Method and system for consistent, prepareable, and safe cryospray treatment of airway tissue

Abstract

To provide a suitable method and system for consistent, prepareable, and safe cryospray treatment of airway tissue. [Solution] A method and system for automated and semi-automated, predictable, consistent, safe, effective, lumen-specific, and patient-specific cryospray treatment of airway tissue, wherein, following input of patient information and treatment location information by the user into the system, the treatment duration is automatically set by the system, and the treatment spray is automatically stopped by the system when the automatically selected treatment duration is achieved as determined by the system.

Description

Technical Field

[0001] (Field of the Invention) The present invention relates to a medical device for treating lung diseases, and more particularly, to a cryospray device.

[0002] (Cross - Reference to Related Applications) This application claims priority under 35 U.S.C.§119 to U.S. Provisional Patent Application No. 62 / 007,518 by Maners, et al., filed on June 4, 2014, entitled "Method and System For Consistent, Repeatable, and Safe Cryospray Treatment of Airway Tissue" and U.S. Provisional Patent Application No. 62 / 047,936 by Hanley et al., filed on September 9, 2014, entitled "Bronchoscopic Sheath For Measuring or Spacing". The foregoing applications are hereby incorporated by reference in their entireties for all purposes.

Background Art

[0003] (Background of the Invention) The human conducting airway is covered by a surface layer of epithelial cells that includes an important primary defense line for the entire respiratory organ. This surface cell layer consists mainly of mucus - producing (goblet) cells and ciliated cells. These cells function in a coordinated manner to capture inhaled biological and inert particulates and remove them from the airway. This "mucociliary escalator" functions with excellent efficiency in the face of potentially harmful stimuli, but this is a delicate balance system that relies on the proper maintenance of the appropriate complement of cilia and mucus - producing cells and their normal function to perform effective clearance. Disruptions in the distribution and function of epithelial cell types can have an adverse effect on health.

[0004] Ciliated cells make up about 80% of the epithelial cells present at the luminal boundaries of the larger airways. While they are the most common type of epithelial cell lining the airways, numerous studies suggest they are also among the most vulnerable to infection, irritation, and contaminant exposure. A distinguishing feature of ciliated cells is their highly organized appendages: cilia that line the luminal boundary.

[0005] Mucus and other non-ciliated cells make up about 20% of the epithelial cells lining the luminal boundaries of the major airways. Mucus cells often swell with their secretions and exhibit a characteristic "cup" shape. Along with submucosal glands, germ cells secrete high molecular weight mucoglycoproteins (mucin). Goblet cells are thought to have the potential to produce significantly more mucus than glands, particularly in response to damage from environmental pollutants and other toxic elements such as tobacco / cigar smoke.

[0006] Other non-ciliary cells, with little or no granules, may also be present along the luminal boundary. These may represent mucinous cells or undifferentiated cells that have released their contents onto the luminal surface. The entire epithelial layer is situated on the basal layer, which contains collagen and connective tissue. All cells of the epithelial layer are anchored to this "basement membrane."

[0007] Chronic bronchitis is a non-infectious inflammatory disease typically resulting from airway damage caused by toxic elements (usually smoking). It is defined by a cough with wet sputum lasting three months for two consecutive years. It is further characterized by excessive mucus in the bronchi (hypermucosalgia / hypersecretion / goblet cell hyperplasia), ciliary damage, and loss of ciliated cells. Toxic irritation leads to airway inflammation with swelling of the lamina propria, resulting in thickening of the airway walls, and this functional narrowing causes shortness of breath. More specifically, this damage causes hyperproliferative goblet cells to overproduce thick, viscous, acidic mucus that is difficult to clear due to ciliary dysfunction. The acidic mucus of chronic bronchitis leads to inflammation of the airway walls and fluctuates viscosity.

[0008] Asthma is a chronic respiratory disease characterized by bronchitis, increased airway smooth muscle, and airway hyperresponsiveness, causing the airways to narrow (stenose) excessively or very easily in response to irritants. The onset or attack of asthma causes narrowing / stenosis of the airways, which makes breathing difficult. Asthma attacks occur at irregular intervals and can be triggered by allergens or irritants inhaled into the lungs, or by stress, cold air, viral infections, or other irritants. Asthma is sometimes, but not always, associated with increased mucus production.

[0009] Airway hypersecretion is also a characteristic of other airway diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, viral bronchitis, and bronchiolitis.

[0010] In individuals suffering from hypersecretion, mucus can accumulate in the airways, potentially causing airway obstruction. The submucosal glands and goblet cells lining the airway epithelium secrete a viscoelastic gel consisting of mucus, viscous substances, water, carbohydrates, proteins, and lipids. In healthy individuals, mucus is the primary defense against inhaled foreign particles and infectious agents, cleared by active columnar ciliated cells / migration, which assist in sweeping the mucus upward, either swallowed or expelled via a wet cough. Mucus traps these particles and agents, facilitating their clearance while also preventing tissue from drying out. Goblet cells and the small airways, including the peripheral airways that cannot be cleared by coughing, are particularly susceptible to mucus accumulation and progressive mucus obstruction.

[0011] Conventional treatments for individuals with airway hypersecretion or chronic bronchitis include the use of systemic or inhaled corticosteroids, anticholinergics, antibiotic therapy, bronchodilators (e.g., methylxanthines), short- or long-acting beta-2 agonists that relax the muscles in the airways and relieve symptoms, aerosol delivery of mucolytics (e.g., water, hypertonic saline), and oral administration of expectorants (guaifenesin). While these drugs are variably approved by the FDA for use in COPD, it should be noted that, with the exception of roflumilast, an inhibitor of an enzyme called phosphodiesterase type 4 (PDE-4), they are not specific to chronic bronchitis.

[0012] Many of the medications described above have serious side effects. For example, inhaled corticosteroids can cause thrush (a yeast infection of the mouth), cough, or hoarseness, while systemic corticosteroids have even more severe side effects such as delayed sexual development, changes in the menstrual cycle, weight gain, and increased blood sugar (diabetes). Side effects of methylxanthines include severe nausea, tremors, muscle spasms, seizures, and irregular heartbeat. Roflumilast commonly induces significant diarrhea. Patient compliance is often low due to these side effects.

[0013] Interventional approaches to managing obstructed airways include surgery, mechanical debulking, close-range radiotherapy, stents, photodynamic therapy, and thermal modalities such as electrocautery, lasers, argon plasma coagulation, and bronchial thermoplasty. Bronchial thermoplasty is a procedure designed to help control severe asthma by reducing the mass of airway smooth muscle by delivering thermal energy to the airway wall and heating the tissue in a controlled manner. Bronchial thermoplasty using RF energy results in a deep resection effect down to the level of airway smooth muscle, leading to reparative healing that results in scar tissue that is inherently fibrous. The thermal treatment denatures proteins, causes enzyme inactivation, and inhibits collagen reconstruction. Therefore, patients who have undergone bronchial thermoplasty cannot be retreated in the same area. Cryoprobes are also used in airway management, but their use can be cumbersome and time-consuming due to the surface area limitations of the probes, which require contact between the probe and the surface of the target lesion or tissue.

[0014] Based on reports of promising results from the use of low-pressure spray cryotherapy for resection of esophageal lesions (Barrett's esophagus, dysplasia, and esophageal cancer), Krimsky, et al. evaluated the safety of cryospray use in airway tissue (Krimsky, et al., 2009). Krimsky, et al. reported the administration of spray cryotherapy to 21 subjects scheduled for lung resection for the treatment of lung cancer, carcinoid tumors, and mycobacterial infections. The treatment area was targeted to the normal and unrestricted portion of the airway distal to the planned anastomosis site. All sites received targeted delivery of low-pressure (2-3 psi) liquid nitrogen at the same dose, in two cycles of 5-second sprays with thawing at 60-second intervals. All patients had a treatment time of less than 5 minutes. Post-treatment bronchoscopy and histopathological examination of the airway were performed from less than 1 day to 106 days post-treatment.

[0015] Findings from the treated area showed consistent changes with varying levels of cryonecrosis limited to the mucosa and submucosa (approximately 1.5 mm), and new tissue injury with no damage to connective tissue. Krimsky, et al. reported early post-treatment loss of epithelium and airway smooth muscle, edema, and damaged submucosal gland, followed by adjacent reepithelialization and healing from the periphery to the center of the injury. Complete reepithelialization of the airway mucosa and thinning or absence of the smooth muscle layer, as well as some degree of continued thinning of the submucosal gland, were reported to persist up to 106 days post-treatment.

[0016] Krimsky, et al. reported that these initial safety and histopathological evaluations suggested that spray cryotherapy could be safe and useful for treating airways by causing localized damage to the underlying connective tissue, i.e., the cellular elements of the treated tissue without damaging the extracellular matrix. While acknowledging the small number of subjects in the study and noting in particular that only normal, unobstructed airways were treated, Krimsky et al. nevertheless hypothesized that the results of their study suggested treatment potential in human thoracic diseases.

[0017] In particular, in addition to treating only healthy, unoccluded tissue (rather than areas characterized by excessive goblet cells, hypersecretion, or damaged or lost cilia), Krimsky, et al. did not report any observations regarding mucus production, goblet cell population or proliferation, and / or ciliary / ciliated cell population, either before or after treatment. Furthermore, Krimsky et al. did not observe or suggest that cryospray treatment could actually cause changes in the architecture of diseased / damaged tissue, nor did they suggest that diseased tissue could be regenerated as healthy tissue. Moreover, no studies addressing these questions have been published since Krimsky, et al. In fact, as of the time of this application, there are no drugs or devices today that propose the reduction of mucus-secreting cells and / or the reconstruction of cilia. [Overview of the Initiative] [Means for solving the problem]

[0018] (Summary of the invention) Prior art cryospray methods and devices are effective in providing an approximate cryospray volume for an appropriate cryospray duration, but are not configured to deliver a strictly consistent cryospray dose per device, or even per use by the same user using the same device. Nevertheless, prior art cryospray devices and methods have met the industry's needs for many years, and excellent treatment outcomes have been reported from the use of prior art cryospray devices. According to current cryospray devices and methods, the spray pedal is pressed, and the surgeon waits for the cryospray to advance through the system and delivery catheter and exit from the catheter tip, observing the application of the cryospray to the desired tissue through an endoscope or bronchoscope, and continuing to spray until the treated tissue turns white, which is generally recognized as indicating that the tissue has achieved a frozen state, and then manually continuing to spray for a measured time such as 5 seconds or up to 10 seconds. The flow of cryogen is immediately stopped by the treating physician releasing the pedal. The treated tissue is allowed to thaw, and the procedure is then repeated in the same manner if desired. In short, current cryospray devices and methods are designed to excise tissue, and the amount of cryospray applied varies from patient to patient and from surgeon to surgeon, based on the surgeon's observation of tissue changes during the procedure, subjectively assessing the progress of the procedure and subjectively determining whether additional treatment of the treated area is indicated. Surgeons and other users of prior art cryospray devices and methods are trained and familiar with current cryospray methods and have reported excellent results. Therefore, there is no perceived need in this field for cryospray methods or devices that function differently from prior art cryospray methods and devices.

[0019] Despite the foregoing, even considering the expertise and experience of surgeon users, the inventors found a need for a cryospray device and method that provides automated or semi-automated cryospray application to airway tissue that is predictable, consistent, and repeatable for each application and device, and is specifically and individually tailored to each patient and each segment of airway tissue, for the purpose of inducing tissue regeneration. To provide such a predictable, consistent, and repeatable cryospray application (the need for which was not previously understood in the art), the inventors developed the device and method described herein.

[0020] Accordingly, according to the present invention, the present invention is a method and system for automated and semi-automated predictable, consistent, effective, lumen-specific, dose-specific, and patient-specific cryospray dilation treatment of airway tissue across one or more treatment sessions. According to one embodiment of the present invention, following the input of patient information and treatment location information by the user into the system, the treatment duration is automatically set by the system, and the treatment spray is automatically stopped by the system when the automatically selected treatment duration is achieved so as determined by the system. According to another embodiment of the present invention, different treatment durations are automatically set for different treatment locations in the airway based on the lumen diameter of the treatment site. According to another embodiment of the present invention, the treatment spray cannot occur until the user inputs patient information and treatment location into the system console.

[0021] According to another embodiment of the system, the device is configured to maintain a constant temperature in the cryospray supply line between the onboard cryogen tank and the delivery catheter port during cryospray operation. According to a preferred embodiment, the cryospray supply line between the cryogen tank and the delivery catheter port is maintained at a constant temperature above -120°C (warmer), preferably about 20°C, using a combination of sensors and heaters in a control valve and end components.

[0022] According to yet another embodiment of the present invention, each individual delivery console is calibrated and adjusted so that each delivery console provides substantially the same automated dose for each set of delivery parameters, namely patient information and treatment site / lumen diameter. According to this embodiment, a fully assembled and operational cryospray delivery console, already filled with cryogen, is connected to an external source of cryogen (in gaseous form) via an adjustable pressure valve. The adjustable pressure valve is used to dial in a specific and precise tank pressure. The cryospray delivery system is then operated in test mode so that its cooling force is measured at the cryospray outlet, i.e., the tip of the cryospray delivery catheter. The adjustable pressure valve is then adjusted, and the system is retested until the desired cooling force is achieved at the outlet. Once the pressure required to achieve the desired cooling force is determined, the console is adjusted to set the nominal cryogen tank pressure to the determined pressure. According to this embodiment, despite machine-to-machine variations due to manufacturing tolerances relating to tubing, valves, and other cryogen supply elements, each cryospray device according to the present invention delivers a precise cryospray dose for each set of delivery parameters, namely patient information and lumen diameter.

[0023] According to a further embodiment of the present invention, there is provided an improved cryogen delivery catheter having a proximal section wider than the working channel of the corresponding bronchoscope and a distal section configured to fit within the working channel of the corresponding bronchoscope. According to yet another embodiment, the treatment of airway tissue is performed circumferentially using a radial spray pattern delivery catheter configured to simultaneously deliver a cryo-spray across the entire circumference of a selected intraluminal cross-section without the need to rotate the delivery catheter. According to this embodiment, the distal end of the catheter is configured to direct the cryo-spray radially with respect to the axis of the delivery catheter rather than forward (i.e., not longitudinally with respect to the axis of the delivery catheter). According to this embodiment, the distal end of the delivery catheter is configured with exactly two rows of eight cryogen delivery ports equally spaced around the catheter, the centerlines of the rows being preferably displaced 0.025 inches from each other and each port being offset 22.5° from an adjacent port in the other row. The inventors have discovered that conventional radial cryo-spray delivery port arrays having more than two rows of delivery ports tend to result in cryogen delivery patterns that extend forward, often beyond the visualization limits of the bronchoscope. Further, the inventors have discovered that the offset two-row delivery ports described herein avoid the forward-propagating cryo-spray characterized by delivery catheters having more than two rows of delivery ports.

