Method of indicating lesions

Abstract

A method for marking a lesion is disclosed herein. The disclosed method can assist a surgeon in identifying the location of a nodule or other lesion by marking the nodule or other lesion using a reference marker impregnated with a luminescent material, such as a reference coil impregnated with a fluorescent dye. In some preferred embodiments, the reference coil is placed using a robotic surgical system during a biopsy. In alternative embodiments, a non-robotic peripheral navigation platform may also be effectively used as an aid to surgical resection. The dye marks the location of the nodule or other lesion, allowing it to be visualized and detected by palpation during surgery. Accordingly, the surgeon can target the tissue to be removed with greater accuracy. The disclosed method enables the reference marker to be placed several days prior to surgery.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims the benefit of U.S. patent application serial number 63 / 598,535 filed on November 13, 2023, the entire disclosure of which is incorporated herein by reference. Background Technology

[0003] Due to the increased use of chest computed tomography (CT) and lung cancer screening efforts, lung nodules can now be identified more easily. The proportion of early-stage lung cancer has also increased. While surgical resection is the standard treatment at this stage, accurate localization techniques are required to achieve optimal outcomes as interest in lung-conserving surgery and supporting literature grows for both new lung cancer and secondary metastasis to the lungs. An ideal localization procedure will provide various options that enable surgeons to clearly identify these nodules and offer the best possible opportunity to preserve as much healthy lung tissue as possible.

[0004] However, there may be various challenges in surgically locating pulmonary nodules. Several tumor factors significantly influence localization and surgical resection, including nodule size, distance from the pleural surface, nodule nature (ground-glass, solid, or mixed), associated structural lung disease, the presence of carbon pigment on the lung surface, and pleural adhesions. Accessibility for the operator / procedure specialist, organizational issues within the medical institution, and reliance on open surgery techniques are included among other potential barriers.

[0005] The diagnosis and treatment of lung nodules can be performed concurrently with surgical resection; however, this approach can result in the resection of benign lesions and excessive normal lung tissue when the location of the lesion is difficult to identify. While marking lung nodules using bronchoscopic guidance prior to surgery can facilitate this process, current technology has limitations, and difficulties are typically encountered as the staining marks may disappear if surgery is performed a few days later.

[0006] With increasing interest in lung-preserving surgery for both primary lung cancer diagnosis and secondary lung metastasis, accurate localization is now more important for achieving desirable outcomes. An ideal localization procedure will provide various options to enable surgeons to accurately identify lung nodules.

[0007] Accordingly, there remains a need for a method to accurately mark lesions in order to confirm the precise location of lung nodules even after a considerable clinical period.

[0008] The present disclosure describes a novel method for addressing the problem of surgically locating lung nodules or other lesions, typically in mammals, such as human patients, thereby enhancing efficiency between diagnosis and subsequent surgery. The disclosed method can assist surgeons in locating the nodules or other lesions by marking them using reference markers impregnated with luminescent dyes, such as reference coils immersed in a fluorescent dye like Indocyanine Green (ICG). In some preferred embodiments, the reference coil is placed using a robotic bronchoscopy system during a biopsy. In alternative embodiments, a non-robotic peripheral navigation platform can also be effectively used as an aid to surgical resection. The dye marks the location of the lung nodules, allowing them to be visualized and detected by palpation during surgery. Consequently, surgeons can target cancerous tissue with greater accuracy, enabling lung-preserving surgery. The disclosed method allows the reference marker to be placed several days prior to surgery.

[0009] In some preferred embodiments, a reference marker, such as a reference coil used in the disclosed method, may include a synthetic fiber attached to the body of the coil.

[0010] Although the above description explains a method for indicating lesions in the lungs, the disclosed method can be used to indicate lesions in other tissues and organs of the body.

[0011] Additionally, while the above description explains a method of marking a lesion using a specific reference coil, it is considered that any biocompatible reference coil suitable for use in the human body may be used in the disclosed method, including coils composed of biocompatible metals or alloys, biocompatible polymers, or other biocompatible materials.

[0012] Furthermore, although the above description explains a method of marking a lesion using a reference coil, any biocompatible reference marker suitable for use in the human body that meets the design requirements for use as a reference marker in a desired application is considered to be usable in the disclosed method, including but not limited to other forms and designs that meet the requirements described herein.

[0013] Additionally, while the foregoing describes the use of specific biocompatible fluorescent dyes, it is considered that any biocompatible fluorescent dye or other luminescent dye suitable for use in the human body may be used in the disclosed method. As described herein, luminescent dyes may include fluorescent dyes, phosphorescent dyes, chemiluminescent dyes, and bioluminescent dyes.

