Apparatus, systems, and methods for mapping tissue oxygenation

Abstract

To provide an apparatus, systems and methods for mapping of tissue oxygenation.SOLUTION: An apparatus, systems and methods are provided that generate in vivo maps of oxygenation measurement of biological tissue. These may include surgical instruments and stand-alone imaging systems with incorporated oxygen sensing capability. Oxygenation maps can be determined via fluorescent or phosphorescent lifetime imaging of an injectable probe with an oxygen-dependent optical response. A probe configuration and methods and an apparatus of injecting the probe into the tissue are provided. Methods and an apparatus for temperature compensation of temperature-dependent lifetime measurement are provided to improve oxygenation measurement accuracy. Oxygen maps may be registered with visible light images to assist in assessing tissue viability or localize anomalies in the tissue.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority to U.S. Provisional Patent Application No. 61 / 975,742, filed on April 5, 2014, and U.S. Provisional Patent Application No. 62 / 061,079, filed on October 7, 2014, each of which is hereby incorporated by reference in its entirety.

[0002] (Government Interests) This invention was made in part or in whole with government support under National Institutes of Health grant CA153571. The government has certain rights in this invention.

[0003] The present invention relates to surgical instruments and medical imaging systems and to molecular agents used by such instruments and systems, specifically to surgical instruments and imaging systems with sensors for detecting properties of biological tissue, and to systems for utilizing information collected by such sensors. The sensing system can be configured to obtain a mapping of the physiological properties of tissue at multiple locations. Further, information from multiple sensing modalities can be used together to provide improved measurement accuracy.

Background Art

[0004] Living organisms are composed of cells. Cells are the smallest structures that maintain life and are capable of self - renewal. Cells have different structures and perform different tasks. Tissues are assemblies of numerous similar cells, with variable amounts and types of acellular intercellular substances between them. Organs are assemblies of several different types of tissues arranged together so as to be able to perform specialized functions.

[0005] Surgery is defined as the medical field related to diseases that require surgical techniques.

[0006] 95% of colorectal cancers develop from a well-understood series of genetic mutations over a 10-15 year period, beginning as tumors, or polyps. Approximately one-third to one-half of adults will develop one or more polyps during their lifetime, and about 10% of these will progress to cancer. Therefore, the vast majority of colorectal cancers can be avoided by identifying and removing polyps in their early stages before they become malignant. Endoscopy is the primary means by which the US population is screened for benign and malignant polyps. While colonoscopy can detect up to 95% of cancerous lesions, polyps are missed at a rate of about 25%, even with current “improved endoscopy” techniques. [Overview of the project] [Means for solving the problem]

[0007] The present invention relates to medical devices and systems capable of measuring the physiological properties of tissue. In one embodiment of the system, tissue oxygenation is assessed using a phosphorescent oxygen-dependent quenching technique, where phosphorescence is produced from innate biological tissue or via an injected phosphorescent oxygen-sensing molecular probe. In alternative embodiments, other phosphorescent materials or molecular markers may be used to identify specific targets or assess other physiological parameters. The techniques and instrument configurations for assessing oxygenation are disclosed in PCT Patent Application No. PCT / US14 / 31267, entitled "Apparatus, Systems and Methods for Determining Tissue Oxygenation," which is incorporated herein by reference in its entirety.

[0008] The present invention includes an imaging system for resolving and mapping physiological states or their substitutes. The imaging system resolves physiological states by utilizing information obtained from two or more sensing modalities. Additional modalities used in combination provide improved accuracy of absolute measurements in physiological states or measurements. One embodiment of the present invention takes the form of a multimodality imaging system, in which one modality assesses the phosphorescence and / or fluorescence lifetime decay of a medium, and another modality assesses the temperature of the medium or its vicinity. In one configuration, the medium is an injectable probe with a phosphorescence lifetime relating to the vicinity / resident / proximity / in-situ oxygen concentration / tension of the biological tissue of interest. Temperature measurement allows for the selection of a precise temperature-dependent calibration coefficient for the probe lifetime used to more accurately resolve oxygenation.

[0009] Embodiments of the imaging system include an optical sensor configured for detecting light emitted by a phosphorescent and / or fluorescent medium resulting from illumination of the medium at one or more excitation wavelengths, and for measuring decay lifetime, and a temperature sensor for detecting temperature at one or more points within the field of view of the optical sensor. The system further includes a processor configured to use the temperature measurement to compensate for temperature-dependent lifetime variations of the phosphorescent and / or fluorescence response. Embodiments of the present invention include a phosphorescent lifetime imaging (PLI) system, which includes both an optical detector for mapping phosphorescent lifetimes and an optical detector for detecting temperature. The system can also align temperature and lifetime images and use both phosphorescent lifetime and temperature at each mapped point to determine the corresponding oxygenation concentration in the target tissue.

[0010] Embodiments of the present invention include an imaging system configured to generate a map of biological tissue oxygenation based on the phosphorescence lifetime of an injectable probe within a region. The system comprises an optical sensor, such as a camera-based device, configured to detect the phosphorescence decay lifetime of a phosphorescent probe within a region, and further comprises a temperature sensor configured to map the temperature of the region. In one configuration, the temperature sensor is a thermal imaging camera. Correspondence between measurement locations by both sensors within the region is identified to compensate for temperature-dependent calibration from the lifetime for oxygenation.

[0011] Embodiments of the present invention are endoscopic systems (including, but not limited to, colonoscopy systems) configured to measure tissue oxygenation and generate an oxygenation map based on the quenching of the phosphorescence / fluorescence lifetime of an injectable phosphorescent / fluorescent probe by ambient oxygen. The endoscopic system further comprises means for detecting temperature within a region corresponding to the oxygenation map, and the oxygen-sensing endoscopic system is configured to compensate for temperature-dependent parameters of the oxygenation measurement based on thermal measurements of a temperature detector. Another embodiment of the present invention takes the form of a sensing system that operates independently of and in conjunction with a scope such as an endoscope or colonoscope. This system maps both the phosphorescence lifetime and the temperature at the tip of the scope, and is configured to generate a temperature-compensated absolute tissue oxygenation map using the temperature map in conjunction with the phosphorescence lifetime map. One configuration of the independently operating sensing system takes the form of an oxygen-sensing system incorporating a microcamera-based thermal imaging camera. An alternative configuration of the independently operating sensing system takes the form of an oxygen-sensing system comprising a thermal camera coupled to a coherent optical fiber imaging bundle with transmission in the infrared range enabling remote sensing of temperature.

[0012] Embodiments of the present invention include an imaging system based on a probe that uses phosphorescence and / or fluorescence. The probe may be a nanosensor molecule, a quantum dot, or other molecular tag or marker. The probe may be whole-body or locally injectable, or otherwise introduced into the body. Alternative embodiments of the imaging system are configured to image the spontaneous or autofluorescence of tissue. The imaging system further includes means for measuring at least one or more physiological or environmental parameters and using the measurements to adjust the calibration of the final measured image and to compensate for the environmental or physiological parameters. Environmental and physiological parameters may include at least one of temperature, pH, concentration of other compounds in the absorber present, measurement of an additional probe, and measurement of a reference probe or probe with secondary reference emission. Embodiments of the imaging system are configured to generate an image that represents the physiological parameters based on the phosphorescence and / or fluorescence response from the introduced probe or spontaneous interaction. The system can utilize temperature or other environmental or physiological parameters to compensate for measurements represented in the image.

[0013] Embodiments of the present invention describe systems and methods for generating images and combining them in image overlays or other augmented reality views. The present invention includes approaches for overlaying physiological parameters onto endoscopic video images. Furthermore, it includes methods for aligning oxygenation maps (or maps of other physiological properties) with visible light or other video images. Embodiments of the present invention incorporate methods for aligning an oxygenation map or a corresponding precursor lifetime map to a thermal map / image and using the aligned temperature information to compensate for temperature-dependent variations in oxygenation measurements. One method for alignment includes the step of acquiring images from multiple cameras using wavelengths of light, such as those in the near-infrared (NIR) band, detected by each camera (e.g., a visible light endoscopy camera and a physiological parameter sensing camera), and using inter-image information and / or other features for alignment. Included in the present invention are embodiments of the present invention in which at least two of thermal images, visible light images, and phosphorescent lifetime images are aligned using the approach. In one configuration of the present invention, an endoscopic imaging device is configured to map tissue oxygenation of the gastrointestinal tract.

[0014] The system is further configured to identify suspected lesions, such as precancerous polyps or other lesions. Incorporated is a method for distinguishing lesions, such as polyps, from healthy intestinal wall tissue by utilizing pattern matching of phosphorescence lifetime or oxygenation in static images. Static images refer to individually captured images, as opposed to time-series images. Static images can be continuously updated. An alternative method for distinguishing lesions from healthy tissue utilizes dynamic changes in the lifetime of time-series images. Included in the present invention is an instrument configured to map tissue oxygenation and use that information to induce the identification of at least one of noncancerous, precancerous, or cancerous lesions. A further embodiment is an endoscopic imaging system configured to generate a tissue oxygenation map, the oxygenation map inducing the identification of lesions. The system incorporates a method for identifying potentially suspicious lesions (such as polyps) through the tissue oxygenation map and optionally generating alerts. The endoscopic imaging instrument is configured to map tissue oxygenation of the intestinal wall. The system is further configured to identify suspected lesions, such as precancerous polyps. One configuration of this system incorporates a method for distinguishing polyps from healthy intestinal wall tissue by utilizing pattern matching of phosphorescence lifetime or oxygenation in static images. An alternative method for distinguishing polyps from healthy intestinal wall tissue utilizes dynamic changes in the lifetime of time-series images. Further configurations of this system also incorporate contour extraction, compartmentalization, and boundary detection. Detection may incorporate techniques such as active contour models, leveling methods, edge detection, or others. Approaches for further identifying or classifying lesion characteristics using oxygenation histograms within identified regions are also included. In an alternative configuration, this system may be configured to detect biological structures using phosphorescence lifetime imaging (or related approaches), and further configured to determine and / or highlight the location of vascular systems.

[0015] Embodiments of the present invention include a sensing scope integrated into or as an accessory to a standard endoscope system. The scope may be coupled to or introduced through a working channel or instrument port on a conventional endoscope. Furthermore, the sensing scope can provide multimodality imaging, including, but not limited to, phosphorescence and / or fluorescence lifetime, visible light imaging, and temperature measurement. The present invention further includes a method for tracking and maintaining the characteristics of acquired oxygen maps (or other properties) after removal or deactivation of the sensing instrument or scope. The method maintains the identified locations on the visible light image so that the images can be used to guide interventions such as biopsy or removal of lesions. The method further uses a registration technique to maintain lesion location data and allow movement of the visible light scope during the intervention.

[0016] One embodiment incorporates an adapter or coupler for interfacing with an existing or standard endoscopic system, the coupler introducing modulated light for the sensing system through an existing optical channel. Furthermore, the adapter enables thermal imaging through the introduction or existing imaging channel, the channel may be a rigid optical guide or a flexible optical fiber bundle. One embodiment incorporates a flexible endoscopic device, where a flexible coherent optical fiber bundle may be used for both infrared thermal imaging and illumination. In alternative embodiments, it is also considered that the flexible coherent optical fiber bundle may be used for both PLI and thermal imaging. The fiber bundle may be configured to have sufficiently high transmission infrared radiation corresponding to the sensitivity wavelength of the thermal imager (i.e., up to approximately 15 μm). An embodiment comprises a flexible endoscopic system, where the illumination fiber bundle is multiplexed to enable its use in both illumination and sensing. The fiber may be used for white light illumination or photoexcitation of a light-emitting probe. The fiber may be used to receive white light images, phosphorescent images, or infrared thermal images.