[0024] These embodiments, along with others as described in more detail herein, provide automated and semi-automated, predictable, consistent, safe, and effective, and lumen-specific and patient-specific cryo-spray treatments of diseased airway tissue.

[0025] Thus, another aspect of the present invention is the therapeutic treatment of epithelial hyperplasia and dysplasia using the methods and devices of the present invention. This treatment can also be therapeutically used to improve the modified epithelial structure, for example, in the context of related inflammatory and infectious disorders characterized by, for example, asthma, bronchitis, bronchiolitis, and / or a similar pattern of goblet cell dysplasia and / or increased airway smooth muscle. This treatment can also be similarly used to treat airway diseases or conditions characterized by hypersecretion of mucus.

[0026] Disease states indicating the need for cryospray therapy include, for example, chronic obstructive pulmonary disease, inflammatory diseases (such as asthma, bronchiectasis, and pulmonary fibrosis), and chronic obstructive pulmonary disease (such as chronic bronchitis).

[0027] The determination of the need for treatment can be evaluated according to any number of methods, including, but not limited to, medical history and physical examination, histopathological diagnosis (biopsy confirmation) consistent with overproduction of mucus or proliferation of goblet cells (such as mucus-producing cough), X-ray or other imaging studies of the airway showing a disease or abnormality associated with overproduction of mucus, or pulmonary function tests showing signs of airway obstruction and / or hyperreactivity.

[0028] According to the present invention, a method for spray cryotherapy directed to the airway surface epithelium is presented that destroys damaged cilia and hypersecretory goblet cells, stimulates and / or induces a reorganization or new tissue / cell growth that results in a regenerative healing response, resulting in new cilia, new epithelium, and reduced mucus production. According to the present invention, the response of airway tissue to cryospray treatment is a regenerative healing response, i.e., it results in tissue reorganization, compared to a reparative healing response that results in scarring / fibrosis. Since cryospray results in preservation of the extracellular matrix with little accompanying scar or fibrous tissue healing, the cryospray-treated area can be retreated in the same area if the treated and reorganized tissue recurs after treatment and reorganization.

[0029] According to one aspect of the present invention, a method for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue is presented, which causes airway reconstruction, restoring the airway epithelium to a healthy structure.

[0030] According to one aspect of the present invention, a method for cryospray treatment to treat airway hypersecretion is presented, which causes airway reconstruction and therapeutic reduction of mucus hypersecretion.

[0031] According to one aspect of the present invention, a method for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue is presented, wherein the application / delivery of cryogen is touch-free.

[0032] According to one aspect of the present invention, a method for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue is presented, which does not require the juxtaposition of a cryospray device to the target tissue.

[0033] According to one aspect of the present invention, a method for cryospray treatment of damaged airway cilia is presented.

[0034] According to one aspect of the present invention, a method for cryospray treatment of chronic bronchitis is presented.

[0035] According to one aspect of the present invention, a method for cryospray treatment of asthma-related bronchial obstruction caused by increased mucus production is presented.

[0036] According to one aspect of the present invention, a method for cryospray treatment of asthma-related bronchial obstruction caused by enlarged airway smooth muscle is presented.

[0037] According to one aspect of the present invention, a method for cryospray treatment of COPD is presented.

[0038] According to one aspect of the present invention, a method for cryospray treatment of excessive production or hyperplasia of goblet cells in the airway is presented.

[0039] According to one aspect of the present invention, a method for using cryospray treatment to reduce airway mucus production is presented.

[0040] According to one aspect of the present invention, a method is presented for using cryospray treatment to reset tissue and reconstitute the treated tissue to a normal number of goblet cells.

[0041] According to one aspect of the present invention, a method for using cryospray treatment to induce cilia regrowth is presented.

[0042] According to one aspect of the present invention, a method is presented for using cryospray treatment to treat airway tissue, which does not damage the underlying connective tissue and causes little to no fibrosis.

[0043] According to one aspect of the present invention, a method is presented for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue, comprising a pre-determined dose based on the luminal diameter / anatomical location in the bronchial tree.

[0044] According to one aspect of the present invention, a method is presented for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue, comprising a delivery dose configured to induce limited cryonecrosis that does not extend into the underlying connective tissue. The depth of cryonecrosis increases with increasing dose, in particular, with increasing spray duration. Since the depth of connective tissue in the airway is generally related to the diameter of blood vessels, this aspect of the present invention includes cryospray doses that depend on the luminal diameter of the anatomical location, e.g., the trachea, main bronchi, lobar bronchi, and subsegmental bronchi. Typical luminal diameters in the average adult bronchial tree are trachea (18 mm), main bronchi (12 mm), lobar bronchi (8 mm), and segmental bronchi (6 mm). However, the thickness of the bronchial tissue layers related to the disease process tends to be substantially the same regardless of the luminal diameter. Therefore, according to this aspect of the present invention, a system and method for excising airway tissue is provided, which excises tissue at a substantially constant depth (0.1–0.5 mm) and axial range (1–2 cm) in a widely variable diameter of the airway. This is achieved by delivering patient and region-specific amounts of cryogen to the airway based on limited user input.

[0045] According to some embodiments within this aspect of the present invention, the dose time may be determined according to the following guidelines. [Table 1]

[0046] According to one aspect of the present invention, the procedure involves multiple lumen-specific doses within the lung and / or trachea. In a preferred embodiment, the procedure begins at the most distal target site and progresses proximal up the respiratory tree. Each dose is applied once to the target procedure site and is allowed to thaw as the bronchoscope is advanced proximal to the next target site. After several doses have been given, manual ventilation may be required, whether or not the bronchoscope is removed, and oxygen levels are monitored and stabilized during the procedure. In addition, more than one procedure session (also referred to as a procedure day) may be required to complete the procedure. For example, the ipsilateral bronchus may be treated on the first procedure day, while the contralateral bronchus is treated on the second procedure day. Accordingly, embodiments of this aspect of the present invention involve the delivery of multiple cryosprays (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or more) to the same, adjacent, or contralateral region of the bronchial tree over a single procedure day or multiple procedure days (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, or more) of cryosprays. In some cases, the previously treated area is re-treated on subsequent procedure days to provide supplemental excision or to excise new tissue growth at the treatment site.

[0047] According to another embodiment of the present invention, a dose-interval sheath may be provided across the bronchoscope. According to this embodiment, the dose-interval sheath extends across the bronchoscope to a length that fully covers the portion of the scope that is visible to the user / operator on the outside of the patient's body during use, including the portion of the scope that is inside the patient's body during part of the procedure, but is withdrawn from the patient's body when the progressive portion of the airway tissue is being treated. The outside of the dose-interval sheath includes markings that can be used by the operator to measure the distance the scope has been moved, i.e., the distance the scope has been withdrawn, in order to treat subsequent locations so that doses do not overlap with each other.

[0048] Therefore, to begin the procedure, the catheter and scope are advanced to the most distal section that will receive the procedure. According to a preferred embodiment, each treatment area / location within the airway section is treated with only a single dose. Once the first anatomical location is treated, the catheter and scope are withdrawn to a more proximal anatomical location within the same or different section of the lung or trachea, moving from distal to proximal. A dose-interval sheath placed across the bronchoscope may be used to assist the operator in indicating the distance the scope and catheter have been moved to avoid dose duplication. Depending on the new location, the dose administered may be the same as or different from the dose administered to the first anatomical section. According to one embodiment of the present invention, a circumferential region of untreated tissue is left between the regions of treated tissue. According to this embodiment, the region of tissue to be treated consecutively extends in length from 5 mm to 15 mm (measured along the axis of the airway section), and the intervening region of untreated tissue extends in length from 1 mm to 5 mm.

[0049] According to one aspect of the present invention, a method for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue is presented, comprising a low-pressure cryospray to airway tissue at a pressure of less than 5 psi (e.g., 4, 3, 2, 1, 0.5, 0.25 psi, or less) of the spray pressure at which the catheter exits.

[0050] According to one aspect of the present invention, a method is presented for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue, wherein the cryogen exiting the delivery catheter is in the range of -150 to -200 degrees Celsius.

[0051] According to one aspect of the present invention, a method is presented for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue, comprising one or more treatment sessions, in which one or more lobes are treated in the same session, for example, one treatment may include the left lower and middle lobes and one main bronchus, and subsequent sessions may include the right lobe, main bronchus, and trachea.

[0052] According to one aspect of the present invention, a method for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue is presented that is effective in resulting in a reduction of mucus / sputum production and cough. Means of verifying cough-specific quality of life include, but are not limited to, the Cough Quality-of-Life Questionnaire (CQLQ) or the St. George Respiratory Questionnaire (SGRQ). Additional tools regarding dyspnea associated with sputum production include, but are not limited to, patient-oriented sputum diary cards and the Breathlessness, Cough and Sputum Score (BCSS (copyright)) as described by IS Woolhouse et al.

[0053] According to one aspect of the present invention, a method for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue is presented, which is effective in improving lung function by 20%, 30%, 50%, 70%, 100%, 150%, or 200%, as measured by spirometry (e.g., forced expiratory volume (FEV1) or FEV1 / FVC ratio). Forced expiratory volume (FEV1) is the amount of air a patient can exhale from their lungs in the first second. Forced vital capacity (FVC) is the maximum amount of air a patient can exhale after taking in their maximum possible exhalation.

[0054] According to one aspect of the present invention, a method for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue is presented that is effective in resulting in symptom reduction, including exacerbations requiring medication or hospitalization. Some accepted measurement tools for exacerbation and symptom assessment include, but are not limited to, diaries for assessing respiratory symptoms in patients with stable COPD, EXACT(copyright)(Chronic Lung Disease Exacerbation Tool), EXACT PRO(copyright)(PRO is an acronym for Patient Reported Results), and EXACT-RS. According to a further aspect of the present invention, a method for cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue is presented that is effective in resulting in reduction of lung biomarkers associated with COPD or other disease / injury.

[0055] The present invention also relates in one aspect to a sheath or sleeve designed to fit snugly over the outer surface of a bronchoscope during a bronchoscopy procedure, such as a procedure according to another aspect of the present invention. The outer surface of the sleeve is marked in pre-determined increments that reflect distances along the length of the sheath, and is designed to be used by a physician to help evaluate and measure the movement of the bronchoscope into and out of the patient's airway. The reference markings are then used to reference or align with another object, such as an endotracheal tube or a rigid bronchoscope.

[0056] According to one embodiment, the sheath is made from braided polymer thread / filament. The braided structure is similar to a Chinese finger trap, increasing in diameter when compressed longitudinally and collapsing / locking when placed under tension. When the sheath is compressed longitudinally, the inner diameter of the sheath expands significantly beyond its braided diameter, allowing it to slide over a wide range of diameters of scopes or catheters. When allowed to slacken and recover to its original braided dimensions, it fits snugly onto the surface of the scope, especially when placed under tension. This allows the sheath to accommodate and provide insulation and reference markings for multiple scope diameters. The inner diameter (ID) of the braided sleeve is intentionally made smaller than the preferred outer diameter (OD) of the bronchoscope so that it expands and fits snugly onto the scope during insertion. Therefore, the sheath remains firmly attached to the outer surface of the flexible bronchoscope during use, but can be easily loaded and removed by pushing the ends of the sheath toward each other and "peristally moving" the sheath downwards along the length of the bronchoscope shaft, inch by inch.

[0057] Reference markings may be printed on the outer surface of the sheath, for example, using a pad printer or other method, or they may be braided inside the sheath, for example, using different colored filaments. In any case, the markings are set at defined intervals, e.g., 0.5 cm, 1.0 cm, 1.5 cm, etc. According to one embodiment of the present invention, the markings may be made in one color, for example, every 10 cm, to indicate a long length, or the markings may be made in different colors, for example, every 1 cm, to indicate a short length. Whatever markings are used, they may be made according to any known method.

[0058] According to one embodiment of the present invention, the proximal end of the sheath may be cuffed and / or widen and / or have a hub to facilitate loading and unloading the sheath from a flexible bronchoscope. The hub may be a molded or machined plastic component joined to the braided sheath by bonding or insert molding, and optionally secures the braided sheath to the bronchoscope using, for example, a sliding locking mechanism that can be engaged and disengaged by the user.

[0059] In yet another embodiment, the distal end of the sheath is tapered and / or cuffed to facilitate insertion of the sheathed bronchoscope into the sealing gasket of the endotracheal tube, to provide a non-traumatic end so that the sheath does not cut tissue when moving from proximal to distal, and / or to prevent fraying and / or unbundling of the braid. In some cases, the cuff is configured to engage (reversibly or irreversibly) with an introducer element, preferably a disposable element slidably around the sheath and having a distal portion sized to internally fit with the proximal portion of the endotracheal tube, or with a rigid molded or machined polymer component. When engaged with the endotracheal tube, the introducer element holds the gasket or valve at the opening of the endotracheal tube in the open position, allowing the sheath to slide freely through the gasket or valve and, consequently, through the endotracheal tube.

[0060] According to the cuffed embodiment, the cuffs at both ends may be thermoformed from the braided material, or they may be formed from different elastic or plastic materials and fixed to the ends of the braided material according to one of any number of known methods. According to an alternative embodiment, the distal end of the braided sleeve may be immersed in a flexible material or otherwise coated using it to produce a distal tip that is stiffer to assist in insertion into the endotracheal gasket, but still flexible enough to be assembled on a bronchoscope.

[0061] According to one embodiment of the present invention, the bronchoscopic measuring sheath is configured to extend across a flexible bronchoscope to a length that fully covers the portion of the scope that is visible to the user / operator outside the patient's body during use, including the portion of the scope that is inside the patient's body during part of the procedure, but which is withdrawn from the patient's body when the progressive portion of the airway tissue is being treated. A portion of the distal end of the scope may be left uncovered to avoid interruption of the bronchoscope, for example, diagnostic and therapeutic devices or gases delivered via LN2 cryospray delivery and LN2 gas outlet.

[0062] According to one embodiment of the present invention, the bronchoscopy sheath provides insulation to the portion of the scope that is inside the patient's body during procedures such as high-frequency, laser, or cryotherapy to provide protection from burns. The braided structure and mixtures of monofilament and multifilament fibers provide both insulation and a physical barrier between the smooth surface of the bronchoscope and the endothelium. Since the braided structure can consist of any combination of polymer materials, there will also be an insulation contribution provided by the polymers. According to another embodiment, the braid may be made from filaments of other compositions (e.g., polypropylene, nylon, polyester), or the braid may be made from a mixture of filaments made from PET and other materials.

