Generator, catheter with electrodes, and method for treatment of lung passageway

Abstract

To provide interventional procedures which are easy to control, match pathophysiologic aberrancies, allow treatment of large surface areas at appropriate depths, and can limit amounts of inflammatory response and remodeling.SOLUTION: Systems and methods are provided for treating pulmonary tissues via delivery of energy to target tissue using a pulmonary tissue modification system (100) such as an energy delivery catheter (102) system. Example pulmonary tissues include the epithelium (goblet cells, ciliated pseudostratified columnar epithelial cells, and basal cells), lamina propria, submucosa, submucosal glands, basement membrane, smooth muscle, cartilage, and / or nerves. The system may be used to treat a variety of pulmonary diseases or pulmonary disorders such as COPD (e.g., chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, primary ciliary dyskinesia (PCD), and / or acute bronchitis.SELECTED DRAWING: Figure 5

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a U.S. patent application Ser. No. 62 / 355,160, filed Jun. 27, 2016. Issue 4 of “Methods, Apparatuses, and Systems for the Treatment of Pulmonary Disorde” rs” and U.S. patent application Ser. No. 62 / 489,753, filed April 25, 2017. ``Methods, Apparatuses, and Systems for the Treatment of Pulmonary Disorders'' The disclosures of both of the above applications are incorporated herein by reference in their entireties. To be incorporated. [Background technology]

[0002] I. Anatomical perspective

[0002] Figure 1 is an illustration of the anatomical structure of the lungs. Air travels down the trachea T ​​into the lungs L, There, the trachea T ​​branches into multiple airways that extend throughout the lung L. The trachea T ​​first branches into the left and right airways in the cervical CA. These main bronchi MB further divide into the lobar bronchi LB, It is divided into segmental bronchi SB and subsegmental bronchi SSB, and ends at the alveoli A. The diameter of the airway is The diameter of the trachea T ​​ranges from about 15 mm to 22 mm. The bronchus MB can have a lumen diameter ranging from about 12 mm to 16 mm, while the lobular bronchus L B can have a lumen diameter ranging from about 9 mm to 12 mm. The length of the airway also varies from segment to segment. In some patients, the length of the trachea T ​​is approximately 12 cm, the length of the main bronchus MB is about 4.8 cm, and the length of the lobar bronchus LB is about 1.9 cm. The length of the bronchus continues to decrease. The airway wall is then expanded toward the lung tissue. As one moves distally, it becomes thinner and has less supporting structure.

[0003]

[0003] The airways of the lung L are made up of various layers, each layer containing one or more types of cells. FIG. 1 is a cross-sectional view of the airway wall W with its various layers and structures. The layer is an epithelium containing pseudostratified columnar epithelial cells PCEC, goblet cells GC, and basal cells BC, or an epithelial layer E Goblet cells (GC) form a mucus blanket that lines the airway lining. PCECs are pseudostratified columnar epithelial cells that contain cilia C that extend into the mucus layer. Cilia C attached to the epithelium E pulsate toward the nose and mouth, pushing mucus M up into the airways. and discharged to the outside.

[0004]

[0004] The basal cells BC are attached to the basement membrane BM, and below the basement membrane BM is the submucosa or mucous membrane. The lamina propria LP is a membrane that contains various types of cells and tissues, such as smooth muscle S. The smooth muscle is responsible for bronchoconstriction and bronchodilation. The lamina propria LP is composed of the submucosal glands S The submucosal glands (SGs) are involved in most inflammatory responses to pathogens and foreign bodies. Similarly, there is a nerve N. The vagus nerve branches on the lateral side of the airway wall or in the airway They run within the walls and interact with mucous glands, airway smooth muscle, and connective tissue, as well as fibroblasts, lymphocytes, and mast cells. Finally, beneath the lamina propria LP is the cartilage layer C, which innervates the lamina propria LP and various other cell types. There exists L.