[0014] Furthermore, while the above description describes the use of specific biocompatible dyes, it is considered that any biocompatible luminescent material suitable for use in the human body may be used in the disclosed method.

[0015] Additionally, although the above description explains a procedure for immersing a coil in a dye immediately before placing the dye-immersed coil as a reference marker, it is considered that, alternatively, the coil may be pre-immersed in an appropriate amount of fluorescent dye or other luminescent dye, and the pre-immersed coil may then be used in the disclosed method. The shelf life of the pre-immersed coil will vary depending on the specific dye and the constituent material of the coil.

[0016] Additionally, while the above description explains the use of a coil completely immersed in dye, it is also considered to immerse only a portion of the coin in dye and to use such a partially immersed coil in the disclosed method.

[0017] Finally, although the above description explains the use of a dye-immersed reference coil as a reference marker, it is considered that the reference marker can alternatively be impregnated with a fluorescent dye or other luminescent dye or other luminescent material by encapsulating a luminescent material inside the reference marker or by impregnating the reference marker with a luminescent material using a technique other than immersion. Brief explanation of the drawing

[0018] FIG. 1 illustrates an embodiment of a dye immersion coil used in the disclosed method. FIGS. 2a and 2b illustrate embodiments of a dye immersion coil delivered via a robotic catheter at a nodular site, where FIG. 2a shows a cross-sectional CT image with a reference marker placed in the right upper lobe with a ground-glass lesion, and FIG. 2b shows a cross-sectional CT image with a reference marker placed in the right upper lobe with a solid nodule. Figure 3 shows a visualization of an embodiment of a dye-immersed coil as a fluorescent target on the surface of the pleura. Figure 4a shows an embodiment of a robotic lung wedge resection successfully performed using luminescence provided by a dye immersion coil. FIG. 4b shows an embodiment of a resected wedge showing a reference coil in the center of the sample. Specific details for implementing the invention

[0019] The present disclosure describes a novel method for addressing the problem of surgically locating lung nodules, typically in mammals, e.g., human patients, thereby enhancing efficiency between diagnosis and subsequent surgery. The disclosed method can assist surgeons in locating a nodule or other lesion by marking it with a luminescent dye, such as a reference coil immersed in a fluorescent dye like indocyanine green (ICG), or by using a reference marker impregnated with another luminescent fuel. In some preferred embodiments, the reference coil is placed using a robotic bronchoscopy system during a biopsy. In alternative embodiments, a non-robotic peripheral navigation platform can also be effectively used as an aid to surgical resection. The dye marks the location of the lung nodule, allowing it to be visualized and detected by palpation during surgery. Consequently, the surgeon can target the cancerous tissue with greater accuracy, enabling lung-preserving surgery.

[0020] The disclosed method allows a reference coil or other marker according to the description of the invention to be placed a few days prior to surgery. “Placement” and “being placed” refer to the marker being delivered to, otherwise contacting, being placed on, at least partially inside, or being placed inside a target site such as a lesion or nodule of the mammalian lung.

[0021] In some preferred embodiments, a label such as the reference coil used in the disclosed method may include a synthetic fiber attached to the body of the coil.

[0022] As used herein, a dye-immersed label, such as a coil, is a coil or other label that has been immersed in a dye for a sufficient amount of time for at least a portion of the coil or other label to be impregnated with the dye, such as a fiber attached to the body of the coil or other label (wherein the dye is trapped between the surfaces of the label and / or penetrates into the structure of the label). Although a dye-immersed coil may also be alternatively referred to as a dye-impregnated coil in this specification, the terms “dye-impregnated coil” and “dye-impregnated label” are not limited to a dye-immersed coil or a dye-immersed label, respectively, and include other types of dye-impregnated coils or other labels, such as a coil or other label in which the dye is completely encapsulated within the coil or other label. Furthermore, as used herein, the dye is deemed to have penetrated into the coil when at least a portion of the coil, such as a fiber attached to the body of the coil, is impregnated with the dye.

[0023] In exemplary studies conducted at multiple locations, ICG dye-immersed coils were placed on lung nodules confirmed to be cancerous by biopsy in patients scheduled for surgery a few days prior, with coil placement performed 0 to 9 days prior to surgery. Because the coils contained the dye, the bright neon green fluorescent dye remained visible to the naked eye for at least 5 days. This bright green luminescence of the dye allowed each thoracic surgeon to identify the precise location to be resected, thereby minimizing the amount of lung tissue removed and consequently leading to better outcomes for the patient. The coils can be palpated or visualized via intraoperative fluoroscopy or ultrasound, providing the surgeon with multiple options to locate the lesion, depending on their experience and expertise. Where possible, imaging techniques such as cone-beam CT or augmented fluoroscopy can also be used to aid in determining the coil's position relative to the nodule, thereby facilitating precise resection.

