plastic and Reconstructive Surgery 120(1):1-12.
Green, H.A. et al. (Jan. 1992). “Burn Depth Estimation Using Indocyanine Green Fluorescence,” Arch Dermatol 128(1):43-49.
Haglund, M. et al. (Feb. 1996). “Enhanced Optical Imaging of Human Gliomas and Tumor Margins,” Neurosurgery 38(2):308-317.
Haglund, M.M. et al. (Nov. 1994). “Enhanced Optical Imaging of Rat Gliomas and Tumor Margins,” Neurosurgery 35(5):930-941.
Hallock, G.G. (Jul. 2003). “Doppler Sonography and Color Duplex Imaging for Planning a Perforator Flap,” Clinics in Plastic Surgery 30(3):347-357. (Per J. Liebes cite with a later OA e-mail dated Mar. 24, 2016).
Hamamatsu Brochure. (May 1997). Specifications for Real-time Microscope Image Processing System: ARGUS-20 with C2400-75i, four pages [Exhibit 1006].
Hamamatsu. (Date unknown). Microscope Video Camera, for Fluorescent Observation, Easy Fluorescent Image Analysis C2400-73I, -75I Series a CCD Camera, seven pages.
Hayashi, J. et al. (Nov. 1993). “Transadventitial Localization of Atheromatous Plaques by Fluorescence Emission Spectrum Analysis of Mono-L Aspartyl-Chlorin e6,” Cardiovascular Research 27(11):1943-1947.
Hayata, Y. et al. (Jul. 1982). “Fiberoptic Bronchoscopic Laser Photoradiation for Tumor Localization in Lung Cancer,” Chest 82(1):10-14.
He, Z. (Feb. 2009). “Fluorogold Induces Persistent Neurological Deficits and Circling Behavior in Mice Over-Expressing Human Mutant Tau,” Current Neurovascular Research 6(1):54-61.
Herts, B.R. (May 2003). “Imaging for Renal Tumors,” Current Opin. Urol. 13(3):181-186.
Hirano, T. et al. (1989). “Photodynamic Cancer Diagnosis and Treatment System Consisting of Pulse Lasers and an Endoscopic Spectro-Image Analyzer,” Laser in Life Sciences 3(2):99-116.
Holm, C. et al. (2002). “Monitoring Free Flaps Using Laser-Induced Fluorescence of Indocyanine Green: A Preliminary Experience,” Microsurgery 22(7):278-287.
Holm, C. et al. (Apr. 2003, e-published on Feb. 25, 2003). “Laser-Induced Fluorescence of Indocyanine Green: Plastic Surgical Applications,” European Journal of Plastic Surgery 26(1):19-25.
Holm, C. et al. (Dec. 1, 2002). “Intraoperative Evaluation of Skin-Flap Viability Using Laser-Induced Fluorescence of Indocyanine Green,” British Journal of Plastic Surgery 55(8):635-644.
Hubel, P.M. et al. (2004). “Spatial Frequency Response of Color Image Sensors: Bayer Color Filters and Foveon X3,” Proceedings of SPIE 5301:402-406.
Humblet, V. et al. (Oct. 2005). “High-Affinity Near-Infrared Fluorescent Small-Molecule Contrast Agents for In Vivo Imaging of Prostate-Specific Membrane Antigen,” Molecular Imaging 4(4):448-462.
Hung, J. et al. (1991). “Autofluorescence of Normal and Malignant Bronchial Tissue,” Lasers in Surgery and Medicine 11(2):99-105.
Hyvärinen, L. et al. (1980). “Indocyanine Green Fluorescence Angiography.” Acta ophthalmologica 58(4):528-538. [Exhibit 1014].
Ikeda, S. (Jul. 1989). “Bronichial Telivision Endoscopy,” Chest 96(1):41S-42S.
Indian Office Action dated Jan. 31, 2018 for Indian Patent Application No. 6532/DELNP/2010 filed on Sep. 16, 2010, six pages.
Indian Office Action dated Jun. 26, 2018 for Indian Patent Application No. 8678/DELNP/2013 filed on Mar. 8, 2012, five pages.
Indian Office Action dated Jan. 16, 2018 for Indian Application No. 2993/DELNP/2011, filed on Apr. 25, 2011, eleven pages.
Indian Office Action dated Jul. 28, 2017 for Indian Application No. 1983/MUMNP/2007, filed on Nov. 27, 2007, seven pages.
Indian Office Action dated Sep. 22, 2016 for Indian Application No. 7566/DELNP/2010, filed on Oct. 27, 2010, nine pages.
International Preliminary Examination Report completed on Jul. 1, 2001 for PCT/US00/22088, filed on Aug. 11, 2000, three pages.
International Preliminary Report On Patentability completed on Aug. 22, 2019, for PCT/CA2017/050564, filed on May 10, 2017, nine pages.
International Preliminary Report on Patentability dated Aug. 22, 2019, for Patent Application No. PCT/CA2017/050564, mailed May 10, 2017, nine pages.
International Preliminary Report on Patentability dated Apr. 4, 2017 for PCT Application No. PCT/CA2015/050973 filed on Sep. 28, 2015, six pages.
International Preliminary Report on Patentability dated Dec. 27, 2018 for International Patent Application No. PCT/CA2017/050734 filed on Jun. 14, 2017, six pages.
International Preliminary Report on Patentability dated Feb. 3, 2009 for International Patent Application No. PCT/CA2007/001335 filed on Jul. 30, 2007, five pages.
International Preliminary Report on Patentability dated May 24, 2018 for International Patent Application No. PCT/CA2016/051315 filed on Nov. 10, 2016, nine pages.
International Preliminary Report on Patentability dated Nov. 6, 2007 for International Patent Application No. PCT/CA2006/000669, filed on Apr. 27, 2006, nine pages.
International Preliminary Report on Patentability dated Sep. 21, 2010 for International Patent Application No. PCT/US2009/037506, filed on Mar. 18, 2009, seven pages.
International Search Report and the Written Opinion of the International Searching Authority, or the Declaration dated Apr. 3, 2008 for PCT/US07/77892, filed on Sep. 7, 2007, ten pages.
International Search Report and written Opinion dated Apr. 24, 2017 for International Patent Application No. PCT/CA2017/050083, filed on Jan. 26, 2017, seven pages.
International Search Report and written Opinion dated Feb. 10, 2017 for International Patent Application No. PCT/CA2016/051315 filed on Nov. 10, 2016, thirteen pages.
International Search Report and Written Opinion dated Jul. 29, 2009 for PCT/US2009/043975 filed on May 14, 2009, eleven pages.
International Search Report and Written Opinion dated Oct. 24, 2017 for PCT Application No. PCT/CA2017/050564 filed on May 10, 2017, fourteen pages.
International Search Report and Written Opinion dated Sep. 18, 2017 for International Patent Application No. PCT/CA2017/050734, filed on Jun. 14, 2017, eight pages.
International Search Report dated Oct. 24, 2017, for Patent Application No. PCT/CA2017/050564, filed on May 10, 2017, six pages.
International Search Report dated Aug. 3, 2006, for International Patent Application No. PCT/CA2006/000669, filed on Apr. 27, 2006, three pages.
International Search Report dated Aug. 3, 2012, for International Patent Application No. PCT/IB2012/000601, filed on Mar. 8, 2012, three pages.
International Search Report dated Dec. 3, 2009 for PCT Patent Application No. PCT/IB2009/005700, filed on Apr. 14, 2009, three pages.
International Search Report dated Dec. 3, 2015 for PCT Application No. PCT/CA2015/050973 filed on Sep. 28, 2015, three pages.
International Search Report dated Dec. 7, 2007, for International Patent Application No. PCT/CA2007/001335, filed on Jul. 30, 2007, two pages.
International Search Report dated Feb. 1, 2012 for PCT Patent Application No. PCT/IB2011/002381, filed on Sep. 20, 2011, five pages.
International Search Report dated Jan. 21, 2002 for International Patent Application No. PCT/US2001/022198, filed on Jul. 13, 2001, three pages.
International Search Report dated Jan. 22, 2014 for PCT Application No. PCT/IB2013/001934, filed on Jun. 20, 2013, four pages.
International Search Report dated Jul. 4, 2008 for PCT Patent Application No. PCT/US2007/080847, filed on Oct. 9, 2007, three pages.
International Search Report dated Jul. 22, 2009 for International Patent Application No. PCT/US09/37506, filed on Mar. 18, 2009, two pages.
International Search Report dated Jun. 2, 2009 for PCT Application No. PCT/EP2008/008547, filed on Oct. 9, 2008, five pages.
International Search Report dated Jun. 8, 2009 for PCT Patent Application No. PCT/CA2009/000073, filed on Jan. 23, 2009, three pages.
International Search Report dated May 13, 2008 for Intentional Patent Application No. PCT/CA2008/00015, filed on Jan. 8, 2008, one page.
International Search Report dated Oct. 18, 2000 for PCT Application No. PCT/US2000/22088, filed on Aug. 11, 2000, one page.
International Search Report dated Sep. 11, 2009 for Application No. PCT/US2009/042606 filed on May 1, 2009, five pages.
Invitation to Pay Additional Fees and, Where Applicable, Protest Fee mailed on Jul. 4, 2017 for PCT/CA2017/050564, filed on May 10, 2017, two pages.
Invitation to Pay additional Fees and, where Applicable, Protest Fee, mailed Jul. 4, 2017, for Patent Application No. PCT/CA2017/050564, filed May 10, 2017, two pages.
Invitation to Pay additional Fees and, where Applicable, Protest Fee, mailed on Dec. 22, 2016 for International Patent Application No. PCT/CA2016/051315, filed on Nov. 10, 2016, two pages.
Jaber, S.F. et al. (Sep. 1998). “Role of Graft Flow Measurement Technique in Anastomotic Quality Assessment in Minimally Invasive CABG,” Ann. Thorac. Surg. 66(3):1087-1092.
Jagoe, J.R. et al. (1989). “Quantification of retinal damage during cardiopulmonary bypass,” Third International Conference on Image Processing and its Applications (Conf. Publ. No.307), IEE, pp. 319-323.
Jamis-Dow, C.A. et al. (Mar. 1996). “Small (< or = 3-cm) Renal Masses: Detection with CT versus US and Pathologic Correlation,” Radiology 198(3):785-788.
Japanese Final Office Action dated Aug. 2, 2013 for Japanese Application No. 2008-509275, filed on Apr. 27, 2006, four pages.
Japanese Final Office Action dated Feb. 5, 2018 for Japanese Patent Application No. 2016-014503, filed on Jan. 28, 2016, six pages.
Japanese Final Office Action dated Jan. 28, 2019 for Japanese Patent Application No. 2016-014503, filed on Jan. 28, 2016, 3 pages.
Japanese Final Office Action dated Sep. 25, 2018 for Japanese Application No. 2017-518785 filed on Apr. 7, 2017, six pages.
Japanese Notice of Allowance dated Apr. 2, 2018 for Japanese Patent Application No. 2017-018858 filed on Feb. 3, 2017, six pages.
Japanese Notice of Allowance dated Jan. 25, 2019 for Japanese Application No. 2017-518785 filed on Apr. 7, 2017, six pages.
Japanese Notice of Allowance dated Jan. 5, 2017 for Japanese Patent Application No. 2015-238784, filed on Dec. 7, 2015, six pages.
Japanese Notice of Allowance dated Jun. 7, 2019 for Japanese Patent Application No. 2017-516925 filed on Mar. 28, 2017, six pages.
Japanese Notice of Allowance dated Jun. 8, 2018 for Japanese Patent Application No. 2016-203798 filed on Oct. 17, 2016, six pages.
Japanese Notice of Allowance dated Jun. 21, 2019 for Japanese Patent Application No. 2018-129970, filed on Jul. 9, 2018, six pages.
Japanese Notice of Allowance dated May 10, 2019 for Japanese Patent Application No. 2017-205499, filed on Nov. 24, 2017, six pages.
Japanese Notice of Allowance dated Nov. 17, 2017 for Japanese Application No. 2016-253736 filed on Dec. 27, 2016, six pages.
Japanese Notice of Allowance dated Nov. 28, 2016 for Japanese Patent Application No. 2015-245598, filed on Mar. 8, 2012, six pages.