[0005]

[0005] FIG. 3 is a cross-sectional view of the epithelium E of the airway wall W, showing the types of cellular connections within the airway. Columnar epithelial cells PCEC and goblet cells GC are connected to each other by tight junctions TJ and adherens junctions AJ. The pseudostratified columnar epithelial cells PCEC and goblet cells GC are connected to the basal cells BC by focal adhesions D. The basal cells BC are connected to the basement membrane BM by hemidesmosomes H.

[0006] II. Pulmonary Disease 4A-4B illustrate the bronchial airway B in a healthy and diseased state, respectively. FIG. 4A shows a bronchial airway B in a healthy state with a normal amount of mucus M and no inflammation. FIG. 4B shows a bronchial airway B in a diseased state such as chronic obstructive pulmonary disease, particularly chronic bronchitis. Chronic bronchitis is a condition that causes persistent airflow obstruction, chronic cough, and phlegm production at least once a year. Both are characterized by the presence of excess mucus and mucus for more than three months and for two consecutive years. The illustration shows both inflammation I, which leads to airway obstruction. Airway inflammation I is consistent with thickening of the epithelial layer E. do.

[0007]

[0007] A variety of lung disorders and diseases can cause airway obstruction. Some of these are briefly described herein. explain.

[0008] A. Chronic obstructive pulmonary disease (COPD) Chronic obstructive pulmonary disease (COPD) is caused by exposure to harmful substances such as tobacco smoke and other pollutants. A condition characterized by chronic, irreversible airflow obstruction and persistent inflammation due to environmental stimuli. COPD is a common disease. It is a group of diseases involving chronic bronchitis that primarily affects the airways. Emphysema, on the other hand, affects the alveoli, the air sacs involved in gas exchange. Some patients will have characteristics of both.

[0009]

[0009] In chronic bronchitis, the structure and function of the airways change. When inhaled harmful stimuli such as tobacco smoke or pollutants are recognized as foreign substances, an inflammatory cascade begins. Neutrophils, lymphocytes, macrophages, cytokines, and other inflammatory markers were found in the airways of people with long-term exposure, suggesting chronic inflammation and airway remodeling. Goblet cells can undergo hyperplasia, which is an increase in cell number, or hypertrophy, which is an increase in the size of goblet cells. In other words, goblet cells may respond to inflammatory stimuli and may also be involved in absorptive processes. To remove toxins, the body produces more mucus. Excess mucus further narrows the airway lumen. This leads to more blockages. Cilia are damaged by harmful stimuli, so excess mucus is released. It remains in the airway lumen and obstructs airflow from proximal to distal during inspiration and from distal to proximal during expiration. The smooth muscles become enlarged and thickened, causing bronchoconstriction. The submucosal glands also become hyperplastic and hypertrophied. This increases the overall thickness of the airway wall and further narrows the luminal diameter.

[0010] In addition to the reduction in airway lumen diameter, excessive mucus secretion can also contribute to the worsening or overall deterioration of health. Excessive mucus secretion and damaged cilia can lead to the infiltration of bacteria (e.g., Haemophilus influenzae). , Streptococcus pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia C. cepacia, opportunistic gram-negative bacilli, Mycoplasma pneumoniae, Chlamydia pneumoniae), Viruses (rhinoviruses, influenza / parainfluenza viruses, respiratory syncytial Viruses, coronaviruses, herpes simplex viruses, adenoviruses) and other organisms The bacteria (e.g. fungi) can multiply and cause an exacerbation, resulting in a series of symptoms. Symptoms include worsening cough, congestion, increased sputum production, increased sputum intensity, and / or shortness of breath. Treatment includes oral or intravenous steroids, antibiotics, oxygen, endotracheal intubation, and Examples of such measures include the use of respiratory tract ventilation.

[0011] B. Asthma

[0011] Asthma is a disease of the airways characterized by airway hyperresponsiveness. In asthma, the epithelium thickens and Overproduction of mucus from goblet cells and submucosal glands leads to excessive secretion of mucus, and smooth muscle hypertrophy occurs. As discussed herein, mucus hypersecretion, or excess mucus, can help pathogens thrive. long term and can lead to infection.