[0063] Turning to further aspects of the present invention, in one aspect, the present invention relates to a computer-controlled method for lumen-specific and sex-specific cryospray treatment of airway tissue that is preferably (but not necessarily) damaged, inflammatory, or hypersecretory. The method includes the steps of receiving user input of patient type and anatomical airway segment to be treated via a cryospray user interface such as a touch-sensitive display, and then automatically delivering a cryospray of a pre-determined and metered cryogen based on the patient type and airway segment entered by the user, which is initiated by user input and automatically terminates when the pre-determined and metered cryospray has been delivered. In various embodiments, the method does not require the cryospray device to be placed alongside the airway tissue, and the method optionally automatically sets different cryospray doses for different airway regions based on their lumen diameter. In some cases, the patient type is sex, and different doses are automatically set for male and female patients. Optionally, or in addition, the treatment spray cannot be initiated until the user enters patient information and treatment location into the system console. The method may also involve a step of maintaining the cryospray supply line between the cryogen tank and the delivery catheter at a constant temperature during cryospray operation, and one or more valves, manifolds, and catheter interfaces along the supply line may be maintained at a temperature warmer than, for example, -120°C.The metered cryospray is optionally delivered via a cryogen delivery catheter having a proximal section wider than the working channel of the corresponding bronchoscope and a distal section configured to fit within the working channel of the bronchoscope, the delivery catheter configured to simultaneously deliver the cryospray throughout the entire circumference of a selected intraluminal section without the need to rotate the delivery catheter, the distal end of the delivery catheter comprising eight cryogen delivery ports in exactly two rows, equally spaced around the catheter, the centerlines of the rows displaced from each other by 0.025 inches (0.635 mm), and each port offset by 20-25° (e.g., 22.5°) from the adjacent port in the other row.

[0064] In another aspect, the present invention relates to a computer-controlled cryospray for a body lumen (not limited to the airway), comprising: a pressure maintenance system; a cryogen level monitoring system; a catheter attachment device; a flow path pre-cooling function; a user control system for user control of the cryogen flow; a display screen; a cryogen supply line between the cryogen source and the catheter attachment device; a plurality of temperature sensors and heaters associated with the supply line and configured to maintain the supply line at a constant temperature during cryospray treatment; and an onboard control system comprising a computer-readable medium including computer-readable commands for monitoring and controlling cryogen tank filling operations, initiating pre-procedure system checks, controlling flow path pre-cooling, and controlling the thermal function during the user's patient treatment. In some embodiments, the control system will prompt the user to input the patient type and anatomical airway segment relating to the treatment, and will not permit the cryospray treatment until the patient type and anatomical airway segment are entered. The control system is further configured to optionally deliver a pre-determined dose of cryospray to the device upon user initiation, based on the input patient type and anatomical airway segment. The cryogen supply line also optionally includes a cryogen valve, a manifold with a fixed orifice for cryogen gas escape, a catheter valve, and a catheter interface with a fixed orifice for cryogen gas escape.

[0065] In yet another aspect, the present invention relates to a system comprising: a reservoir equipped with cryogen; a flow path between the reservoir and a connector port for a cryospray catheter, comprising at least one valve controllable by a processor; an input for a temperature sensor attached to the cryospray catheter; a graphical output device; a user input device; a non-transient computer-readable medium storing instructions executable by the processor; and a processor configured to (a) execute instructions stored on the non-transient computer-readable medium; (b) receive input from the temperature sensor; (c) deliver an output to the graphical output device; (d) receive input from the user input device; and (e) provide an output to at least one valve. The instructions on the computer-readable medium include several steps, namely, receiving user input that identifies the sex of the patient and the patient's airway region to be treated; calculating the amount of cryogen to be delivered to excise the endothelial layer of the patient's airway based on the user input and temperature input from the cryospray catheter; and delivering the calculated amount of cryogen to the airway region through a catheter connected to the system.The command may also optionally include the steps of: comparing the temperature received from the catheter's temperature sensor with a threshold temperature selected based on user input of the airway location; calculating the rate of change of the temperature received from the temperature sensor over a certain time interval and comparing the rate of change with a threshold rate of change selected based on user input; measuring the elapsed time since the opening of at least one valve during the step of delivering cryogen to the catheter and comparing the timer with a threshold time, and (a) the temperature received from the temperature sensor is at or below the threshold temperature; (b) the rate of change is by an amount predetermined from the threshold rate of change; (c) the elapsed time is equal to or exceeds the threshold time. (d) User input to sustain cryogen flow is terminated before the elapsed time reaches 2 seconds, and / or (e) cryogen flow is interrupted and neither condition (a) or condition (c) is detected, the procedure includes terminating cryogen flow by closing at least one valve if at least one of the following conditions is detected: provide an output to a graphical output device based on the number of cryosprays delivered during the procedure session and the temperature output from a temperature sensor, display a user prompt on the graphical output device for an additional spray, or terminate the procedure.

[0066] In yet another aspect, the present invention relates to a system comprising a cryogen source in fluid communication with a cryogen delivery device, one or more adjustable pressure valves configured to regulate the pressure of the cryogen source in response to a control signal, and a controller configured to receive a target pressure indication, measure the pressure of the cryogen source while the cryogen delivery device is operating, determine whether the measured pressure matches the target pressure, and transmit a control signal to one or more adjustable pressure valves to regulate the pressure of the cryogen source toward the target pressure. The controller optionally determines the target pressure by (a) receiving a cooling force measurement indicating the cooling force of the cryogen delivery device when the cryogen delivery device is delivering cryogen, and (b) when the cryogen delivery device has achieved a cooling force corresponding to the cooling force measurement, receiving a cryogen source pressure indication, identifying that the cooling force measurement matches the target cooling force, and storing the indicated cryogen source pressure as the target pressure. Steps (a) and (b) are optionally repeated until the cooling force measurement matches the target cooling force. In some cases, the adjustable pressure valve includes a first valve configured to provide a rough reduction in the pressure of the cryogen source, and second and third valves configured to control the pressure venting and pressure boosting functions of the cryogen source. In this array, the processor optionally triggers the first valve when the pressure of the cryogen source exceeds a predetermined threshold amount, while the second and third valves optionally respond to a pulse-width modulation controller that modulates its duty cycle based on a control voltage provided by a control signal. The control signal may optionally be modified based on the target pressure, the current rate of pressure change, and the pressure history of the cryogen source, and may be driven by a proportional-integral-derivative (PID) control algorithm preferably (but not necessarily) configured to avoid cycles between venting and boosting operations.

[0067] In yet another aspect, the present invention relates to a catheter for cryospray treatment of the airway, comprising a proximal interface bayonet configured to connect to a cryospray console; an ergonomic plastic bayonet cover configured to interface with the console together with the bayonet; an insulating sheath distributed over the proximal portion of a catheter assembly configured to be located outside the working channel of the scope; a proximal tube portion made of laser-cut metal hypotubing having a diameter exceeding the inner diameter of the working channel of the scope; and a distal tube portion made of laser-cut stainless steel hypotubing having a diameter and length configured to function within the working channel of the scope. The catheter includes an outer cover in the form of a polymer layer covering the entire length of the catheter to provide a liquid-tight lumen, the distal tube portion terminates in a cylindrical section including a non-traumatic tip and a plurality of cryogen delivery ports formed proximal to the tip as circular windows having a diameter of 0.015 inches (0.381 mm) within the section, the section having eight cryogen delivery ports in just two rows equally spaced around the catheter, the centerlines of the rows displaced from each other by 0.025 inches (0.635 mm), and each port offset by 22.5° from the adjacent port of the other row. Optionally, or in addition, the catheter is configured to include a thermocouple placed at or near the distal tip of the catheter to provide temperature feedback to a cryospray console and / or to deliver cryogen to the airway in an annular region centered on the plurality of windows. The annular region preferably has substantially uniform (e.g., uniform when visually verified) axial and radial edges. The catheter may also include multiple markings on the outer surface of the proximal catheter in the distal section, with these markings spaced at a constant distance apart (e.g., separated by defined distances such as 1, 2, and 5 mm).

[0068] In yet another aspect, the present invention relates to a method of treating a patient by a step of excising lung epithelium, which involves cooling an annular region of the airway to a depth not exceeding 0.5 mm from the airway surface (internal or luminal) by delivering a certain amount of cryogen, calculated by an automated system, to an annular region of the airway through a catheter, wherein the catheter terminates in a cylindrical section, which includes a non-traumatic tip and a plurality of cryogen delivery ports formed as circular openings within the section proximal to the tip, the section comprising eight cryogen delivery ports in just two rows, equally spaced around the catheter, the centerlines of the rows being displaced 0.025 inches (0.635 mm) from each other, and each port being offset by 22.5° from an adjacent port in the other row and by 45° from an adjacent port in the same row. The cryogen may be liquid nitrogen, and the pre-determined amount may be based in part on the region of the airway to be treated / excised. In some cases, the catheter includes markings on its outer surface as described above, in which case the procedure includes the step of moving the catheter by a fixed distance between cryogen applications. In one embodiment, a first system-calculated amount of cryogen is delivered to a first annular region of the airway, and the catheter can be advanced or retracted by a fixed distance, and a second system-calculated amount of cryogen can be delivered to a second annular region of the airway adjacent to the first annular region. The second pre-determined amount of cryogen is determined based in part on a temperature reading after delivery of the first pre-determined amount of cryogen, provided by a temperature sensor located near the distal end of the catheter, and the temperature of a second material outside the catheter.

[0069] In yet another aspect, the present invention relates to a sheath configured to be placed along a portion of its length across the outer surface of a bronchoscope during airway cryospray treatment or other bronchoscopic procedures, the sheath comprising: an extension tube having a lumen configured to receive a bronchoscope; an attachment device configured at one end of the tube to fix the sheath to the proximal end of the bronchoscope; and a plurality of markings configured along a portion of the outer surface of the tube to represent the distance the scope is moved relative to a patient's fixed position, patient features, or other fixed reference point. The markings vary, being a circumferential marker band, located outside the working channel of the scope, and / or associated with printed numbers.