[0017] Embodiments of the present invention teach a camera-based phosphorescence lifetime imaging system in which the light source for exciting a phosphorescent probe also comprises a broadband white light emitter, etc. The system is capable of providing both visible light images and PLI measurements, and the output from the light source may be modulated as required. Further consideration is a camera-based phosphorescence lifetime imaging system in which the light source for exciting a phosphorescent probe comprises an emitter positioned circumferentially around the camera lens. The circumferentially positioned emitter, referred to as a ring light, allows for the directing of light to a region of interest within the camera's field of view. The ring light may incorporate one or more lenses. The ring light may incorporate both light sources for exciting the phosphorescent response and for providing visible light. In alternative embodiments, it is considered that the combined light source is located externally and directed to the region of interest, and in one further embodiment, the light source is mounted with or incorporated into a procedure / operating room (OR) light.

[0018] The present invention teaches the combined use of at least two unique probe types in a medium, one serving as a reference to compensate for the reading of the other for improved accuracy. In one embodiment of the approach, a temperature-dependent probe, not significantly affected by other factors, is introduced along with an oxygen-sensitive probe and a temperature-dependent response, and a substantially oxygen-insensitive probe is used to compensate for the measurement of the oxygen-sensitive probe. In one configuration, a fluorescent or phosphorescent probe with a temperature-dependent decay lifetime is introduced along with an oxygen-sensitive probe, and the two probes have separately different excitation and / or emission wavelengths. In another embodiment, two oxygen-dependent probe types with different temperature dependencies are introduced, and the lifetimes from the probes are used to accurately produce oxygenation measurements robust to temperature fluctuations, and the two probes have separately different excitation and / or emission wavelengths. In a further embodiment, the two probes are mixed and configured to allow for substantially similar distributions within the tissue upon injection. The probes may be identical in structure, with different core materials having different spectral and temporal response characteristics. The lifetimes of the two probes may be read in an alternating pattern, or one may be read repeatedly for real-time sensing and the other at a reduced rate for temperature compensation.

[0019] The present invention also includes a surgical stapler anvil with the ability to sense taken-up oxygen based on phosphorescence lifetime. In a further embodiment, the anvil comprises a camera used for sensing. One configuration of the surgical stapler anvil incorporates the ability to map oxygen to two or more points based on phosphorescence lifetime. In a further embodiment, the anvil incorporates temperature sensing, and the temperature map is used to compensate for the map of oxygen measurement. A sensing instrument with a needle integrated for microinjection of the probe is taught in the present invention. One configuration further comprises an injector that is coupled to a surgical stapler anvil and injects a medium into the working surface of the anvil (i.e., the staple-forming surface) or the tissue in its vicinity. The medium contains one or more phosphorescent oxygen-sensing probe deformations. The present invention also includes a standalone instrument that is coupled to a surgical stapler anvil and has the ability to sense taken-up oxygen based on phosphorescence lifetime for assessing the oxygenation of the working surface of the anvil (i.e., the staple-forming surface) or the tissue in its vicinity. The instrument includes one or more sensors configured to rotate or otherwise completely image the anastomosis. Also included is an interrogator wand with an integrated injector for delivering a probe and / or sensing tissue oxygenation. The injector may allow for internal injection of tissue, such as inside the colon wall, or external injection, such as from outside through the colon wall. The instrument further comprises means for measuring the temperature of tissue at the working surface. In a further embodiment of the present invention, a camera-based phosphorescent lifetime imaging system comprises means for attaching an anvil of a surgical stapler, the attachment being made via a quick-release connector to the anvil. The system is configured to generate an oxygenation map of the anastomosis during surgery. The system further comprises a thermal imaging camera that images substantially the same area as the PLI system and uses its measurements to improve the accuracy of the oxygenation measurement.

[0020] One embodiment of the present invention is based on a small secondary imaging system, such as a CMOS microcamera, that fits into the working channel of an existing colonoscope and generates an oxygen map of the colon wall. The system displays the map and / or highlights suspicious lesions using a graphic overlay on a synchronously acquired conventional scope video image. If a suspicious lesion is identified, the system would allow the oxygen map camera to be replaced with another instrument while the highlighted lesion is held / tracked on the video monitor. In one embodiment, the oxygen mapping would be achieved using phosphorescent lifetime imaging (PLI) of an oxygen-sensitive whole-body infusion molecular probe. In one embodiment of the present invention, temperature sensing is coupled with PLI to generate a temperature-compensated map of oxygen concentration. The present invention is not limited to being coupled only with a colonoscope for assessing cancerous lesions in colon wall tissue. The present invention includes all scope and camera types and configurations, including flexible and rigid, monitoring or visualization of all internal and external tissues, and identification of any type of variation in tissue parameters.

[0021] One representative application of the present invention is in the generation and monitoring of tissue flaps. Various types of cancers, such as breast and skin cancers, often result in the removal of significant tissue volume during attempts at curative excision. Traumatic injuries can result in limb amputation or detachment of a portion of tissue. The resulting tissue loss is often replaced by native tissue translocated from other parts of the patient's body. A free tissue flap is a flap that is completely removed from its original location along with its supplying vascular peduncle. The free flap vascular system is then reconnected to a blood vessel near the tissue cavity. The vascular anastomosis can fail due to leakage from improper clot formation, stenosis, or occlusion. The present invention enables the resolution of flap oxygenation through a tissue oxygenation map for both intraoperative confirmation and postoperative monitoring of tissue perfusion. Current techniques are limited to qualitative measurements of blood flow. The present invention presents a real-time quantitative assessment of tissue oxygenation. Embodiments of the present invention combine a camera-based phosphorescence lifetime detector with a thermal imaging camera, and a aligned temperature map is used to correct the calibration coefficient used to convert phosphorescence lifetime to oxygen concentration. Similar configurations may be used to monitor both internal and external tissues. Another embodiment application is in the diagnosis, assessment, or monitoring of peripheral vascular disease (PVD) treatment.

[0022] Other potential applications, though not limited to, include monitoring / recording physiological / biomechanical parameters in transplanted organs or appendages, intracranial, intramedullary, intraocular, intraaortic, intranasal, sinusoidal capillaries, intrapharynx, intralarynx, intraesophagus, intratrachea, intrathoracic, intrabronchial, intrapericardial, intracardiac, intravascular, intraabdomen, intrastomach, intragallbladder, intraintestinal, intracolon, intrarectum, intracystic, intraureteral, intrauterine, intravaginal, intrascrotal, intracerebral, intrapulmonary artery, intrahepatic, intrapancreatic, intrarenal, intraadrenal, intrasplenic, intraovarian, intratesticular, intrapenile, intramuscular, intraosseous, and intracutaneous physiological / biomechanical parameters. The present invention provides, for example, the following: (Item 1) An imaging system for resolving and mapping a physiological state or a surrogate thereof, the imaging system utilizing information obtained from two or more sensing modalities to resolve the physiological state or a surrogate thereof, the sensing modalities being used in combination to provide improved accuracy in the absolute measurement of the physiological state or measurement. (Item 2) The imaging system according to item 1, wherein one sensing modality assesses the phosphorescence and / or fluorescence lifetime associated with a medium, and another sensing modality assesses the temperature of the medium or in the vicinity thereof. (Item 3) The imaging system according to item 2, wherein the medium comprises a probe with a phosphorescence lifetime associated with the ambient oxygen concentration, and the temperature measurement is used to compensate for variations in the temperature-dependent calibration factor of the lifetime of the probe with respect to oxygenation. (Item 4) The system comprises an optical sensor configured to detect the decay lifetime of a phosphorescent and / or fluorescent medium after being illuminated externally, a temperature sensor for detecting the temperature at one or more points within the field of view of the optical sensor, a processor configured to use the temperature measurement to compensate for temperature-dependent lifetime variations of the medium, and the imaging system according to item 1. (Item 5) The imaging system according to item 2, wherein one modality is configured for phosphorescence lifetime imaging, the system comprising both an optical detector for mapping the phosphorescence lifetime and an optical detector for detecting the temperature, and the system is configured to align the temperature and lifetime images and utilize both the phosphorescence lifetime and temperature at each mapped point to determine the corresponding oxygenation. (Item 6) An endoscopic imaging system configured to sense oxygenation and generate a map of the oxygenation based on the phosphorescence lifetime of an injectable probe. (Item 7) The imaging system according to item 6, further comprising a sensor for detecting the temperature within a region corresponding to the oxygenation map, wherein the imaging system is configured to compensate for temperature-dependent oxygenation measurements based on thermal measurements. (Item 8) The endoscopic imaging system according to item 6, wherein a secondary imaging scope is configured to detect oxygenation, and the secondary imaging scope operates independently of and in conjunction with the primary scope. (Item 9) The endoscopic imaging system according to item 8, wherein the primary scope is a flexible endoscope, and the secondary scope is configured to pass through the instrument port of the endoscope. (Item 10) The imaging system according to item 8, wherein the system is configured to align a video image and the oxygenation map, and further configured to display the video image together with an overlay of the oxygenation map. (Item 11) The imaging system according to item 10, wherein the system tracks features and maintains the integrity of the acquired oxygen map after the removal or disabling of the secondary imaging scope configured to sense oxygenation. (Item 12) The imaging system according to item 6, wherein the system is configured to selectively excite phosphorescent responses within tissue, and the selective excitation provides a means for uniquely identifying oxygenation associated with tissue layer or depth. (Item 13) The imaging system according to item 12, comprising a light source attached to the tip of an extending arm, the arm capable of selectively illuminating a region or layer of tissue. (Item 14) A method comprising the steps of: aligning an oxygenation map or its corresponding precursor lifetime map with a thermal image; and using the aligned information to compensate for temperature-dependent variations in oxygenation measurements. (Item 15) The method according to item 14, wherein images from multiple cameras are acquired using near-infrared illumination, the near-infrared illumination is detectable using a visible light endoscopy camera, the camera is configured to detect phosphorescence or fluorescence response, and mutual information between the images from the multiple cameras is used for alignment. (Item 16) The method according to item 14, further comprising a step of mapping tissue oxygenation of the intestinal wall. (Item 17) The method described in item 16, further comprising the step of distinguishing between lesions and healthy intestinal wall tissue. (Item 18) The method according to item 17, further comprising the step of distinguishing polyps based on pattern matching of static images of phosphorescence lifetime or oxygenation. (Item 19) The method according to item 18, further comprising the step of distinguishing polyps based on the dynamic changes of time-series images. (Item 20) The method according to item 18, wherein the tissue oxygenation map induces the identification of the lesion, and the lesion is identified using an identifier overlaid on an endoscopic video image.