Japanese Notice of Allowance dated Sep. 16, 2016 for Japanese Patient Application No. 2015-517876 filed on Jun. 20, 2013, six pages.
Japanese Notice of Allowance dated Sep. 25, 2017 for Japanese Patent Application No. 2013-529729, filed on Mar. 21, 2013, six pages.
Japanese Office Action dated Jan. 10, 2020, for Japanese Patent Application No. 2018-516161, filed Nov. 10, 2016, five pages.
Japanese Office Action dated Apr. 1, 2016 for Japanese Patent Application No. 2013-529729, filed on Mar. 21, 2013, seven pages.
Japanese Office Action dated Apr. 20, 2012 for Japanese Patent Application No. 2011-500921, filed Mar. 18, 2009, four pages.
Japanese Office Action dated Apr. 3, 2015 for Japanese Patent Application No. 2013-058356, filed Mar. 18, 2009, four pages.
Japanese Office Action dated Aug. 20, 2018 for Japanese Patent Application No. 2017-205499, filed on Nov. 24, 2017, six pages.
Japanese Office Action dated Dec. 8, 2017 for Japanese Patent Application No. 2017-018858, filed on Feb. 3, 2017, six pages.
Japanese Office Action dated Feb. 1, 2016 for Japanese Patent Application No. 2015-517876 filed on Jun. 20, 2013, eight pages.
Japanese Office Action dated Feb. 17, 2012 for Japanese Application No. 2008-509275, filed on Apr. 27, 2006, six pages.
Japanese Office Action dated Jul. 12, 2019, for Patent Application No. 2018-51661, filed Nov. 10, 2016, twenty-one pages.
Japanese Office Action dated Jul. 22, 2014 for Japanese Patent Application No. 2013-557187 filed Mar. 8, 2012, seven pages.
Japanese Office Action dated Jul. 28, 2017 for Japanese Patent Application No. 2016-203798 filed on Oct. 17, 2016, four pages.
Japanese Office Action dated Jul. 30, 2013, issued in counterpart Japanese Application No. 2011-504574, filed on Apr. 14, 2009, six pages.
Japanese Office Action dated Mar. 3, 2017 for Japanese Patent Application No. 2016-014503, filed on Jan. 28, 2016, ten pages.
Japanese Office Action dated Mar. 19, 2018 for Japanese Application No. 2017-518785 filed on Apr. 7, 2017, eight pages.
Japanese Office Action dated Mar. 31, 2017 for Japanese Patent Application No. 2013-529729, filed on Mar. 21, 2013, eleven pages.
Japanese Office Action dated Mar. 9, 2015 for Japanese Patent Application No. 2013-557187, filed Mar. 8, 2012, five pages.
Japanese Office Action dated May 7, 2018 for Japanese Patent Application No. 2017-516925 filed on Mar. 28, 2017, four pages.
Japanese Office Action dated May 26, 2014 in Japanese Patent Application No. 2013-058356, filed on Mar. 18, 2009, w/Concise Explanation of the Relevance, three pages.
Japanese Office Action dated Nov. 11, 2011 for Japanese Application No. 2009-521077, filed on Jul. 30, 2007, four pages.
Japanese Office Action dated Nov. 19, 2018 for Japanese Patent Application No. 2017-516925 filed on Mar. 28, 2017, four pages.
Japanese Office Action dated Sep. 13, 2019 for Japanese Patent Application No. 2018-153572, filed on Oct. 9, 2014, 3 pages.
Japanese Office Action dated Sep. 14, 2012 for Japanese Application No. 2008-509275, filed on Apr. 27, 2006, seven pages.
Japanese Office Action dated Sep. 14, 2015 for Japanese Patent Application No. 2011-504574, filed on Apr. 14, 2009, three pages.
Japanese Office Action dated Sep. 19, 2014 for Japanese Application No. 2013-246636, filed on Apr. 27, 2006, six pages.
Japanese Office dated Dec. 26, 2012 for Japanese Patent Application No. 2011-500921, filed on Mar. 18, 2009, two pages.
Jolion, J. et al. (Aug. 1991). “Robust Clustering with Applications in Computer Vision,” IEEE Transactions on Pattern Analysis and Machine Intelligence 13(8):791-802.
Kamolz, L.-P. et al. (Dec. 2003). “Indocyanine Green Video Angiographies Help to Identify Burns Requiring Operation,” Burns 29(8):785-791.
Kapadia, C.R. et al. (Jul. 1990). “Laser-Induced Fluorescence Spectroscopy of Human Colonic Mucosa. Detection of Adenomatous Transformation,” Gastroenterology 99(1):150-157.
Kato, H. et al. (Jun. 1985). “Early Detection of Lung Cancer by Means of Hematoporphyrin Derivative Fluorescence and Laser Photoradiation,” Clinics in Chest Medicine 6(2):237-253.
Kato, H. et al. (Jun. 1990). “Photodynamic Diagnosis in Respiratory Tract Malignancy Using an Excimer Dye Laser System,” Journal of Photochemistry and Photobiology, B. Biology 6(1-2):189-196.
Keon, W.J. et al. (Dec. 1979). “Coronary Endarterectomy: An Adjunct to Coronary Artery Bypass Grafting,” Surgery 86(6):859-867.
Kim, S. et al. (Jan. 2004, e-published Dec. 7, 2003). “Near-Infrared Fluorescent Type II Quantum Dots for Sentinel Lymph Node Mapping,” Nature Biotechnology 22(1):93-97.
Kiryu, J. et al. (Sep. 1994). “Noninvasive Visualization of the Choriocapillaris and its Dynamic Filling,” Investigative Ophthalmology & Visual Science 35(10):3724-3731.
Kitai, T. et al. (Jul. 2005). “Fluorescence Navigation with Indocyanine Green for Detecting Sentinel Lymph Nodes in Breast Cancer,” Breast Cancer 12(3):211-215.
Kleszcyńska, H. et al. (Mar. 2005). “Hemolysis of Erythrocytes and Erythrocyte Membrane Fluidity Changes by New Lysosomotropic Compounds,” Journal of Fluorescence 15(2):137-141.
Köbbert, C. et al. (Nov. 2000). “Current Concepts in Neuroanatomical Tracing,” Progress in Neurobiology 62(4):327-351.
Kokaji, K. et al. (Date Unknown). “Intraoperative Quality Assessment by Using Fluorescent Imaging in Off-pump Coronary Artery Bypass Grafting,” The Department of Cardiovascular Surgery, University of Keio, Tokyo, Japan, one page (Abstract only).
Kolaman, A. et al. (2016). “Amplitude Modulated Video Camera—Light Separation in Dynamic Scenes,” IEEE Conference on Computer Vision and Pattern Recognition (CVPR), located at https://www.cv-foundation.org/openaccess/content_cvpr_2016/app/S15-50.pdf last visited on Jun. 8, 2020, nine pages.
Kömürcü, F. et al. (Feb. 2005). “Management Strategies for Peripheral latrogenic Nerve Lesions,” Annals of Plastic Surgery 54(2):135-139.
Korean Decision on the Trial Against Final Rejection from the Intellectual Property Tribunal (IPT) dated Sep. 25, 2017 for Korean Patent Application No. 2013-7026479, filed on Oct. 7, 2013, seventeen pages.
Korean Notice of Allowance dated Apr. 27, 2017 for Korean Patent Application No. 10-2016-7007994, filed on Mar. 25, 2016, three pages.
Korean Notice of Allowance dated Apr. 29, 2016 for Korean Patent Application No. 10-2010-7024977, filed on Apr. 14, 2009, three pages.
Korean Notice of Allowance dated Dec. 13, 2017 for Korean Patent Application No. 10-2017-7008654, filed on Mar. 29, 2017, three pages.
Korean Notice of Allowance dated Jan. 2, 2017 for Korean Patent Application No. 10-2015-7033310, filed on Nov. 20, 2015, three pages.
Korean Notice of Allowance dated May 20, 2019 for Korean Patent Application No. 2019-7005800, filed on Feb. 26, 2019, three pages.
Korean Notice of Allowance dated Nov. 30, 2018 for Korean Patent Application No. 10-2017-7012463, filed on May 8, 2017, three pages.
Korean Office Action dated Apr. 17, 2018 for Korean Patent Application No. 10-2017-7012463, filed on May 8, 2017, six pages.
Korean Office Action dated Aug. 20, 2015 for Korean Patent Application No. 20137026479 filed on Mar. 8, 2012, three pages.
Korean Office Action dated Aug. 30, 2016 for Korean Patent Application No. 10-2015-7033310 filed on Mar. 8, 2012, seven pages.
Korean Office Action dated Dec. 4, 2018 for Korean Patent Application No. 2017-7011565, filed on Apr. 4, 2017, nine pages.
Korean Office Action dated Dec. 8, 2015 for Korean Patent Application No. 20157033310 filed on Mar. 8, 2012, seven pages.
Korean Office Action dated Jun. 25, 2014 in Korean Patent Application No. 10-2013-7035027, filed on May 14, 2009, fifteen pages.
Korean Office Action dated Jun. 27, 2017 for Korean Patent Application No. 2017-7008654, filed on Mar. 29, 2017, ten pages.
Korean Office Action dated Nov. 30, 2015 for Korean Patent Application No. 10-2010-7024977, filed on Apr. 14, 2009, two pages.
Korean Office Action dated Sep. 25, 2019, for Patent Application No. 10-2017-7011565, filed Sep. 28, 2015, 7 pages, including the English translation.
Krishnan, K. G. et al. (Apr. 1, 2005). “The Role of Near-Infrared Angiography in the Assessment of Post-Operative Venous Congestion in Random Pattern, Pedicled Island and Free Flaps”, British Journal of Plastic Surgery 58(3):330-338.
Kuipers, J.A. et al. (1999). “Recirculatory and Compartmental Pharmacokinetic Modeling of Alfentanil Pigs, the Influence of Cardiac Output,” Anesthesiology 90(4):1146-1157.
Kupriyanov, V.V. et al. (Nov. 2004; , e-publication Sep. 28, 2004). “Mapping Regional Oxygenation and Flow in Pig Hearts In Vivo Using Near-infrared Spectroscopic Imaging,” Journal of Molecular and Cellular Cardiology 37(5):947-957.
Kurihara, K. et al. (Jun. 1984). “Nerve Staining with Leucomethylene Blue: An Experimental Study,” Plastic and Reconstruction Surgery 73(6):960-964.
Kyo, S. (Date Unknown). “Use of Ultrasound Cardiology during Coronary Artery Bypass Surgery,” Heart and Blood Vessel Imaging II, three pages.
Lam, S. et al. (1991). “Mechanism of Detection of Early Lung Cancer by Ratio Fluorometry,” Lasers in Life Sciences 4(2):67-73.
Lam, S. et al. (Feb. 1990). “Detection of Early Lung Cancer Using Low Dose Photofrin II,” Chest 97(2):333-337.
Lam, S. et al. (Jul. 1, 1990). “Detection of Lung Cancer by Ratio Fluorometry With and Without Photofrin II,” Proc. SPIE—Optical Fibers in Medicine V 1201:561-568.
Lam, S. et al. (Nov. 1-4, 1990). “Fluorescence Imaging of Early Lung Cancer,” Annual International Conference of the IEEE Engineering in Medicine and Biology Society 12(3):1142-1143.
Lam, S.C. et al. (1993). “Fluorescence Detection,” Chapter 20 in Lung Cancer, Roth, J.A. (ed.), et al., Blackwell Scientific Publications Inc., 238 Main Street, Cambridge, Massachusetts, 02142, pp. 325-338, sixteen pages.
Lanciego, J.L. et al. (Jun. 1998). “Multiple Neuroanatomical Tracing in Primates,” Brain Research Protocols 2(4):323-332.
Lanciego, J.L. et al. (Oct. 1998). “Multiple Axonal Tracing: Simultaneous Detection of Three Tracers in the Same Section,” Histochemistry and Cell Biology 110(5):509-515.
Laub, G.W. et al. (Nov. /Dec. 1989). “Experimental Use of Fluorescein for Visualization of Coronary Arteries,” Vascular and Endovascular Surgery 23(6):454-457.