[0012] C. Interstitial pulmonary fibrosis

[0012] Interstitial pulmonary fibrosis is thought to be caused by acute damage to lung tissue that induces chronic and abnormal inflammation. Fibroblasts are activated in response to inflammation and contribute to pulmonary fibrosis, scarring, and impaired lung function. Only 20-30% of patients survive for five years after diagnosis.

[0013] D. Cystic Fibrosis (CF) Cystic fibrosis (CF) is a systemic, pulmonary, and inflammatory disease defined by a genetic defect. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause Chronic inflammation leads to airway remodeling via goblet cells and submucosal glands. This leads to excessive secretion and, in turn, to intractable airway narrowing and infection.

[0014] D. Bronchiectasis Bronchiectasis is a condition in which the airways become enlarged, thickened, and even scarred. It is usually caused by an infection that damages the walls of the airways, prevents the airways from clearing mucus, or both. Or they may develop other conditions. When this happens, the airways lose their ability to clear mucus. Each infection causes more damage and eventually It causes moderate airflow obstruction. Bronchiectasis can occur in patients with genetic disorders such as primary ciliary dyskinesia syndrome. It is caused by sexually transmitted diseases, but may also be of idiopathic origin.

[0015] III. Treatment of Pulmonary Disease In some cases, the most effective treatment for lung disease is lifestyle changes, particularly smoking cessation. This is especially true for COPD. However, many patients quit smoking. Currently, there are a variety of treatments available to ease the symptoms of lung disease. The law is available.

[0016] A. Drugs

[0016] COPD is treated with short-acting beta agonists (SABAs) and long-acting beta agonists (LAs). BA), long-acting anticholinergics (LAMA), steroids, chronic antibiotic therapy, or It can be managed with one or more medications, such as PDE4 inhibitors, such as roflumilast. SABAs and LABAs act on the β-receptors of airway smooth muscle to dilate the bronchi. AMA acts through anticholinergic pathways, inhibiting the release of acetylcholine and causing bronchodilation. LABAs and LAMAs can reduce shortness of breath and frequency of exacerbations, improving quality of life. The effect of LAMA on reducing mortality has not been demonstrated. Tropium slows the rate of decline in lung function and prolongs the time to exacerbation. Steroids directly target inflammation. Inhaled corticosteroids reduce exacerbations have been demonstrated, but have little effect on lung function or mortality. A. Combinations of inhaled corticosteroids have been tried. Inhaled oxygen helps relieve shortness of breath. It is known that the effects of serotonin-dependent oxidative stress on blood flow to the brain and improve mortality rates are not well understood, but these results are expressed using strict criteria. Only in patients with progressive disease, requiring chronic administration via nasal cannula or alternative device do.

[0017]

[0017] COPD can be treated with one or more oral medications, such as PDE4 inhibitors, steroids, or antibiotics. It can also be managed with medication. Roflumilast is a selective, long-acting inhibitor of the PDE4 enzyme. It is an oral medication that acts as an anti-inflammatory agent. It has a very strong anti-inflammatory effect, but it also causes diarrhea, weight loss, nausea, and appetite suppressant. It is associated with adverse effects such as loss of appetite and abdominal pain, and is poorly tolerated. Patients can be prescribed oral steroids such as rednisone, as stopping the treatment can lead to other complications. It is known that when this occurs, patients must continue oral steroids for an extended period of time. Oral steroids also have various side effects, including weight gain, insomnia, and Thyroid dysfunction, osteoporosis, etc. Long-term administration of azithromycin or antibiotics Antibiotics have been shown to reduce the frequency of COPD exacerbations. Elimination of the drug or, as macrolide antibiotics have shown, the suppression of mucus secretion This can be accomplished by antimicrobial action, by other mechanisms including reduction. Side effects of long-term use of the substance include hearing loss and antibiotic resistance.