[0023] Additional features, advantages, and embodiments of the present invention are described in or evident from the embodiments, drawings, and claims for carrying out the invention described below. Furthermore, it should be understood that both the summary of the invention described above and the embodiments for carrying out the invention described below are illustrative and intended to provide further explanation without limiting the scope of the invention as claimed. [Brief explanation of the drawing]

[0024] [Figure 1] Figure 1 shows a representation of the components of one embodiment of the present invention. [Figure 2a] Figure 2a shows an embodiment of the present invention in which the system generates a graphic overlay for identifying lesion locations on synchronously acquired endoscopic video images. [Figure 2b]Figure 2b shows a representative oxygen map overlaid on an endoscopic video image. [Figure 3] Figure 3 shows an embodiment in which the oxygen mapping system is combined with a conventional endoscopic imaging system. [Figure 4] Figure 4 shows an enlarged view of one embodiment of a microcamera endoscopic imaging system that fits into the instrument channel work port of an endoscope. [Figure 5] Figure 5 shows a coupler that enables the injection of modulated excitation light from an external control unit into the optical path of a conventional endoscopic imaging system. [Figure 6a] Figure 6a shows an embodiment in which a microcamera-based secondary imaging system is fitted inside the work port of a scope with a dedicated optical channel. [Figure 6b] Figure 6b shows an embodiment in which a microcamera-based secondary imaging system is fitted inside the work port of the scope, and light is injected along the existing optical path. [Figure 6c] Figure 6c shows an embodiment in which the optical fiber path of the secondary imaging system is fitted inside the working port of the scope, and light is injected along the existing optical path. [Figure 7a] Figure 7a shows a schematic diagram of one embodiment of the present invention in which an external sensing camera system is used to generate measurements. [Figure 7b] Figure 7b shows a schematic diagram of one embodiment of an oxygen mapping system configured for connection with an endoscope. [Figure 7c] Figure 7c shows a typical oxygen mapping system configured for tracking small animals using a rigid endoscope. [Figure 8] Figure 8 illustrates an embodiment of the system in which a microcamera device passes through the working channel instrument port of the endoscope. [Figure 9] Figure 9 shows a timing diagram of one embodiment of a sensing system that uses a frequency domain approach. [Figure 10a] Figure 10a depicts a surgical stapler anvil with an integrated sensor. [Figure 10b] Figure 10b shows a magnified view of the working surface of a surgical stapler anvil with integrated sensors. [Figure 11a] Figure 11a depicts an embodiment of a medical device with an integrated sensor in the form of a sensing clip. [Figure 11b] Figure 11b depicts an embodiment of a medical device with an integrated sensor in the form of a minimally invasive surgical instrument. [Figure 12] Figure 12 shows a cross-sectional view of an embodiment of a self-contained sensing device that is detachably coupled to the anvil of a surgical stapler. [Figure 13a] Figure 13a depicts an embodiment of an imaging system with a light source capable of selectively illuminating areas of tissue. [Figure 13b] Figure 13b shows a light source with an extending arm that allows it to extend and rotate. [Figure 14a] Figure 14a shows an injector system that attaches to a surgical stapler anvil. [Figure 14b] Figure 14b shows a cross-sectional view of an embodiment of the injector. [Figure 14c] Figure 14c shows another embodiment of the injector system that is coupled to a surgical stapler anvil. [Figure 15] Figure 15 shows typical uses of injectors and sensing anvils in colorectal resection procedures. [Figure 16a] Figure 16a shows a typical embodiment of an imaging system configured to assess fluorescence and / or phosphorescence lifetimes. [Figure 16b] Figure 16b shows a typical embodiment of an imaging system configured to assess the fluorescence and / or phosphorescence lifetime of tissue at an anastomosis site. [Modes for carrying out the invention]

[0025] Tissue parameters can be measured by various methods. One technique utilized by the present invention measures tissue oxygenation levels by utilizing the oxygen-dependent quenching of phosphorescence via a whole-body or locally injected phosphorescent oxygen-sensing molecular probe for oxygen measurement, as disclosed in U.S. Patent Nos. 4,947,850, 5,837,865, 6,362,175, 6,165,741, 6,274,086, 7,575,890, and U.S. Patent Application Publication No. 2013 / 0224874, which disclose and are incorporated herein by reference as a whole method of measurement. The phosphorescent oxygen-sensing probe comprises a phosphorescent metallic porphyrin core encapsulated inside a hydrophobic dendrimer that forms a protective shell, isolating the chromophore from direct contact with the environment, controlling oxygen diffusion, and enabling control over the probe's dynamic range and sensitivity. The metallic porphyrin core can be constructed with different elements. Palladium and platinum are two elements that can be used. The advantage of platinum-based cores over palladium-based cores lies in their quantum efficiency. The increased quantum efficiency of phosphors allows for a significant increase in optical output compared to Pd-based molecules. The more light returned per molecule, the less molecules can be used to achieve the same signal returned to the device. Alternatively, the injection of the same amount of molecules allows for the use of less sensitive (inexpensive) photodetectors. Peripheral pegylation of dendrimer branching ensures high aqueous solubility of the probe while preventing interaction with biological macromolecules. The overall size of the molecular probe affects its ability to be eliminated by the kidney. Faster elimination limits the exposure of the agent to the patient. Size can be varied through modifications of dendrimer length, number of dendrimers, and the size / pegylation range of the PEG.

[0026] In one embodiment of the probe, the core Pd-meso-tetra-(3,5-dicarboxyphenyl)tetrabenzoporphyrin (PdTBP) is encapsulated by eighth-generation 2-polyarylglycine (AG2) dendrons, each pegylated with monomethoxy-polyethylene glycolamine (PEG-NH2) groups (average MW 1,000 Da), each having an average of 21-22 monomer-(CH2CH2O)-units. The molecular weight of the probe dendrimer was found to be in the range of approximately 26,000-44,000 Da, with a maximum of 35,354 Da, as determined by MALDI mass spectrometry. Phosphorescent quenching relies on the ability of molecular oxygen (O2) to quench the phosphorescence of excited triplet-state molecules in the environment. In biological systems, phosphorescent quenching by oxygen occurs in a diffusion-controlled manner, and O2 is highly specific because it is the only small-molecule dynamic quencher present at sufficiently high concentrations. The dependence of phosphorescence lifetime (τ) on oxygen partial pressure (pO2) throughout the biomagnification range is described in detail by the Stern-Volmer equation: 1 / τ = 1 / τ0 + kq × pO2, where τ is the phosphorescence lifetime at a given oxygen pressure pO2, τ0 is the phosphorescence lifetime in the absence of oxygen (pO2=0), and kq is the extinction constant. One molecular oxygen probe has an extinction constant kq of approximately 326 mmHg. -1 s -1 It has a physiological pH range of 6.2 to 7.8, a τ0 of 210 μs, and a constant temperature of 36.5°C.

[0027] The probe calibration parameters kq and τ0 change linearly with temperature. The extinction constant kq has a temperature coefficient of 7.8 mmHg. -1 s -1 Corresponding to / ℃, the temperature rises from 22℃ to 38℃, resulting in 211mmHg -1 s -1 ~338mmHg -1 s -1The value increases. The probe's absorption spectrum has maximum values ​​at approximately 448 nm and 637 nm, with a maximum phosphorescence emission value of 813 nm. Excitation at multiple wavelengths allows for the examination of structural characteristics at different penetration depths or layers, resulting in distinguishable application-specific advantages. Combinations of multiple pO2 values ​​within the field of view will appear as lifetime combinations (sums of exponential decay). Multiple pO2 values ​​and their corresponding concentrations can be determined through the means described herein.

[0028] Due to the dependence of the measured phosphorescence lifetime on temperature, it is essential to assess the temperature at the measurement site and use that information to apply an appropriate relationship between phosphorescence lifetime and oxygen concentration. By measuring the temperature at the measurement point, an appropriate temperature-dependent extinction coefficient kq can be selected, which may enable improved accuracy in measuring oxygen concentration at that point. The average temperature of the measurement area may be used to improve accuracy, but further location-dependent compensation may be obtained by mapping the temperature to multiple points and relating the correspondence of those points to the lifetime measurement when converted to oxygen concentration. Note that oxygen concentration and oxygenation may be used interchangeably in this disclosure, and both relate to the amount of oxygen present in the tissue.

[0029] Embodiments of the present invention are intended to detect quantitative differences in stromal tissue oxygenation of non-cancerous, precancerous, and cancerous lesions when measured against surrounding normal tissue. Specific embodiments further described aim to identify lesions within the gastrointestinal tract. One application of the present invention targets the improvement of detection of precancerous colon polyps. Through mapping of stromal tissue oxygenation during video colonoscopy, the present invention aims to improve the detection of preneoplastic and neoplastic lesions during colonoscopy screening compared to conventional white light and "dilated" endoscopic techniques. Furthermore, the present invention aims to differentiate various latent malignant lesions based on tissue oxygenation patterns. It should be noted that "white light" and "visible light" imaging may be used interchangeably for the purposes of this application. Sensing accuracy can be improved by using lifetime temperature-dependent calibration for tissue oxygenation by simultaneously mapping temperature within the same area of ​​interest. For the purposes of this application, it should be noted that phosphorescent lifetime image / imaging (PLI) refers to a precursor used to calculate physiological parameters such as oxygenation, and may be an actual calibrated lifetime measured in microseconds, or may be represented by relevant raw data including clock cycles, camera frames, phase delay, or other measurement parameters.

[0030] Currently, there are no clinically practical methods for quantitatively assessing tissue oxygenation during colonoscopy, nor are there any methods to improve polyp detection using such information. This approach may also be used for various other tissue imaging, including, but is not limited to, gastrointestinal imaging to guide surgical procedures such as colon or rectal anastomoses. The term "imaging" refers to taking measurements at multiple locations. This includes, but is not limited to, a 2D map such as a camera-based sensor or an array of discrete points such as multiple sensor elements on an instrument.

[0031] Figure 1 shows a representation of an endoscopic system 100, which is a component of one embodiment of the present invention, comprising an oxygen-sensing molecular probe 101, a phosphorescence lifetime imaging interface 103, and a secondary camera 105. This system assists in the detection of non-cancerous, precancerous, and cancerous lesions by utilizing the oxygen difference present between healthy tissue and lesions. This system generates a quantitative oxygen mapping of the gastrointestinal tract. An example of a lesion is a colonic polyp found in the colon. The oxygen-sensitive phosphorescent oxygen-sensing probe 101 is a nanosensor injected systemically into the bloodstream or locally into the interstitial space. The phosphorescence lifetime imaging interface 103 determines tissue oxygenation based on the optical response of the phosphorescent probe 101 (related to the oxygen-dependent quenching of the phosphorescence lifetime). The phosphorescence lifetime is imaged by a secondary camera 105, which passes through the working channel of a conventional scope such as a colonoscope. In one embodiment, the secondary imaging system 105 is a miniature microcamera endoscope inserted into the proximal end of the working channel of a conventional colonoscope and passing through to the distal end of the colonoscope. The camera may be integrated into a flexible cannula and may be a single-use or limited-life device. In another embodiment, the secondary imaging system comprises an optical fiber imaging bundle inserted into the proximal end of the working channel and passing distally. The proximal end of the imaging bundle is coupled to the camera. In yet another embodiment, the proximal end of the imaging bundle is coupled to an image enhancement device coupled to the camera. The camera itself may employ image enhancement optics. Light in or passing through the imaging bundle may pass through an optical filter. The system may further include a thermal imaging system capable of mapping temperature within the region of oxygenation measurement. In one embodiment, infrared radiation is passed through a coherent optical fiber bundle to the thermal imaging camera. The optical fiber bundle may be the same as that used in the secondary imaging system, a bundle also used for illumination, or an alternative bundle.

[0032] The present invention includes a configuration of an oxygen-dependent quenching molecular probe 101 that allows for a controlled residence time within the body or a part thereof. Controlled variations in the size and shape of the probe affect the residence time and elimination rate. In one embodiment, the probe is excreted from the body within 24 hours. The molecular probe 101 may be integrated or bound to, completely or partially, within bioabsorbable beads or other objects to maintain a sufficient probe at a site for a long period after injection. As an alternative approach to maintaining the probe at a site or directing the probe toward a site, the molecular probe may be coupled to a magnetic carrier for control of its position or to maintain a sufficient probe at a site for a long period. The present invention may also incorporate phosphorescent materials and other markers for various physiological parameters other than oxygenation, such as glucose levels, pH, lactate, or disease markers. Measurement of multiple physiological parameters can occur simultaneously.

[0033] Figure 2a depicts an embodiment of the present invention in which the system generates a graphic overlay (205, 211) on a synchronously acquired endoscopic video image 201 that identifies the location of lesions or vascular systems (203, 209), including polyps or other abnormalities, within the target tissue. Tissue 201 represents colon tissue, however, the endoscopic system can be used to image any biological tissue. Figure 2b shows an embodiment of the overlay that presents a map of tissue oxygenation (221, 233), which may appear as a pseudo-color translucent overlay 219. In other embodiments, other physiological characteristics may be displayed along with the corresponding anatomical images. The system is capable of measuring oxygenation through several visual obstructions, such as tissue folds, and is typically capable of identifying lesions hidden behind folds 215 or other obstructions. In one embodiment, the system automatically identifies suspicious lesions (203, 209) and generates an overlay that highlights the suspicious lesions (205, 211) based on resolved oxygenation (221, 223). The overlay may be one of the following: a general mark (e.g., a crosshair or a box as in Figure 2a), a lesion contour, a probability map, or an overlaid oxygen map as shown in Figure 2b. The identification process may incorporate statistical data when assessing whether the measurement indicates the presence of a non-cancerous, precancerous, or cancerous lesion, or other feature of interest. Colonic lesions may include, but are not limited to, inflammatory, hypertrophic, adenomatous, or tubular villous polyps. Furthermore, a certainty level associated with the assessment may be incorporated. The overlaid oxygen map (or other feature) may be aligned with the endoscopic video to ensure consistency. In further embodiments, features in the endoscopic video are tracked through a bidirectionally updated image-based alignment process to maintain the image overlay even when the secondary imaging system / camera system is removed (such as inserting an instrument along the work channel). In one embodiment, sensors such as electromagnetic tracking sensors or inertial measuring sensors are used to monitor the absolute position or relative changes of the imaging system at a fixed position.The system may be configured to automatically detect lesions or other physiological structures based on oxygenation, and may be rendered in a live oxygen map video feed or static image with pseudocolors (i.e., a color map) representing the measurements. The system may also detect and identify the vascular system, and in one configuration, this information may be used to guide surgical interventions. Such guidance may be used to help identify blood vessels and to avoid unintentional damage to them.