Lee, E.T. et al. (Mar. 1997). “A New Method For Assessment of Changes in Retinal Blood Flow,” Medical Engineering & Physics 19(2):125-130.
Leissner, J. et al. (Jan. 2004). “Extended Radical Lymphadenectomy in Patients with Urothelial Bladder Cancer: Results of a Prospective Multicenter Study,” The Journal of Urology 171(1):139-144.
Leithner, C. (Jul. 14, 2003). “Untersuchung der Sauerstoffkonzentrationsveranderungen in der Mikrozirkulation des Hirnkortex von Ratten bei funktioneller Stimulation mittels Phosphorescence Quenching,” [dissertation], Jul. 14, 2003; retrieved from the Internet: <http://edoc.hu-berlin.de/d issertationen/leith ner-ch ristoph-2003-07-14/>, two hundred and eight pages.
Li, X. et al. (May 12, 2004). “Method for Retinal Vessel Detection and Diameter Measurement,” Presented at Medical Imaging 2004:Image Processing, San Diego, CA, Proceedings of SPIE 5370:1746-1754.
Liedberg, F. et al. (2003). “Sentinel-Node-Diagnostik Beim Invasiven (Bladder Cancer and the Sentinel Node Concept),” Aktuel Urol. 34:115-118.
Liedberg, F. et al. (Jan. 2006). “Intraoperative Sentinel Node Detection Improves Nodal Staging in Invasive Bladder Cancer,” The Journal of Urology 175(1):84-89.
Lippincott's New Medical Dictionary. “Perfusion,” p. 707 (1897), three pages.
Liptay, M.J. (Mar. 2004). “Sentinel Node Mapping in Lung Cancer,” Annals of Surgical Oncology 11(Supplement 3):271S-274S.
Little, J.R. et al. (May 1979). “Superficial Temporal Artery to Middle Cerebral Artery Anastomosis: Intraoperative Evaluation by Fluorescein Angiography and Xenon-133 Clearance,” Journal of Neurosurgery 50(5):560-569. [Exhibit 1002].
Liu, Q.P. et al. (Apr. 2007). “Bacterial Glycosidases for the Production of Universal Red Blood Cells” Nature Biotechnology 25(7):454-464.
Lund, F. et al. (Nov. 1997). “Video Fluorescein Imaging of the Skin: Description of an Overviewing Technique for Functional Evaluation of Regional Cutaneous Blood Evaluation of Regional Cutaneous Perfusion in Occlusive Arterial Disease of the Limbs,” Clinical Physiology 17(6):619-633.
Lyon, R.E. et al. (2002). “Eyeing the Camera: Into the Next Century,” 10 Color and Imaging Conference Final Program & Proceedings 349-355.
Mack, M.J. et al. (Sep. 1998). “Arterial Graft Patency in Coronary Artery Bypass Grafting: What Do We Really Know?,” Ann. Thorac. Surg. 66(3):1055-1059.
Magnani, M. et al. (1998). “Erythrocyte Engineering for Drug Delivery and Targeting,” Biotechnol. Appl. Biochem. 28:1-6.
Magnani, M. et al. (Jul. 15, 1992). “Targeting Antiretroviral Nucleoside Analogues in Phosphorylated Form to Macrophasges: In Vitro and In Vivo Studies,” Proc. Natl. Acad. Sci. USA 89(14):6477-6481.
Malmstrom et al. (Nov. 2002). “Early Metastatic Progression of Bladder Carcinoma: Molecular Profile of Primary Tumor and Sentinel Lymph Node,” The Journal of Urology 168(5):2240-2244.
Malmström, P.U. et al. (Jul. 2004). “RE: Extended Radical Lymphadenectomy in Patients With Urothelial Bladder Cancer: Results of a Prospective Multicenter Study,” J. of Urol. 172(1):386, one page.
Marangos, N. et al. (Dec. 2001). “In Vivo Visualization of the Cochlear Nerve and Nuclei with Fluorescent Axonal Tracers,” Hearing Research 162(1-2):48-52.
Martinez-Pérez, M. et al. (Sep. 19, 1996). “Unsupervised Segmentation Based on Robust Estimation and Cooccurrence Data,” Proceedings of the International Conference on Miage Processing (ICIP) Lausanne 3:943-945.
Martinez-Perez, M.E. et al. (Aug. 2002). “Retinal Vascular Tree Morphology: A Semi-Automatic Quantification,” IEEE Transactions of Biomedical Engineering 49(8):912-917.
May, S. (May/Jun. 1995). “Photonic Approaches to Burn Diagnostics,” Biophotonics International pp. 44-50.
Mckee, T.D. et al. (Mar. 1, 2006). “Degradation of Fibrillar Collagen in a Human Melanoma Xenograft Improves the Efficacy of an Oncolytic Herpes Simplex Virus Vector,” Cancer Research 66(5):2509-2513.
Merriam Webster Medline Plus Medical Dictionary. “Perfusion,” located at http://www.merriam-webster.com/medlineplus/perfusion, last visited on Apr. 15, 2015, one page.
Mexican Office Action dated May 30, 2013, issued in counterpart Mexican Application No. MX/a/2010/011249. no translation.
Minciacchi, D. et al. (Jul. 1991). “A Procedure for the Simultaneous Visualization of Two Anterograde and Different Retrograde Fluorescent Tracers-Application to the Study of the Afferent-Efferent Organization of Thalamic Anterior Intralaminar Nuclei” Journal of Neuroscience Methods 38(2-3):183-191.
Mitaka USA, Inc. (2015). “PDE Breast Free Flap Evaluation,” located at <http://mitakausa.com/category/pde_education/flaps/>, last visited on Oct. 7, 2016, four pages.
Mitaka USA, Inc. (2015). “PDE-Neo” located at <http://mitakausa.com/pde-neo/>, last visited on Oct. 7, 2016, two pages.
Mohr, F.W. et al. (May 1997). “Thermal Coronary Angiography: A Method for Assessing Graft Patency and Coronary Anatomy in Coronary Bypass Surgery,” Ann Thorac. Surgery 63(5):1506-1507.
Montán, S. et al. (Feb. 1, 1985). “Multicolor Imaging and Contrast Enhancement in Cancer-Tumor Localization Using Laser-Induced Fluorescence in Hematoporphyrin-Derivative- Bearing Tissue,” Optics Letters 10(2):56-58.
Mothes, H. et al. (Nov. 2004). “Indocyanine-Green Fluorescence Video Angiography Used Clinically to Evaluate Tissue Perfusion in Microsurgery,” The Journal of Trauma Injury, Infection, and Critical Care 57(5):1018-1024.
Motomura, K. et al. (1999). “Sentinel Node Biopsy Guided by Indocyanine Green Dye in Breast Cancer Patients,” Japan J. Clin. Oncol. 29(12):604-607.
Mullooly, V.M. et al. (1990). “Dihematoporphyrin Ether-Induced Photosensitivity in Laryngeal Papilloma Patients,” Lasers in Surgery and Medicine 10(4):349-356.
Murphy (2001). “Digital CCD Microscopy,” Chapter 14 in Fundamentals of Light Microscopy and Electronic Imaging, John Wiley and Sons, pp. i-xi and 259-281.
Murray et al., U.S. Notice of Allowance and Fee(s) due dated Jul. 13, 2020, directed to U.S. Appl. No. 29/562,795; 7 pages.
Murray et al., U.S. Office Action dated Aug. 31, 2020, directed to U.S. Appl. No. 16/746,539; 16 pages.
Murray et al., U.S. Notice of Allowance and Fee(s) Due dated Dec. 22, 2020, directed to U.S. Appl. No. 16/746,539; 7 pages.
Nahlieli, O. et al. (Mar. 2001). “Intravital Staining with Methylene Blue as an Aid to Facial Nerve Identification in Parotid Gland Surgery” J. Oral Maxillofac. Surgery 59(3):355-356.
Nakamura, T. et al. (1964). “Use of Novel Dyes, Coomassie Blue and Indocyanine Green in Dye Dilution Method,” Tohoka University, Nakamura Internal Department, The Tuberculosis Prevention Society, Tuberculosis Research Laboratory, 17(2):1361-1366, seventeen pages.
Nakayama, A. et al. (Oct. 2002). “Functional Near-Infrared Fluorescence Imaging for Cardiac Surgery and Targeted Gene Therapy,” Molecular Imaging 1(4):365-377.
Naumann, T. et al. (Nov. 15, 2000). “Retrograde Tracing with Fluoro-Gold: Different Methods of Tracer Detection at the Ultrastructural Level and Neurodegenerative Changes of Back-Filled Neurons in Long-Term Studies,” Journal of Neuroscience Methods 103(1):11-21.
Newman et al. (Oct. 31, 2008). “Update on the Application of Laser-Assisted Indocyanine Green Fluorescent Dye Angiography in Microsurgical Breast Reconstruction,” American Society of Plastic Surgeons, Plastic Surgery 2008, 2 pages.
Nimura, H. et al. (May 2004, e-published on Mar. 22, 2004). “Infrared Ray Electronic Endoscopy Combined with Indocyanine Green Injection for Detection of Sentinel Nodes of Patients with Gastric Cancer,” British Journal of Surgery 91(5):575-579.
Novadaq Technologies Inc. (Jan. 29, 2007). “Novadaq Imaging System Receives FDA Clearance for use During Plastic Reconstructive Surgery,” PR Newswire three pages.
Novadaq Technologies Inc. (Jan. 19, 2005). 510(k) Summary—Showing X-Ray Fluoroscopy as Predicate Device, Fluorescent Angiographic System, six pages, [Exhibit 1012].
Novadaq Technologies Inc.'s Preliminary Response filed on Aug. 23, 2017 to Petition for Inter Partes Review of U.S. Pat. No. 8,892, 190, sixty one pages.
Oddi, A. et al. (Jun. 1996). “Intraoperative Biliary Tree Imaging with Cholyl-Lysyl-Fluorescein: An Experimental Study in the Rabbit” Surgical Laparoscopy & Endoscopy 6(3):198-200.
Office Action dated Jul. 2, 2020, directed to CN Application No. 201680066060.0; 30 pages.
Office Action dated Jul. 6, 2020, directed to CA Application No. 3,009,419; 3 pages.
Office Action dated Nov. 18, 2020, directed to CA Application No. 3,027,592; 3 pages.
Office Action dated Sep. 16, 2020, directed to EP Application No. 16 186 321.2; 4 pages.
Ogata, F. et al. (Jun. 2007). “Novel Lymphography Using Indocyanine Green Dye for Near-Infrared Fluorescence Labeling,” Annals of Plastic Surgery 58(6):652-655.
Ohnishi, S. et al. (Jul.-Sep. 2005). “Organic Alternatives to Quantum Dots for Intraoperative Near-Infrared Fluorescent Lymph Node Mapping” Molecular Imaging 4(3):172-181.
Ooyama, M. (Oct. 12-15, 1994). The 8th Congress of International YAG Laser Symposium, The 15th Annual Meeting of Japan Society for Laser Medicine, Sun Royal Hotel, Japan, eight pages.
Ott, P. (1998). “Hepatic Elimination of Indocyanine Green with Special Reference to Distribution Kinetics and the Influence of Plasma Protein Binding,” Pharmacology & Toxicology 83(Supp. II):5-48.
Oxford Concise Medical Dictionary. “Perfusion,” p. 571 (1980), three p.
Pagni, S. et al. (Jun. 1997). “Anastomotic Complications in Minimally Invasive Coronary Bypass Grafting,” Ann. Thorac. Surg. 63(6 Suppl): S64-S67.
Palcic et al. (1991). “Lung Imaging Fluorescence Endoscope: A Device for Detection of Occult Lung Cancer,” Medical Design and Material, thirteen pages.
Palcic, B. et al. (1990). “Development of a Lung Imaging Fluorescence Endoscope,” Annual International Conference of the IEEE Engineering in Medicine and Biology Society 12(1):0196-0197.
Palcic, B. et al. (Aug. 1, 1990). “The Importance of Image Quality for Computing Texture Features in Biomedical Specimens,” Proc. SPIE 1205:155-162.