[0018]

[0018] In many cases, patients are not compliant with prescribed respiratory medications. Inhalation therapy is a method of This requires not only rapid breathing but also deep breathing, which most patients, especially the elderly, are unable to perform. If you don't take the correct dosage, you may suffer cost, side effects, or both. Taken together, all factors lead to inappropriate and inconsistent dosing.

[0019]

[0019] Asthma ranges in severity in adult patients from mild to persistent. Asthma is a disease that affects a wide range of people. For mild asthma, avoidance of causative factors and short-acting beta-blockers are effective. However, the mainstream treatment for persistent asthma is to use a single anti-asthma drug (SABA). The method is inhaled glucocorticoids. Clinical trials have established that inhaled glucocorticoids are Taking it regularly reduces the need to carry an inhaler, improves lung function, reduces symptoms, and reduces the risk of developing It has been confirmed that the prevention of leukotriene formation can be effective. ABA has been added to the treatment and has been shown to be more effective. It may be another option to improve lung function rather than coid alone, especially in severe cases. , temporary or long-term treatment with oral corticosteroids may be required.

[0020] There is no known cure for interstitial pulmonary fibrosis (IPF). The main treatments are Preventive measures include oxygen supplementation and vaccinations. Approved for IPF, which seeks to slow lesions, collagen deposition, and inflammatory cell infiltration In clinical trials, pirfenidone was shown to reduce lung capacity (a measure of lung function). ) and a reduction in all-cause mortality has been demonstrated. Azathioprine is another drug approved for IPF that inhibits fibrogenic growth factors (e.g., erythropoietin). Platelet-derived growth factor, vascular endothelial growth factor, and fibroblast growth factor are some of the factors that mediate the synthesis of these factors. This works through a receptor blocker for phosphoinositide kinase, which slows the progression of IPF. There are no approved device therapies for IPF.

[0021]

[0021] Treatment for cystic fibrosis ranges from chest physiotherapy and supplemental oxygen therapy to mutations in the CFTR gene. Therapies have rapidly evolved to target the underlying defect. Ivacaftor is a CFT R enhancer, which improves chloride transport through ion channels and inhibits some CFTR genes It has been approved by the FDA for the treatment of pulmonary hypertension and pulmonary hypertension. Clinical trials have shown that it improves FEV1 and reduces the frequency of exacerbations. It has also been shown to improve mucociliary and cough clearance. However, it has not been used alone in patients with the most common delta F508 deletion. Other targeted therapies are in clinical trials. Chronic antibiotics include azithromycin, which is known to have anti-inflammatory effects, and azithromycin, which is used to treat Pseudomonas aeruginosa. These include inhaled tobramycin, which is used to treat CF. As with other obstructive diseases, In particular, CF patients respond well to bronchodilators, including LABAs and LAMAs. Drugs that promote airway clearance include inhaled DNase, which reduces the viscosity of mucus, and inhaled hypertonic saline, which draws water out of the mucus; In cases of exacerbation, oral steroids are used, but Guidelines recommend long-term use of inhaled corticosteroids.

[0022] Bronchiectasis is an anatomical manifestation of a host injury response that results in hyperdilation of the airway lumen. Therefore, treatment is often directed at the primary disease cause. These are, among others, non-tuberculous Mycobacterial infections, primary immunodeficiencies, allergic bronchopulmonary, and aspergillosis Treatment of acute exacerbations focuses on treating harmful bacterial pathogens with antibiotics. Macrolide and nonmacrolide antibiotics have been shown to reduce the frequency of exacerbations. The use of absorbed antibiotics in the absence of CF is unclear, as is the efficacy of mucolytics. Bronchodilators may be administered to patients who show signs of airway obstruction on spirometry.

[0023] Treatment for primary ciliary dyskinesia (PCD) involves daily chest physical therapy. Prompt treatment of respiratory infections improves clearance of secretions and reduces respiratory infections. The role of aerosolized DNase and other mucolytic agents is less clear. There is none.