[0034] Figure 3 shows an embodiment of the present invention in which the oxygen mapping system includes an oxygen mapping system control unit 301 that seamlessly couples with a commercially available endoscopic interface unit, which includes a control unit 303 and a light source 305 (which may be a combined or separate component). A coupler 309 in the optical path can be used to inject the required modulated light from the secondary light source 311 into an existing illumination fiber bundle 315, which can be passed through a flexible endoscope 319, irrigation, or other connection as needed. If a suspicious lesion is identified, the system can allow the exchange of the oxygen mapping camera 323 with another instrument while the highlighted lesion is held / tracked on a video monitor. Oxygen mapping can be achieved using oxygen-dependent quenching of phosphorescence utilizing molecular probes injected throughout the body. In one embodiment, the secondary video feed 323 can be used for PLI imaging and may take the form of an electrical connection to a microcamera at the distal tip of a catheter. In an alternative embodiment, the secondary video feed 323 may take the form of a coherent fiber bundle that directs the light to an imaging system inside the oxygen mapping system control unit. The imaging system may be a microcamera (such as a CMOS image sensor), a conventional camera (such as a CMOS or CCD camera unit), or an amplified scientific imaging system as further described herein. In one embodiment, the oxygen mapping system also includes temperature measurement capabilities. In one configuration, a coherent fiber optic bundle capable of passing infrared light may be used for thermal imaging. The fiber optic bundle may be an independent bundle, a multiplexed illumination fiber bundle, or a multiplexed fiber bundle of an oxygen mapping secondary imaging system. In an alternative configuration, discrete point temperatures such as thermocouples may be used to assess tissue temperature at the imaging site. In a further configuration, an external sensing system for measuring core body temperature may be fed into the PLI system.

[0035] Figure 4 shows an enlarged view of one embodiment of a microcamera endoscope 401 that fits into an instrument channel work port 403 of an endoscopic range 405, such as a colonoscope. Incident light is emitted through an integrated light source such as an optical fiber 409 or an LED, eliciting phosphorescence, fluorescence, or other photore-emission response from a target tissue or object. A camera 413, such as a micro CMOS sensor which may include a control circuit, is placed near an optical filter 415 (long-pass filter) that removes the incident light and leaves the re-emitted light. The sensing approach may be time-domain, frequency-domain, or an alternative method. The use of a time-domain method may eliminate the need for the filter 415 or reduce its required optical density. A wide-angle lens 419 may be used to obtain a wide field of view. Microlenses may be incorporated on the camera sensor. The camera 413 and lens 419 may be configured to provide an angled view of the tissue. A micro thermal imaging camera may further be incorporated to assess the tissue temperature at the imaging site. The camera may be a standalone device or a combined imaging unit capable of both PLI and temperature mapping. Additional approaches known in the art for temperature measurement at one or more points may also be incorporated. A camera or multiple cameras transmits its data along cable 423. A secondary imaging system may be contained within a flexible outer sheath 427.

[0036] One embodiment of a PLI system based on either distal imaging (e.g., a microcamera at the tip) or proximal imaging (e.g., a fiber bundle to an external camera) can provide an ultra-wide field of view. Providing a wide field of view can make it possible to visualize behind objects such as polyps, tissue folds, stenoses, or anastomoses. The distal end of the imaging system may be capable of being actively flexed to provide a sufficient view to see the rear side of an object. This embodiment may incorporate a pre-flexed shape memory alloy to provide a predetermined curved shape when extended. In one embodiment, a cylindrical prism-like device is used to generate a very large angle of refraction, and thus a view exceeding 180 degrees. In another configuration, a stacked layer of a high refractive index medium is used to create an ultra-wide field of view lens.

[0037] In one embodiment of the present invention, the medium may contain a fluorescent or phosphorescent oxygen-sensing molecular probe. The light source may be a narrowband light source such as an LED or laser, or a broadband light source such as a white light source. The peak emission wavelength of the narrowband source may be selected to be the absorption peak of the molecular probe in the medium or near it. An optical filter may be used to further restrict the incident light to wavelengths within or near the absorption wavelength region of the molecular probe. The molecular probe can re-emit light, which then optionally passes through the filter, isolating the emitted light from the incident light. A photodetector can sense the intensity of the received light. In one configuration, the detector may be a single-point detector such as a PD, APD, SiPM, or similar device. In an alternative configuration, the detector may be a multi-point detector such as a camera or an image sensor or an array of single-point detectors. The camera may be a CCD, CMOS, or other technology, and may be directly on the tissue contact surface of the instrument or optically coupled to a remote location via a bundle of optical fibers, etc. The array of single-point detectors may be a PD array, SiPM array, linear CCD, or other technology. The light source may be directed over a wide area or precisely directed to a point of interest and scanned. The photodetector may be directed over a wide area or precisely directed to a point of interest and scanned. In one configuration, a processor commands light pulses from the light source and analyzes the time response of the signal received by the detector using time-domain signal processing techniques. In an alternative configuration, the processor can command modulated light, such as a sinusoidal intensity profile, from one or more light sources and analyze the signal measured from the detector through frequency-domain signal processing techniques to determine the phase delay. In one configuration, the medium may contain a phosphorescent molecular probe. The probe emits phosphorescence when excited by a wavelength of light within the probe's absorption band. The phosphorescence lifetime may respond to the oxygen content near the probe, due to the ability of oxygen to quench the phosphorescence. The relationship between oxygenation and phosphorescence lifetime may follow the Stern-Volmer relation.Time-domain or frequency-domain techniques may be used by a signal processor to quantitatively resolve the corresponding oxygen content or concentration at one or more locations in a tissue. The term “resolve” is intended to be interpreted broadly as calculating, calculating, determining, assessing, or obtaining a solution regarding the oxygen content or concentration within a target tissue. Exemplary implementations of time-domain or frequency-domain techniques are disclosed in U.S. Patent No. 6,701,168, which is incorporated herein by reference in its entirety. Oxygen content may be represented as a number or shown as an oxygenation map on an instrument or external display unit. Oxygen content may be used to predict the likelihood of success or failure of a surgical procedure or to guide a surgical procedure. Exemplary implementations of prediction or guidance techniques are disclosed in U.S. Patent Publication No. 2009 / 0054908A1. In one embodiment, the instrument is an endoscopic imaging system. In another embodiment, the instrument may be an accessory to a surgical instrument, such as an accessory to a surgical stapler anvil.

[0038] Figure 5 demonstrates one embodiment of a coupler 501 that can enable the injection of modulated light along an optical path 503 (such as a fiber optic cable) from an external control unit 505 into the optical path 509 of an existing endoscope system 511. The optical path 509 typically passes white light from a standard endoscopy light source in or associated with an endoscope camera controller 511. This enables multiplexing of the optical fibers 515 of a conventional endoscope 519 to allow for white light for conventional video imaging and modulated wavelength-specific light for incorporating sensing such as PLI. The light source coupler 523 meshes with the optical port 509 of the endoscopy light source. In one embodiment, a motorized mirror unit 527 can switch between the white light input source 523 and a modulated light source from an oxygen mapping system 503. In alternative embodiments, solid-state or MEM switching or mirrors such as DLP-like devices may be used. The endoscope coupler 529 can be coupled to a standard endoscope 519 and allow the combined optical output to pass into the optical path 515.

[0039] Figures 6a and 6b show embodiments of the system in which a microcamera endoscope or fiber optic scope 601 can be mated inside the work port of a conventional commercially available or customized scope 603. An optical coupler 607, as described in Figure 5, can inject light from the PLI control unit 611 into the existing scope illumination / fiber optic 613. Figure 6a shows a dedicated optical channel for the PLI system and a shutter unit for the scope interface. Figure 6b shows an alternative embodiment in which light is injected along the existing optical path 613.

[0040] Figure 6c depicts an embodiment of an imaging system in which a coherent optical fiber imaging bundle 621 is configured to pass through the working channel / port 623 of an endoscope 603. The endoscope 603 may be an optical fiber imaging flexible endoscope or a flexible endoscope with a microcamera integrated at the distal end 625. The secondary imaging fiber bundle 621 is coupled to an imaging system 631. In one embodiment, the imaging system 631 comprises a gate image augmentation device and a high-sensitivity high-speed camera. The imaging system 631 can be coupled to a phosphorescence lifetime imaging system 635. The PLI system 635 controls camera exposure timing, augmentation device gating, and modulation of the light source 639. The excitation light from the modulated source 639 may be combined with a visible light source 643 of a conventional commercially available endoscope controller 645 using a coupler 607 and fed into the scope 603 via an optical fiber 613. The video feed from the camera control unit 649 from a conventional commercially available endoscope imaging system 645 can transmit the endoscope video image to the PLI system 611. The image processing unit 653 of the PLI system 611 can align video images from phosphorescent lifetime imaging and white light endoscopic imaging. The video images from the commercially available endoscopic system 645 may be white light video only, or a combination of white light images and infrared images.

[0041] The use of infrared (IR) imaging based on illumination from a light source 637 (shown in Figures 6a and 6b, and also applicable to embodiments described in Figure 6c) fed into the coupler 641 along with modulated light 639 can enable common features to become visible in both images captured by the camera unit 649 and the imager 631, aiding in alignment. The visual output of the PLI system 611 can be displayed on an internal or external display 657, which may incorporate the teachings described in Figures 2a and 2b. Note that the detailed description provided with respect to Figure 6c also applies to Figures 6a, 6b, and other embodiments of the invention.

[0042] Figure 7a shows a schematic diagram of one embodiment of the present invention in which an external sensing camera system 701 can be used to generate measurements. The system may be directly coupled to a lens or to a rigid or flexible endoscope 705 for external imaging or invasive surgical procedures, etc. In one embodiment, a subject can be injected whole-body with an oxygen-dependent phosphorescent probe and then imaged using the system to obtain an oxygen map and video images of the subject tissue. A light source 709 is used to illuminate and excite the probe within the subject tissue 711. Alternatively, the fluorescence or phosphorescence of the tissue itself may be detected by direct illumination, with or without the molecular probe. The light source 709 may include multiple wavelengths to excite different molecular probes, different absorption peaks of the molecular probes, and vary the depth of light transmission (the representative wavelengths shown in Figure 7a are not intended to imply that other wavelengths are exclusive). Discrete wavelength and broadband sources may be used. The light source may be an LED, laser, or other source. The source may be modulated by an optical control system 715 to enable time-domain, frequency-domain, or other sensing techniques. A splitter 721 can be used to direct light between an imaging camera 723 (such as a visible light camera) for obtaining white light endoscopic images and a sensing camera 701. In one embodiment, the sensing camera is a high-speed sensitizing scientific camera 701. A filter 763 can allow only light re-emitted from the probe or natural tissue to pass to the sensing camera. The splitter 721 may be a beam splitter, an adjustable mirror, or another method for splitting the light. In one configuration, the light can be split based on wavelength to transmit re-emitted phosphorescent IR light to the sensing camera, while the visible light can be directed towards the imaging camera. Figure 7b shows details of one embodiment of the system. Figure 7c depicts one embodiment of the system in a preclinical trial. The device may be used clinically in humans, for animal applications, or in laboratory scenarios.