Palcic, B. et al. (Jun. 1, 1991). “Lung Imaging Fluorescence Endoscope: Development and Experimental Prototype,” Proc. SPIE 1448:113-117.
Palcic, B. et al. (Mar. 1991). “Detection and Localization of Early Lung Cancer by Imaging Techniques,” Chest 99(3):742-743.
Pandharlpande, P.V. et al. (Mar. 2005). “Perfusion Imaging of the Liver: Current Challenges and Future Goals,” Radiology 234(3):661-673.
Paques, M. et al. (Mar. 2003). “Axon-Tracing Properties of Indocyanine Green,” Arch Ophthalmol. 121(3):367-370.
Parungo, C.P. et al. (Apr. 2005). “Intraoperative Identification of Esophageal Sentinel Lymph Nodes with Near-Infrared Fluorescence Imaging,” The Journal of Thoracic and Cardiovascular Surgery 129(4):844-850.
Parungo, C.P. et al. (Dec. 2004, e-published on Nov. 15, 2004). “In Vivo Optical Imaging of Pleural Space Drainage to Lymph Nodes of Prognostic Significance,” Annals of Surgical Oncology 11(12):1085-1092.
Peak, M.J. et al. (1986). “DNA-to-Protein Crosslinks and Backbone Breaks Caused by FAR- and NEAR-Ultraviolet and Visible Light Radiations in Mammalian Cells,” in Mechanism of DNA Damage and Repair, Implications for Carcinogenesis and Risk Assessment, SIMIC, M.G. (ed.) et al., Plenum Press, 233 Spring Street, New York, N.Y. 10013, pp. 193-202.
Peiretti et al. (2005). “Human erythrocyte-ghost-mediated choroidal angiography and photocoagulation.” Database Biosis [online] Biosciences Information Service, Philadelphia, PA, US, XP002725023, Database accession No. Prev200600056121 (abstract), three pages.
Peiretti, E. et al. (May 2005). “Human Erythrocyte-Ghost-Mediated Choroidal Angiography and Photocoagulation,” Investigative Ophthalmology & Visual Science, ARVO Annual Meeting Abstract 46(13):4282, located at <http://iovs.arvojournals.org/article.aspx?articleid=2403707>, last visited on Oct. 7, 2016, two pages.
Perez, M.T. et al. (Sep. 2002). “In Vivo Studies on Mouse Erythrocytes Linked to Transferrin,” IUBMB Life 54(3):115-121.
Petition for Inter Partes Review of U.S. Patent No. 8,892, 190 (May 11, 2017), filed on by Visionsense Corp., fifty four pages.
Pfister, A.J. et al. (Dec. 1992). “Coronary Artery Bypass Without Cardiopulmonary Bypass,” Ann. Thorac. Surg. 54(6):1085-1092, (Discussion by S.R. Gundry).
Phillips, R.P. et al. (1991). “Quantification of Diabetic Maculopathy by Digital Imaging of the Fundus,” Eye 5(1):130-137.
Piermarocchi, S. et al. (Apr. 2002). “Photodynamic Therapy Increases the Eligibility for Feeder Vessel Treatment of Choroidal Neovascularization Caused by Age-Related Macular Degeneration,” American Journal of Ophthalmology 133(4):572-575.
Profio, A.E. et al. (Jul.-Aug. 1984). “Fluorometer for Endoscopic Diagnosis of Tumors,” Medical Physics 11(4):516-520.
Profio, A.E. et al. (Jun. 1, 1991). “Endoscopic Fluorescence Detection of Early Lung Cancer,” Proc. SPIE 1426:44-46.
Profio, A.E. et al. (Nov./Dec. 1979). “Laser Fluorescence Bronchoscope for Localization of Occult Lung Tumors,” Medical Physics 6:523-525.
Profio, A.E. et al. (Sep.-Oct. 1986). “Digital Background Subtraction for Fluorescence Imaging,” Medical Physics 13(5):717-721.
Puigdellivol-Sanchez, A. et al. (Apr. 15, 2002). “On the Use of Fast Blue, Fluoro-Gold and Diamidino Yellow for Retrograde Tracing After Peripheral Nerve Injury: Uptake, Fading, Dye Interactions, and Toxicity,” Journal of Neuroscience Methods 115(2):115-127.
Pyner, S. et al. (Nov. 2001). “Tracing Functionally Identified Neurones in a Multisynaptic Pathway in the Hamster and Rat Using Herpes Simplex Virus Expressing Green Fluorescent Protein,” Experimental Physiology 86(6):695-702.
Raabe et al. (2009, e-published on Nov. 12, 2008). “Laser Doppler Imaging for Intraoperative Human Brain Mapping”, NeuroImage 44:1284-1289.
Raabe, A. et al. (Jan. 2003). “Near-Infrared Indocyanine Green Video Angiography: A New Method for Intraoperative Assessment of Vascular Flow,” Neurosurgery 52(1):132-139.
Rava, R.P. et al. (Jun. 1, 1991). “Early Detection of Dysplasia in Colon and Bladder Tissue Using Laser-Induced Fluorescence,” Proc. SPIE 1426:68-78.
Razum, N. et al. (Nov. 1987). “Skin Photosensitivity: Duration and Intensity Following Intravenous Hematoporphyrin Derivatives, HpD and DHE, ” Photochemistry and Photobiology 46(5):925-928.
Report on Observation by C2400-75i and ARGUS20 Under Low illumination conditions, Jan. 17, 2008, six pages.
Request for Invalidation dated Jun. 29, 2007 for Japanese Patent No. JP-3881550, filed by Hamamatsu Photonics, Inc., eighty five pages.
Reuthebuch, O et al. (Feb. 2004). “Novadaq SPY: Intraoperative Quality Assessment in Off Pump Coronary Artery Bypass Grafting,” Chest 125(2):418-424.
Reuthebuch, O.T. et al. (May 2003). “Graft Occlusion After Deployment of the Symmetry Bypass System,” Ann. Thorac. Surg. 75(5):1626-1629.
Richards-Kortum, R. et al. (Jun. 1991). “Spectroscopic Diagnosis of Colonic Dysplasia: Spectroscopic Analysis,” Biochemistry and Photobiology 53(6):777-786.
Roberts, W.W. et al. (Dec. 1997). “Laparoscopic Infrared Imaging,” Surg. Endoscopy 11(12):1221-1223.
Rodnenkov, O.V. et al. (May 2005). “Erythrocyte Membrane Fluidity and Haemoglobin Haemoporphyrin Conformation: Features Revealed in Patients with Heart Failure,” Pathophysiology 11(4):209-213.
Ropars, C. (ed.) et al. (1987). Red Blood Cells as Carriers for Drugs. Potential therapeutic Applications, Pergamon Press, Oxford, New York, pp. v-vii, (Table of Contents only), four pages.
Ross, G.L. et al. (Dec. 2002). “The Ability of Lymphoscintigraphy to Direct Sentinel Node Biopsy in the Clinically N0 Neck for Patients with Head and Neck Squamous Cell Carcinoma,” The British Journal of Radiology 75(900):950-958.
Ross, G.L. et al. (Jul. 2004, e-published on Jun. 14, 2000). “Sentinel Node Biopsy in Head and Neck Cancer: Preliminary Results of a Multicenter Trial,” Annals of Surgical Oncology 11(7):690-696.
Rossi, L. et al. “RBC-mediated delivery of dexamethasone in patients with chronic obstructive pulmonary disease”, Biotechnol Appl Biochem. 2001; 33:85-89.
Rossi, L. et al., “Heterodimer-Loaded RBCs as Bioreactors for Slow Delivery of The Antiviral Drug Azidothymidine and the Antimycobacterial Drug Ethambutol.” AIDS Res Hum Retrovir 1999; 15:345-353.
Rossi, L. et al., “Low doses of dexamethasone constantly delivered by autologous RBCs slow the progression of lung disease in cystic fibrosis patients”, Blood Cells Mol Dis. 2004; 33:57-63.
Rozen, W.M. et al. (Jan. 2008). “Preoperative Imaging for DIEA Perforator Flaps: A Comparative Study of Computed Tomographic Angiography and Doppler Ultrasound,” Plastic and Reconstructive Surgery 121(1):9-16. (Per J. Liebes cite with a later OA e-mail dated Mar. 24, 2016).
Rübben, A. et al. (Mar. 1994). “Infrared Videoangiofluorography of the Skin with Indocyanine Green—Rat Random Cutaneous Flap Model and Results in Man,” Microvascular Research 47(2):240-251.
Rubens, F.D. et al. (2002). “A New and Simplified Method for Coronary and Graft Imaging During CABG,” The Heart Surgery Forum 5(2):141-144.
Russian Notice of Allowance dated Jul. 29, 2013, issued in counterpart Russian Application No. 2011111078.14, five pages.
Russian Notice of Allowance dated Aug. 19, 2016 for Russian Patent Application No. 2013144845/07, filed on Mar. 8, 2012, thirteen pages.
Russian Office Action dated Mar. 29, 2013, issued in counterpart Russian Application No. 2011111078.14, three pages.
Sakatani, K. et al. (Nov. 1997). “Noninvasive Optical Imaging of the Subarchnoid Space and Cerebrospinal Fluid Pathways Based on Near Infrared Fluorescence,” J. Neurosurg. 87(5):738-745.
Salmon, E.D. et al. (Oct. 1994). “High Resolution Multimode Digital Imaging System for Mitosis Studies In Vivo and In Vitro,” Biol. Bull 187(2):231-232.
Sato, M. et al., (1991). “Development of a Visualization Method for the Microcirculation of Deep Viscera Using an Infrared Intravital Microscope System,” Research on ME Devices and ME Technology (with English Translation), five pages.
Satpathy G.R. et al. (Oct. 2004; , e-publication Aug. 7, 2004). “Loading Red Blood Cells with Trehalose: A Step Towards Biostabilization,” Cryobiology 49(2):123-136.
Schaff, H.V. et al. (Oct. 15, 1996). “Minimal Thoracotomy for Coronary Artery Bypass: Value of Immediate Postprocedure Graft Angiography,” Supplement to Circulation 94(8):1-51, (Abstract No. 0289), two pages.
Schellingerhout, D. et al. (Oct. 2000). “Quantitation of HSV Mass Distribution in a Rodent Brain Tumor Model,” Gene Therapy 7(19):1648-1655.
Schmued, L. et al. (Aug. 27, 1990). “In Vivo Anterograde and Retrograde Axonal Transport of the Fluorescent Rhodamine-Dextran-Amine, Fluoro-Ruby, Within the CNS,” Brain Research 526(1):127-134.
Schmued, L.C. et al. (Oct. 29, 1993). “Intracranial Injection of Fluoro-Gold Results in the Degeneration of Local but not Retrogradely Labeled Neurons,” Brain Research 626(1-2):71-77.
Schneider Jr., H.C. et al. (Jan. 1975). “Fluorescence of Testicle, an Indication of Viability of Spermatic Cord After Torsion,” Urology V(1):133-136.
Seeman, P. (Jan. 1, 1967). “Transient Holes in the Erythrocyte Membrane During Hypotonic Hemolysis and Stable Holes in the Membrane After Lysis by Saponin and Lysolecithin,” Journal of Cell Biology 32(1):55-70.
Sekijima, M. et al. (Sep. 2004). “An Intraoperative Fluorescent Imaging System in Organ Transplantation,” Transplantation Proceedings 36(7):2188-2190.
Sensitization (photography), definition from Wikipedia, original language German, 6 pages.
Serov, A. et al. (Mar. 1, 2002). “Laser Doppler Perfusion Imaging with a Complimentary Metal Oxide Semiconductor Image Sensor,” Optics Letters 27(5):300-302.
Serov, A.N. et al. (Sep. 23, 2003). “Quasi-Parallel Laser Doppler Perfusion Imaging Using a CMOS Image Sensor,” Proc. SPIE 5067:73-84.
Sezgin, M. et al. (Jan. 2004). “Survey Over Image Thresholding Techniques and Quantitative Performance Evaluation,” Journal of Electronic Imaging 13(1):146-165.
Sherif, A. et al. (Sep. 2001). “Lymphatic Mapping and Detection of Sentinel Nodes in Patients with Bladder Cancer,” The Journal of Urology 166(3):812-815.