[0070] In yet another aspect, the present invention relates to a method of treating a patient comprising the steps of: inserting a bronchoscope into the patient's airway, wherein at least a portion of the bronchoscope is covered with a braided polymer sheath bearing a plurality of external markings separated from each other by a fixed distance; extending a cryospray delivery catheter into the airway through the working channel of the bronchoscope and delivering a metered cryospray to a first portion of the airway; advancing or retracting the bronchoscope by a predetermined distance using the plurality of markings on the sheath as indicators of a predetermined distance; and delivering the metered cryospray to a second portion of the airway. This specification also provides, for example, the following items: (Item 1) A computer-controlled method for lumen-specific and sex-specific cryospray treatment of damaged, inflammatory, or hypersecretory airway tissue, The steps include receiving the patient type of the patient to be treated from the user via the cryospray user interface to the computer console, The steps include receiving an anatomical airway segment to receive the treatment from the user via the cryospray user interface, A step of automatically delivering a pre-determined, metered cryogen cryospray based on the identified patient type and the identified airway segment, the step of starting when the user initiates the cryospray treatment and automatically stopping when the metered cryogen cryospray has been delivered. Methods that include... (Item 2) The method of item 1, which does not require the juxtaposition of the cryospray device to the aforementioned airway tissue. (Item 3) The method according to item 1, wherein different cryospray doses are automatically set for different treatment sites in the airway based on the lumen diameter of the treatment site. (Item 4) The method according to item 1, wherein the patient type is gender, and different cryospray doses are automatically set for male and female patients. (Item 5) The method according to item 1, wherein the treatment spray cannot occur until the user enters patient information and treatment location into the system console. (Item 6) The method according to item 1, further comprising the step of maintaining a constant temperature in the cryospray supply line between the cryogen tank and the delivery catheter port during cryospray operation. (Item 7) The method according to item 6, wherein one or more of the valves, manifolds, and catheter interfaces of the cryospray supply line between the cryogen tank and the delivery catheter port is maintained at a constant temperature above -120°C (warmer). (Item 8) The metered cryogen cryospray is delivered via a cryogen delivery catheter having a proximal section wider than the working channel of the corresponding bronchoscope and a distal section configured to fit into the working channel of the bronchoscope, wherein the delivery catheter is configured to simultaneously deliver the cryospray throughout the entire circumference of a selected intraluminal cross section without the need to rotate the delivery catheter, and the distal end of the delivery catheter is configured with eight cryogen delivery ports in exactly two rows equally spaced around the catheter, wherein the centerlines of the rows are displaced 0.635 mm (0.025 inches) from each other, and each port is offset by 20° to 25° from the adjacent port of the other row, as described in Item 1. (Item 9) Each cryogen delivery port is offset by 22.5° from the adjacent port in the other column, as described in item 1. (Item 10) A device for cryospray treatment controlled by a computer in the body's tubal lumen, Cryogen pressure maintenance system, Cryogen level monitoring system, Catheter attachment device and Flow channel pre-cooling function, A user control system for cryogen-based user control, Display screen and A cryogen supply line between the cryogen source and the catheter attachment device, Multiple temperature sensors and heaters, associated with the supply line and configured to maintain the supply line at a constant temperature during cryospray treatment, An onboard control system, comprising computer-readable media, includes computer-readable instructions for monitoring and controlling cryogen tank filling operations, initiating pre-procedure system checks, controlling flow path pre-cooling, and controlling thermal functions during the user's patient procedure. A device equipped with the following features. (Item 11) The control system is configured to prompt the patient to input anatomical airway segments related to patient type and treatment, The control system is configured not to allow cryospray treatment until the patient type and anatomical airway segment are entered. The control system is further configured to deliver a pre-determined dose of cryospray to the device in response to an initiation by the user, based on the input patient type and anatomical airway segment. The device described in item 10. (Item 12) The apparatus according to item 10, wherein the cryogen supply line comprises a cryogen valve, a manifold having a fixed orifice for the escape of cryogen gas, a catheter valve, and a catheter interface having a fixed orifice for the escape of cryogen gas. (Item 13) It is a system, A reservoir equipped with cryogen, A flow path between the reservoir and the connector port for the cryospray catheter, comprising at least one valve controllable by a processor, An input for a temperature sensor that attaches to a cryospray catheter, Graphical output devices and User input devices and, A non-transient computer-readable medium that stores instructions executable by the processor, A processor configured to (a) execute the instructions stored on the non-transient computer-readable medium, (b) receive input from the temperature sensor, (c) deliver output to the graphical output device, (d) receive input from the user input device, and (e) provide output to the at least one valve, The instruction is provided, A step of receiving user input that identifies the patient's sex and the airway area of ​​the patient to be treated, A step of calculating the amount of cryogen to deliver to excise the endothelial layer of the patient's airway based on the user input and the temperature input from the cryospray catheter, The steps include delivering the calculated amount of cryogen to the airway region through a catheter connected to the system, A system that includes this. (Item 14) The aforementioned instruction further states, The steps include comparing the temperature received from the temperature sensor of the catheter with a threshold temperature selected based on user input of the airway location, The steps include: calculating the rate of change of temperature received from the temperature sensor over a certain time interval, and comparing the rate of change with a threshold rate of change selected based on the user input; The steps include measuring the elapsed time since the opening of at least one valve during the step of delivering the cryogen to the catheter, and comparing the timer with a threshold time, The steps include: (a) the temperature received from the temperature sensor is at or below the threshold temperature; (b) the rate of change fluctuates by an amount predetermined from the threshold rate of change; (c) the elapsed time is equal to or exceeds the threshold time; and (d) the user input for sustaining the flow of the cryogen is terminated before the elapsed time reaches a predetermined threshold; in such cases, terminating the flow of the cryogen by closing at least one valve; The system described in item 13, including the system described in item 13. (Item 15) The system according to item 14, wherein the instruction further includes the step of providing an output to the graphical output device based on the number of cryosprays delivered during the treatment session and the temperature output from the temperature sensor, if the flow of the cryogen is interrupted and neither state (a) or state (c) is detected, displaying a user prompt on the graphical output device for an additional spray, or terminating the procedure. (Item 16) It is a system, A cryogen source that communicates fluidly with a cryogen delivery device, One or more adjustable pressure valves configured to adjust the pressure of the cryogen source in response to a control signal, Upon receiving instructions for the target pressure, During the operation of the cryogen delivery device, the pressure of the cryogen source is measured. Determine whether the measured pressure matches the target pressure. The control signals are transmitted to the one or more adjustable pressure valves to adjust the pressure of the cryogen source toward the target pressure. A controller configured as follows, A system equipped with these features. (Item 17) The aforementioned controller, (a) When the cryogen delivery device is delivering cryogen, the step of receiving a cooling force measurement value indicating the cooling force of the cryogen delivery device, (b) When the cryogen delivery device achieves the cooling force corresponding to the cooling force measurement, the step of receiving an instruction for the cryogen source pressure, The steps include identifying that the measured cooling force matches the target cooling force, The steps include storing the specified cryogen source pressure as the target pressure, The system according to item 16, configured to determine the target pressure by means of the system. (Item 18) The system according to item 17, further comprising the step of repeating steps (a) and (b) until the cooling force measurement matches the target cooling force. (Item 19) The one or more adjustable pressure valves mentioned above are: A first valve, configured to provide a rough reduction in the pressure of the cryogen source, A second valve and a third valve are configured to control the pressure ventilation and pressure enhancement functions of the cryogen source, The system described in item 16, comprising: (Item 20) The system according to item 19, wherein the processor triggers the first valve when the pressure of the cryogen source exceeds a pre-determined threshold amount. (Item 21) The system according to item 19, wherein the processor triggers the first valve during the filling operation of the cryogen source. (Item 22) The system according to item 19, wherein the second and third valves respond to a pulse width modulation controller that adjusts their duty cycle based on a control voltage provided by the control signal. (Item 23) The control signal is driven by a proportional-integral-derivative (PID) control algorithm, as described in item 19. (Item 24) The system according to item 23, wherein the PID control algorithm adjusts the control signal based on the target pressure, the current rate of pressure change, and the pressure history of the cryogen source. (Item 25) The system according to item 23, wherein the PID control algorithm is configured to avoid cycles between ventilation and enhancement operations. (Item 26) A catheter for cryospray treatment of the airway, A proximal interface bayonet, configured to connect to a cryospray console, An ergonomic plastic bayonet cover, configured to interfacially contact the console together with the bayonet, An insulating sheath, distributed over the proximal portion of the catheter assembly, configured to be located outside the working channel of the scope, The scope includes a laser-cut metal hypo tube and a proximal tube portion having a diameter exceeding the inner diameter of the working channel of the scope, A distal tube portion comprising a laser-cut stainless steel hypo tube having a diameter and length configured to work within the working channel of the scope, The catheter further comprises an outer cover in the form of a polymer layer covering the entire length of the catheter in order to provide a liquid-tight lumen. The distal tube portion terminates within a cylindrical section, the section comprising a non-traumatic tip and a plurality of cryogen delivery ports formed proximal to the tip as circular openings having a diameter of 0.015 inches (0.381 inches) within the section, the section comprising eight cryogen delivery ports in exactly two rows, equally spaced around the catheter, the centerlines of the rows being displaced 0.635 mm (0.025 inches) from each other, and each port being offset by 22.5° from the adjacent port of the other row. (Item 27) The catheter according to item 26, further comprising a thermocouple positioned at or near the distal tip of the catheter and configured to provide temperature feedback to a cryospray console. (Item 28) The cryospray catheter according to item 26, wherein the catheter is configured to deliver cryogen to the airway within an annular region around the plurality of openings. (Item 29) The cryospray catheter according to item 26, wherein the annular region has substantially uniform axial and radial edges. (Item 30) The cryospray catheter according to item 26, further comprising a plurality of markings on the outer surface of the catheter located proximal to the aforementioned section, wherein the markings are spaced apart from each other by a defined distance. (Item 31) A method for treating a patient, comprising the step of excising lung epithelium by cooling an annular region of the airway to a depth not exceeding 0.5 mm from the airway surface to -20°C. (Item 32) The method according to item 31, wherein the annular region is cooled by delivering a certain amount of cryogen, calculated by an automated system, to the annular region of the airway through a catheter, the catheter terminating in a cylindrical section including a non-traumatic tip and a plurality of cryogen delivery ports formed as circular openings within the section proximal to the tip, the section comprising eight cryogen delivery ports in exactly two rows equally spaced around the catheter, the centerlines of the rows being displaced from each other by 0.635 mm (0.025 inches), and each port being offset by 22.5° from an adjacent port in the other row and by 45° from an adjacent port in the same row. (Item 33) The method according to item 32, wherein the cryogen is liquid nitrogen, and the pre-determined amount is determined on a partial basis to the area of ​​the airway to be resected. (Item 34) The method according to item 32, wherein the catheter includes a plurality of markings on its outer surface, the markings being separated from each other by a fixed distance, and the step of delivering the cryogen to the airway includes delivering a first system computation amount of cryogen to a first annular region of the airway, advancing or retracting the catheter by the fixed distance, and delivering a second system computation amount of cryogen to a second annular region of the airway adjacent to the first annular region. (Item 35) The method according to item 34, wherein a predetermined second amount of cryogen is determined in part on a temperature reading after delivery of a predetermined first amount of cryogen, a reading provided by a temperature sensor located near the distal end of the catheter, and the temperature of a second material outside the catheter. (Item 36) A sheath, configured to be placed along a portion of its length across the outer surface of a bronchoscope during airway cryospray treatment or other bronchoscopy procedures, An extension tube having a lumen configured to receive a bronchoscope, An attachment device is provided at one end of the tube, configured to fix the sheath to the proximal end of the bronchoscope. A plurality of markings are provided along a portion of the outer surface of the tube, configured to represent the distance the scope moves relative to a fixed position of the patient, patient characteristics, or other fixed reference point. A sheath equipped with this feature. (Item 37) The aforementioned marking is a circumferential marker band, as described in item 36 of the dose interval sheath. (Item 38) The marking is located outside the working channel of the scope, on the dose interval sheath as described in item 36. (Item 39) The aforementioned marking may be associated with printed numbers, as described in item 36. (Item 40) A method of treating a patient, A step of inserting a bronchoscope into the patient's airway, wherein at least a portion of the bronchoscope is covered with a braided polymer sheath bearing a plurality of external markings separated from each other by a fixed distance, The steps include extending a cryospray delivery catheter into the airway through the working channel of the bronchoscope and delivering the measured cryospray to a first portion of the airway, The steps include using the multiple markings on the sheath as indicators of a predetermined distance to advance or retract the bronchoscope by the predetermined distance, The steps include delivering the measured cryospray to the second portion of the airway, Methods that include... [Brief explanation of the drawing]

[0071] The following figures illustrate the methods and results of specific examples of the practical application and success of the present invention, and are accompanying the embodiments for carrying out the invention.

[0072] [Figure 1]Figure 1 is a perspective view of a cryosurgery system according to one embodiment of the present invention. [Figure 2] Figure 2 is a perspective view of another embodiment of the cryosurgery system according to the present invention. [Figure 3] Figure 3 is an internal perspective view of one embodiment of a cryosurgery system according to one embodiment of the present invention. [Figure 4A] Figure 4A is a schematic diagram showing a cryogen storage, delivery, and pressure control device according to one embodiment of the present invention. [Figure 4B] Figure 4B is a schematic diagram showing a cryogen storage, delivery, and pressure control device according to another embodiment of the present invention. [Figure 4C] Figure 4C is a three-dimensional perspective view of the cryogen manifold and valve assembly according to the embodiment shown in Figure 4B. [Figure 5] Figure 5 is an isometric view of a radial spray catheter according to one embodiment of the present invention. [Figure 6] Figure 6 is a side view of the proximal steel tube structure of a catheter according to the present invention, with a variable laser cut pattern to adjust the tube's flexibility. [Figure 7] Figure 7 shows a side view of one embodiment of joining a hypotube with a large ID to a hypotube shaft with a small ID. [Figure 8] Figure 8 shows the area of ​​the insulation material and connector housing with a bayonet according to one embodiment of the present invention. [Figure 9] Figure 9 shows an embodiment of the present invention which includes an S-shaped curve centering feature on a radial spray catheter and includes axial marker lines to assist in the visual positioning of such an S-shaped curve to the scope centerline relative to the centering of such an offset. [Figure 10] Figure 10 shows the S-shaped curve centering feature and axial line as visible by the scope optics during use. [Figure 11A]Figure 11A is a perspective view including a close-up of part of a cryogen delivery device 41 having a cryogen delivery device 42, which includes a bronchoscope 40, a gas outlet tube 43, and an S-shaped catheter tip 42 exiting the working channel of the bronchoscope. [Figure 11B] Figure 11B shows a close-up view of an alternative embodiment that includes a straight catheter tip but lacks a gas outlet tube. [Figure 12] Figure 12 is a flowchart illustrating a method according to an exemplary embodiment. [Figure 13-1] Figures 13A-L show exemplary interfaces for performing setting procedures according to exemplary embodiments. [Figure 13-2] Figures 13A-L show exemplary interfaces for performing setting procedures according to exemplary embodiments. [Figure 13-3] Figures 13A-L show exemplary interfaces for performing setting procedures according to exemplary embodiments. [Figure 14-1] Figures 14A-P show exemplary interfaces for performing a resection procedure according to an exemplary embodiment. [Figure 14-2] Figures 14A-P show exemplary interfaces for performing a resection procedure according to an exemplary embodiment. [Figure 14-3] Figures 14A-P show exemplary interfaces for performing a resection procedure according to an exemplary embodiment. [Figure 14-4] Figures 14A-P show exemplary interfaces for performing a resection procedure according to an exemplary embodiment. [Figure 15] Figure 15 is a block diagram illustrating an electronic computing device suitable for use in conjunction with the exemplary embodiment. [Figure 16-1]Figures 16A–16F illustrate various radial spray pattern embodiments that can be located at the distal tip of the catheter. Figures 16G–H illustrate cryospray delivery patterns resulting from the radial spray design illustrated in Figure 16D, while Figures 16I–J illustrate cryospray delivery patterns resulting from the radial spray design illustrated in Figure 16A. [Figure 16-2] Figures 16A–16F illustrate various radial spray pattern embodiments that can be located at the distal tip of the catheter. Figures 16G–H illustrate cryospray delivery patterns resulting from the radial spray design illustrated in Figure 16D, while Figures 16I–J illustrate cryospray delivery patterns resulting from the radial spray design illustrated in Figure 16A. [Figure 16-3] Figures 16A–16F illustrate various radial spray pattern embodiments that can be located at the distal tip of the catheter. Figures 16G–H illustrate cryospray delivery patterns resulting from the radial spray design illustrated in Figure 16D, while Figures 16I–J illustrate cryospray delivery patterns resulting from the radial spray design illustrated in Figure 16A. [Figure 17] Figure 17 shows a dose-treatment map according to one embodiment of the present invention. [Figure 18] Figure 18 shows a dose-interval sheath according to one embodiment of the present invention. [Figure 19A] Figure 19A shows the temperature curves obtained in an airway model, such as when the same amount of cryospray is delivered through the catheter at a fluctuating starting temperature, measured at or near the distal tip of the catheter, and Figure 19B shows the temperature curves in an airway model when the same cryospray volume is delivered to a dry working channel and a working channel containing mucus. [Figure 19B]Figure 19A shows the temperature curves obtained in an airway model, such as when the same amount of cryospray is delivered through the catheter at a fluctuating starting temperature, measured at or near the distal tip of the catheter, and Figure 19B shows the temperature curves in an airway model when the same cryospray volume is delivered to a dry working channel and a working channel containing mucus. [Figure 20] Figure 20 shows a bronchoscopic measurement sheath according to one embodiment of the present invention, which is loaded onto the proximal end of a bronchoscope. [Figure 21] Figure 21 is an enlarged view of a bronchoscopy measuring sheath according to one embodiment of the present invention, showing a voluntary widening proximal end and a voluntary tapered distal end, with voluntary elastic cuffs at both ends. [Figure 22] Figure 22 is an enlarged view of a bronchoscopy measurement sheath according to another embodiment of the present invention, mounted on a flexible optical fiber bronchoscope. [Figure 23] Figure 23 shows a proximal hub according to one embodiment of the present invention. [Figure 24] Figure 24 is an enlarged view of a bronchoscopy measuring sheath according to one embodiment of the present invention, specifically illustrating how the sheath expands when both ends are compressed. [Figure 25] Figure 25 shows the proximal end of a bronchoscopic measurement sheath according to one embodiment of the present invention, adjacent to a flexible bronchoscope. [Figure 26] Figure 26 shows the proximal end of a bronchoscopic measurement sheath according to one embodiment of the present invention, which is mounted on the outside of a flexible bronchoscope. [Modes for carrying out the invention]

[0073] (Detailed description of the invention) Cryospray system and method Certain methods and devices described herein are improvements on the cryospray methods and devices described in concurrently pending U.S. Patent Application No. 13 / 784,596, filed on 4 March 2013 and titled “Cryosurgery System” and concurrently pending U.S. Patent Application No. 14 / 012,320, filed on 28 August 2013 (each of these applications is incorporated herein by reference in its entirety for any purpose).