[0043] In one embodiment, the processor can interface with a sensing camera 701, an imaging camera 723, and a light source 709. In one embodiment, a computing system 731 can be connected to the sensing camera 701, and the processor of the computing system 731 can perform calculations on the collected image data. The calculations may be used to determine and map fluorescence or phosphorescence lifetime or related parameters. The processor of the computing system 731 may be a microprocessor and / or a graphics processing unit (GPU). In an alternative configuration, data from one or more cameras passes through a field-programmable gate array (FPGA), and the FPGA is configured to perform some or all of the data processing, such as determining and mapping fluorescence or phosphorescence lifetime or related parameters. One embodiment of the present invention incorporates a gated image augmentation device coupled to a high-speed imaging sensor. The imaging sensor is communicatively coupled to the FPGA. The FPGA controls the imaging (including exposure timing) and gating of the image augmentation device. The FPGA can also control pulsed or modulated light sources. The FPGA can control timing and image acquisition. The FPGA also performs image processing on the acquired images. In one embodiment, the FPGA determines a phosphorescence or fluorescence lifetime map for each measurement cycle. One approach to the calculation is to assess the exponential decay time constant for each pixel. Performing onboard calculations within the FPGA reduces the need for high-speed data transfer, and therefore, the embodiment may have output of the phosphorescence or lifetime map at a frame rate similar to that of a typical endoscope camera over conventional communication channels such as standard PC video, composite video, component video, or similar, such as USB, Ethernet®, Firewire, VGA or HDMI®.

[0044] Figure 7b schematically shows one embodiment of an oxygen mapping system configured to be coupled to an endoscope 741, which may be rigid or flexible. A light source 743 is fed into the illumination port of the endoscope and may contain white light and modulated / pulsed excitation light. An adapter (e.g., a C-mount endoscope adapter) 745 can be coupled to a lens tube 747, which includes a focusing optic 749. A splitter box (e.g., a cube holder) 751 may contain a splitter 753, which may take the form of a wavelength-dependent hot (IR) mirror splitter. The focusing optic, including an adjustable lens tube and adapter, can couple one output of the splitter 751 to a visible light endoscopy camera 757. The other output of the splitter can pass through a focusing optic 761 and a long-pass or band-pass optical filter 763 to reach a sensing camera 765. The long-pass filter can effectively remove incident light, allowing only the re-emitted light to pass through. The wavelength selectivity of the filter will depend on the optical absorption and emission characteristics of the probe used as well as the incident light source. The sensing camera can be used for phosphorescent lifetime imaging and may take the form described in Figure 7a.

[0045] Figure 7c shows a typical oxygen mapping system configured for tracking small animals using a rigid endoscope 771. The scope 771 may also include, or be coupled with, an air supply channel 773. A multi-wavelength LED light source 775, including remotely selectable white light and pulsed / modulated light, is coupled to the illumination port of the scope 771. A lens assembly and splitter with a filter block 777 (as described in Figure 7b) couples the scope 771 to a sensing imaging system 781 and a visible light imaging system 783. In this embodiment, the sensing imaging system 781 is an IR-sensitive, high-speed gating camera. A control unit, such as a data acquisition system (DAQ) 787, may provide illumination waveform and camera synchronization control and be coupled to a control computer 791. Illumination of the light source 775 may be controlled by a modulated light driver 789. The term “modulated light” may refer to pulsed light in the case of a time-domain approach, or a sinusoidal input in the case of a frequency-domain approach. The display of computer 791 can show the white light video endoscope output 793 as well as the calculated oxygen and / or phosphorescence lifetime map 795. For experimental evaluation, gas mixer 797 allows control of the inhaled O2 concentration of the subject.

[0046] Figure 8 depicts an embodiment of the system in which a microcamera device 803 passes through the working channel instrument port of the endoscope to its distal tip 807 to image the target tissue 809. This embodiment can be compatible with coupling with both fiber and integrated videoscopes. This embodiment can operate similarly to that of Figure 7a, but the camera 803 can be located at the distal tip 807 of the scope. The system depicted shows a phosphorescent lifetime imaging control system connected to the microcamera and an optical coupler 811 for injecting light into the illumination port 815 of the scope. The PLI control system 819 can control the camera controller 821, the light source 825, and the map generation functionality 829. In one embodiment, visible light images can also be acquired from an external camera unit or another source, and a map of tissue oxygenation or its substitutes can be aligned with the video image and displayed through an augmented reality image overlay to show tissue oxygenation or other information.

[0047] Figure 9 shows an exemplary timing diagram of one embodiment of the sensing system. The figure depicts a frequency-domain approach to sensing, where excitation light is modulated 901 at a frequency with a period Tmod = 1 / fmod, identified as 903, and the system acquires a timed image during a repeating period Ts, identified as 905. Ts is defined as Ts(k) = k × N × Tmod + k × dq for each increment k, where k = sample number (starting from 0), N = number of periods between samplings (based on the camera frame rate), Tmod = period length of the excitation modulated sine wave (1 / fmod), dq = increment along the period for each subsequent sample (corresponding to the sampling interval), and q = k × dq = offset from the start of the period in the current cycle to trigger sampling. The optically modulated waveform (plot above) consists of a sine wave 901 with a frequency fmod for the desired number of samples × N. Each period is shifted by a small amount of q, identified as 909, to sweep the imaging trigger 913 over the entire range of the periodic response. The camera trigger waveform 921 (plot below) consists of a pulse train with a rising edge at time Ts(k) for each sample k. Multiple accumulation or integration may be performed by synchronizing the shutter or gate with a portion of the period. This portion can be gradually shifted to acquire the entire waveform. The phase delay induced in the waveform can then be related to oxygenation. Multiple frequencies may be used to enable more robust measurements, assist in the removal of incident light that passes through a filter, or determine the oxygenation spectrum. In alternative embodiments, time-varying frequencies, such as a linear chirp signal, are used to excite the probe and obtain information from multiple frequencies. Acquisition may be performed continuously over multiple periodic repetitions or may be acquired using a high-speed camera unit. Scanning or binning of camera sensor pixels may be used to obtain high-speed imaging of a small subset of the field of view. In another embodiment, a similar approach may be used for time-domain measurements. In this approach, multiple points along the optical response are read across a series of repeated excitations with a time-varying phase delay, and then decay.This includes approaches for reducing sample rate or frame rate requirements through synchronized gate imaging of multiple consecutive periods. Further approaches may involve multiple acquisitions or accumulations during a given period being summed together to increase the measured signal or improve the signal-to-noise ratio (SNR) during that period.

[0048] The present invention includes an algorithm for determining oxygenation based on a frequency-domain approach. The approach may include a single modulated optical excitation frequency, two frequencies to reduce the effect of residual excitation light, or multiple frequencies to resolve the presence and amount of multiple oxygenation levels (i.e., a spectral map of oxygenation). Embodiments include an approach in which the frequency is tuned to maintain a substantially fixed phase. The present invention may include an optimization process for determining the optimal frequency for acquisition. In some embodiments, the oxygenation calculation may be based on a time-domain approach and a maximum entropy approach. Alternative embodiments may utilize a two-photon excitation technique.

[0049] The present invention includes an approach for time-domain oxygenation measurement in which temperature measurement information can be incorporated into the conversion from measured phosphorescence lifetime to oxygenation. Further included is an approach for frequency-domain oxygenation measurement in which temperature measurement information can be incorporated into the change from measured phase to oxygenation of the phosphorescence response.

[0050] Figure 10a depicts a surgical instrument with an integrated sensor. In one embodiment, a surgical stapler anvil 1001 or an accessory device coupled to the anvil incorporates a sensor. The sensor 1005 on the working surface 1021 (the surface that forms the staple crimp) of the anvil may include an optical emitter and receiver for phosphorescent lifetime imaging of tissue on the working surface of the instrument. One embodiment of the sensing anvil 1001 includes a sensor element 1005 located within a cutout 1007 on the anvil surface. The sensing anvil includes control electronics coupled to a wireless transceiver 1009 powered by an onboard battery 1011. The sensing components are encapsulated inside a cap 1013.

[0051] Figure 10b shows an enlarged view of the anvil working surface 1021. In one configuration, an LED light source 1025 and a photodiode 1027 are sandwiched within a cutout 1007 between the staple-forming sections. A pressure sensor 1031 is also located within the cutout 1007 to assess tissue interaction forces. One embodiment of the instrument further includes one or more temperature sensors 1033, such as a thermocouple or resistance temperature detector (RTD). In one configuration, the temperature sensors may be sandwiched between the staple-forming sections 1029, circumferentially distributed around the anvil surface 1021, or located within the cutout 1007 between the staple-forming sections. In an alternative configuration, a camera may be integrated into the sensing anvil to image tissue through an optical fiber or other optical guide. This embodiment can be functionally analogous to the microcamera endoscope described above. In a further alternative embodiment, the sensor may sweep across the device and take measurements at multiple points.

[0052] Figure 11a depicts an embodiment of a medical device with an integrated sensor in the form of a sensing clip. In one embodiment, the clip 1101 may be configured to traverse and encapsulate and sense intestinal tissue. The tissue may be placed between the upper surface 1103 and the compression surface 1105. A clasp 1107 can close and hold the sensor around the tissue, while a tissue compression bladder or balloon 1105 can compress the tissue to a specified pressure through an air or fluid connection 1109. One or more sensors 1111 are positioned along the tissue contact portion of the surface 1103. In one configuration, a linear array of oxygenation sensors can generate a linear 2D map or 3D array of oxygenation in the tissue. The sensors 1111 may include an optical emitter and receiver for PLI measurement. The sensors may further include one or more temperature sensors associated with each measurement point, which may enable temperature compensation for the oxygenation measurement. The sensor interfaces with control electronics (including an LED or laser driver and a photodetector amplifier) ​​and a microcontroller or other processor 1113 and can be powered by an onboard battery 1115. The system can communicate wirelessly using a wireless transceiver 1117. The sensing system can be sealed with a sealant and / or cap 1119. Figure 11b depicts an embodiment of a medical device with an integrated sensor in the form of a minimally invasive surgical instrument configured as an endoscope wand 1141. The sensing head 1143 may comprise an array of sensors 1145 that interfaces with control electronics 1149. The array of sensors on the instrument may comprise one or more of oxygenation sensors, pressure sensors, and temperature sensors.

[0053] The present invention includes various sensing surgical instruments and imaging system configurations. One or more sensing surgical instruments may be used in conjunction with the imaging system. In one use of the system, an endoscopic PLI system (as described in Figure 3) may be used inside the colon, a wand-shaped device (as shown in Figure 11b) may be used on the outer surface, and a sensing anvil (as described in Figure 10a) may be used to assess tissue oxygenation at the anastomosis site. The sensors may communicate wirelessly with a base station, which may also include a PLI imaging system.

[0054] Figure 12 depicts a cross-sectional view of an embodiment of a medical device 1201 with an integrated sensor. This embodiment may include one or more sensor elements within a self-contained instrument that detachably connects to an anvil 1203 of a surgical stapler. The body 1205 of the instrument 1201 acts as a grip or handle, and the tissue contact surface 1209 compresses the tissue 1211 against the surface 1213 of the anvil 1203. In one configuration, the tissue 1211 is a portion on the proximal end of intestinal tissue, such as colon tissue, where an anastomosis is to be performed. The head of the anvil 1203 can be inserted into the intestinal tissue 1215 (e.g., the proximal end of a colorectal anastomosis), and the purse-string closure 1217 can tighten the tissue 1211 against the anvil handle 1221. The anvil handle 1221 can be inserted into the handle coupling cavity 1223 to align the anvil with the device 1201. Alternatively, the handle connector 1223 (engaging member) is a pin (spike) similar to that at the distal end of a circular surgical stapler, which is inserted into the anvil handle 1221. In one embodiment, the tissue contact surface 1209 can act as a sensor window, being substantially optically transparent and allowing optical sensing through the sensor window. The tissue contact surface 1209 may include one or more pressure sensor elements 1229, allowing the processor 1231 to determine the tissue compression pressure. The tissue compression pressure may be used to gate the oxygenation measurement of the device.