[0024] The use of the disclosed method for placing markers and the extension of the time interval between subsequent surgeries provide substantial benefits to patients in small rural hospitals with limited access to on-site cardiothoracic surgery. Patients may require time to schedule, prepare, and travel to larger medical centers for surgery. The reference marking method means that proper localization and visualization are enabled to assist the surgeon in performing the resection when the patient arrives at the surgical center for the surgical procedure.

[0025] The disclosed method provides benefits to patients by offering surgeons a more efficient, rapid, and accurate surgical method while better preserving healthy tissue. The disclosed method will substantially improve the trajectory of successful lung-sparing surgery for both primary and secondary malignancies of the lung.

[0026] Although the above description explains a method for marking lesions in the lungs, as discussed below, the disclosed method can be used to mark lesions in other tissues and organs of the body.

[0027] Additionally, while the use of robotic assisted navigation bronchoscopy (RANB) for the placement of a dye-labeled reference coil in lung tissue is described in the embodiments below, other techniques may be considered to be used to position the dye-labeled reference coil into lung tissue or into other organs or tissues, including, but not limited to, image-guided endoscopic techniques using an endoscope, catheter, or needle, or image-guided percutaneous techniques using a needle or catheter. Such techniques include, for example, endoscopic ultrasound and CT-guided needle placement.

[0028] Additionally, while the following examples illustrate a method of marking a lesion using a specific coil, it is considered that any biocompatible coil suitable for use in the human body may be used in the disclosed method, including coils composed of biocompatible metals or alloys, biocompatible polymers, or other biocompatible materials.

[0029] Furthermore, although the above description explains a method of marking a lesion using a reference coil, any biocompatible reference marker suitable for use in the human body that meets the design requirements for use as a reference marker in a desired application is considered to be usable in the disclosed method, including but not limited to other forms and designs that meet the requirements described herein.

[0030] The reference marker used for location identification may be a reference coil, or alternatively, another design or form that meets the requirements for use as a reference marker in the desired organ to be buried for location identification.

[0031] Ideally, the reference marker remains embedded within the placed tissue over time without significant displacement, and being configured to remain embedded may include a number of different structures and textures that facilitate stable and non-displacement placement. The reference marker must not have any sharp outer edges exposed to the tissue. While sharp outer edges can induce displacement, blunt or smooth surfaces significantly inhibit displacement and / or reduce its occurrence. This requirement is particularly important for moving organs, such as the movement of the lungs during respiration.

[0032] Desired reference markers used for positioning in the lungs must be flexible, meaning they must have sufficient flexibility to conform to lung and airway tissues, be able to be firmly fixed to the tissue where they are placed without significant displacement over time, and remain in place for a sufficient period to achieve the intended purpose of the marker. A circular coil form satisfies the above requirements. Other forms and / or designs possessing most or all of the aforementioned characteristics may be used alternatively. Such forms and / or designs include, but are not limited to, S-shapes, figure-eights, etc.

[0033] The reference marker and the luminescent dye impregnated therein most preferably do not have clinically significant interactions with the tissue surrounding the placed reference marker after placement, and the luminescent dye most preferably maintains its luminescence properties for a known period after placement.

[0034] Although the use of specific biocompatible fluorescent dyes is described in the foregoing, it is considered that any biocompatible fluorescent dye or other luminescent dye suitable for use in the human body may be used in the disclosed method. As described herein, luminescent dyes may include fluorescent dyes, phosphorescent dyes, chemiluminescent dyes, and bioluminescent dyes.

[0035] Furthermore, although the use of specific biocompatible dyes is described in the above description, it is considered that any biocompatible luminescent material suitable for use in the human body may be used in the disclosed method.

[0036] Additionally, although the above description explains a procedure for immersing a coil in a dye immediately before placing the dye-immersed coil as a reference marker, it is considered that, alternatively, the coil may be pre-immersed in an appropriate amount of fluorescent dye or other luminescent dye, and the pre-immersed coil may then be used in the disclosed method. The shelf life of the pre-immersed coil will vary depending on the specific dye and the constituent material of the coil.

[0037] Furthermore, the following examples illustrate the use of a coil with attached fibers impregnated with a dye, but it is considered that a coil without fibers composed of a material capable of absorbing the dye, such as a coil composed of a polymer capable of absorbing the dye, may be used alternatively.

[0038] Additionally, the following examples illustrate a procedure comprising mounting a dye immersion coil onto a delivery catheter and using a guidewire to place the coil, but it is considered that a pre-packaged dye immersion coil delivery system comprising a dye immersion coil mounted on a placement device such as a catheter may be used alternatively.