[0074] Simplified perspective views of exemplary cryosurgery systems in which embodiments of the present invention may be implemented are illustrated in Figures 1-3. The cryosurgery system 100 comprises a pressurized cryogen storage tank 126 for storing cryogen under pressure. In the following description, the cryogen stored in the tank 126 is liquid nitrogen, but the cryogen may be other materials as described in detail below. The pressure of the liquefied gas in the tank can range from 5 psi to 50 psi. According to a more preferred embodiment, the pressure in the tank during storage is 40 psi or less, and the pressure in the tank during operation is 35 psi or less. According to a more preferred embodiment, the pressure in the tank during storage is 35 psi or less, and the pressure during operation is 25 psi or less. According to the most preferred embodiment, the operating pressure in typical nitrogen flow is 20 ± 4 psi.

[0075] The nominal tank pressure in a preferred embodiment of the present invention is established to ensure that different systems have a normalized energy output, i.e., the nominal energy output of a standard system used to successfully deliver a procedure in an animal model or human patient, for example, according to one of the various embodiments of the present invention. The energy output of individual systems is evaluated using one or more of a standard catheter and / or standard airway phantoms equipped with one or more of several temperature-sensing elements (e.g., one or more thermocouples), and the temperature change measured by the phantom is used to calculate the total energy output in a spray, and multiple sprays are performed at variable pressures to establish a pressure-energy relationship, which is then used to select a pressure value that yields the energy output of the standard system within a predetermined error (e.g., ±5% of the standard energy output).

[0076] In alternative embodiments, the cryogen pressure may be controlled down to 45 psi for delivery through smaller lumen catheters and additional feature sets. In such alternative embodiments, the pressure in the storage tank may be 55 psi or less.

[0077] Liquid nitrogen (LN2) is present at the bottom of the tank, and liquid nitrogen gas / vapor (GN2) occupies the upper portion of the tank. The tank level is electronically monitored via sensors inside the tank, the value of which changes along with the liquid level inside the tank. This can be done in various ways, including, but not limited to, by measuring capacitively (e.g., Rotarex C-Stic), resistively, or differential pressure.

[0078] Referring to Figures 4A and 4B, the present invention utilizes a valve and a pressure sensor 174 to continuously monitor and control the pressure of liquid nitrogen in a tank during use. The console monitors the current pressure of the tank via the pressure sensor 174. The software reads the current pressure from the sensor and adjusts the pressure as appropriate. If the pressure is too low, the software activates the pressure boosting circuit valve 176 to increase the pressure to a specified threshold and then turns it off. If the pressure is too high, the software turns on the vent valve 178 until the pressure reaches a specified threshold.

[0079] In some cases, the system charge pressure is actively controlled by a set of three solenoid valves. If the tank pressure significantly exceeds the desired set pressure (>5 psi), or during a filling operation where the tank pressure must be completely relieved, a cryogenic solenoid valve connected to the headspace is used for a rough reduction of the tank pressure. A set of proportional solenoid valves controls the pressure venting and pressure boosting functions. The proportional solenoid valves are driven by pulse-width modulation (PWM) controllers that adjust their duty cycle based on a control voltage, allowing the valve plunger position to open in proportion to the control signal. The control signal is driven by a standard proportional-integral-derivative (PID) control algorithm executable by the system's central processor. The PID controller collects data from precision capacitive pressure sensors and modulates the valve control signal based on the setpoint, the current rate of pressure change, and the current pressure deviation relative to the pressure history. The PID output control signal determines whether venting or boosting operation occurs. This control scheme has the advantage of allowing software changes to the pressure setpoint while implementing precise pressure adjustment. The PID controller is tuned to provide a rapid response with minimal overshoot or undershoot while avoiding unstable cycles between aeration and enhancement (inputting P, I, and D).

[0080] A mechanical relief valve 182 on the console tank ensures that the tank pressure remains within a safe pressure range. Constant pressure monitoring and regulation allows the setpoint on the mechanical relief valve to be set to 35 psi, enabling a low tank storage pressure. A redundant burst disk 184 provides protection in case the mechanical relief valve fails. For optimal safety, both an electronic and a mechanical pressure valve are present to regulate the pressure and provide triple redundancy in case of failure. In addition, a redundant pressure switch 180 can provide accurate tank pressure readings and is checked during self-testing. In an alternative embodiment, the mechanical relief valve 182 may be set to 60 psi, but still allow the tank to remain at a low pressure.

[0081] The system of the present invention utilizes a manifold assembly including a cryogen valve 186, a manifold 196, a catheter valve 188, a defrost valve 190, fixed orifices 191 and 192, and a catheter interface 193 to control liquid nitrogen delivered through a catheter. When the cryogen valve 186 is activated, liquid nitrogen exits the tank through the lance 194 and proceeds through the cryogen valve 186 to the manifold 196 where the fixed orifice 192 is located, allowing the cold expanding gas and liquid nitrogen to exit the line and cool the internal cryogen circuit. During this pre-cooling, the catheter valve 188 downstream of the manifold remains closed. A data acquisition board collects data from a thermocouple 195 located on the manifold body. In the pre-cooling function, the system software monitors the data from the thermocouple 195, and when its temperature exceeds a desired setpoint, it opens the cryogen valve 186 to cool the manifold 196. According to a preferred embodiment, a fixed orifice 191 is provided on the catheter interface 193, allowing the line to exit while a cold expansion gas is sprayed through it.

[0082] According to preferred embodiments of the present invention shown in Figures 4B and 4C, the cryogen valve 186, manifold 192, catheter valve 188, and catheter interface 193 are each provided with a temperature thermocouple or sensor 195a and heater 199 to maintain the cryogen flow path at a constant selected temperature and prevent overcooling of the system resulting from the continuous flow of cryogen through the valve and manifold assembly. According to various embodiments of the present invention, the heaters may each be controlled to maintain the valve, manifold, and catheter interface at the same or different temperatures. According to a preferred embodiment, the system is configured to control the temperatures of the valve, manifold, and catheter interface to be maintained above -120°C during cryospray treatment. According to the most preferred embodiment, the system is configured to control the temperatures of the valve, manifold, and catheter interface to be maintained at +20°C during cryospray treatment. According to another embodiment, the valve, manifold, and catheter interface are each controlled and maintained at a constant temperature, although each constant temperature may differ from or exceed one of the constant temperatures of the others.

[0083] The defrosting function is useful for defrosting the catheter after cryogen spraying and before removal from the scope. The defrosting circuit directs gaseous nitrogen from the top of the tank through heater 187 and defrosting valve 190 to the catheter 128. When the defrost button on the software screen is pressed, the defrosting circuit is activated for a specified time (e.g., 30 seconds), but can be stopped earlier at the user's discretion. The low-voltage (24VDC) DC defrosting heater delivers a minimum heating / defrosting performance of 6W compared to conventional line-voltage (120V) AC heaters, while minimizing fluctuations caused by line voltage and limiting the maximum gas temperature.

[0084] The console of the present invention features an insulated, quick-release custom filling hose 164 that fills the tank through an external filling port 166 in a semi-automatic cryogen filling process. The filling port switch on the console is activated only when the filling hose is in the locked position. During the filling process, liquid nitrogen passes through a filter 172 and a transfer valve 170 on its way to the tank. The software automatically shuts off the electronic transfer valve 170 when the tank is full and the hose is vented prior to removal from the console. According to an alternative embodiment, manual filling can be performed by mechanically bypassing the electronic transfer valve and vent valve using a manual valve, thus allowing the tank to be filled without the need for a computer console.

[0085] The catheter is designed to transport liquid nitrogen (or other cryogen) from a console to a patient treatment site. According to one embodiment, the catheter 1 may include a bayonet 2 and a hub 3 for attachment to a console at its proximal end, a laser-cut hypotubule for minimizing twisting and breakage, a polymer layer positioned across the hypotubule and thereby sealing the catheter 1, an insulating layer 4 for protecting the user from cold air, a strain relief section 4a that helps prevent twisting when torque is applied by the user, and a non-traumatic rounded tip (10) at its distal end for preventing tissue damage. The hypotubule is preferably helically cut to impart radial flexibility while maintaining some axial stiffness and pushability, and the relative flexibility of the hypotubule is variable along the length of the catheter 1, in some cases through the use of variable-pitch helical cutting. For example, the spiral cuts may be characterized, firstly, by a relatively large pitch proximally and secondly by a smaller pitch more distally, allowing the distal end, particularly the tip, to bend around a sharper curve than the proximal portion of the catheter. The strength and flexibility provided by the catheter according to these embodiments allow the user (e.g., a physician) to retroflex the catheter during the procedure as needed.

[0086] The polymer layer may be any suitable flexible polymer that is substantially gas-impermeable (e.g., fluorinated ethylene propylene or urethane) and may be arranged across the hypotube in the form of one or more extruded layers, attached by heat shrinkage, or by dipping, melt coating, or spray coating. The catheter package may include an RFID tag that the user scans prior to use to prevent reuse and to track disposable information.

[0087] The catheter package may also include an introducer that provides reinforcement to the catheter and helps prevent twisting during use and when the catheter is placed in the scope. When the catheter is connected to the system, the alternative structure positions the RFID tag on the connector area adjacent to the bayonet so that the RFID tag is scanned by the system.

[0088] According to a preferred embodiment, the delivery catheter is constructed from hypotubes of different inner diameters that interlock with each other to form a proximal and distal shaft, the distal shaft may have a smaller ID. The proximal and distal shafts may be joined at a connector, which may be covered by a molded handle to allow the user to bring fine adjustments to the catheter 1. The proximal shaft may include a bayonet and hub at its proximal end for mounting to a console. The distal shaft preferably has a reduced ID to allow mating through a working channel of a bronchoscope. The distal tip of the catheter includes radial spray pattern holes that constitute a nozzle configured to deliver cryogen spray onto target tissue. The end of the catheter may preferably be configured to have a rounded tip, which may be made from a welded stainless steel sphere. This rounded tip may help reduce tissue trauma during catheter insertion into or manipulation of the body cavity. The thermocouple is located along the catheter shaft, preferably at or near the distal end of the catheter, and provides temperature feedback to the control console, allowing for better determination of the precise moment when the cryospray exits the tip of the catheter. All hypotubes are laminated using polymer heat shrinkage to seal the laser-cut pattern from the fluid intended to flow inside the catheter. In addition, both hypotubes have a variable laser-cut pattern that provides rigidity as needed and more flexibility as needed. This is achieved not only by varying the shape of the pattern itself, but also by varying the separation of the helical or repeating cut pattern.

[0089] According to an alternative embodiment, the delivery catheter may be constructed from one or more layers of flexible polyimide surrounded by a stainless steel braid, which is, in turn, coated with an outer layer of Pebax. It has been found that the extrusion of Pebax across the stainless steel braid allows Pebax to penetrate through the pitch of the steel braid, helping to prevent twisting, fracture, or delamination during catheter retroflexion. Pebax also provides a desirable balance between hardness, which is important for the smooth sliding and general robustness of the catheter, and softness, which is important for a certain degree of stickiness, allowing the user to feel the movement of the catheter within the scope. The pitch of the stainless steel braid is configured to be fine enough to provide the required strength, but still allowing Pebax to penetrate. The distal end of the catheter is provided with a non-traumatic tip with a rounded tip, consisting solely of Pebax. This novel structure allows catheter retroflexion without twisting, fracture, or delamination of the catheter. For the purposes of this invention, retroflexion is used to refer to the ability of a catheter to bend or change direction by approximately 210° around a radius of curvature of 0.375 inches or greater.

[0090] Figure 5 shows a catheter structure of a preferred embodiment of the cryospray catheter 1 according to the present invention. This includes a bayonet connector 2, a catheter connector housing 3, an insulating material 4, a laser-cut hypotube 5 with FEP or Pebax heat-shrink wrap, a nozzle connector 6 with a shrinking inner diameter, a second laser-cut hypotube 7 with a smaller ID with FEP or Pebax heat-shrink wrap, a radial spray pattern hole 8, a spray pattern indicator marking band 9 (two are shown, but three or more may be provided to account for spraying in smaller distal sections), and a rounded tip 10.

[0091] By adding a very thin layer of metal to the catheter shaft, or by increasing the heat transfer coefficient in the shaft, for example by using hypotube or braided metal, the catheter may be constructed to provide optimal cryogen delivery to the tip of the device within a very short cycle time.

[0092] Figure 6 shows a typical hypotube 19 used for constructing the proximal end of the catheter shaft 5. It typically has a length of 45 inches, but can vary from 24 to 96 inches. The inner diameter of the tube 19 is usually 0.104 inches, but can vary from 0.045 to 0.150 inches. In a preferred embodiment, the hypotube 19 may be laser-cut in a spiral shape, although other variable cuts may exist. The cut provides flexibility to the metal tube.

[0093] Figure 7 shows a transition section 25 from a large-diameter hypotube shaft 19 to a smaller-diameter laser-cut hypotube shaft 8. The transition section is necessary because the smaller diameter can be inserted into the working channel of the scope. In addition, the transition section from large to small diameter acts as a mixing point to allow the biphase flowing gas and liquid to interact along the catheter path and for the gas to regain the velocity of the liquid as they progress down the pipe. This transition section is referred to as a “nozzle” transition section. This transition section can occur between two hypotubes, between two polymer shafts, or between a coil and a hypotube, or between a coil and a polymer shaft.

[0094] Figure 8 shows the insulation material 4 and connector housing 3 that are added to the catheter assembly 1.

[0095] Figure 9 is an isometric view of an alternative embodiment of the catheter, which has an S-shaped centering feature built into its distal tip shape. It shows the bend 12 and the alignment line 29, which is a feature used to visually align the catheter with respect to the scope working channel offset.

[0096] Figure 10 shows an S-curve 12 of an alternative embodiment, as seen through the visualization system of the scope 20. The method of use involves locating the catheter section 11 between the marking bands and then targeting the area to be treated by rotating the catheter axially until the axial line 29 is visible and horizontal within the line of view. At this point, the catheter tip is centered relative to the centerline of the scope 20. This axial line is typically generated via a pad printing or laser marking process.