[0055] In one embodiment, an internal structure 1235 within the outer housing 1205 can rotate one or more sensor elements 1239 to provide a complete circumferential reading around the anastomosis. In one embodiment, the rotating sensor element 1239 may comprise at least one light source and one photodetector. The sensor may be used for oxygen measurement, fluorescence imaging, phosphorescence lifetime imaging, or other optical sensing approaches. In a further embodiment, the light source may be an LED configured to excite a phosphorescence response within an oxygen-sensing phosphorescent probe, and the photodetector may be a photodiode configured to detect the phosphorescence response of the probe. The rotating sensor element 1239 may also comprise one or more temperature sensors, such as a thermocouple or resistance temperature detector (RTD). The temperature sensors may also be fixed to the body 1205 and non-rotatable. A signal processor 1231 can control one or more light sources and receive and analyze signals from the photodetector. The signal processor 1231 may be used to determine the phosphorescence lifetime. To obtain a set of readings (i.e., an oxygen map) around the anastomotic tissue 1211, the internal structure 1235 can rotate about an axis 1245. In one embodiment, the rotation can be performed by a motor or other rotary actuator 1241, and in another embodiment, the internal structure can be rotated manually. An angle sensor 1243 can be used to determine the rotation angle of the internal structure 1235 relative to the outer housing 1205. In an alternative configuration, a stepper motor can be used, and the relative rotation angle can be estimated from a motion control signal. In one embodiment, the internal structure 1235 is a reusable and durable instrument, while the outer housing 1205 is disposable and single-use. A signal processor 1231 can utilize an optical sensor element to generate measurements at a defined rotation angle, or record that angle at the time of reading. The signal processor 1231 can reconstruct a map of measurements corresponding to the position of the sensor element at the time the reading was made. In one embodiment, a 360-degree map of tissue oxygenation can be generated on the surface of the intestinal anastomosis by rotating the sensing element 1239 and taking readings at discrete intervals.In one embodiment, a wireless transceiver 1247 may transmit data to a base station and receive commands from the base station. One or more indicators 1251 may be used to indicate the status of the instrument and / or the tissue being measured. The sensing instrument 1201 may be powered by an internal battery 1255.

[0056] In one embodiment, if a region of tissue is determined to be defective / abnormal and require attention (e.g., poor oxygenation), the rotation-sensing structure can rotate to indicate the location of the defect. In a further embodiment, the instrument can align with a region of tissue with impaired oxygenation, then illuminate it, and notify the user. The embodiments described herein generally refer to an instrument having at least one sensor element 1239 coupled with another surgical instrument (e.g., a circular stapler anvil 1203 or housing) to perform one or more sensor readings on a tissue surface 1211. In a more specific configuration, the sensor element may be configured for PLI and can rotate to determine an oxygen map of intestinal tissue on the surface of the circular stapler anvil 1213 at a proposed site of the anastomosis 1211. Readings may be performed at a number of rotation angles and at a number of radial distances. Radial placement may be performed inside the staple-forming portion, in an anvil configuration (along the proposed staple line), and outside the staple-forming portion, or beyond one of these.

[0057] The device may be used inside or outside a body cavity. The device may incorporate an injector unit or work in conjunction with a separate injector unit. The instrument may have external marks or indicators to facilitate system alignment with external anatomical structures, such as the mesenteric side of the intestine. The external marks or indicators can be mechanically, electrically, or magnetically aligned with the internal system electronics, providing recognition of the positional relationship between the system and the externally aligned biostructure. The instrument may have an integrated interlocking member 1223 to enable a stable and secure coupling (connection) with the anvil or housing. In one embodiment, the interlocking member may take the form of a spike on a stapler that interlocks with the anvil handle and the anvil is opposed to. The secure connection provides stability during instrument operation, but can be configured to allow for easy release of the anvil once instrument operation is complete. The easy release functionality prevents tissue damage when the anvil is released from the instrument. The interlocking member may be fixed to the instrument or movably coupled. In one embodiment, the engaging member is positioned around the central axis of the instrument and can be removably coupled to the anvil handle. The engaging member has a central bore that receives a coaxial rod enabling movement along the axis. The engaging member may be mechanically coupled to the instrument by a motorized slide, such as a linear stage or solenoid, to enable precise control of tissue interaction forces, such as a constant force spring or contact pressure applied to the tissue between the anvil and the tissue contact surface of the instrument. The instrument may have an integrated interaction force sensor that allows a processor to adjust the interaction force to a set range by operating the motorized slide. Similarly, the processor may indicate the state to the end user in response to the magnitude of the converted interaction force.

[0058] In one configuration of the present invention, the device can be configured to sense oxygenation within multilayer tissue or to determine oxygenation at different depths of tissue. By using a phosphorescent oxygen-sensing probe having multiple absorption wavelengths in a medium, the device can irradiate and excite a subset of probes injected into the tissue based on the excitation wavelength emitted from the device, since the penetration depth within the tissue is wavelength-dependent. Oxygenation can be determined at two or more depths or layers by successively exciting the tissue with multiple emission wavelengths at or near the absorption peak and determining the sense of the corresponding extinction lifetime response. Sensing deeper values ​​is the sum of multiple layers, and oxygenation in deeper layers can be determined by considering the oxygen sensed in shallower layers. In an alternative approach, the phosphorescent decay of various oxygenation levels within a heterogeneous emission system (i.e., mixed oxygenation in a tissue sample) can be determined through a deconvolution method to produce an oxygenation spectrum. In one embodiment of a sensing medical device, multiple sinusoidally modulated excitation light outputs are generated (simultaneously, separately, or combined with time-varying frequency signals such as chirps), and frequency-domain techniques are used to determine the spectrum of phase delays of the signals received from the injected phosphorescent medium. By determining the relative contribution of each phase delay, a quantitative spectrum of tissue oxygenation can be generated. In another embodiment, time-domain techniques can be used to determine the time response of the medium to the pulse of light. Multiple exponential function fitting of decay can be used to generate a quantitative spectrum of tissue oxygenation.

[0059] The system described in Figure 12 teaches a standalone sensing device for performing circumferential measurements of tissue. The described device can be rotated to allow for the maximum number of measurement points using a minimum number of sensing elements. However, it should be understood that multiple fixed sensing elements, such as those described in Figure 10a, may also be used in similar configurations for the device 1201. Furthermore, the methods described herein may be applicable to multiple configurations of the sensing device and should not be construed as being limited only to the configuration shown in Figure 12.

[0060] Figure 13a depicts an embodiment of an imaging system with a light source capable of selectively illuminating a tissue region. The imaging system 1301 may be an endoscope, and in one embodiment, it may be a flexible endoscope such as a colonoscope, which is inserted transanally into the colon tissue 1303 at the distal end of the anastomosis junction. The imaging system may be used to image the anastomosis 1305 and assess its viability (e.g., through unilateral or bilateral oxygenation mapping). The imaging system 1301 is configured to be used to image light re-emitted from phosphorescent or fluorescent probes injected into the anastomosis surface 1307 and the proximal side 1309 of the anastomosis, as well as the anastomosis surface 1311 and the distal side 1313 of the anastomosis. The imaging system 1301 includes a light source 1321 that provides illumination 1323 and is used to excite a light re-emitting probe residing in the distal 1311 and / or proximal 1307 tissue of the anastomosis 1305. The excited probe then re-emits a phosphorescent or fluorescent response, which is imaged by the imager 1325. The imager 1325 may take the form of a camera embedded within the distal end of the imaging system 1301 and coupled to control electronics and / or a signal processor 1327. In an alternative embodiment, the imager 1325 is the tip of a coherent fiber optic bundle that transmits light to a remote camera. The light received by the imager 1325 is focused through a lens 1329, which may also incorporate optical filtering.

[0061] Figure 13b depicts an imaging system 1301 with an extended retrograde or recursive view light source. The light source 1341 has an extending arm 1341 that allows it to extend and rotate. The arm 1341 may comprise a pre-bent nitinol wire that provides a defined curvature by extending and retracting the wire. In one embodiment, the light source is configured to provide both advancing (as shown in Figure 13a) and retracting (as shown in Figure 13b) illumination of tissue locations inside the lumen. In a further configuration, the light source is configured to illuminate the proximal 1307 and distal 1311 surfaces of a bowel anastomosis 1305.

[0062] A method for determining and distinguishing tissue oxygenation in multiple tissue layers includes: 1) injecting a phosphorescent oxygen-sensitive probe (or other photore-emitting probe) into the tissue locally or systemically; 2) inserting an imaging system 1301 at the tip of a rigid or flexible shaft 1347 into the lumen of the tissue 1323; 3) illuminating the anastomosis on the distal surface 1311 with light 1323 at an absorption wavelength (such as blue to UV range) of the phosphorescent probe having a shallow penetration depth in the tissue (as shown in Figure 13a); and 4) imaging device 1325 (CCD, CMOS, or fiber optic bundle, etc., relative to the camera system). The method includes the steps of: 5) acquiring a signal using a ) and generating an oxygen map of the distal surface 1311 using an onboard or external signal processor 1327; 6) extending a light source 1321 (or an additional / alternative light source) along a curved arm 1341; 7) illuminating the anastomosis on the proximal surface 1307 using light 1343 (blue to UV range) at the absorption wavelength of a phosphorescent probe having a shallow penetration depth in the tissue (as shown in Figure 13b); and 8) acquiring a signal using an imager (CCD, CMOS, or fiber bundle, etc., relative to a camera system) and generating an oxygen map of the proximal surface using an onboard or external signal processor. The method described allows for the measurement of tissue oxygenation at a shallow depth of approximately the thickness of the intestinal wall, and therefore, by illumination from the proximal side, only (or substantially only) the probe on the proximal side is excited. When illuminated from the distal side, only (or substantially only) the probe on the distal side is excited. The phosphorescence response will be in the red to IR range and will penetrate through the tissue on one or both sides of the imager. In an alternative embodiment, the light source 1321 includes emitters for at least two wavelengths. One wavelength is used to image only the distal side, at the absorption peak of the probe with poor tissue penetration, and the other wavelength is used to illuminate both layers, at the absorption peak of the probe with high tissue penetration depth. By measuring the oxygenation of the distal tissue and the combination of both layers, the signal processor determines distal and proximal layer oxygenation.

[0063] The present invention, as illustrated in Figures 13a and 13b, may be configured with either an internal or external imager 1325 coupled through a coherent fiber optic bundle. In either case, an image processor 1327 used to generate an oxygen map may be located externally. With respect to the internal camera, signal processing may be onboard, external, or a combination thereof. The light source 1321 may be an electron emitter located at the tip of the instrument, or it may be located externally and optically coupled to the tip of the instrument through a fiber optic bundle or other means. The light source may be configured to illuminate both sides of the anastomosis to determine oxygenation from both the proximal and distal sides. One or more temperature sensors 1351 may be integrated into the imaging system instrument 1301, or the temperature may be assessed through fiber optics coupled to an external thermal imager. Temperature information may be used to compensate / calibrate the temperature-dependent phosphorescence lifetime for the oxygenation of the target tissue.

[0064] Figure 13b shows a retrograde light source for selectively illuminating tissue regions. The retrograde light source configuration can illuminate the distal or proximal side of the intestinal anastomosis and excite an oxygen-sensing molecular probe on only one side at a time. In a further configuration, the light source may comprise a coherent fiber optic bundle capable of transmitting infrared light, and the fiber bundle may be used both to provide tissue illumination and to transmit light from the tissue to a thermal imaging system for temperature mapping. The antegrade / retrograde imaging system may be configured to produce PLI measurements from both the distal and proximal sides of the intestinal anastomosis, as described. Embodiments of the system are multimodality-sensing capable and, in one embodiment, incorporate thermal imaging capabilities. In one embodiment, the instrument takes the form of an imaging system with a large field of view configured to generate an oxygen map of the distal side of the anastomosis using a forward-facing or substantially forward-facing camera. The system may be configured with prisms or stacked high-refractive-index elements to generate the large field of view. The present invention teaches a method for distinguishing physiological properties within various layers using an injectable probe and a light source that selectively illuminates layers. In a further method, anterior / retrograde light sources selectively illuminate the tissue or its backside.