[0024]

[0024] Respiratory tract infections caused by pathogens in the respiratory tract, regardless of type, may accompany the above diseases. Unfortunately, drug development in this field has The disease is on the decline and there are currently limited treatments available. The problem is that there is no single drug that can treat a wide variety of pathogens. In this case, the sampling method or collection mode that affects other methods and collection modes can be specified. Specimens must be obtained by bronchoscopy using special techniques to avoid contamination of the bronchus. Another problem is that pathogens are developing resistance to these treatments, so the currently available The medicines are not always effective.

[0025] B. Intervention Procedures More recently, several groups have developed interventional procedures for COPD. The usefulness of endoscopic volume reduction (LVR) as a treatment has already been proven, but most patients Because of their fragility, morbidity and mortality are extremely high. BLVR) can be performed using one-way valves, coils, steam cauterization, or by using biological tissue adhesives or high This can be achieved by delivering a molecular-based tissue adhesive to the target lobe. The physical goal is to treat emphysema and to alleviate the patient's symptoms, particularly hyperinflation. Studies have demonstrated that BLVR can improve lung function and quality of life. The method is not effective for patients with chronic bronchitis, which is an airway disease rather than an alveolar disease.

[0026] Another novel therapy is pulmonary denervation, which essentially removes the parasympathetic nerves that run through the airways. Theoretically, this is a method to neutralize reactive airway smooth muscle and trigger chronic bronchiectasis. It produces similar effects to bronchodilators such as ABA and LAMA, but without the usual disparities associated with the medication. It is the only proximal treatment using this modality that can provide long-term results without side effects. Therefore, the effect is limited to the upper airways, but the higher the resistance in the respiratory tract, the lower the airways will be. do.

[0027]

[0027] Various thermal cauterization techniques have also been described for the treatment of airway diseases, but these However, there are problems and challenges associated with controlling the ablation and / or targeting specific cell types. Liquid nitrogen therapy is used to remove superficial airway cells and produce a regenerative effect on the bronchial wall. This is a type of therapy in which a spray of aerosolized liquid is directly applied to the bronchial wall. The operator (e.g., a physician) usually applies a “spray” to the wall. Since the application of "plaque coating" is performed, the coverage, dose and / or depth of treatment can be controlled by the appropriate controller. Unless nitrogen is directly sprayed, it tends to be operator dependent. In the kip area, there is a high possibility of incomplete treatment. In addition, precise depth control is lacking. This may result in changes in the thickness of the airway wall, particularly in the treatment targets such as the lamina propria and cartilage. Radiofrequency and microwave ablation techniques may cause unintended damage to non-invasive tissue. also described in, in which energy is delivered to various locations in the airway wall and the affected tissue is Uncontrolled heat conduction, actual tissue temperature can be measured to control energy delivery The inability to treat with bronchial catheters, the risk of duplicate treatment, and variable bronchial wall thickness may result in the treatment of tissues that are not the target of treatment. In addition, the catheter is used in a variety of applications, which may cause unintended damage. These thermal imaging procedures may require repositioning of the implant, and may even result in incomplete treatment. All ablation techniques nonselectively ablate various layers of the airway wall, resulting in non-target tissue rather than the epithelium. This often results in unwanted cauterization of tissues other than the epithelium, resulting in damage to tissues that are not the target of treatment. When exposed to these substances, an inflammatory cascade can occur, inducing inflammation and leading to exacerbation and remodeling. As a result, the airway lumen is further reduced, thus limiting the extent of inflammatory responses and remodeling. While providing a method for controlling interventions at specific depths and structures that correspond to physiological disorders, There is a need for continuous improvement in the

[0028]

[0028] Asthmatx previously developed a radiofrequency ablation system for bronchial thermoplasty. The operator inserts a catheter into the airway and activates electrodes to heat the airway tissue. Many patients experience acute inflammation due to the heat generated during the procedure. In the AIR2 clinical trial, the "Asthma QOL Questionnaire" was administered. The results showed that compared with the sham group, patients did not show clinically significant improvement at 12 months. However, the treatment group had fewer exacerbations and fewer emergency room visits. It has been approved for use in the United States, but it has side effects and is designated by insurance companies as an "investigational treatment." So it is not yet in common use.