Sheth, S.A. et al. (Apr. 22, 2004). “Linear and Nonlinear Relationships between Neuronal Activity, Oxygen Metabolism, and Hemodynamic Responses,” Neuron 42(2):347-355.
Shoaib, T. et al. (Jun. 1, 2001). “The Accuracy of Head and Neck Carcinoma Sentinel Lymph Node Biopsy in the Clinically No Neck,” Cancer 91(11):2077-2083.
Siemers, B.M. et al. (Nov. 2001). “The Acoustic Advantage of Hunting at Low Heights Above Water: Behaviorual Experiments on the European ‘Trawling’ Bats Myotis capaccinii, M dasycneme and M. daubentonii,” J. Experimental Biol. 204(Pt. 22):3843-3854.
Skalidis, E.I. et al. (Nov. 16, 2004). “Regional Coronary Flow and Contractile Reserve in Patients with Idiopathic Dilated Cardiomyopathy,” Journal of the American College of Cardiology 44(10):2027-2032.
Slakter, J.S. et al. (Jun. 1995). “Indocyanine-Green Angiography,” Current Opinion in Ophthalmology 6(III):25-32.
Smith, G.A. et al. (Mar. 13, 2001). “Herpesviruses Use Bidirectional Fast-Axonal Transport to Spread in Sensory Neurons,” Proceedings of the National Academy of Sciences of the United States of America 98(6):3466-3470.
Soltesz, E.G. et al. (Jan. 2005). “Intraoperative Sentinel Lymph Node Mapping of the Lung Using Near-Infrared Fluorescent Quantum Dots,” Ann. Thorac. Surg. 79(1):269-277.
Sony Corporation. The Sony U-Matic Videocassette Recorder, VO-9800, ten pages, [Exhibit 1015].
Staurenghi, G. et al. (Dec. 2001). “Combining Photodynamic Therapy and Feeder Vessel Photocoagulation: A Pilot Study,” Seminars in Ophthalmology 16(4):233-236.
Stern, M.D. (Mar. 6, 1975). “In Vivo Evaluation of Microcirculation by Coherent Light Scattering,” Nature 254(5495):56-58.
Still, J. et al. (Mar. 1999). “Evaluation of the Circulation of Reconstructive Flaps Using Laser-Induced Fluorescence of Indocyanine Green,” Ann. Plast. Surg. 42(3):266-274.
Still, J.M. et al. (Jun. 2001). “Diagnosis of Burn Depth Using Laser-Induced Indocyanine Green Fluorescence: A Preliminary Clinical Trial,” Burns 27(4):364-371.
Stoeckli, S.J. et al. (Sep. 2001). “Sentinel Lymph Node Evaluation in Squamous Cell Carcinoma of the Head and Neck,” Otolaryngol Head Neck Surg. 125(3):221-226.
Subramanian, V.A. et al. (Oct. 15, 1995). “Minimally Invasive Coronary Bypass Surgery: A Multi-Center Report of Preliminary Clinical Experience,” Supplement to Circulation 92(8):I-645, (Abstract No. 3093), two pages.
Sugi, K. et al. (Jan. 2003). “Comparison of Three Tracers for Detecting Sentinel Lymph Nodes in Patients with Clinical N0 Lung Cancer,” Lung Cancer 39(1):37-40.
Sugimoto, K. et al. (Jun. 2008, e-published on Mar. 19, 2008). “Simultaneous Tracking of Capsid, Tegument, and Envelope Protein Localization in Living Cells Infected With Triply Fluorescent Herpes Simplex Virus 1,” Journal of Virology 82(11):5198-5211.
Suma, H. et al. (2000). “Coronary Artery Bypass Grafting Without Cardiopulmonary Bypass in 200 Patients,” J. Cardiol. 36(2):85-90.
Summary of Invention Submitted to EPO, “Development of Novadaq SPY™ Cardiac Imaging Invention,” five pages, Exhibit 1011].
Taggart, D.P. et al. (Mar. 2003). “Preliminary Experiences with a Novel Intraoperative Fluorescence Imaging Technique to Evaluate the Patency of Bypass Grafts in Total Arterial Revascularization,” Ann Thorac Surg. 75(3):870-873.
Taichman, G.C. et al. (Jun. 1987). “The Use of Cardio-Green for Intraoperative Visualization of the Coronary Circulation: Evaluation of Myocardial Toxicity,” Texas Heart Institute Journal 14(2):133-138.
Takahashi, M. et al. (Sep. 2004). “SPY™: An Innovative Intra-Operative Imaging System to Evaluate Graft Patency During Off-Pump Coronary Artery Bypass Grafting,” Interactive Cardio Vascular and Thoracic Surgery 3(3):479-483.
Takayama, T. et al. (Apr. 1992). “Intraoperative Coronary Angiography Using Fluorescein Basic Studies and Clinical Application,” Vascular and Endovascular Surgery 26(3):193-199.
Takayama, T. et al. (Jan. 1991). “Intraoperative Coronary Angiography Using Fluorescein” The Annals of Thoracic Surgery 51(1):140-143. [Exhibit 1013].
Tanaka, E. et al. (Jul. 2009). “Real-time Assessment of Cardiac Perfusion, Coronary Angiography, and Acute Intravascular Thrombi Using Dual-channel Near-infrared Fluorescence Imaging,” The Journal of Thoracic and Cardiovascular Surgery 138(1):133-140.
Tang, G.C. et al. (1989). “Spectroscopic Differences between Human Cancer and Normal Lung and Breast Tissues,” Lasers in Surgery and Medicine 9(3):290-295.
Taylor, K.M. (Apr. 1998). “Brain Damage During Cardiopulmonary Bypass,” Annals of Thoracic Surgery 65(4):S20-S26.
The American Heritage Medical Dictionary. “Perfuse.” p. 401 (2008), three pages.
Thelwall, P.E. et al. (Oct. 2002). “Human Erythrocyte Ghosts: Exploring the Origins of Multiexponential Water Diffusion in a Model Biological Tissue with Magnetic Resonance,” Magnetic Resonance in Medicine 48(4):649-657.
Török, B. et al. (May 1996). “Simultane digitale Indocyaningrün—und Fluoreszeinangiographie (Simultaneous Digital ICG and Fluorescein Angiography),” Klin Monatsbl Augenheilkd 208(5):333-336.
Torok, B. et al. (May 1996). “Simultaneous Digital Indocyanine Green and Fluorescein Angiography,” Klinische Monatsblatter Fur Augenheilkunde 208(5):333-336, (Abstract only), two pages.
Translation of Decision of Japanese Patent Office Trial Board revoking Counterpart Patent No. Patent No. 3,881,550, twenty six pages, [Exhibit 1010].
Tsutsumi, D. et al. “Moisture Detection of road surface using infrared camera,” Reports of the Hokkaido Industrial Research Institute (No. 297), Issued on Nov. 30, 1998, two pages.
Tubbs, R.S. et al. (Apr. 2005). “Anatomic Landmarks for Nerves of the Neck: A Vade Mecum for Neurosurgeons, ” Neurosurgery 56(2 Suppl.):ONS256-ONS260.
U.S. Ex Parte Quayle Action dated Jul. 23, 2020, directed to U.S. Appl. No. 29/724,647; 5 pages.
U.S. Ex Parte Quayle Action dated Jul. 23, 2020, directed to U.S. Appl. No. 29/724,650; 5 pages.
U.S. Ex Parte Quayle Action dated Jul. 23, 2020, directed to U.S. Appl. No. 29/724,651; 5 pages.
U.S. Ex Parte Quayle Action mailed on Mar. 23, 2020, for U.S. Appl. No. 15/584,405, filed May 2, 2017, five pages.
U.S. Final Office Action dated Apr. 2, 2013 for U.S. Appl. No. 13/419,368, filed Mar. 13, 2012, five pages.
U.S. Final Office Action dated Apr. 4, 2017 for U.S. Appl. No. 12/933,477, filed Sep. 20, 2010, twelve pages.
U.S. Final Office Action dated Apr. 10, 2008 for U.S. Appl. No. 11/106,154, filed Apr. 14, 2005, six pages.
U.S. Final Office Action dated Apr. 12, 2017 for U.S. Appl. No. 14/543,429, filed Nov. 17, 2014, nine pages.
U.S. Final Office Action dated Apr. 20, 2016 for U.S. Appl. No. 14/543,429, filed Nov. 17, 2014, seven pages.
U.S. Final Office Action dated Apr. 24, 2015 for U.S. Appl. No. 12/933,512, filed Nov. 24, 2010, nineteen pages.
U.S. Final Office Action dated Apr. 27, 2011 for U.S. Appl. No. 11/515,419, filed Sep. 1, 2006, nine pages.
U.S. Final Office Action dated Aug. 10, 2012 for U.S. Appl. No. 11/912,877, filed Aug. 13, 2008, ten pages.
U.S. Final Office Action dated Aug. 10, 2017 for U.S. Appl. No. 15/343,034, filed Nov. 3, 2016, twelve pages.
U.S. Final Office Action dated Aug. 11, 2017 for U.S. Appl. No. 14/860,687, filed Sep. 21, 2015, seventeen pages.
U.S. Final Office Action dated Aug. 7, 2017 for U.S. Appl. No. 15/343,038, filed Nov. 3, 2016, eleven pages.
U.S. Final Office Action dated Dec. 4, 2014 for U.S. Appl. No. 12/776,835, filed May 10, 2010, thirteen pages.
U.S. Final Office Action dated Dec. 14, 2018 for U.S. Appl. No. 15/584,405, filed May 2, 2017, seven pages.
U.S. Final Office Action dated Dec. 31, 2015 for U.S. Appl. No. 14/177,050, filed Feb. 10, 2014, eighteen pages.
U.S. Final Office Action dated Feb. 1, 2013 for U.S. Appl. No. 12/776,835, filed May 10, 2010, thirteen pages.
U.S. Final Office Action dated Feb. 1, 2018 for U.S. Appl. No. 15/584,405, filed May 2, 2017, ten pages.
U.S. Final Office Action dated Feb. 4, 2015 for U.S. Appl. No. 13/314,418, filed Dec. 8, 2011, six pages.
U.S. Final Office Action dated Feb. 13, 2015 for U.S. Appl. No. 14/543,429, filed Nov. 17, 2014, six pages.
U.S. Final Office Action dated Feb. 18, 2010 for U.S. Appl. No. 11/106,154, filed Apr. 14, 2005, six pages.
U.S. Final Office Action dated Feb. 27, 2017 for U.S. Appl. No. 15/247,419, filed Aug. 25, 2016, ten pages.
U.S. Final Office Action dated Feb. 7, 2020, for U.S. Appl. No. 15/343,038, filed Nov. 3, 2016, sixteen pages.
U.S. Final Office Action dated Jan. 11, 2019 for U.S. Appl. No. 15/343,038, filed Nov. 3, 2016, twelve pages.
U.S. Final Office Action dated Jan. 14, 2019 for U.S. Appl. No. 14/860,687, filed Sep. 21, 2015, sixteen pages.
U.S. Final Office Action dated Jan. 22, 2019 for U.S. Appl. No. 15/343,034, filed Nov. 3, 2016, twelve pages.
U.S. Final Office Action dated Jul. 9, 2015 for U.S. Appl. No. 14/543,356, filed Nov. 17, 2014, eight pages.
U.S. Final Office Action dated Jul. 21, 2016 for U.S. Appl. No. 14/543,356, filed Nov. 17, 2014, seven pages.
U.S. Final Office Action dated Jul. 23, 2008 for U.S. Appl. No. 11/122,267, filed May 4, 2016, six pages.
U.S. Final Office Action dated Jul. 25, 2019 for U.S. Appl. No. 15/416,876, filed Jan. 26, 2017, 13 pages.
U.S. Final Office Action dated Jun. 1, 2015 for U.S. Appl. No. 14/543,429, filed Nov. 17, 2014, nine pages.
U.S. Final Office Action dated Jun. 13, 2014 for U.S. Appl. No. 12/776,835, filed May 10, 2010, thirteen pages.
U.S. Final Office Action dated Jun. 18, 2015 for U.S. Appl. No. 14/154,177 filed Jan. 13, 2014, eight pages.