[0065] Figure 14a shows an injector system 1401 coupled to a surgical stapler anvil 1403. The injector 1401 is used to inject a medium 1405 into the intestinal tissue containing the anvil. The handheld device is coupled to an injector 1407 filled with the medium 1405. The injector may be filled with a single injection volume or multiple doses of the medium 1405. The injector may also be an injector capable of providing multiple metered doses using either a conventional simple plunger 1409 or a manually or electrically metered injector. An internal fluid channel 1413 delivers the medium 1405 from the injector 1407 through an internal Luer lock or slip tip fitting 1415 to the needle 1417. The tissue resides between the tissue contact surface 1421 of the handheld device body and the working surface of the anvil 1403. The anvil handle 1423 is connected to and aligned with the instrument 1401 through an anvil handle connector 1425. In one configuration, alignment includes the step of aligning the rotation of the anvil handle 1423 so that the needle injection point 1417 aligns with the sensor location of the sensing version of the anvil 1403, as described in Figures 10a and 10b. The small needle 1413 protrudes into the tissue. As shown in Figure 14b, the needle 1417 has one or more lateral holes 1431 and a solid tip to direct the medium into the tissue. The tissue contact surface of the device body 1435 may have a contoured surface to apply different compressions to the tissue against the anvil working surface 1437 at different locations in order to further direct the medium. In one embodiment, the surface is inclined to direct the medium radially outward from the needle having outward-facing holes. From the viewpoint of radial placement, the needle may be used to inject the medium into the staple-forming section 1439, into the staple-forming section, or outside the staple-forming section. In one embodiment, the medium may contain a phosphorescent oxygen-sensing probe, and oxygenation is detected from a sensing anvil (as described in Figures 10a and 10b), a standalone device (as described in Figure 12), and / or an imaging system (as described in Figures 13a and 13b).Figure 14c shows an alternative embodiment of an injector unit 1443 that engages with a circular surgical stapler 1403 and injects a medium circumferentially into the tissue surrounding the working surface of the anvil. A handle 1445 is attached to the body 1443 of the injector. The injector 147 is connected to the fluid channel 1447 through a Luer lock or slip tip connector 1449. The use of a standard fluid coupling 1449 allows for a pre-prepared and pre-filled injector 1407.

[0066] Figure 15 shows the configuration of the present invention, in which the system is configured to assess oxygenation at a colorectal anastomosis. The colon 1501 is divided during surgery, and a sensing surgical stapler anvil 1503 (located inside the colon and hidden from the figure), as described in Figures 10a and 10b, is inserted into the proximal end 1505 of the resected colon 1501. An injector 1511 (as described in Figures 14a, 4b, and 14c) injects an oxygen-sensitive phosphorescent probe 1513 through a needle 1521 into the colonic tissue 1523 at the proximal end 1505 or nearby the anastomosis site. The sensing anvil 1503 measures oxygenation at one or more points at the location of the anastomosis surface 1523. In one embodiment, the sensing anvil 1503 measures oxygenation using a set of 12 sensors sandwiched between staple-forming sections configured for phosphorescence lifetime sensing. In further embodiments, a temperature sensor is also integrated into the sensing anvil 1503 for temperature compensation of oxygenation measurement. As shown in Figure 15, the distal end 1505 of the resected colon 1501 is left free; however, alternative configurations of the present invention can be adapted for injection and sensing at both the proximal 1505 and distal 1507 ends of the colon 1501. Figure 10 shows a typical procedure for low anterior resection (LAR), but the present invention also includes applications for all colorectal and coloanectomy procedures as well as other gastrointestinal procedures and other locations in the body.

[0067] In one embodiment, a pressure sensor may be incorporated into the sensing anvil 1503 to detect the compression pressure of the tissue within the anastomosis 1523 and may also be used to normalize the tissue compression pressure. In one use, the sensing anvil 1503 is activated to generate an oxygenation map of the anastomosis at various points in the procedure. In a typical embodiment, the sensing anvil can examine the proximal anastomosis tissue 1523 before the creation of the anastomosis, while the proximal 1523 and distal 1507 tissues are being approached, and immediately after firing the stapler, joining the tissues, and creating the anastomosis. This information may be used to guide the surgical procedure so as to influence corrective measures. Alternatively, the results may be used to classify the patient's risk of anastomosis failure and to assist the surgical team in deciding whether to form a temporary or permanent fistula.

[0068] Figure 16a shows a typical embodiment of an imaging system configured to assess fluorescence and / or phosphorescence lifetime. In one embodiment, the system is configured to detect tissue oxygenation through phosphorescence lifetime imaging of an oxygen-sensitive probe injected into tissue. In one configuration, the PLI system comprises a highly sensitive and low-noise high-speed scientific camera 1601 coupled to a high-speed gated image augmentation unit 1603. However, in other embodiments, a lower-cost conventional camera base or other imaging system may be utilized. The augmentation unit 1603 and camera 1601 are coupled to an interface unit 1605 via a coupler 1607 that controls the timing of augmentation unit gating and camera exposure and streams images from the camera to a processor for analysis. In one embodiment, a computer is used for camera interface and image processing, and a computer-controlled data acquisition device provides timing control by acting as a dynamic delay generator (DDG). The augmentation unit 1603 and camera 1601 may be separate components or may be integrated into an augmented camera. Furthermore, as illustrated in Figures 7a, 7b, and 7c, some or all of the functionality of the control interface unit 1605 may be integrated into the camera. In one embodiment, the integrated intensified camera includes an FPGA or processor for pre-processing images and thus reducing the bandwidth requirements of the connection 1607 to the external interface unit 1605.

[0069] The camera system includes a lens 1611 that focuses on a region of interest in the tissue where the probe 1615 resides (either through local or systemic injection). In an overhead type system, the lens 1611 would focus on either external or visible tissue in open surgery. The lens receives light 1637 re-emitted from the probe 1615, excited by excitation light 1633. The re-emitted light is selectively passed to the lens 1611 through a filter 1639. In this configuration, the system may be mounted on a mounting arm 1619, such as a ceiling-mounted or floor-mounted boom arm. The system may also be mounted on a balanced mounting arm similar to that of a surgical microscope, and furthermore, the head may have acts that allow for control of its position and alignment through robotic means. In an alternative configuration, the imaging system shown is a handheld unit configured to easily allow for snapshots of tissue oxygenation, similar to the use of a standard autofocus camera.

[0070] The imaging system incorporates an illuminator light source 1631 to excite a probe 1615 within tissue 1613. The illuminator 1631 light may be modulated and pulsed for time-domain measurements or sinusoidal excitation for frequency-domain measurements. In one configuration, the illuminator 1631 contains a number of light emitters forming a circumferential ring around the optical axis of the camera lens 1611. The illumination light 1633 is focused within the same target region as the camera lens. In one embodiment, the illuminator contains light emitters of multiple wavelengths to provide excitation of the probe 1615 at multiple wavelengths, or to selectively excite multiple different probe types. Furthermore, the illuminator 1631 may include both excitation light and visible light, which are switched or multiplexed to allow clear visualization of biological structures in alternation with oxygenation imaging. In another configuration, the illuminator is an independent light source aimed at the target tissue and does not necessarily have to be aligned along the optical axis of the camera.

[0071] In one embodiment, the imaging system further comprises means for assessing the temperature of the tissue containing the probe. Assessing the target tissue temperature allows for temperature compensation for the temperature-dependent phosphorescence decay of the probe. The use of temperature measurement allows for improved accuracy and robustness of absolute oxygen concentration measurement, which is invariant to tissue temperature. Other physiological and environmental factors may also be measured to compensate for lifetime for oxygen concentration calculations. In one embodiment, temperature is sensed at one or more discrete points through contact (e.g., thermocouple, RTD) or non-contact (e.g., optical) means. In one configuration, a thermal imager 1641 is coupled to the imaging system to create a temperature map of substantially the same area as the camera performing lifetime sensing. The thermal imaging camera 1641 may be rigidly coupled to the camera system 1601 via a mechanical coupler 1643. Alignment may be performed to determine the correspondence between points in the lifetime image and the temperature map. This correspondence may be performed in real time using image-based alignment techniques or a priori for a given configuration. One embodiment of the present invention incorporates a camera-based PLI system coupled with an infrared thermal imaging camera to detect both phosphorescence lifetime and temperature. Both the temperature and lifetime of a given pixel or region are used in determining the corresponding oxygenation. In one approach, the temperature is explicitly calculated and used directly, using a priori known temperature coefficient of the phosphorescence quenching process, when calculating the conversion from phosphorescence lifetime to oxygenation. The thermal imaging camera 1641 may incorporate polarizing or other filters to minimize / reduce infrared reflection.

[0072] The PLI system may include a laser or other matching device attached to the camera system 1601 and / or light source 1631 to assist in directing alignment to the desired field of view 1615. The matching device may be one of the shapes that represent a point source, a crosshair, and a region. The PLI system may also include an electromechanically actuated head instead of, or coupled to, the arm 1619. The actuated head may be a robotic device. In one embodiment, the head is configured for dynamic tracking of a target or region of interest due to motion / misalignment.

[0073] The imaging system described in Figure 16a may be used for a variety of applications. One application is to image gastrointestinal tissue, such as colorectal tissue, during colorectal cancer resection. Furthermore, it may be used to assess tissue oxygenation and / or perfusion during organ transplantation or vascular surgery. One use of the system is to assess the viability of skin flaps by measuring their oxygenation. In one application, the system assesses the oxygenation of surrounding biological structures and uses that oxygenation to screen for peripheral vascular disease and / or induce interventions for peripheral vascular disease. The system in this method may be a boom-mounted imaging device, a handheld imaging device, or an alternative configuration. The system may generate individual images or multiple images over a specified time course at a specified repetition rate. Absolute tissue oxygenation and / or time-dependent variations in oxygenation may be presented.

[0074] Figure 16b shows a further representative embodiment of the imaging system described in Figure 16a, configured to assess the fluorescence and / or phosphorescence lifetime of tissue at an anastomosis site, specifically at the colon tissue anastomosis site as described above. The system can also be used to image other gastrointestinal anastomoses of other organs, including, but not limited to, the esophagus, stomach, and small intestine. In one configuration, the imaging system assesses the phosphorescence lifetime of an injected oxygen-sensitive probe. The probe 1651 is injected into colorectal tissue 1653 (typically the proximal end as described in Figure 15), which has a surgical stapler anvil 1655 inserted therein in preparation for surgical anastomosis. The anvil 1655 may be a conventional non-sensitive anvil or a sensitive anvil as described in Figures 10a and 10b. The probe 1651 is injected into the tissue 1653 using an injector as described in Figures 14a, 15b, and 14c, or by other means. The tissue in contact with the working surface (i.e., the staple-forming surface of the anvil) contains a probe and is directed toward the optical axis of the imaging system 1601. The imaging system further comprises a camera 1601, an augmentation device 1603, and a matching guide 1659 coaxial with the optical axis of the lens 1611. The matching guide may be repeatedly attached to and removed from the lens 1611 via a quick-connect fitting 1661. A coupler 1655, which may be a quick-connect type fitting, connects the matching guide 1659 to the handle 1667 of the surgical stapler anvil 1655. The system ensures that the proximal end of the anastomosis 1671 is fully imaged using the PLI system. In one embodiment, the PLI system further comprises a thermal imager 1641 which determines the temperature of the same tissue imaged by PLI as described in Figure 16b. The temperature may be used to compensate for temperature-dependent phosphorescence lifetime when converting from lifetime to oxygen concentration. Temperature measurement may be performed via an imaging system of the target region using an injectable probe to assist in temperature assessment, contact temperature measurement, or other means.