[0039] It is also considered that a self-expanding foldable coil can be used as a reference coil, which allows the coil to be folded after placement is initiated, thereby enabling adjustment to the precise desired position or location and achieving placement.

[0040] Additionally, the following examples illustrate the use of a coil completely immersed in the dye, but the use of a coil partially immersed in the dye and the use of such partially immersed coil in the disclosed method is also considered.

[0041] Finally, although the above description explains the use of a dye-immersed reference coil as a reference marker, it is considered that the reference marker can alternatively be impregnated with a fluorescent dye or other luminescent dye or other luminescent material by encapsulating a luminescent material inside the reference marker or by impregnating the reference marker with a luminescent material using a technique other than immersion.

[0042] For example, the luminescent material may be encapsulated within a reference label, such as a fluorescent dye-immersed fiber contained within a reference coil comprising a reference coil or an inner chamber containing a dye. Alternatively, the luminescent material may be coated on one or more inner surfaces of the reference label, such as a reference coil having a fluorescent dye coated on one or more inner surfaces.

[0043] Reference markers impregnated with a luminescent material are also disclosed herein. In some embodiments, the reference marker is a dye-immersed reference coil. A dye-immersed reference coil is a coil that is immersed in a dye for a sufficient amount of time so that at least a portion of the coil, such as a fiber attached to the coil body, can be impregnated with the dye. As defined above, the disclosed dye-immersed coil is a coil in which the dye has penetrated into the interior of the coil, that is, a coil in which at least a portion of the coil, such as a fiber attached to the coil body, is impregnated with the dye. This dye-immersed coil is a biocompatible coil suitable for use in the human body. For example, this dye-immersed coil may be composed of one or more biocompatible metals or alloys, one or more biocompatible polymers and / or one or more other biocompatible materials.

[0044] In some preferred embodiments, the dye-immersed coil comprises a fiber attached to the coil body. In some embodiments, the fiber is a synthetic fiber, such as nylon or polyester fiber. In some embodiments, the fiber is not attached to at least one end of the coil.

[0045] In some embodiments, the dye-immersed coil is composed of a material that absorbs dye. In these embodiments, since the body of the coil is impregnated with dye, there is no need for fibers to be attached to the coil body.

[0046] In some preferred embodiments, the coil is composed of a shape memory material.

[0047] A dye immersion coil delivery system comprising a dye immersion coil mounted on a placement device such as a catheter is also disclosed herein. The dye immersion coil used in this delivery system may be any dye immersion coil described herein.

[0048] In some embodiments, the reference label is impregnated with a dye coated on one or more internal surfaces of the reference label, wherein the internal surface refers to a surface that is completely encapsulated by the reference label and is not exposed to tissues or other elements outside the label when the reference label is placed. The reference label may be, for example, a reference coil.

[0049] In some embodiments, the reference label is impregnated with a dye encapsulated within the reference label, and there is a reference coil in which a dye-impregnated material, such as a dye-impregnated fiber or another dye-impregnated polymer, is encapsulated inside the coil.

[0050] Examples

[0051] The following examples are provided as specific examples of the disclosed method. However, it should be understood that the present invention is not limited to the specific details presented in the examples.

[0052] Furthermore, any numerical range mentioned in describing or asserting various aspects of the invention in the paragraphs above or below, such as a specific set of characteristics, units of measurement, conditions, physical states, or percentages, is intended to literally include any number within such range, including any subset of the number or range included within the specified range, either by explicit reference in this specification or otherwise. When used as a modifier for a variable or in conjunction with a variable, the term "approximately" is intended to indicate that the numbers and ranges disclosed in this specification may be flexible to the extent understood by those skilled in the art, and that desired results can be achieved even if the disclosed invention is practiced using temperatures, concentrations, amounts, contents, and characteristics outside of the literal range.

[0053] Case Study

[0054] The following case study exemplifies the initiated method,

[0055] Materials and Methods

[0056] One patient from El Camino Hospital / Palo Alto Medical Foundation in Mountain View, California, USA, and three patients from Aurora Medical Center in Kenosha, Wisconsin, USA, who were incidentally found to have lung nodules, were selected for a proof-of-concept study of the disclosed method. Selection was based on the scheduled time interval between the labeling procedure and thoracic surgery (time between ICG dye immersion coil placement and surgical resection was 0, 4, 5, and 9 days).

[0057] The material used in the procedure was a reference coil (G10417 Tornado embolization coil 7 mm x 3 mm x 0.035 in x 8 cm, Cook Medical, Bloomington, Indiana, USA) immersed in indocyanine green dye (ICG) (NDC-70100-424-02, HUB Pharmaceuticals, Scottsdale, Arizona, USA) for 10 minutes, which was subsequently placed by robotic bronchoscopy using the Ion Endoluminal System (Intuitive Surgical, Sunnyvale, California, USA) 0 to 9 days prior to thoracic surgery.