U.S. Final Office Action dated Jun. 25, 2014 for U.S. Appl. No. 12/933,477, filed Sep. 20, 2010, fifteen pages.
U.S. Final Office Action dated Jun. 5, 2014 for U.S. Appl. No. 12/761,462, filed Apr. 16, 2010, fourteen pages.
U.S. Final Office Action dated Mar. 20, 2017 for U.S. Appl. No. 14/177,050, filed Feb. 10, 2014, twenty-three pages.
U.S. Final Office Action dated Mar. 22, 2016 for U.S. Appl. No. 14/873,842, filed Oct. 2, 2015, eighteen pages.
U.S. Final Office Action dated Mar. 28, 2013 for U.S. Appl. No. 12/063,349, filed May 12, 2010, twenty pages.
U.S. Final Office Action dated May 11, 2011 for U.S. Appl. No. 11/412,715, filed Apr. 26, 2006, eight pages.
U.S. Final Office Action dated May 21, 2012 for U.S. Appl. No. 11/964,330, filed Dec. 26, 2007, twelve pages.
U.S. Final Office Action dated May 29, 2013 for U.S. Appl. No. 12/933,477, filed Sep. 20, 2010, twelve pages.
U.S. Final Office Action dated Nov. 6, 2013 for U.S. Appl. No. 13/419,368, filed Mar. 13, 2012, five pages.
U.S. Final Office Action dated Nov. 24, 2009 for U.S. Appl. No. 11/009,965, filed Dec. 10, 2004, fourteen pages.
U.S. Final Office Action dated Oct. 7, 2011 for U.S. Appl. No. 11/851,312, filed Sep. 6, 2007, ten pages.
U.S. Final Office Action dated Sep. 13, 2011 for U.S. Appl. No. 11/106,154, filed Apr. 14, 2005, five pages.
U.S. Final Office Action dated Sep. 17, 2014 for U.S. Appl. No. 11/515,419, filed Sep. 1, 2006, eleven pages.
U.S. Final Office Action dated Sep. 17, 2015 for U.S. Appl. No. 12/933,477, filed Sep. 20, 2010, six pages.
U.S. Final Office Action dated Sep. 23, 2004 for U.S. Appl. No. 09/744,034, filed Apr. 27, 2001, seven pages.
U.S. Final Office Action dated Sep. 29, 2016 for U.S. Appl. No. 13/922,996, filed Jun. 20, 2013, fourteen pages.
U.S. Non-Final Office Action dated Jul. 23, 2019, for U.S. Appl. No. 15/517,895, thirteen pages.
U.S. Non-Final Office Action dated Apr. 1, 2015 for U.S. Appl. No. 12/933,477, filed Sep. 20, 2010, fourteen pages.
U.S. Non-Final Office Action dated Apr. 3, 2019 for U.S. Appl. No. 15/416,876, filed Jan. 26, 2017, thirteen pages.
U.S. Non-Final Office Action dated Apr. 2, 2009 for U.S. Appl. No. 11/009,965, filed Dec. 10, 2004, thirteen pages.
U.S. Non-Final Office Action dated Apr. 26, 2012 for U.S. Appl. No. 12/776,835, filed May 10, 2010, nine pages.
U.S. Non-Final Office Action dated Apr. 28, 2010 for U.S. Appl. No. 11/946,672, filed Nov. 28, 2007, nine pages.
U.S. Non-Final Office Action dated Apr. 3, 2020, for U.S. Appl. No. 16/746,539, filed Jan. 17, 2020, 15 pages.
U.S. Non-Final Office Action dated Aug. 10, 2016 for U.S. Appl. No. 14/177,050, filed Feb. 10, 2014, twenty pages.
U.S. Non-Final Office Action dated Aug. 15, 2018 for U.S. Appl. No. 15/348,664, filed Nov. 10, 2016, eleven pages.
U.S. Non-Final Office Action dated Aug. 16, 2013 for U.S. Appl. No. 12/761,462, filed Apr. 16, 2010, ten pages.
U.S. Non-Final Office Action dated Aug. 16, 2013 for U.S. Appl. No. 12/761,523, filed Apr. 16, 2010, nine pages.
U.S. Non-Final Office Action dated Aug. 2, 2019 for U.S. Appl. No. 15/623,100, filed Jun. 14, 2017, twelve pages.
U.S. Non-Final Office Action dated Aug. 21, 2019 for U.S. Appl. No. 15/584,405, filed May 2, 2017, six pages.
U.S. Non-Final Office Action dated Aug. 23, 2019 for U.S. Appl. No. 14/860,687, filed Sep. 21, 2015, fourteen pages.
U.S. Non-Final Office Action dated Aug. 23, 2019 for U.S. Appl. No. 15/343,034, filed Nov. 3, 2016, eighteen pages.
U.S. Non-Final Office Action dated Aug. 23, 2019 for U.S. Appl. No. 15/343,038, filed Nov. 3, 2016, fourteen pages.
U.S. Non-Final Office Action dated Aug. 29, 2014 for U.S. Appl. No. 12/063,349, filed May 12, 2010, nineteen pages.
U.S. Non-Final Office Action dated Dec. 10, 2010 for U.S. Appl. No. 11/412,715, filed Apr. 26, 2006, ten pages.
U.S. Non-Final Office Action dated Dec. 14, 2011 for U.S. Appl. No. 11/412,715, filed Apr. 26, 2006, eight pages.
U.S. Non-Final Office Action dated Dec. 16, 2016 for U.S. Appl. No. 14/868,369, filed Sep. 28, 2015, seven pages.
U.S. Non-Final Office Action dated Dec. 20, 2013 for U.S. Appl. No. 12/933,477, filed Sep. 20, 2010, thirteen pages.
U.S. Non-Final Office Action dated Dec. 30, 2010 for U.S. Appl. No. 11/106,154, filed Apr. 14, 2005, six pages.
U.S. Non-Final Office Action dated Feb. 1, 2011 for U.S. Appl. No. 11/851,312, filed Sep. 6, 2007, seven pages.
U.S. Non-Final Office Action dated Feb. 5, 2016 for U.S. Appl. No. 14/543,356, filed Nov. 17, 2014, seven pages.
U.S. Non-Final Office Action dated Feb. 5, 2019 for U.S. Appl. No. 15/623,100, filed Jun. 14, 2017, ten pages.
U.S. Non-Final Office Action dated Feb. 1, 2017 for U.S. Appl. No. 14/860,687, filed Sep. 21, 2015, fifteen pages.
U.S. Non-Final Office Action dated Feb. 3, 2010 for U.S. Appl. No. 11/626,308, filed Jan. 23, 2007, eleven pages.
U.S. Non-Final Office Action dated Jan. 8, 2018 for U.S. Appl. No. 15/077,677, filed Mar. 22, 2016, nine pages.
U.S. Non-Final Office Action dated Jan. 9, 2009 for U.S. Appl. No. 11/106,154, filed Apr. 14, 2005, six pages.
U.S. Non-Final Office Action dated Jan. 16, 2020, for U.S. Appl. No. 15/416,876, filed Jan. 26, 2017, thirteen pages.
U.S. Non-Final Office Action dated Jan. 2, 2008 for U.S. Appl. No. 11/122,267, filed May 4, 2005, five pages.
U.S. Non-Final Office Action dated Jan. 20, 2016 for U.S. Appl. No. 14/629,473, filed Feb. 23, 2015, fifteen pages.
U.S. Non-Final Office Action dated Jan. 22, 2014 for U.S. Appl. No. 11/851,312, filed Sep. 6, 2007, ten pages.
U.S. Non-Final Office Action dated Jan. 26, 2017 for U.S. Appl. No. 15/343,034, filed Nov. 3, 2016, seventeen pages.
U.S. Non-Final Office Action dated Jan. 27, 2012 for U.S. Appl. No. 11/912,877, filed Aug. 13, 2008, eleven pages.
U.S. Non-Final Office Action dated Jan. 27, 2017 for U.S. Appl. No. 15/343,038, filed Nov. 3, 2016, fifteen pages.
U.S. Non-Final Office Action dated Jan. 31, 2018 for U.S. Appl. No. 15/799,727, filed Oct. 31, 2017, seven pages.
U.S. Non-Final Office Action dated Jul. 2, 2015 for U.S. Appl. No. 14/177,050, filed Feb. 10, 2014, nineteen pages.
U.S. Non-Final Office Action dated Jul. 8, 2014 for U.S. Appl. No. 13/314,418, filed Dec. 8, 2011, seven pages.
U.S. Non-Final Office Action dated Jul. 17, 2003 for U.S. Appl. No. 09/905,642, filed Jul. 13, 2001, six pages.
U.S. Non-Final Office Action dated Jul. 2, 2013 for U.S. Appl. No. 12/933,512, filed Nov. 24, 2010, twelve pages.
U.S. Non-Final Office Action dated Jul. 22, 2015 for U.S. Appl. No. 13/314,418, filed Dec. 8, 2011, six pages.
U.S. Non-Final Office Action dated Jun. 1, 2007 for U.S. Appl. No. 10/899,648, filed Jul. 26, 2004, seven pages.
U.S. Non-Final Office Action dated Jun. 11, 2013 for U.S. Appl. No. 11/515,419, filed Sep. 1, 2006, eleven pages.
U.S. Non-Final Office Action dated Jun. 20, 2008 for U.S. Appl. No. 11/009,398, filed Dec. 10, 2004, fifteen pages.
U.S. Non-Final Office Action dated Jun. 23, 2010 for U.S. Appl. No. 11/009,965, filed Dec. 10, 2004, fifteen pages.
U.S. Non-Final Office Action dated Jun. 27, 2014 for U.S. Appl. No. 13/415,561, filed Mar. 3, 2012, fourteen pages.
U.S. Non-Final Office Action dated Jun. 28, 2012 for U.S. Appl. No. 12/063,349, filed May 12, 2010, seventeen pages.
U.S. Non-Final Office Action dated Jun. 5, 2018 for U.S. Appl. No. 14/860,687, filed Sep. 21, 2015, eighteen pages.
U.S. Non-Final Office Action dated Jun. 8, 2018 for U.S. Appl. No. 15/343,034, filed Nov. 3, 2016, thirteen pages.
U.S. Non-Final Office Action dated Jun. 8, 2018 for U.S. Appl. No. 15/584,405, filed May 2, 2017, eight pages.
U.S. Non-Final Office Action dated Jun. 9, 2011 for U.S. Appl. No. 11/830,323, filed Jul. 30, 2007, five pages.
U.S. Non-Final Office Action dated Mar. 6, 2007 for U.S. Appl. No. 11/106,154, filed Apr. 14, 2005, eight pages.
U.S. Non-Final Office Action dated Mar. 10, 2004 for U.S. Appl. No. 09/744,034, filed Apr. 27, 2001, seven pages.
U.S. Non-Final Office Action dated Mar. 13, 2015 for U.S. Appl. No. 14/543,356, filed Nov. 17, 2014, eight pages.
U.S. Non-Final Office Action dated Mar. 22, 2018 for U.S. Appl. No. 15/610,102, filed May 31, 2017, eleven pages.
U.S. Non-Final Office Action dated Mar. 22, 2019 for U.S. Appl. No. 15/799,727, filed Oct. 31, 2017, eight pages.
U.S. Non-Final Office Action dated May 6, 2015 for U.S. Appl. No. 12/063,349, filed May 12, 2010, seventeen pages.
U.S. Non-Final Office Action dated May 18, 2004 for U.S. Appl. No. 10/050,601, filed Jan. 15, 2002, eight pages.
U.S. Non-Final Office Action dated May 21, 2015 for U.S. Appl. No. 13/922,996, filed Jun. 20, 2013, fourteen pages.
U.S. Non-Final Office Action dated May 25, 2018 for U.S. Appl. No. 15/343,038, filed Nov. 3, 2016, eleven pages.
U.S. Non-Final Office Action dated May 5, 2020, for U.S. Appl. No. 15/623,100, filed Jun. 14, 2017, twelve pages.
U.S. Non-Final Office Action dated Nov. 5, 2014 for U.S. Appl. No. 13/930,225, filed Jun. 28, 2013, six pages.