[0097] The preferred radial spray pattern at the distal tip of the catheter is two rows of holes equally distributed around the circumference of the shaft, with each row containing eight holes measuring 0.016 inches. The first and second rows are separated along the length of the shaft by a distance of 0.025 inches, measured from the centerline of the first row to the centerline of the second row, and the holes are aligned at an angle of 22.5° from each other, as seen in Figure 16D. As shown in Figures 16G-H, this radial spray design results in a cryospray delivery pattern that is uniform radially and axially around the circumference of the airway, which, when used to deliver a "metered" cryospray volume (i.e., the cryospray volume determined by the automated system of the present invention, delivered using a delivery protocol generated and executed by the automated system of the present invention), enables reliable and repeatable resection of the mucosa without the risk of damage to deeper tissues, including airway cartilage tissue. Generally, resections achieved using the radial spray design according to Figure 16D, in conjunction with the automated cryospray system of the present invention, result in annular resections to a depth of 0.1–0.5 mm, characterized by uniform radial and axial edges, and the depth of resection can be increased in some cases while preserving its uniformity (not shown). Importantly, the axial range of the cryospray delivery is generally equal to the length of the spray pattern in Figure 16D and is not axially offset as observed in other systems. Therefore, users of a system incorporating the tip design of Figure 16D can reasonably ensure that when the cryospray is delivered to the airway, it is delivered within the area where the catheter tip is actually positioned. The inventors have found that other designs, such as the design of Figure 16A, are generally less advantageous for use in automated systems, as they result in more variable and more frequently deeper resection patterns.For example, Figures 16I-J show a cryospray delivery pattern that exhibits a "scalloped" shape in both depth and axial range, obtained using the tip design of Figure 16A. While such a scalloped shape may be appropriate or even useful for certain applications, it is not optimal for mucosal resection applications, such as treating chronic bronchitis, because it increases the risk of simultaneous overtreatment of one area (potentially causing damage to airway cartilage tissue) and undertreatment of other areas (potentially leaving portions of the mucosa untreated that contribute to the disease process).

[0098] The holes are located around the circumference of short, rigid sections of the hypotube that do not involve laser cutting, and such sections are as small as 0.050 inches in diameter to allow the hypotube to advance through a retroflexed bronchoscope or any other tortuous area.

[0099] Alternative patterns for alternative embodiments are shown in Figures 16B-16F. The embodiment shown in Figure 16A has two rows of four circular holes with a diameter of 0.023 inches. The embodiments shown in Figures 16B and 16C have two rows of three elliptical holes whose length is 2 to 4 times the diameter of the ends. The embodiment shown in Figure 16E has three rows of six circular holes, each with a diameter of 0.022 inches. The embodiment shown in Figure 16F has four rows of eight holes, each with a diameter of 0.016 inches.

[0100] Referring to Figure 11A, the bronchoscope 40 may be positioned within the trachea 44 or a bronchus such as the patient's main bronchus 45. The catheter 48 is placed within the working channel lumen 46 of the scope 40 and exits the working channel at the distal tip of the scope. The cryogen delivery device 42 comprises a radial spray cryogen delivery catheter 42 at its distal end and one or more holes 47. After insertion of the cryogen delivery device into the patient, cryogen is supplied from the cryogen source to the cryogen delivery catheter 48. A gas outlet tube 43 surrounding the scope may be used to provide an additional means 49 for evacuating cryogenic gas from the treatment area from the patient. A passive lumen outlet 50 is also present via airway management to ensure proper ventilation during the procedure. Figure 11B shows a close-up view of an alternative embodiment in which a straight-tip catheter is used and there is no gas outlet tube.

[0101] Referring to Figure 18, a dose-interval sheath is shown, configured to be placed along a portion of its length across the outer surface of a bronchoscope during airway cryospray treatment or other bronchoscopic procedures. The dose-interval sheath 401 may be constructed from an extension tube 403 having a lumen configured to receive a bronchoscope 40, an attachment device 405, e.g., Tuohy-Borst, configured at one end of the tube to fix the proximal end of the sheath to the proximal end of the bronchoscope, and a number of markings 407 along a portion of the outer surface of the tube, configured to represent the distance the scope is moved relative to a patient's fixed position, patient features, or other fixed reference point. The markings may be a circumferential marker band outside the working channel of the scope and may optionally be associated with printed numbers. When aligned with a tracheal insulator (e.g., a rigid bronchoscope or endotracheal tube), the markings provide an extracorporeal proximal reference marking prior to drug delivery. In subsequent doses, reference markers assist physicians in avoiding dose duplication when the scope is moved proximal to the next administration site.

[0102] Figures 13-14 show various screens displayed by the system during an exemplary procedure according to one embodiment of the present invention. A home screen (not shown, but similar to that shown in Figure 13A) is displayed during system power-on and self-testing. Self-testing can be canceled so that the user can proceed directly to the step of filling in the console. Once self-testing is complete, the system proceeds to the next screen.

[0103] Figure 12 illustrates an exemplary method 600 for setting up a cryosurgery system 100 and performing a resection procedure. The following description of the steps illustrated in Figure 12 is supplemented by reference to exemplary interfaces as shown in Figures 13A–14P.

[0104] It should be noted that the steps depicted in Figure 12 are intended to be illustrative only. Those skilled in the art will recognize that exemplary embodiments may include more, fewer, or different steps. Furthermore, unless otherwise noted, the order of the steps may be rearranged.

[0105] As an initial step, a computing device associated with the cryosurgery system 100 may be initialized, and the cryosurgery system 100 may be initialized. For example, as shown in Figure 13A, the initialization process may include, among other actions, the steps of performing a self-check, configuring the system to accept a new load of cryogen, establishing communication between the various components of the cryosurgery system 100, and reading any relevant patient records.

[0106] Once the system is initialized, in step 605, the computing device may receive a procedure identifier. For example, as shown in Figure 13B, an interface may be presented to the user, asking whether the procedure is a new therapy or a continuation of a previous procedure. If the procedure is a continuation of a previous procedure, the user may be prompted to provide an identification of the previous procedure, and the relevant procedure record may be read from the computing device's storage. Details of the continuation therapy may be attached to the record as the procedure is performed.

[0107] On the other hand, if the therapy is a new therapy, the computing device may present an interface that allows the user to either enter a new therapy identifier or have the system automatically generate a new therapy identifier (see Figure 13C). The new therapy identifier may be associated with patient records in the computing device's storage. If the computing system receives a selection that indicates it should generate an identifier, it may create a unique identifier based on any appropriate creation scheme (for example, by selecting a sequential identifier or by generating a random identifier and checking to ensure that the identifier is not already in use). If the computing device receives a selection that indicates the user will enter a custom identifier, it may present a new interface (for example, as shown in Figure 13D) that allows the user to enter a custom therapy identifier. Optionally, the computing device may verify that the custom therapy identifier entered by the user is not already in use.

[0108] The process may then proceed to step 610, in which the computing device may receive a procedure setting. The procedure setting represents patient information used to determine the amount of cryospray to deliver to a target area of ​​the patient's lung. According to an exemplary embodiment, the cryosurgery system 100 and the associated computing device are configured to determine the target amount of cryospray based on limited information only. For example, as shown in Figure 13E, the procedure setting may consist of the patient's sex and lung terms defining the airway location to be selected later. Combined with the target area of ​​the lung to be treated, these procedure settings may be sufficient to determine the target amount of cryospray to be applied. Optionally, the computing device may present an interface, as shown in Figure 13F, requiring the procedure setting to be confirmed by a physician.

[0109] In step 615, the computing device may receive the catheter type and / or a catheter identifier corresponding to a specific catheter. For example, each catheter may be provided with some form of identification, such as an RFID tag or barcode, and the tag or code may be scanned by a suitable scanning device communicating with the computing device. Figure 13G shows an exemplary interface for receiving the scanning of an RFID tag associated with a catheter.

[0110] In step 620, the computing device may determine that the catheter or thermocouple is plugged into the cryosurgery system 100 and / or establish a connection to the catheter and thermocouple. The computing device may identify one or more data ports associated with the catheter or thermocouple that enable one-way or two-way communication between the catheter / thermocouple and the computing device. The computing device may display a prompt requesting that the catheter and thermocouple be connected to the ports, as shown in Figures 13H-13I. Once the presence of the catheter and thermocouple is detected and communication with the catheter and thermocouple is established, the computing device may update its display to indicate that the catheter and thermocouple are successfully connected (see, for example, Figure 13J).

[0111] In step 625, the computing device may perform a cryospray flow check. The computing device may automatically start the cryospray flow by sending a command to the cryosurgery system 100 (as shown in Figure 13K), or may prompt the user to manually activate the cryospray. The computing device may prevent the cryospray from being applied, either manually or automatically, if certain safety parameters are not met. For example, prior to performing a cryospray flow check, the computing device may read a temperature from a thermocouple associated with the catheter. If the thermocouple reports a temperature reading that substantially corresponds to body temperature (e.g., approximately 37°C), the computing device may determine that the catheter has already been deployed inside the patient's body. Since the flow check is designed to occur outside the patient's body, the computing device may, in this case, prevent the cryospray from being applied.

[0112] The computing device evaluates the output of the cryosurgery system 100 (Figure 13L) and may update the interface using the results of the flow check. If the flow is determined to be abnormal (e.g., a flow velocity outside the pre-determined range is detected), the interface may be updated and require the cryosurgery system to undergo maintenance before continuing. If the flow is determined to be normal, the process may continue to step 630.

[0113] In step 630, the computing device may receive a selection of the anatomical region and / or subregions in which the resection procedure will be performed. The computing device may provide prompts to allow the user to input identification of the region / subregion to be treated. The prompts may be text or graphic, as shown in Figures 14A–14E.

[0114] In step 635, the computing device may calculate the target amount of cryospray. The calculation may be performed based on the procedure settings received in step 610 and the region / subregion identified in step 630. For example, the patient's sex and lung terminology, as well as the target region / subregion, may be provided as input to an algorithm or a set of algorithms that relate these values ​​to the amount of cryospray needed to excise tissue within the target region / subregion without damaging surrounding tissue. Once the target amount of cryospray is determined, the process may proceed to step 640.

[0115] In step 640, the computing system may instruct the cryosurgery system 100 to deliver a target amount of cryospray as calculated in step 635. For example, the computing system may automatically start the delivery of the cryospray, as shown in Figure 14F, or it may prompt the user to manually start the delivery of the cryospray. The computing system may receive a signal indicating that the application of the cryospray has begun.

[0116] Once cryospray application begins, the computing system can monitor cryospray delivery. The computing system can measure the amount of cryospray delivered. This can be done, for example, by calculating the amount of cryospray delivered based on the time elapsed since the start of cryospray application and the flow rate, as determined in step 625, or based on the temperature, as measured by the thermocouple. In some embodiments, multiple thermocouples may be strategically positioned at various locations on the catheter, and the thermocouple measurements may be related to parameters that enable the measurements to act as proxies for spray output. Once the amount of cryospray delivered matches the target amount of cryospray, the computing device may automatically terminate cryospray delivery, for example, by sending a termination command to the cryosurgery system 100. Furthermore, spray application may be stopped when the temperature, as measured by the thermocouple, indicates that the desired amount of spray has been applied.

[0117] During the cryospray delivery procedure, the computing device may measure the temperature of the catheter, associated with a thermocouple attached to the outside of the catheter at a certain distance from the tip. Under certain conditions, the computing device may stop the spray (for example, by sending a termination command as described above) prior to the delivery of a target amount of cryospray. For example, cryospray application may be terminated if (a) the temperature drops sharply below a safety threshold, (b) the slope of the temperature curve generated by the device in real time deviates from the threshold safety range (either too high or too low), or (c) the duration of the spray extends beyond a threshold time.

[0118] In step 645, the computing device may identify that the catheter has thawed. Before performing additional steps (such as reapplying cryospray or moving the catheter), it may be important to ensure that the catheter has returned to a safe temperature to prevent damage to the patient's tissue or the catheter / thermocouple. Therefore, the catheter temperature, such as that measured by the thermocouple, may be determined and compared to a pre-determined threshold representing a safe temperature value. If the temperature exceeds the threshold, the computing device may determine that the catheter has thawed, and processing may proceed to step 650. If the temperature does not exceed the threshold, the computing device may wait for a pre-determined time (e.g., 1 second) and read the temperature threshold again from the thermocouple. Exemplary interfaces for verifying that the catheter has thawed are depicted in Figures 14G-14H.

[0119] In step 650, the computing device may determine whether the target amount of cryospray calculated in step 635 has been successfully delivered. As noted above, in step 640, the computing system may monitor various parameters associated with the catheter and / or thermocouple, which are preferably used to calculate cryospray parameters, evaluate the progress of the cryospray during its application, and / or may be used to terminate or interrupt the cryospray if (e.g.) (a) the temperature drops sharply below a safety threshold, (b) the slope of the temperature curve generated by the device in real time deviates from the threshold safety range (either too high or too low), or (c) the duration of the spray extends beyond a threshold time. If the flow of the cryospray is stopped for these or other reasons before the target amount of cryospray is delivered, the computing device may determine in step 650 that the target amount of cryospray has not been successfully delivered. If step 640 proceeds without interruption, the computing device may determine in step 650 that the target amount of cryospray has been successfully delivered.

[0120] If the determination in step 650 is "no" (i.e., the target amount of cryospray was not successfully delivered), then in step 655, the computing device may determine whether to respray the cryospray. For example, the computing device may present an interface, such as that depicted in Figure 14I, to receive instructions on whether to respray the cryospray.

[0121] If the determination in step 655 is "no" (i.e., the computing device determines that no respray will occur), the process may proceed to step 660, and the procedure is recorded as a partial spray. For example, a flag may be set in the patient's record to indicate that the procedure is incomplete, and optionally, the degree of completion of the procedure may be indicated.

[0122] Returning to step 650, if the determination in step 650 is "yes" (i.e., the target amount of cryospray was successfully delivered) and / or if the determination in step 655 was "no" (i.e., the computing system did not determine that a respray should be applied), the process may proceed to step 665, where the computing system determines whether any further areas to be treated remain. For example, the computing system may read a treatment plan associated with the patient's record or present a prompt to inquire whether any additional areas to be treated remain. Alternatively, the computing device may present an interface for receiving a selection of additional areas to be treated, and if no further areas to be treated remain, it may present further options to terminate the process.

[0123] If the determination in step 665 is "yes" (i.e., there are further areas to treat), the process may return to step 630, and the computing device may receive a new selection of anatomical areas and / or subregions to be treated. The new selection may be identical to the previous selection (i.e., the same area may be selected for multiple treatments). Figures 14J-14N illustrate an example of the selection of additional areas and subregions for further treatment.

[0124] If the determination in step 665 is "no" (i.e., there are no further areas to treat), the process may proceed to step 670, and the computing device may terminate the procedure. As part of step 670, the computing device may generate or modify a patient record, indicate the status of any procedures performed, prompt the user to remove the catheter from the patient, shut down communication with the catheter, thermocouple, or other parts of the system, and perform any necessary housekeeping steps. Exemplary interfaces for terminating the procedure are depicted in Figures 14O-14P.

[0125] One or more of the actions described above may be encoded as a computer executable instruction that can be executed by processing logic. The computer executable instruction may be stored on one or more non-transient computer-readable media. One or more of the actions described above may be performed in a preferably programmed electronic device. Figure 15 depicts an embodiment of an electronic computing device 700 that may be suitable for use in conjunction with one or more of the actions disclosed herein.