[0058] All patients underwent Robot-Assisted Navigation Bronchoscopy (RANB) using the Ion Endoluminal System (Intuitive Surgical, Sunnyvale, California, USA), and cone-beam computed tomography or 3D fluoroscopy was used as an additional tool for secondary confirmation. El Camino Hospital (n=1) used a ceiling-mounted Artis Zee cone-beam scanner (Siemens Medical Solutions, Malvern, Pennsylvania, USA), while Aurora Medical Center, Kenosha (n=3) used a mobile C-arm Cios Spin (Siemens Medical Solutions, Malvern, Pennsylvania, USA). All patients had newly detected nodules incidentally (2 solid nodules and 2 ground-glass opacities). None of the patients had a history of allergic reactions to contrast agents. The procedure was planned to consist of a diagnostic bronchoscopy with post-biopsy labeling (if atypical cells were found on cytopathology during the procedure or malignancy was confirmed) and subsequent surgical resection (scheduled for a later date at the Kenosha, Wisconsin facility and on the same day at the Mountain View, California facility).

[0059] As shown in Figure 1, a procedure was performed to mark the lesion using a Cook Tornado coil immersed in ICG dye using robot-assisted navigation bronchoscopy. Using a standard 1 ml tuberculin syringe with a Luer lock, 0.25 ml of a pre-diluted ICG mixture (25 mg of ICG dye mixed in 10 ml of sterile water to produce an ICG dye concentration of 2.5 mg / ml) was drawn and injected into the outer shell of the Cook Tornado coil cartridge to prime the shell and immerse the coil in the ICG dye. The retention time for the dye to completely soak the coil was 10 minutes. This duration was selected to ensure that the synthetic fibers of the coil were sufficiently immersed and impregnated with the dye. After the retention time had elapsed, another 0.25 ml of the same ICG dye mixture was injected into the coil shell for additional priming immediately before placing the ICG dye-immersed coil within the target nodule. Afterwards, the ICG-impregnated coil was posteriorly mounted onto the superDimension delivery catheter, and the guidewire included in the catheter kit (superDimension™ marker delivery kit, Medtronic, Minnesota, USA) was pushed in for placement.

[0060] In another embodiment not described herein, a reference coil was successfully placed using a brush instead of a placement catheter. The brush was pushed in by a guidewire as described above.

[0061] As shown in Figure 2, once the ICG immersion coil was placed within the target lesion, one patient in Mountain View was transferred to the operating room immediately on the same day for robotic wedge resection as a single anesthesia procedure (da Vinci, Intuitive Surgical, Sunnyvale, California, USA), while three patients in Kenosha were transferred to the recovery room and discharged. These patients underwent robotic thoracic surgery at another facility at Aurora Medical Center, which offers thoracic surgery services, 4, 5, and 9 days later, respectively.

[0062] result

[0063] The procedure described in the embodiment of the disclosed method described herein was performed on four patients. All lesions were less than 2 cm on chest CT prior to the procedure (two ground-glass nodules of sizes 12 mm and 15 mm and two solid nodules of sizes 10 mm and 15 mm), were located in the lateral one-third of the lung, and had no bronchial signs.

[0064] ICG dye-immersed coils were placed on lung nodules of biopsy-confirmed cancer patients preparing for surgery immediately after the procedure (Day 0) and a few days later (Days 4, 5, and 9). Using the Firefly Fluorescence Imaging Vision System of the da Vinci robotic system (da Vinci, Intuitive Surgical, Sunnyvale, California, USA), successful localization of the nodules was achieved by visualizing the dye-immersed coils as neon green targets on the pleural surface for all nodules, as shown in Fig. 3. As shown in Figs. 4a and 4b, wedge resections were successfully performed with clean margins in all four cases through precise localization and resection using the neon green emission from the dye-immersed coils. Based on the cryopathology results of the wedge resections, patients meeting the criteria for additional anatomical lung resection subsequently underwent additional resection while under anesthesia. No complications were found during or after the procedure. Because the coil is made of platinum and spaced synthetic fibers, the ICG dye attached to the coil remains fluoresced and bright neon green, visible to the naked eye even after at least nine days. The bright green dye emission allows thoracic surgeons to pinpoint the exact location to be resected, which potentially reduces the amount of lung tissue removed. Previously, without the use of coils, it was impossible to locate nodules after nine days of labeling with ICG dye, as the dye's effects wear off within hours due to its metabolism and half-life.ICG dye-immersed coils mark the location of nodules, making them visible to the naked eye via the da Vinci robotic system's Firefly Fluorescence Imaging system, thereby enabling surgeons to target lesions more accurately and perform lung-preserving surgery. Since the coils can be palpated with surgical forceps or visualized via intraoperative fluoroscopy or ultrasound, they provide multiple options for surgeons to locate lesions based on their experience and expertise, utilizing the chemical and mechanical properties of the dye-impregnated coils.