U.S. Non-Final Office Action dated Nov. 9, 2015 for U.S. Appl. No. 14/177,045, filed Feb. 10, 2014, seven pages.
U.S. Non-Final Office Action dated Nov. 18, 2016 for U.S. Appl. No. 12/933,477, filed Sep. 20, 2010, six pages.
U.S. Non-Final Office Action dated Nov. 23, 2009 for U.S. Appl. No. 11/969,974, filed Jan. 7, 2008, seven pages.
U.S. Non-Final Office Action dated Nov. 27, 2015 for U.S. Appl. No. 14/543,429, filed Nov. 17, 2014, six pages.
U.S. Non-Final Office Action dated Oct. 3, 2013 for U.S. Appl. No. 12/776,835, filed May 10, 2010, twelve pages.
U.S. Non-Final Office Action dated Oct. 12, 2016 for U.S. Appl. No. 14/543,429, filed Nov. 17, 2014, nine pages.
U.S. Non-Final Office Action dated Oct. 13, 2017 for U.S. Appl. No. 13/922,996, filed Jun. 20, 2013, seventeen pages.
U.S. Non-Final Office Action dated Oct. 23, 2013 for U.S. Appl. No. 13/415,561, filed Mar. 8, 2012, ten pages.
U.S. Non-Final Office Action dated Oct. 26, 2017 for U.S. Appl. No. 14/543,429, filed Nov. 17, 2014, nine pages.
U.S. Non-Final Office Action dated Oct. 28, 2016 for U.S. Appl. No. 14/543,356, filed Nov. 17, 2014, eight pages.
U.S. Non-Final Office Action dated Oct. 5, 2016 for U.S. Appl. No. 15/247,419, filed Aug. 25, 2016, eight pages.
U.S. Non-Final Office Action dated Oct. 7, 2011 for U.S. Appl. No. 11/964,330, filed Dec. 26, 2007; ten pages.
U.S. Non-Final Office Action dated Sep. 5, 2012 for U.S. Appl. No. 12/933,477, filed Sep. 20, 2010, seven pages.
U.S. Non-Final Office Action dated Sep. 12, 2014 for U.S. Appl. No. 14/154,177, filed Jan. 13, 2014, four pages.
U.S. Non-Final Office Action dated Sep. 15, 2010 for U.S. Appl. No. 11/106,154, filed Apr. 14, 2005, six pages.
U.S. Non-Final Office Action dated Sep. 25, 2017 for U.S. Appl. No. 15/584,405, filed May 2, 2017, eight pages.
U.S. Non-Final Office Action dated Sep. 27, 2017 for U.S. Appl. No. 14/177,050, filed Feb. 10, 2014, twenty-two pages.
U.S. Non-Final Office Action dated Sep. 27, 2019, for U.S. Appl. No. 29/562,795, filed Apr. 28, 2019, 6 pages.
U.S. Non-Final Office Action dated Sep. 30, 2010 for U.S. Appl. No. 11/515,419, filed Sep. 1, 2006, eleven pages.
U.S. Non-Final Office Action dated Sep. 6, 2016 for U.S. Appl. No. 14/873,842, filed Oct. 2, 2015, seven pages.
U.S. Non-Final Office Action with Restriction Requirement dated Mar. 4, 2011 for U.S. Appl. No. 11/830,323, filed Jul. 30, 2007, nine pages.
U.S. Notice of Allowance dated Jan. 14, 2020, for U.S. Appl. No. 15/517,895, filed Apr. 7, 2017, thirteen pages.
U.S. Notice of Allowance dated Apr. 17, 2014 for U.S. Appl. No. 13/419,368, filed Mar. 13, 2012, five pages.
U.S. Notice of Allowance dated Apr. 7, 2004 for U.S. Appl. No. 09/905,642, filed Jul. 13, 2001, six pages.
U.S. Notice of Allowance dated Aug. 7, 2014 for U.S. Appl. No. 13/850,063, filed Mar. 25, 2013, nine pages.
U.S. Notice of Allowance dated Aug. 26, 2004 for U.S. Appl. No. 10/050,601, filed Jan. 15, 2002, eight pages.
U.S. Notice of Allowance dated Aug. 6, 2015 for U.S. Appl. No. 13/853,656, filed Mar. 29, 2013, seven pages.
U.S. Notice of Allowance dated Dec. 2, 2016 for U.S. Appl. No. 14/598,832, filed Jan. 16, 2015, seven pages.
U.S. Notice of Allowance dated Dec. 4, 2018 for U.S. Appl. No. 11/515,419, filed Sep. 1, 2006, seven pages.
U.S. Notice of Allowance dated Dec. 6, 2017 for U.S. Appl. No. 15/476,290, filed Mar. 31, 2017, nine pages.
U.S. Notice of Allowance dated Dec. 10, 2012 for U.S. Appl. No. 11/964,330, filed Dec. 26, 2007, seven pages.
U.S. Notice of Allowance dated Dec. 18, 2018 for U.S. Appl. No. 13/922,996, filed Jun. 20, 2013, six pages.
U.S. Notice of Allowance dated Dec. 30, 2016 for U.S. Appl. No. 14/873,842, filed Oct. 2, 2015, eleven pages.
U.S. Notice of Allowance dated Feb. 14, 2020, for U.S. Appl. No. 14/860,687, filed Sep. 21, 2015, eight pages.
U.S. Notice of Allowance dated Feb. 14, 2020, for U.S. Appl. No. 15/343,034, filed Nov. 3, 2016, seven pages.
U.S. Notice of Allowance dated Feb. 25, 2010 for U.S. Appl. No. 11/969,974, filed Jan. 7, 2008, four pages.
U.S. Notice of Allowance dated Jan. 2, 2008 for U.S. Appl. No. 10/899,648, filed Jul. 26, 2004, three pages.
U.S. Notice of Allowance dated Jan. 10, 2019 for U.S. Appl. No. 15/610,102, filed May 31, 2017, five pages.
U.S. Notice of Allowance dated Jul. 10, 2017 for U.S. Appl. No. 15/247,419, filed Aug. 25, 2016, eight pages.
U.S. Notice of Allowance dated Jul. 10, 2019 for U.S. Appl. No. 15/799,727, filed Oct. 31, 2017, seven pages.
U.S. Notice of Allowance dated Jul. 12, 2017 for U.S. Appl. No. 14/868,369, filed Sep. 28, 2015, nine pages.
U.S. Notice of Allowance dated Jul. 13, 2016 for U.S. Appl. No. 14/598,832, filed Jan. 16, 2015, seven pages.
U.S. Notice of Allowance dated Jul. 16, 2019, for U.S. Appl. No. 12/776,835, filed May 10, 2010, seven pages.
U.S. Notice of Allowance dated Jun. 15, 2018 for U.S. Appl. No. 11/515,419, filed Sep. 1, 2006, five pages.
U.S. Notice of Allowance dated Jun. 25, 2015 for U.S. Appl. No. 12/933,512, filed Nov. 24, 2010 fourteen pages.
U.S. Notice of Allowance dated Mar. 7, 2005 for U.S. Appl. No. 09/744,034, filed Apr. 27, 2001, five pages.
U.S. Notice of Allowance dated Mar. 10, 2005 for U.S. Appl. No. 10/050,601, filed Jan. 15, 2002, five pages.
U.S. Notice of Allowance dated Mar. 12, 2020, for U.S. Appl. No. 16/441,493, filed Jun. 14, 2019, 8 pages.
U.S. Notice of Allowance dated Mar. 15, 2016 for U.S. Appl. No. 14/598,832, filed Jan. 16, 2015, seven pages.
U.S. Notice of Allowance dated Mar. 22, 2013 for U.S. Appl. No. 11/964,330, filed Dec. 26, 2007, eight pages.
U.S. Notice of Allowance dated Mar. 28, 2016 for U.S. Appl. No. 13/853,656, filed Mar. 29, 2013, eight pages.
U.S. Notice of Allowance dated Mar. 29, 2018 for U.S. Appl. No. 14/177,050, filed Feb. 10, 2014, ten pages.
U.S. Notice of Allowance dated May 15, 2019 for U.S. Appl. No. 15/610,102, filed May 31, 2017, eight pages.
U.S. Notice of Allowance dated May 18, 2015 for U.S. Appl. No. 13/930,225, filed Jun. 28, 2013, nine pages.
U.S. Notice of Allowance dated May 19, 2020, for U.S. Appl. No. 15/584,405, filed May 2, 2017, seven pages.
U.S. Notice of Allowance dated May 26, 2016 for U.S. Appl. No. 14/177,045, filed Feb. 10, 2014, eight pages.
U.S. Notice of Allowance dated Nov. 23, 2015 for U.S. Appl. No. 13/853,656, filed Mar. 29, 2013, seven pages.
U.S. Notice of Allowance dated Nov. 25, 2015 for U.S. Appl. No. 14/598,832, filed Jan. 16, 2015, seven pages.
U.S. Notice of Allowance dated Nov. 30, 2010 for U.S. Appl. No. 11/946,672, filed Nov. 28, 2007, six pages.
U.S. Notice of Allowance dated Oct. 4, 2013 for U.S. Appl. No. 11/912,877, filed Aug. 13, 2008, nine pages.
U.S. Notice of Allowance dated Oct. 6, 2014 for U.S. Appl. No. 13/419,368, filed Mar. 13, 2012, five pages.
U.S. Notice of Allowance dated Oct. 10, 2014 for U.S. Appl. No. 12/761,462, filed Apr. 16, 2010, ten pages.
U.S. Notice of Allowance dated Oct. 16, 2014 for U.S. Appl. No. 13/850,063, filed Mar. 25, 2013, eight pages.
U.S. Notice of Allowance dated Oct. 17, 2018 for U.S. Appl. No. 12/933,477, filed Sep. 20, 2010, seven pages.
U.S. Notice of Allowance dated Oct. 18, 2012 for U.S. Appl. No. 12/841,659, filed Jul. 22, 2010, seven pages.
U.S. Notice of Allowance dated Oct. 29, 2018 for U.S. Appl. No. 12/063,349, filed May 12, 2010, eight pages.
U.S. Notice of Allowance dated Oct. 5, 2007 for U.S. Appl. No. 10/899,648, filed Jul. 26, 2004, six pages.
U.S. Notice of Allowance dated Sep. 6, 2018 for U.S. Appl. No. 12/776,835, filed May 10, 2010, five pages.
U.S. Notice of Allowance dated Sep. 6, 2018 for U.S. Appl. No. 13/922,996, filed Jun. 20, 2013, nine pages.
U.S. Notice of Allowance dated Sep. 10, 2013 for U.S. Appl. No. 11/412,715, filed Apr. 26, 2006, eight pages.
U.S. Notice of Allowance dated Sep. 11, 2018 for U.S. Appl. No. 15/799,727, filed Oct. 31, 2017, eight pages.
U.S. Notice of Allowance dated Sep. 14, 2012 for U.S. Appl. No. 11/830,323, filed Jul. 30, 2007, eight pages.
U.S. Notice of Allowance dated Sep. 26, 2018 for U.S. Appl. No. 15/610,102, filed May 31, 2017, eight pages.
U.S. Appl. No. 15/810,911, filed Nov. 13, 2017. (The U.S. Patent Application is not submitted herewith pursuant to the waiver of 37 C.F.R. § 1.98(a)(2)(iii) issued by the Office on Sep. 21, 2004.).
U.S. Appl. No. 29/562,795, filed Apr. 28, 2016. (The U.S. Patent Application is not submitted herewith pursuant to the waiver of 37 C.F.R. § 1.98(a)(2)(iii) issued by the Office on Sep. 21, 2004.).
U.S. Restriction Requirement dated Feb. 7, 2019 for U.S. Appl. No. 29/562,795, filed Apr. 28, 2016, seven pages.
U.S. Restriction Requirement dated Jun. 26, 2017 for U.S. Appl. No. 15/077,677, filed Mar. 22, 2016, seven pages.
Unno, N. et al. (Feb. 2008, e-published on Oct. 26, 2007). “Indocyanine Green Fluorescence Angiography for intraoperative assessment of Blood flow: A Feasibility Study,” Eur J Vasc Endovasc Surg. 35(2):205-207.
Uren, R.F. (Jan. 2004). “Cancer Surgery Joins the Dots,” Nature Biotechnology 22(1):38-39.