[0126] Computing devices 700 may take many forms, including, but are not limited to, computers, workstations, servers, network computers, internet appliances, integrated circuits, mobile devices, tablet computers, smart sensors, and custom application-specific processing devices.

[0127] The computing device 700 is illustrative and may take other forms. For example, alternative implementations of the computing device 700 may have fewer components, more components, or components in a different configuration than that of Figure 15. The components of Figure 15 and / or other figures described herein may be implemented using hardware-based logic, software-based logic, and / or a combination of hardware and software-based logic (e.g., hybrid logic), and therefore the components illustrated in Figure 15 and / or other figures are not limited to specific types of logic.

[0128] The computing device 700 may include a processor 705. The processor 705 includes a device that executes instructions and / or performs mathematical, logical, control, or input / output operations. The processor 705 may include hardware-based logic or a combination of hardware-based logic and software to execute instructions on behalf of the computing device 700. The processor 705 may include logic that can interpret, execute, and / or otherwise process information contained in memory 715, for example. This information may include computer-executable instructions and / or data that can implement one or more embodiments as described herein.

[0129] The processor 705 may comprise various homogeneous or heterogeneous hardware. The hardware may include, for example, any combination of one or more processors, microprocessors, field-programmable gate arrays (FPGAs), application-specific instruction set processors (ASIPs), element-specific integrated circuits (ASICs), composite programmable logic devices (CPLDs), graphics processing units (GPUs), or other types of processing logic capable of interpreting, executing, manipulating, and / or otherwise processing this information. Furthermore, the processor 705 may include a system-on-a-chip (SoC) or a system-in-package (SiP).

[0130] The processor 705 may be a central processing unit (CPU) having one or more processing cores 710. The cores 710 include independent processing units that are physically or logically separate from each other and are typically configured to perform parallel processing tasks. The processor 705 may further include one or more coprocessors and / or on-chip caches. Such a processor 705 may implement a composite instruction set computing (CISC) architecture. Embodiments of such a processor 705 include Celeron(R), Pentium(registered trademark), and Core from Intel Corporation (Santa Clara, California). TM The group includes processors and Accelerated Processing Unit (APU) and Central Processing Unit (CPU) processors from Advanced Micro Devices (AMD), Inc. (Sunnyvale, California).

[0131] Alternatively, or in addition, the processor 705 of the computing device 700 may be a specialized processor having relatively limited processing power and designed to boot in a low-power environment. For example, the processor 705 may implement a reduced instruction set computing (RISC) or Acorn RISC Machine (ARM) architecture. An example of such a processor 705 is the Atom from Intel Corporation (Santa Clara, California). TM The A4 series processors from Apple, Inc. (Cupertino, California) and Snapdragon processors from Qualcomm Technologies, Inc. (San Diego, California) TM It includes a group of processors and Cortex(R) group processors from ARM Holdings, PLC (Cambridge, England).

[0132] The 705 processor may also be a custom processor.

[0133] The computing device 700 may include one or more tangible, non-transient, computer-readable storage media for storing one or more computer executable instructions or software, which may implement one or more embodiments of the present invention.

[0134] The non-transient computer-readable storage medium may be, for example, a memory 715 or a storage device 750. The memory 715 may consist of RAM, which may include RAM devices capable of storing information. The RAM devices may be volatile or non-volatile and may include, for example, one or more DRAM devices, flash memory devices, SRAM devices, zero-capacitor RAM (ZRAM) devices, twin-transistor RAM (TTRAM) devices, read-only memory (ROM) devices, ferroelectric RAM (FeRAM) devices, magnetoresistive RAM (MRAM) devices, phase-change memory (PRAM) devices, or other types of RAM devices. Examples of the memory 715 are provided in Secure Digital from the SD Association. TM (SD) memory, as well as single in-line memory modules (SIMMs) and double in-line memory modules (DIMMs) from various manufacturers. Memory 715 may also be custom memory.

[0135] The computing device 700 may include a virtual machine (VM) 720 for executing instructions loaded into memory 715. The virtual machine 720 may be provided to handle processes running on multiple processors such that a process may be considered to be using only one computing resource, rather than multiple computing resources. Virtualization may be employed in the computing device 700 to dynamically share infrastructure and resources within the electronic device. Multiple VMs 720 may reside on a single computing device 700.

[0136] The hardware accelerator 725 may be implemented within an ASIC, FPGA, or some other device. The hardware accelerator 725 includes specialized logic implemented in hardware to perform functions that would otherwise be performed more slowly by software. Thus, the hardware accelerator 725 may be configured to reduce the general processing time of the computing device 700.

[0137] The computing device 700 may include a network interface 730 to interface with a network through one or more types of connections. The network may be, for example, a local area network (LAN), a wide area network (WAN), or the internet. The network interface 730 may be, for example, a network interface controller (NIC) for establishing a wired connection to a computer network, a fiber optic interface for connecting to a fiber optic network, a cable interface for connecting to a cable television network, a telephone jack for connecting to a telephone network, a power line interface for connecting to a power line communication network, an area network connection for receiving information on a LAN or WAN link (e.g., T1, T3, 56kb, X.25), a broadband connection for connecting to an Integrated Services Digital Network (ISDN), a frame relay connection, an asynchronous transfer mode connection (ATM), a wireless connection (e.g., an 802.11x compatible network), a high-speed interconnect (e.g., InfiniBand, Gigabit Ethernet®, Myrinet), or any combination of any or all of the above.

[0138] The network interface 730 may include an internal network adapter, a network interface card, a Personal Computer Memory Card International Association (PCMCIA) network card, a CardBus network adapter, a wireless network adapter, a Universal Serial Bus (USB) network adapter, a modem, or any other device suitable for interface the computing device 700 to any type of network capable of communication and for performing the operations described herein.

[0139] The computing device 700 may include hardware and / or software for connecting to one or more input devices 735, such as a keyboard, a multipoint touch interface, a pointing device (e.g., a mouse), a gyroscope, an accelerometer, a haptic device, a tactile device, a neural device, a microphone, or a camera that may be used to receive input from a user. Note that the computing device 700 may also include hardware or software for interacting with other suitable I / O peripherals.

[0140] The input device 735 may be configured to provide input that is registered on the visual display device 740. A graphical user interface (GUI) 745 may be displayed on the display device 740. The GUI 745 may correspond to the GUI depicted in either Figure 13A-14P. Note that, in addition to the visual display device, other types of output devices may be used with the computing device 700.

[0141] The computing device 700 may also interface with the cryosurgery system 100 to receive inputs from the cryosurgery system 100 and provide outputs to it. The computing device 700 may issue commands to the cryosurgery system 100 and perform any or all of the steps described in Figure 12. Alternatively, or in addition, the computing device 700 may be integrated with the cryosurgery system 100.

[0142] A storage device 750 may also be associated with a computing device 700. The storage device 750 includes a device that persistently stores data on one or more tangible, non-transient, computer-readable media. The storage device 750 may store information including data and / or computer-executable instructions, which may implement one or more embodiments of the present invention. The information may be executed, interpreted, manipulated, and / or otherwise processed by the processor 705. The storage device 750 may include, for example, magnetic disks, optical disks (e.g., CD-ROMs, DVD players), random access memory (RAM) disks, tape units, and / or flash drives.

[0143] The storage device 750 (and other components depicted in Figure 15) may be accessible to the processor 705 via the I / O bus.

[0144] The storage device 750 may further store files 755, applications 760, and an operating system (OS) 765. Embodiments of OS 765 may include embedded operating systems such as Microsoft® Windows® operating systems, UNIX® and Linux® operating systems, MacOS® for Macintosh computers, Symbian OS, real-time operating systems, open-source operating systems, dedicated operating systems, operating systems for mobile electronic devices, or other operating systems that can be booted on an electronic device and perform the operations described herein. Operating system 765 may be booted in native mode or emulated mode.

[0145] Furthermore, the memory device 750 may store logic for controlling the cryosurgery system 100, such as the logic for realizing the cryosurgery process 600 as described in Figure 12.

[0146] Figures 13A-L show a series of procedure setting screens according to one embodiment of the present invention, which initiate the steps required to perform a procedure using the system of the present invention. The procedure setting screen may consist of a tank level indicator and various selectable procedure settings, including, but not limited to, patient type selection (e.g., gender, weight-based, age-based, or any other patient category or information that can be used as a criterion for delivering an appropriate cryospray dose), ventilation method, and exit reminder selection. The procedure setting screen may also consist of text or symbols to guide the user through setting consumables for the procedure. Once this setting is complete, the user can proceed to the next screen. Alternatively, if the user is accessing the system to refill a console or to perform maintenance on a console, the user may access those functional screens by selecting from drop-down menus (not shown).

[0147] The catheter is scanned by placing an RFID tag on a scanning device located on the side of the console. Once the catheter is successfully scanned, the catheter ID appears on the screen, which guides the user to the next step. The step of scanning the catheter initiates a pre-cooling process. According to another embodiment, the RFID tag may be provided on a part of the catheter itself, preferably within a connector housing, i.e., a "hub," which is then automatically detected when the catheter is plugged into the console. According to this alternative embodiment, the RFID scanning device is placed within the console, close to where the catheter is plugged into the console, and therefore automatically reads the RFID located within the catheter's connector housing when the catheter is plugged into the console.

[0148] The settings screen contains a list of requirements that must be met before proceeding to the next screen. The list may include, but is not limited to, the following:

[0149] Ventilation method or gas outlet route verification - This system will respond with an affirmative response that the gas outlet route has been checked.

[0150] Valid catheter - This system will respond with an affirmative response that the catheter has been scanned successfully.

[0151] Catheter insertion - This system detects when the user has successfully inserted the catheter into the control panel.

[0152] Gender Selection - This system affirms that the patient's gender has been selected. Any type of patient category may be used, including gender, weight-based, age-based, etc., which can serve as a criterion for delivering an appropriate cryospray dose.

[0153] When this system is pre-cooling, a status indicator box labeled "Pre-cooling system" will be displayed.

[0154] OK button - Pressing this button allows you to proceed to the next screen, provided all requirements have been met. Once all requirements on the procedure setting screen are met, pressing the next button will allow the user to proceed to the procedure screen.

[0155] The treatment screen shown in Figure 14A-P guides the user through the procedure for lung treatment and generally includes a bronchial tree schematic diagram 501 with anatomical structure markers 503 for each section to be treated, a dose location marker 504, a dose status indicator 505, a cryogen tank remaining volume display 507, a total spray indicator 509, a status indicator 511, a test spray button 513, and a defrost button 515. The user selects a dose location marker button for the location where the treatment will be received. The selection of one of the marker buttons sets the dose time for that spray.

[0156] When one of the anatomical structure labeling buttons is selected, the system automatically sets the dose and time for the treatment site and patient gender (or other patient type or category as determined by the system design).

[0157] Once a dose is completed, the first dose status indicator for that treatment site will change color. The number of dose status indicators for a particular dose location button depends on the length of the section. For example, the tracheal dose location button 504 shown in Figure 14 has six dose status indicators 505. This means that there are six potential treatment locations within the trachea. Once the trachea is selected for treatment, the status indicators will change color one by one as each different site within the trachea is completed. If an incomplete dose is delivered, the indicators will not change color. In contrast, the left bronchial section #9 location button has only two dose status indicators because it is a much shorter section and typically requires only two separate doses to cover the entire treatmentable section. Once a spray dose is initiated, this indicator may count down to zero. Once this reaches zero, the spray will automatically stop and an audible beep may sound.

[0158] A thermocouple or other temperature-sensing element (e.g., a flex-circuit temperature sensor) is preferably positioned near the distal tip on the catheter to provide temperature information to the console. The temperature information is used in some of the processes described above, and is used to provide feedback to the system during cryospray delivery, as it is used to determine the amount of cryospray to be delivered by the system, to determine when the cryospray is exiting the tip of the catheter, to control the delivery of the medication, and to configure the system to preferably interrupt the flow of cryospray if the measured temperature decreases below a certain threshold or if the rate of change of the measured temperature deviates from a standard rate of change. As shown in Figure 19A, the catheter temperature at the time the cryospray is initiated can significantly affect any tissue temperature change caused by the cryospray, and therefore the system may reduce the amount of cryospray delivered over a series of cryospray pathways, which may be caused at least in part by a gradual decrease in catheter temperature over multiple treatment pathways.

[0159] Figure 19B shows that the rate of temperature change, such as that measured by a temperature sensor placed on the catheter, may vary depending on the presence or absence of mucus in the working channel. Therefore, the temperature information of the catheter used in a preferred embodiment is used to evaluate the rate of temperature change during cryospray delivery. If the rate of change deviates from a standard rate of change beyond a threshold, or if the elapsed time during cryospray exceeds a threshold time, the system may interrupt the cryospray.

[0160] According to one embodiment, the timing of the spray dose may then be initiated not from the time the user presses down the pedal, but from the moment the cryospray leaves the catheter, based on feedback from the thermocouple.

[0161] The defrost button can be pressed to facilitate the removal of a frozen catheter from a scope or other operating tool if it is necessary to remove the catheter before it would naturally defrost. When the defrost button is pressed, a defrost indicator will appear. Defrosting will be initiated for a predetermined time. To interrupt the defrosting operation before the predetermined time has elapsed, the user simply needs to press the defrost button again.

[0162] The test spray button can be pressed if the user wishes to demonstrate the spray outside of the patient.

[0163] The "Procedure Complete" button can be pressed once the procedure is complete. By pressing this button, the user can proceed to a procedure summary report, which can summarize the dosage and location for that procedure day.

[0164] Nitrogen gas aeration is achieved through passive ventilators. Before commencing the procedure, the appropriate type and size of passive ventilator should be determined at the discretion of the performing physician. A rigid bronchoscope or endotracheal ventilator may provide an annular ventilator area through which the scope passes the center of the tube.

[0165] A scope guide is provided within the catheter kit to assist in the introduction of the catheter into the scope and may reduce catheter twisting. The tapered end of the guide should be positioned approximately 1 cm into the working channel of the scope, or until any built-in mechanical fastener engages within the guide.

[0166] A sheath (referred to herein as a “dose interval sheath”) is placed on the outer surface of a flexible bronchoscope to assist in the discrete arrangement of doses and prevent dose duplication when multiple doses are delivered into an anatomical lumen of the same diameter.

[0167] The flexible bronchoscope is introduced through the nose or mouth as needed, and the airway is examined before the procedure begins. The user then advances the bronchoscope to the target site and positions it so that the target treatment site is visible.