[0065] Exemplary Procedure Analysis

[0066] Locating nodules facilitates surgical resection and prevents the resection of benign disease and healthy lung tissue. However, successful lesion localization is difficult to define clearly and is usually judged subjectively by the operator. If a surgeon cannot clearly visualize or palpate the lesion, it may fail, leading to increased procedure time, resection of normal lung tissue, changes in the surgical approach, and the possibility of failure to remove the targeted area. More than 60% of lung nodules greater than 5 mm from the pleural surface and smaller than 10 mm are not detected by image-assisted thoracoscopy. Additionally, pure ground-glass lesions are not easily palpable. In the exemplary patient presented, all lesions were less than 15 mm in size, located in the outer one-third of the lung, and lacked bronchial signs. Two lesions were solid, and two were ground-glass. All lesions showed no staining diffusion and were localized during surgery up to 9 days after indication.

[0067] The reference coil immersed in ICG was used because it is made of platinum and spaced synthetic fibers, allowing the ICG dye to adhere well to the coil. The placement coil, with its wide base and gradually narrowing shape, is suitable for placement in small airways or lung parenchyma. The placed coil is also easily felt with a finger or forceps. In some embodiments, the reference coil may preferably be composed of a shape-memory material to retain its original shape after placement in a targeted lesion or nodule. In some embodiments, one end of the reference coil may be fiber-free to prevent the fiber from becoming entangled with placement devices such as catheters, brushes, or guidewires. The placed shape of the dye-impregnated coil is clearly visible to the naked eye via fluoroscopy, ultrasound, or illumination methods. It was considered that this structure would remain visible to the naked eye after several days due to the fluorescent and bright neon green dye, and in an exemplary patient, it was visible after at least 9 days. The luminescence of the bright green dye allowed thoracic surgeons to identify the precise location to be resected, potentially reducing the amount of lung tissue removed and enabling lung-preserving surgery. Previously, it was impossible to locate a nodule nine days after marking with ICG dye without coils, as the dye's effects wore off within hours due to its metabolism and half-life. ICG dye-immersed coils mark the location of nodules and make them visible to the naked eye via the Firefly Fluorescence Imaging system of the da Vinci robotic surgery system, allowing surgeons to target lesions more accurately and enabling lung-preserving surgery. Since the coils can be palpated with surgical forceps or visualized via intraoperative fluoroscopy or ultrasound, they provide surgeons with multiple options for locating lesions based on their experience and expertise, utilizing the chemical and mechanical properties of the dye-impregnated coils.

[0068] The retention of the dye after several days is assumed to be based on the interaction between the ICG dye and the synthetic fibers of the coil. The ICG dye penetrates the fibers of the coil upon immersion. Although ICG has a short half-life, non-specific protein binding, and low photostability when injected, these limitations can be overcome by conjugating ICG with other materials such as lipids, metals, or nanoparticles. Consequently, it is considered that conjugating ICG to the synthetic fibers of the coil can mitigate these limitations while maintaining the beneficial properties of ICG, namely enhanced visualization. Furthermore, coils composed of materials that do not absorb the dye, such as metals, and do not contain fibers capable of enabling dye impregnation are considered unsuitable for use in the disclosed method because they fail to retain the dye for an extended period.

[0069] In the exemplary patients, dye immersion coils were placed on lesions confirmed or suspected of being malignant by biopsy; however, the disclosed method can also be used on undiagnosed lesions highly suspected of malignancy for which surgical biopsy or resection is planned. The use of this ICG reference marker method enables extended time before surgery, which can provide substantial benefits to patients in small rural hospitals or medically underserved areas who have limited access to or availability of on-site thoracic surgery. Similarly, this method can be beneficial at large academic medical centers where it may be difficult to plan a single anesthesia procedure for immediate surgery after localization due to scheduling or operational conflicts. Patients may also require time for scheduling, preparation, and travel to large medical institutions.

[0070] As a result of performing surgical resection within a time range of 0 to 9 days following robot-assisted nodule marking, the neon green luminescence intensity emitted from the ICG dye immersion coil was found to remain constant across the entire pleural surface over time, rather than weakening or dispersing. This approach facilitates surgical assistance by enabling proper localization and visualization when the patient undergoes surgery a few days later. This has the potential to improve the ability to successfully perform lung-sparing surgery for both primary and secondary lung malignancies.

[0071] In vitro test

[0072] In vitro evaluation of ICG residue was performed using a reference coil label.