Valero-Cabré, A. et al. (Jan. 15, 2001). “Superior Muscle Reinnervation after Autologous Nerve Graft or Poly-L-Lactide-ϵ-Caprolactone (PLC) Tube Implantation in Comparison to Silicone Tube Repair,” Journal of Neuroscience Research 63(2):214-223.
Van Son, J.A.M. et al. (Nov. 1997). “Thermal Coronary Angiography for Intraoperative Testing of Coronary Patency in Congenital Heart Defects,” Ann Thorac Surg. 64(5):1499-1500.
Verbeek, X. et al. (2001). “High-Resolution Functional Imaging With Ultrasound Contrast Agents Based on RF Processing in an In Vivo Kidney Experiment”, Ultrasound in Med. & Biol. 27(2):223-233.
Wachi, A. et al. (Apr. 1995). “Characteristics of Cerebrospinal Fluid Circulation in Infants as Detected With MR Velocity Imaging,” Child's Nerv Syst 11(4):227-230.
Wagnieres, G.A. et al. (Jul. 1, 1990). “Photodetection of Early Cancer by Laser Induced Fluorescence of a Tumor-Selective Dye: Apparatus Design and Realization,” Proc. SPIE 1203:43-52.
Weinbeer, M. et al. (Nov. 25, 2013). “Behavioral Flexibility of the Trawling Long-Legged Bat, Macrophyllum Macrophyllum (Phyllostomidae),” Frontiers in Physiology 4(Article 342):1-11.
Westwick et al., U.S. Office Action dated Aug. 27, 2020, directed to U.S. Appl. No. 15/343,038; 16 pages.
What is Perfusion? A Summary of Different Typed of Perfusion. (Sep. 1, 2004). Located at, <http://www.perfusion.com/cgi-bin/absolutenm/templates/articledisplay.asp?articleid=1548#.Vo8Hv02FPGj>, last visited on Jan. 7, 2016, two pages.
Wise, R.G. et al. (Nov. 2005). “Simultaneous Measurement of Blood and Myocardial Velocity in the Rat Heart by Phase Contrast MRI Using Sparse q-Space Sampling” Journal of Magnetic Resonance Imaging 22(5):614-627.
Woitzik, J. et al. (Apr. 2005). “Intraoperative Control of Extracranial-Intracranial Bypass Patency by Near-Infrared Indocyanine Green Videoangiography,” J. Neurosurg. 102(4):692-698.
Wollert, H.G. et al. (Dec. 1989). “Intraoperative Visualization of Coronary Artery Fistula Using Medical Dye,” The Thoracic and Cardiovascular Surg. 46(6):382-383.
Written Opinion of the International Searching Authority dated Dec. 3, 2009 for PCT Patent Application No. PCT/IB2009/005700, filed on Apr. 14, 2009, six pages.
Written Opinion of the International Searching Authority dated Dec. 3, 2015 for PCT Patent Application No. PCT/CA2015/050973 filed on Sep. 28, 2015, five pages.
Written Opinion of the International Searching Authority dated Feb. 1, 2012 for PCT Patent Application No. PCT/IB2011/002381, filed on Sep. 20, 2011, four pages.
Written Opinion of the International Searching Authority dated Jan. 22, 2014 for PCT Patent Application No. PCT/IB2013/001934, filed on Jun. 20, 2013, six pages.
Written Opinion of the International Searching Authority dated Jul. 4, 2008 for PCT Patent Application No. PCT/US2007/080847, filed on Oct. 9, 2007, six pages.
Written Opinion of the International Searching Authority dated Jun. 2, 2009 for PCT Patent Application No. PCT/EP2008/008547, filed on Oct. 9, 2008, eleven pages.
Written Opinion of the International Searching Authority dated Jun. 8, 2009 for PCT Patent Application No. PCT/CA2009/000073, filed on Jan. 23, 2009, four pages.
Written Opinion of the International Searching Authority dated Oct. 24, 2017, for Patent Application No. PCT/CA2017/050564, seven pages.
Written Opinion of the International Searching Authority dated Aug. 3, 2006 for International Patent Application No. PCT/CA2006/000669, filed on Apr. 27, 2006, eight pages.
Written Opinion of the International Searching Authority dated Dec. 7, 2007 for International Patent Application No. PCT/CA2007/001335, filed on Jul. 30, 2007, four pages.
Wu, C. et al. (Apr. 15, 2005). “CGMP (Guanosine 3′,5′-Cyclic Monophosphate) Transport Across Human Erythrocyte Membranes,” Biochemical Pharmacology 69(8):1257-1262.
Yada, T. et al. (May 1993). “In Vivo Observation of Subendocardial Microvessels of the Beating Porcine Heart Using a Needle-Probe Videomicroscope with a CCD Camera,” Circulation Research 72(5):939-946.
Yamaguchi, S. et al. (Apr. 2005). “Evaluation of Skin Perfusion After Nipple-Sparing Mastectomy by Indocyanine Green Dye” Journal of Saitama Medical University, Japan, 32(2):45-50.
Yoneya, S. et al. (Jun. 1998). “Binding Properties of Indocyanine Green in Human Blood,” IOVS 39(7):1286-1290.
Yoneya, S. et al. (Sep. 1993). “Improved Visualization of the Choroidal Circulation with Indocyanine Green Angiography,” Arch Opthalmol. 111(9):1165-1166.
Young. I.T. et al. (1993). “Depth of Focus in Microscopy,” SCIA '93, Proc. of the 8th Scandinavian Conference on Image Analysis, Tromso, Norway, pp. 493-498, six pages.
Decision of Refusal dated Nov. 11, 2022, directed to JP Application No. 2020-128414; 5 pages.
Decision to Grant a Patent dated Jun. 23, 2023, directed to JP Application No. 2021-132340; 6 pages.
Decision to Grant a Patent dated Jul. 16, 2021, directed to JP Application No. 2019-540067; 6 pages.
European Extended Search Report dated Sep. 18, 2023, directed to EP Application No. 23174549.8; 11 pages.
Extended European Search Report dated Feb. 10, 2023, directed to EP Application No. 22187529.7; 10 pages.
Fengler et al., U.S. Notice of Allowance and Fee(s) Due dated Dec. 2, 2021, directed to U.S. Appl. No. 17/234,461; 8 pages.
Fengler et al., U.S. Notice of Allowance and Fee(s) Due dated Jan. 10, 2024, directed to U.S. Appl. No. 17/658,815; 7 pages.
Fengler et al., U.S. Notice of Allowance and Fee(s) Due dated May 1, 2023, directed to U.S. Appl. No. 16/951,684; 7 pages.
Fengler et al., U.S. Office Action dated Aug. 25, 2023, directed to U.S. Appl. No. 17/658,815; 13 pages.
Fengler et al., U.S. Office Action dated Feb. 24, 2022, directed to U.S. Appl. No. 16/951,684; 12 pages.
Fengler et al., U.S. Office Action dated Jan. 12, 2023, directed to U.S. Appl. No. 17/658,815; 14 pages.
Fengler et al., U.S. Office Action dated Sep. 14, 2022, directed to U.S. Appl. No. 16/951,684; 14 pages.
Fengler et al., U.S. Restriction Requirement dated Oct. 13, 2021, directed to U.S. Appl. No. 16/951,684; 7 pages.
Fengler et al., U.S. Restriction Requirement dated Oct. 17, 2018, directed to U.S. Appl. No. 15/623,100; 7 pages.
First Office Action dated Jul. 30, 2021, directed to JP Application No. 2020-128414; 8 pages.
Intention to Grant dated Dec. 6, 2022, directed to EP Application No. 17 895 908.6.
Intention to Grant dated Feb. 25, 2022, directed to EP Application No. 17 743 524.5; 7 pages.
Intention to Grant dated May 17, 2021, directed to EP Application No. 16 186 321.2; 7 pages.
Intention to Grant dated Oct. 30, 2023, directed to EP Application No. 16 863 277.6; 8 pages.
Kim et al., (Aug. 5, 2014). “Multi-spectral imaging with infrared sensitive organic light emitting diode,” Scientific Reports 4(5946): 1-5.
Moore et al., U.S. Advisory Action dated Oct. 11, 2022, directed to U.S. Appl. No. 16/933,900; 3 pages.
Moore et al., U.S. Office Action dated Dec. 13, 2022, directed to U.S. Appl. No. 16/933,900; 15 pages.
Moore et al., U.S. Office Action dated Jun. 16, 2023, directed to U.S. Appl. No. 16/933,900; 14 pages.
Moore et al., U.S. Office Action dated May 16, 2022, directed to U.S. Appl. No. 16/933,900; 13 pages.
Moore et al., U.S. Office Action dated Nov. 9, 2021, directed to U.S. Appl. No. 16/933,900; 14 pages.
Moore et al., U.S. Restriction Requirement dated May 3, 2018, directed to U.S. Appl. No. 15/348,664; 5 pages.
Murray et al., U.S. Notice of Allowance and Fee(s) Due dated Oct. 25, 2018, directed to U.S. Appl. No. 29/588,898; 14 pages.
Murray et al., U.S. Notice of Allowance and Fee(s) dated Jan. 19, 2021, directed to U.S. Appl. No. 29/724,647; 6 pages.
Murray et al., U.S. Notice of Allowance dated Jan. 13, 2021, directed to U.S. Appl. No. 29/724,650; 6 pages.
Murray et al., U.S. Notice of Allowance dated Jan. 19, 2021, directed to U.S. Appl. No. 29/724,651; 6 pages.
Notice of Filing Divisional Application(s) dated Oct. 27, 2023, directed to CN Application No. 202110658728.3; 4 pages.
Notice of Reasons for Refusal dated Apr. 1, 2022, directed to JP Application No. 2020-128414; 11 pages.
Notice of Reasons for Refusal dated Sep. 9, 2022, directed to JP Application No. 2021- 132340; 8 pages.
Office Action dated Dec. 1, 2022, directed to EP Application No. 16 863 277.6; 6 pages.
Office Action dated Feb. 25, 2022, directed to EP Application No. 18 178 620.3; 4 pages.
Office Action dated Jun. 16, 2021, directed to EP Application No. 16 863 277.6; 5 pages.
Office Action dated Jun. 7, 2022, directed to EP Application No. 17 812 362.6; 5 pages.
Office Action dated Oct. 1, 2021, directed to EP Application No. 17 895 908.6; 4 pages.
Westwick et al., U.S. Notice of Allowance and Fee(s) Due dated May 12, 2023, directed to U.S. Appl. No. 17/243,002; 7 pages.
Westwick et al., U.S. Office Action dated Dec. 16, 2021, directed to U.S. Appl. No. 17/243,002; 19 pages.
Westwick et al., U.S. Office Action dated May 18, 2022, directed to U.S. Appl. No. 17/243,002; 13 pages.
Westwick et al., U.S. Office Action dated Nov. 16, 2022, directed to U.S. Appl. No. 17/243,002; 11 pages.
Moore et al., U.S. Advisory Action dated May 19, 2020, directed to U.S. Appl. No. 15/591,909; 3 pages.
Moore et al., U.S. Notice of Allowance and Fee(s) due dated Jun. 1, 2021, directed to U.S. Appl. No. 15/591,909; 6 pages.
Moore et al., U.S. Office Action dated Nov. 19, 2020, directed to U.S. Appl. No. 15/591,909; 13 pages.
U.S. Final Office Action dated Feb. 4, 2020, for U.S. Appl. No. 15/591,909, filed May 10, 2017, fourteen pages.
U.S. Restriction Requirement dated Jan. 17, 2019 for U.S. Appl. No. 15/591,909, filed May 10, 2017, seven pages.
U.S. Non-Final Office Action dated Aug. 6, 2019 for U.S. Appl. No. 15/591,909, filed May 10, 2017, ten pages.

Related Publications (1)

	Number	Date	Country
	20220030149 A1	Jan 2022	US

Provisional Applications (1)

	Number	Date	Country
	62457690	Feb 2017	US

Divisions (1)

	Number	Date	Country
Parent	15591909	May 2017	US
Child	17493799		US

Open-field handheld fluorescence imaging systems and methods

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