[0168] Once the bronchoscope is advanced to the target treatment site, the catheter can be supplied into the bronchoscope's working channel through the introducer. Once the catheter is properly positioned at the target site, the user selects an anatomical location button on the treatment screen based on which anatomical location will be treated.

[0169] Prior to dose delivery, the system may prompt the user to verify the gas outlet route.

[0170] To start the cryospray, the user presses and holds the foot pedal. The system will spray until a pre-determined temperature is measured by the catheter, or until a predefined time has elapsed based on the anatomical structure and patient type / category / gender selection on the screen, whichever comes first.

[0171] During spraying, the monitor may count down the remaining time for the dose. Once the dose is complete, the display may indicate that the dose is finished, and the user can move to the next dose location by pressing a location on the user interface.

[0172] If the spray is stopped before the correct dose is delivered, the system may not acknowledge this as the dose, and the user may be advised to have the dose resent.

[0173] Referring to Figure 17, as an example of the use of the present invention in the right lung, after making the appropriate console sex and anatomical selection, the user would proceed to the distal point of RB9 (right lateral basal lobe), activate the spray, then wait until the spray automatically stops after a prescribed dose, and then wait for thawing. The user would then move the catheter and bronchoscope proximally to RB10 (right posterior basal lobe), indicate its treatment location on the user interface, and repeat the procedure steps (i.e., start the spray, wait until it automatically stops, and then wait for thawing). The user would then move the catheter and bronchoscope proximally to RB8 (right anterior basal lobe) and repeat again. The user would then proceed to RB7 (right intermediate basal lobe) and repeat. After spraying the basal segment, the user would move the catheter to the right lower lobe, indicate its treatment location on the user interface, and repeat the procedure steps with the lobe treatment time pre-programmed for the system. At each anatomical site, depending on the length of the segment, there may be more than one spray / dose, but the dose / spray should only be applied once to the same site. This may continue until all surviving segments, lobes, and bronchial sites have been treated.

[0174] For intervals long enough to allow more than one spray / dose, the user may spray more than one spray / dose, but only one dose / spray is applied to the same site. In an embodiment involving the right lobe bronchus, the user would proceed as follows: Proceed to the distal point of the RLL (right lower lobe), paying attention to the fixation point, e.g., the marking on the dose interval sheath relative to the endotracheal tube, spray, defrost, retract using the marking on the dose interval sheath, spray a second dose in the RLL, and defrost. Move the catheter and bronchoscope proximally to the intermediate trunk bronchus. Manual ventilation may be required, whether or not the bronchoscope is removed.

[0175] In the main bronchus, depending on the length of the segment, there may be more than one spray / dose, but the dose / spray is applied only once to the same site. Again, after moving the catheter and bronchoscope distally to proximal and changing the console's anatomical setting to the bronchus, the user will, noting the fixation point, e.g., the marking on the dose interval sheath for the endotracheal tube, spray, defrost, retract using the marking on the dose interval sheath, spray a second dose, defrost, and repeat until the main bronchus and intermediate bronchus are treated. Manual ventilation may be required after several doses have been administered, regardless of whether the bronchoscope is removed.

[0176] In the trachea, depending on the length of the trachea, there may be more than one spray / dose, but the dose / spray should only be applied once to the same site. Starting at the major tracheal bifurcation, the catheter and bronchoscope are moved distally to proximal, paying attention to the fixation point, e.g., the marking on the dose interval sheath relative to the endotracheal tube, spray, thaw, retract using the marking on the dose interval sheath, spray a second dose, thaw, and repeat until the appropriate length of the trachea has been treated. Manual ventilation may be required after several doses have been administered, regardless of whether the bronchoscope is removed.

[0177] Bronchoscope sheath for measurement and spacing Referring to Figure 21, a bronchoscopic measurement sheath is shown, configured to be positioned along a portion of its length across the outer surface of a flexible fiber optic bronchoscope during a bronchoscopic procedure. The bronchoscopic measurement sheath 401 may be made from an extension tube 403 having a lumen configured to receive a bronchoscope 40, and a fixation device 405, e.g., Tuohy-Borst, configured at one end of the tube to fix the proximal end of the sheath to the proximal end of the bronchoscope. According to another embodiment, the fixation device is a hub fixed to the proximal end of the sheath (e.g., see Figure 4). The sheath preferably has a plurality of markings 407 along a portion of the outer surface of the tube, configured to represent the distance the scope is moved relative to a patient's fixed position, patient features, or other fixed reference point. The markings may be a circumferential marker band outside the working channel of the scope and may optionally be associated with printed numbers. When aligned with a tracheal insulator (e.g., rigid bronchoscope or endotracheal tube), the markings provide an extracorporeal proximal reference marking prior to administration. For subsequent doses or procedures, the reference markers assist the physician when the scope is moved to a new procedure site. For dose intervals, the reference markers assist the physician in avoiding dose duplication.

[0178] The bronchoscopy measurement sheath is placed on the outer surface of the flexible bronchoscope and provides reference markings, which can assist physicians in measuring the movement of the bronchoscope into and out of the patient's airway during diagnostic or therapeutic bronchoscopy.

[0179] The bronchoscopic measurement sheath is placed on the outer surface of the flexible bronchoscope and can assist in the discrete arrangement of doses, preventing dose duplication when multiple doses are delivered into an anatomical lumen of the same diameter.

[0180] Figure 21 shows an enlarged view of an embodiment of a bronchoscopic measuring sheath according to one embodiment of the present invention, in which the proximal end of the sheath is cuffed or hubmed, and the distal end of the sheath is cuffed or tapered. The optional hub at the proximal end is configured to assist in loading the sheath onto the bronchoscope, and the optional taper at the distal end is configured to assist in introducing the sheathed bronchoscope into the endotracheal canal.

[0181] According to various embodiments, the sheath may be made from braided PET (polyethylene terephthalate) polymer monofilament, and the markings are printed on the outside of the sheath. According to other embodiments, the braid may be made from filaments of other compositions (e.g., polypropylene, nylon, polyester), or the braid may be made from a mixture of filaments made from PET and other materials. According to a preferred embodiment, the braid is a 72-carrier structure in two patterns, one at the top and two at the bottom, and the 72 elements include 24 elements of 0.0052-inch PET monofilament and 48 elements of 85 / 24 PET multifilament (85 denier / 24 filaments) at each end. The material may be braided at 38 ppi (filaments per inch) on a 0.076-inch acetal substrate core. According to other embodiments, the braid may consist of up to 150 elements of filaments of different diameters ranging from 0.004 inches to 0.01 inches and up to 50 ppi (filaments per inch). Alternatively, the braid is a 26 ppi (measured after construction) braid formed over a 2 mm mandrel, with 12 carriers in each direction (24 in total) each having two ends of 0.006 inch (0.015 mm) monofilament, and another 12 carriers in each direction (24 in total) consisting of 440 denier monofilament, and is heat-solidified at 340°F (171.1°C) for 5 minutes.

[0182] As shown in Figure 21, one or both ends of the sheath may be formed with or joined to a cuff to prevent or stop the braid from fraying and / or unraveling and to assist in insertion and removal from the scope.

[0183] The end cuff may be the heat-melted end of the braid itself, or it may be a separate elastic (e.g., polyurethane, silicone, etc.) or rigid plastic hub fixed or joined to the end of the braid. When a proximal hub is used, it is preferably molded to fit into the tapered portion of the bronchoscope that connects the working end to the handpiece. According to one embodiment, the hub may be a separate elastic element that clamps the end of the braid. The hub may be attached to the braid by any known method, including dipping, heat bonding, joint bonding, UV curing, adhesive, or mechanical bonding. According to a preferred embodiment, the hub may be fabricated with an annular recess (see Figure 4) configured to receive the heat-sealed edge of the braid. Once the end of the braid tube is inserted into the annular recess of the hub, adhesive may be dispensed to fill the annular space that receives the braid, thereby joining the braid in the annular recess. As shown in Figure 21, the distal end may be tapered for non-traumatic insertion into anatomical structures. According to another embodiment, the distal end is constructed to have greater rigidity than the rest of the braid, which may assist in the insertion of the bronchoscope and the mounted measuring sheath into the endotracheal tube sealing gasket or other laryngeal mask airway, preventing the sheath from buckling and retracting itself and the bronchoscope as it passes through the tight passage.

[0184] Figure 22 shows an embodiment of a bronchoscopic measuring sheath mounted on the proximal end of a bronchoscope. The proximal portion of the braided sheath may be a heat-melted end of the braid itself, or it may have a separate elastic (e.g., polyurethane, silicone, etc.) or rigid plastic element fixed to the end of the braid (see, for example, Figures 6 and 7), in order to allow the sheath to slide on the scope and fix it in place. According to a preferred embodiment, the proximal end has a thermoplastic molded component, i.e., a “hub” (see, for example, Figure 4), which is molded on the braid and has a tapered internal outer shape, to adapt to the tapered joint between the proximal end (“working portion”) of the flexible fiber optic bronchoscope and the handpiece.

[0185] Figure 24 illustrates how the braiding of the sheath is configured to expand and release when both ends of the sheath are compressed. To advance the sheath across the bronchoscope prior to the procedure, or to remove the sheath from the bronchoscope after the procedure, the user simply needs to firmly compress one end of the sheath against the bronchoscope and advance the other end toward the fixed end. When the clamped / fixed end is released, the sheath will slacken in that direction. However, when one end of the sheath is pulled, the braiding configuration causes the sheath to tighten around the bronchoscope. Thus, the braiding of the sheath makes the sheath function similarly to a Chinese finger trap. Therefore, the sheath will not slip out of the bronchoscope as it is advanced down the patient's airway into the endotracheal canal. According to a preferred embodiment, the sheath is packaged in a pre-loaded compressed state, so as to be already compressed and braided expanded when removed from the packaging for use, facilitating its application to the outer surface of the scope.

[0186] Figure 25 shows an embodiment of the braided sheath according to the present invention, having a rigid plastic cuff at its proximal end, adjacent to a flexible bronchoscope into which it can be loaded. Figure 26 shows an embodiment of the braided flexible sheath according to the present invention, in which the rigid plastic cuff at the proximal end of the sheath is loaded onto the outer surface of a flexible bronchoscope, which is tightly fitted onto the tapered portion of the bronchoscope that connects the working end of the bronchoscope to the handpiece of the bronchoscope.

[0187] According to one embodiment of the present invention relating to dose intervals, the present invention is first designed to be used in conjunction with cryospray treatment of the patient's airway using a bronchoscope, to allow the user to carefully monitor the distance the bronchoscope has advanced into and / or withdrawn from the patient's airway, and to ensure that all desired portions of the trachea receive the treatment, but no portion of the trachea receives more than one treatment. The flexible bronchoscope is introduced through the nose or mouth as needed, and the airway is examined before commencing the procedure. The user then advances the bronchoscope to the target site and positions the bronchoscope so that the target treatment site is visible. The dose interval sheath, when referenced to a fixed reference point such as the endotracheal tube, provides dose interval guidance, allowing the bronchoscopist not to administer more than one dose to the same anatomical location.

[0188] For example, using a dose-interval sheath to assist with cryospray treatment in the right lobe bronchus, the user would advance the sheath-mounted bronchoscope to the distal point of the RLL (right lower lobe), noting a fixation point, such as a marking on the dose-interval sheath relative to the endotracheal tube. The user would then initiate the spray treatment, allowing the area to thaw, then withdraw the bronchoscope by a discrete distance using the marking on the dose-interval sheath, and then spray a second dose to a second non-overlapping location in the RLL. The same procedure would be used at any location within the trachea, ensuring that multiple continuous or nearly continuous areas are treated without overlap.

[0189] While the use of a bronchoscopic measuring sheath and the concept of dose intervals are described herein in the context of cryospray therapy, this can be used for any type of airway procedure where distance measurement is important.

[0190] While the use of a bronchoscopic measuring sheath is described herein in the context of airway reference measurement and procedure, it can be used for any type of bronchoscopic or endoscopic procedure in which distance measurement is important.

[0191] In addition to assisting with medication delivery, the dose interval sheath of the present invention may be used as a measuring device for any bronchoscopy procedure to record the location of lesions, stenosis, treatment sites, or lengths of airway segments.

[0192] conclusion While the embodiments presented above focus on the treatment of the airway, it will be understood by those skilled in the art that the systems, methods, and principles illustrated herein are applicable to cryotherapy of other organ systems and disorders where delivery of cryogen to a site within a body lumen is desired, including the esophagus, stomach, duodenum, small intestine, large intestine, rectum, uterus, fallopian tubes, etc. In addition, the automated cryospray systems and catheters described above can be adapted to treat such organ systems, and such adapted catheters and systems, as well as the use of such systems, are generally within the scope of the present invention.

[0193] The phrase "and / or" should be understood, as used herein, to mean "one or both" of the elements thus joined, i.e., elements that exist together in some cases and discretely in others. Unless explicitly stated otherwise, other elements may optionally exist in addition to those specifically identified by the "and / or" clause, whether or not they are related to those specifically identified elements. Thus, in non-restrictive embodiments, when used in conjunction with non-restrictive language such as "comprising," the reference "A and / or B" may, in one embodiment, refer to A without B (optionally including elements other than B), in another embodiment, refer to B without A (optionally including elements other than A), and in yet another embodiment, refer to both A and B (optionally including other elements), and so on.

[0194] The term "consists essentially of" means, unless otherwise defined herein, the exclusion of other materials that contribute to the function. Nevertheless, such other materials may be present in trace amounts, collectively or individually.

[0195] As used herein, the terms “substantially” or “about” mean ±10% (for example, by weight or volume), and in some embodiments, ±5%. Throughout this specification, any reference to “one embodiment,” “a particular example,” “one embodiment,” or “a particular embodiment” means that a particular feature, structure, or property described in relation to an example is included in at least one embodiment of the Art. Thus, occurrences of the phrases “one embodiment,” “a particular example,” “one embodiment,” or “a particular embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, certain features, structures, routines, steps, or properties may be combined in any preferred manner in one or more embodiments of the Art. The headings provided herein are for convenience only and are not intended to limit or imply any limitation or interpretation of the scope or meaning of the claimed Art.

[0196] Some embodiments of the present invention have been described above. However, it should be explicitly noted that the present invention is not limited to those embodiments, and rather, its intent is that additions and modifications to those expressly described herein are also within the scope of the invention. Furthermore, it should be understood that the features of the various embodiments described herein are not mutually exclusive, and such combinations and permutations may exist in various combinations and permutations without departing from the spirit and scope of the invention, even if not explicitly stated herein. In fact, modifications, alterations, and other implementations of those described herein will be conceivable to those skilled in the art without departing from the spirit and scope of the invention. Thus, the present invention is not defined solely by the illustrative descriptions set forth above.

Claims

[Claim 1] The invention described herein.

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