[0073] In an exemplary study, a 25 mg ICG vial was placed in 10 cm of sterile water. 3 It was reconstituted and prepared to the same dilution concentration as used in in vivo experiments. For the experiment, two types of coils were selected: a Cook Medical Tornado 7 mm x 3 mm coil with nylon fibers and a Boston Scientific Vortex 18 2 mm x 3 mm coil with polyester fibers. The diluted ICG solution was slowly injected into the coil cartridge to move the coil 0.5 cm 3 of It was immersed in diluted ICG. The coil injected with ICG was then left for 10 minutes. Before transplanting into the tissue, another 0.5 cm 3 The coil cartridge casing was flushed with a diluted ICG solution.

[0074] In this experiment, freshly harvested and refrigerated beef liver was used. The entire organ was cut into large pieces (approximately 10 cm x 5 cm in size). Two small incisions were made in the liver tissue at least 5 cm apart using a blade. Each incision was approximately 2 cm deep, and the depth was verified using a graduated measuring tape. Subsequently, one Tornado 7 x 3 mm ICG-impregnated coil and one Vortex 2 x 3 mm ICG-impregnated coil were inserted into the tissue at least 5 cm apart and to a depth of 2 cm using forceps. The incision sites were then sutured with 2-0 silk thread, and tape was applied over them to identify the incisions. Five pieces were prepared in this manner. Each piece was then individually packaged in an airtight plastic bag and placed in a container. The container was then stored in a freezer.

[0075] The chilled tissues were removed from the freezer 77 days after the initial transplant. The tissues were removed from the container and thawed at room temperature for approximately 60 minutes. Tape and sutures were removed from the tissue surface. In all specimens, the incision sites were sealed, and no coils were visible on the surface upon visual inspection. The analysis room was darkened, and each tissue section was individually illuminated using the firefly light of the Intuitive Surgical Xi robot. All coils glowed and were easily visible.

[0076] conclusion

[0077] A novel method for addressing the issue of surgical localization of lesions or nodules in tissues or organs is described. The disclosed method increases efficiency between diagnosis and subsequent surgery. The disclosed method can assist surgeons in identifying the location of nodules by marking small crystals using a reference coil immersed in a fluorescent dye. The reference coil can be used, for example, to mark lung nodules and can be placed using a robotic bronchoscopy system during a biopsy. Alternatively, non-robotic peripheral navigation platforms can also be effectively used as an adjunct to surgical resection. The dye marks the location of the nodule, allowing it to be visually observed and palpably detected during surgery. Consequently, surgeons can target cancerous tissue more accurately. The disclosed method makes it possible to place the reference coil several days prior to surgery.

[0078] The above embodiments illustrate a method for marking lesions in the lung or, alternatively, the liver, but the disclosed method may also be used to mark lesions in other tissues and organs of the body.

[0079] Additionally, while the embodiments describe a method for placing a dye-labeled reference coil in lung tissue using a robot-assisted navigation bronchoscopy (RANB), it is considered that the dye-labeled reference coil may be placed in lung tissue or other organs or tissues using other techniques, including but not limited to image-guided endoscopic techniques using an endoscope, catheter, or needle, and image-guided percutaneous techniques using a needle or catheter. Such techniques include, for example, endoscopic ultrasound and CT-guided needle placement.

[0080] Additionally, while the embodiments illustrate a method of marking a lesion using a specific coil, it is considered that any biocompatible coil suitable for use in the human body may be used in the disclosed method, including coils composed of biocompatible metals or alloys, biocompatible polymers, or other biocompatible materials.

[0081] Furthermore, although the above description explains a method of marking a lesion using a reference coil, any biocompatible reference marker suitable for use in the human body that meets the design requirements for use as a reference marker in a desired application is considered to be usable in the disclosed method, including but not limited to other forms and designs that meet the requirements described herein.

[0082] Additionally, while the foregoing describes the use of specific biocompatible fluorescent dyes, it is considered that any biocompatible fluorescent dye or other luminescent dye suitable for use in the human body may be used in the disclosed method. As described herein, luminescent dyes may include fluorescent dyes, phosphorescent dyes, chemiluminescent dyes, and bioluminescent dyes.

[0083] Furthermore, while the above description describes the use of specific biocompatible dyes, it is considered that any biocompatible luminescent material suitable for use in the human body may be used in the disclosed method.

[0084] Additionally, although the foregoing describes a procedure for immersing a coil in a dye immediately before placing the dye-immersed coil as a reference marker, it is considered that, alternatively, the coil may be pre-immersed in an appropriate amount of fluorescent dye or other luminescent dye, and the pre-immersed coil may then be used in the disclosed method. The shelf life of the pre-immersed coil will vary depending on the specific dye and the material(s) constituting the coil and any fiber attached thereto.