[0075] In one application, the system in Figure 16b generates an oxygen map of the proximal end of the anastomosis post-excision and prior to grafting with the distal end, and this information is used to guide the procedure. Guidance may incorporate corrective measures such as additional dissection to reduce tension and improve blood supply. The system in Figure 16a, which may be the same system as the one described in Figure 16b, with the matching guide removed, may then be used to image the distal and / or proximal end externally. This system may also be used in conjunction with a sensing anvil as described in Figures 10a and 10b.

[0076] The present invention includes, but is not limited to, a step of sensing and mapping tissue oxygenation based on phosphorescence lifetime. The sensing technique may be used in combination with other techniques. The sensing techniques associated with the present invention may sense mechanical or biological properties. The sensing instrument may include one or more sensing modalities. The sensing modality may include mechanical, optical, chemical, electrical, or other means to generate a signal that characterizes the tissue of interest. In one embodiment, the sensing element measures oxygenation through the use of a phosphorescent probe or a medium containing a phosphorescent material delivered into the tissue. In other embodiments, oxygenation is measured through an oxygen measurement-based technique. Further embodiments measure perfusion or flow rate through the time response of a fluorescent or phosphorescent medium introduced into the tissue.

[0077] Therefore, one embodiment includes a sensing surgical instrument and associated probes, injectors, processing, and visualization. The instrument performs phosphorescence lifetime sensing at a number of discrete points and can generate a temperature-compensated oxygen map using phosphorescence lifetime measurement.

[0078] Another embodiment includes an imaging system and associated probes, injectors, processing, and visualization. The imaging system performs phosphorescence lifetime imaging of an array of points and is capable of generating a temperature-compensated oxygen map using phosphorescence lifetime measurements, the oxygen map being aligned with endoscopic video images and used to identify suspicious areas based on oxygenation measurements.

[0079] In some embodiments, the sensing component is incorporated into or coupled to a surgical instrument. The instrument may include conventional open surgeons, laparoscopes, endoscopes, bronchoscopes, otoscopes, ophthalmoscopes, laryngoscopes, cystoscopes, vaginal speculums, intravascular, intraluminal, robotic, or other minimally invasive tools such as specialized tissue interrogators or standard instruments with instruments, including grasping devices, needle drivers, staplers, clip applicators, catheters, scissors, cauters, or retractors. The instrument may also include interrogators or other devices, which may or may not be minimally invasive. In alternative embodiments, the sensing component is incorporated into a primary or secondary imaging system for endoscopic examination.

[0080] The imaging system may be used for monitoring or guiding diagnostic procedures or surgical operations. The technology may be incorporated into or associated with rigid or flexible endoscopic instruments. The technology may further be coupled with endoscopic instruments based on optical transmission through lenses or optical fibers, or integrated with a digital imaging system with a microcamera at the distal end. In further embodiments, the imaging system disclosed herein may be a standalone camera-based system. This camera-based system may be used for external monitoring of tissue (such as a skin flap), internal imaging through either invasive surgical procedures or minimally invasive endoscopic procedures, precise mapping of retinal oxygenation in conjunction with robotic surgery, or other means. As stated above, the present invention includes phosphorescence lifetime imaging of a phosphorescent material with oxygen-dependent quenching of the phosphorescence response to excitation. The present invention also includes the steps of sensing other physiological parameters, sensing using other fluorescence or phosphorescence probes, measuring intrinsic fluorescence or phosphorescence responses from tissue, or imaging other biomarkers or tags such as imaging agents or quantum dots. The optical sensing element includes, but is not limited to, an optical emitter, including light-emitting diodes (LEDs) and laser diodes, and an optical receiver, including photodiodes (including avalanche photodiodes, photomultiplier tubes, silicon photomultipliers, and similar sensitivity-enhancing detectors), photodiode arrays, CCD arrays (including sensitivity-enhancing detectors such as electron-multiplier EMCCDs), CMOS sensors, cameras, holographic imaging systems, image enhancement devices (which may be coupled with or integrated into other detectors), and spectrometers.

[0081] The optical sensing element is configured to measure at least one of tissue oxygenation, oxygen delivery, oxygen utilization, tissue characterization, and overall tissue health using oxygen measurement, phosphorescence techniques, or spectroscopic techniques, and at least one of tissue perfusion, tissue fluid dynamics, tissue oxygen content, histochemical composition, tissue immune activity, tissue pathogen concentration, or tissue water content using fluorescence or phosphorescence-based techniques. Fluorescence and phosphorescence-based techniques include, but are not limited to, the steps of: monitoring and analyzing the intensity and time course of a fluorescence response in response to the injection or activation of a fluorescent medium; determining the amount of oxygen by measuring the oxygen-dependent quenching of fluorescence or phosphorescence emission using a photosensitive material such as ruthenium by both intensity and time-resolution methods; determining the oxygen concentration based on the quenching time response of an injectable oxygen-sensitive phosphorescent probe; and determining target tissue characteristics by quantitative fluorescence or phosphorescence methods, including the use of quantum dots or other biomarkers incorporating photore-emission properties. In one configuration, the device senses perfusion using fluorescein, or IC green, or other imaging agents. In one other configuration, the device senses the oxygen quenching of innate tissue phosphorescence.

[0082] The present invention includes a method for gating signal acquisition from a phosphorescent lifetime imaging system to physiological parameters. Measurements of tissue oxygenation or other tissue properties can be measured in a gated manner to standardize the measurements and enable comparison. One representative embodiment of gated image acquisition is triggered by pulse and / or respiration and / or peristalsis. Gated acquisition may also be based on measurements of peristalsis, respiratory motion, cardiac motion, cardiac output or pulsatile flow, EEG readings, EMG readings, motion sensors, or other inputs. A further method captures PLI measurements gated by at least one of respiration, cardiac output (i.e., pulse), peristalsis, or other internal or external motion. A further method provides a step of dynamically comparing PLI measurements at two or more time points within a physiological cycle. One method determines a gated cycle from images acquired by a PLI system, and further, the method provides a step of determining cardiac cycle gating based on acquired images of the vascular system.

[0083] In one configuration of the present invention, the instrument is configured to sense oxygenation within multilayer tissue or to determine oxygenation at different depths of tissue. By using a phosphorescent oxygen-sensing probe having multiple absorption wavelengths, the instrument can irradiate and excite a subset of probes injected into the tissue based on the excitation wavelength emitted from the device, since the penetration depth within the tissue is wavelength-dependent. Oxygenation is determined at two or more depths or layers by successively exciting the tissue with multiple emission wavelengths at or near the absorption peak and determining the corresponding quenching response. Sensing deeper values ​​is the sum of multiple layers, and oxygenation in deeper layers can be determined by considering oxygen sensed in shallower layers. In an alternative approach, the phosphorescent decay of various oxygenation levels in heterogeneous emission systems (i.e., mixed oxygenation in a tissue sample) can be determined through a deconvolution method to produce an oxygenation spectrum.

[0084] The present invention includes medical imaging systems, probes, and methods for assessing the phosphorescence or fluorescence lifetime of an injectable probe or a naturally autofluorescent probe. In one configuration, at least one sensor is configured to obtain bio-tissue oxygenation at multiple points by utilizing an oxygen-dependent quenching technique for the phosphorescence of an injectable probe. In another embodiment, the present invention measures the lifetime of a marker or other probe in or over the body. In a further embodiment, the lifetime of phosphorescence or fluorescence produced from a naturally occurring biological tissue is assessed. Included in the present invention are systems and methods for microinjecting a probe or imaging agent from the tip of an endoscope or other instrument at one or more points, and devices for microinjecting a probe or imaging agent into tissue in the circumferential direction of the working surface of a surgical stapler anvil.

[0085] The embodiments described above demonstrate how oxygen-sensitive probes can be used in conjunction with imaging systems for tissue oxygen mapping. These embodiments are intended for illustrative purposes only. The sensing configurations and approaches described can be adapted to provide the described functionality for other surgical instruments. Furthermore, the techniques discussed should be interpreted as not being limited solely to their use with phosphorescent oxygen-sensing probes.

[0086] The present invention can be put into practice by employing conventional materials, methodologies, and equipment. Therefore, details of such materials, equipment, and methodologies are not described in detail herein. Numerous specific details, such as specific materials, structures, chemicals, and processes, are described in the foregoing description to provide a complete understanding of the present invention. However, it should be recognized that the present invention can be put into practice without relying on the specifically described details. In other instances, well-known processing structures are not described in detail to avoid unnecessarily obscuring the present invention.

[0087] Only some exemplary embodiments of the present invention and some examples of its versatility are illustrated and described herein. It should be understood that the present invention can be used in a variety of other combinations and environments and can be modified or altered within the scope of the concept of the invention as presented herein.

[0088] While the foregoing description covers preferred embodiments of the present invention, it should be noted that other variations and modifications will be obvious to those skilled in the art and may be made without departing from the spirit or scope of the invention. Furthermore, features described in connection with one embodiment of the present invention may be used in conjunction with other embodiments, even if not explicitly stated above.

Claims

1. A surgical instrument configured to resolve tissue oxygenation of a target tissue by sensing an injectable light re-emission probe, wherein the surgical instrument is At least one optical emitter configured to excite the implantable photore-emission probe within the absorption band of the implantable photore-emission probe, At least one optical detector configured to receive light re-emitted from the injectable light re-emission probe, At least one temperature sensor configured to detect the temperature of the target tissue, A signal processor configured to resolve tissue oxygenation based on the received re-emitted light and to compensate for temperature-dependent oxygenation based on the temperature detected by the at least one temperature sensor. Equipped with, The signal processor is configured to resolve the tissue oxygenation at multiple points in the target tissue by analyzing the received re-emitted light and the temperature detected by the at least one temperature sensor using time-domain techniques and / or frequency-domain techniques. The surgical instrument is further configured to detect at least one of the following: blood oxygenation, tissue perfusion, tissue immune activity, tissue pathogen concentration, tissue neoplastic cell content, or tissue malformed cell content.

2. The surgical instrument according to claim 1, further comprising an applicator configured to provide a medium to the target tissue, wherein the medium contains the injectable photore-emitting probe.

3. The surgical instrument according to claim 1, wherein the signal processor is configured to resolve the tissue oxygenation based on the lifetime of the received re-emitted light.

4. The surgical instrument according to claim 1, wherein the surgical instrument is an endoscopic instrument.

5. The surgical instrument according to claim 2, wherein the applicator is at least one injector configured to inject the medium into the target tissue.

6. The surgical instrument according to claim 1, further comprising an interrogator instrument configured to examine the target tissue.

7. The surgical instrument according to claim 1, further comprising at least one pressure sensor configured to detect tissue compression pressure of the target tissue.

8. The surgical instrument according to claim 1, wherein the injectable light re-emission probe is a phosphorescent probe having multiple absorption wavelengths.

9. The surgical instrument according to claim 1, wherein the surgical instrument is communicably coupled to a base station.

10. A surgical staple anvil configured to resolve tissue oxygenation of a target tissue by sensing an injectable photore-emission probe, wherein the surgical staple anvil is At least one optical emitter configured to excite the injectionable photore-emission probe, At least one optical detector configured to receive light re-emitted from the injectable light re-emission probe, A signal processor configured to resolve the tissue oxygenation based on the received re-emitted light, Equipped with, The signal processor is configured to resolve the tissue oxygenation at at least one point in the target tissue by analyzing the received re-emitted light using time-domain techniques and / or frequency-domain techniques. A surgical staple anvil further configured to detect at least one of the following: blood oxygenation, tissue perfusion, tissue immune activity, tissue pathogen concentration, tissue neoplastic cell content, or tissue dysplasia cell content.

11. The surgical stapler anvil according to claim 10, wherein the surgical stapler anvil is communicably coupled to a base station.

12. The surgical staple anvil according to claim 10, further comprising a temperature sensor configured to detect the temperature of the target tissue.

13. The surgical stapler anvil according to claim 10, further comprising at least one pressure sensor configured to detect tissue compression pressure of the target tissue.

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