[0085] Furthermore, the following examples illustrate the use of a coil with attached fibers impregnated with a dye, but it is considered that a coil without fibers composed of a material capable of absorbing the dye, such as a coil composed of a polymer capable of absorbing the dye, may be used alternatively.

[0086] Additionally, the following examples illustrate a procedure comprising mounting a dye immersion coil onto a delivery catheter and using a guidewire to place the coil, but it is considered that a pre-packaged dye immersion coil delivery system comprising a dye immersion coil mounted on a placement device such as a catheter may be used alternatively.

[0087] It is also considered that a self-expanding foldable coil can be used as a reference coil, which allows the coil to be folded after placement is initiated, thereby enabling adjustment to the precise desired position or location and achieving placement.

[0088] Additionally, the following examples illustrate the use of a coil completely immersed in the dye, but the use of a coil partially immersed in the dye and the use of such partially immersed coil in the disclosed method is also considered.

[0089] Finally, although the above description explains the use of a dye-immersed reference coil as a reference marker, it is considered that the reference marker can alternatively be impregnated with a fluorescent dye or other luminescent dye or other luminescent material by encapsulating a luminescent material inside the reference marker or by impregnating the reference marker with a luminescent material using a technique other than immersion.

[0090] The above description of the disclosed embodiments is provided to enable those skilled in the art to make or use the invention disclosed herein. While various aspects of the invention are disclosed in the context of the specific embodiments, embodiments, and examples illustrated, those skilled in the art should understand that the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and / or uses of the invention and obvious variations and equivalents thereof. Furthermore, although various variations of the various aspects of the invention have been illustrated and described in detail, other variations within the scope thereof will be easy and obvious to those skilled in the art by reviewing the disclosure. Additionally, it should be understood that the scope of the disclosure includes various combinations or partial combinations of specific features and aspects of the embodiments disclosed herein, and accordingly, various features, embodiments, and aspects of the subject matter disclosed herein may be combined or substituted for one another. General principles defined in this specification may be applied to other embodiments without departing from the spirit or scope of the disclosure. Therefore, the disclosure should not be limited to the embodiments shown in this specification, but should be interpreted in the broadest scope consistent with the principles and novel features disclosed herein.

[0091] All references mentioned in this specification are explicitly incorporated by reference.

Claims

Claim 1 A method for marking a lesion or nodule within an organ of a mammal for subsequent surgical resection, comprising the step of placing a dye-impregnated reference marker impregnated with a luminescent dye on or inside the lesion or nodule identified within the organ of a mammal for subsequent surgical resection, wherein the dye penetrates at least a portion of the reference marker, and after placing the dye-impregnated reference marker on or inside the lesion or nodule, the dye-impregnated reference marker is identifiable using an imaging technique. Claim 2 In paragraph 2, the dye-impregnated reference marker is positioned on or inside a lesion or nodule using an image-guided endoscopic technique using an endoscope, needle, or catheter, or an image-guided percutaneous technique using a needle or catheter. Claim 3 A method according to paragraph 2, wherein the organ is the lung, and the dye-impregnated reference marker is positioned on or inside a lesion or nodule using robotic assisted navigation bronchoscopy (RANB). Claim 4 A method according to paragraph 2 or 3, wherein the dye is a fluorescent dye. Claim 5 In paragraph 4, the fluorescent dye is indocyanine green. Claim 6 A method in which, in any one of paragraphs 2 to 5, the mammal is a human. Claim 7 A method according to any one of claims 2 to 6, wherein the position of the dye-impregnated reference marker within the organ can be confirmed at least 5 days after the reference marker is placed, thereby allowing the lesion or nodule to be surgically excised by organ-preserving surgery. Claim 8 A method in which, in any one of paragraphs 2 through 7, the reference indicator is a reference coil. Claim 9 A method according to any one of paragraphs 2 through 8, wherein the dye is coated on one or more internal surfaces of a reference marker. Claim 10 A method according to any one of paragraphs 2 through 8, wherein the dye is encapsulated within a reference label. Claim 11 A dye-impregnated reference marker comprising a reference marker configured to remain embedded within a target tissue of a mammal without significant displacement over time, and a luminescent dye impregnated within the reference marker, wherein the reference marker is sufficiently flexible to be placed in the target tissue. Claim 12 In Clause 11, the above-mentioned indicator is a coil, a reference indicator. Claim 13 In Clause 11, the above-mentioned marker is a standard marker of the S form. Claim 14 In paragraph 11, the above-mentioned marker is a standard marker in the form of the number 8. Claim 15 A reference label, wherein in any one of paragraphs 11 to 14, the luminescent dye is a fluorescent dye.

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