[0029]

[0029] Therefore, it is easy to control, can be adapted to the pathophysiological abnormality, and can provide a large surface area at an appropriate depth. For interventions that can be used in a phased manner to limit the extent of inflammatory responses and remodeling. The present invention seeks to meet at least some of these objectives. It is of the following. Summary of the Invention

[0030]

[0030] Described herein are methods for treating or manipulating lung tissue and / or treating COPD ( For example, chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis , Primary Ciliary Dyskinesia (PCD), acute bronchitis, and other lung diseases or disorders and / or other pulmonary diseases or disorders. One or more of the features of any of these embodiments may be combined with one or more of the features of one or more other embodiments. The present invention may be combined with one or more of the features to form novel embodiments of the present invention. Examples of cells include, but are not limited to, epithelium (goblet cells, pseudostratified ciliated columnar cells, basal cells) , lamina propria, submucosa, submucosal gland, basement membrane, smooth muscle, cartilage, nerve, near or within tissue pathogens present in the food supply, or a combination of these.

[0031]

[0031] The methods, devices, and systems disclosed herein include a pulmonary tissue modification system (e.g., The energy delivery catheter system (e.g., In some embodiments, the energy delivered to the target tissue is used to treat the lung tissue. In this study, energy delivery ablates targeted tissue without any clinically significant inflammatory healing response. However, in other embodiments, some degree of inflammatory healing response is acceptable. Within days of placement, new, healthy target tissue will be regenerated. The energy delivery is directed at the airway structures without substantially affecting or damaging other airway structures. Remove pathogens by destruction or other means.

[0032] In a first aspect, a system for reducing mucus hypersecretion in the pulmonary passages of a patient is provided. The system includes: a) at least one electrode located near a distal end; The probe is positioned within a pulmonary passageway of the patient, and at least one electrode directs non-thermal energy into the pulmonary passageway. a catheter configured to transmit electrical current to the airway wall; and b) at least one electrode and an electrical The researchers are investigating whether the cells in the airway walls are involved in the secretion of mucus, and how they can selectively treat the airway. The present invention provides a non-thermal electrical signal that can be transmitted to the airway walls, reducing the excessive secretion of mucus in the walls. a generator having at least one energy delivery algorithm configured to Includes.

[0033] In some embodiments, the selective treatment selectively targets specific cells from the airway wall. In some embodiments, the removal comprises cell detachment. For example, In some embodiments, cell detachment may be performed by dielectrophoresis. For example, cell death may be achieved by electroporation. Alternatively, other media Similarly, removal may be accomplished by dielectrophoresis and electroporation, or other techniques. It may include a combination with the mechanism.

[0034] In some embodiments, the particular cells include epithelial cells rather than basal cells. For example, the epithelial cells may comprise abnormal or hyperplastic goblet cells. It may contain abnormally multistratified ciliated columnar epithelial cells.

[0035] In some embodiments, the specific cells include cells of the basement membrane, and selective Potential treatments include modifying the cells of the basement membrane and altering the permeability of the basement membrane. In some embodiments, the specific cells include submucosal glands, and the selective treatment induces cell death in the submucosal glands. In some embodiments, the specific cells include pathogens and The selective treatment includes causing cell death of the pathogen. Selective treatment involves selectively modifying certain cells to alter mucus production.

[0036] In some embodiments, the electrical signal comprises at least one energy packet. In one example, each pulse has a waveform including about 5 pulses. In another example, each pulse is about 500 to 4000V.

[0037] In some embodiments, at least one energy packet comprises about 500 In some embodiments, each pulse has a frequency in the range of 100 kHz to 800 kHz. It is biphasic.

[0038] In some embodiments, the system is positioned along the catheter and the airway. In some embodiments, the airway wall is in contact with a temperature sensor that monitors the temperature inside and outside the airway wall. In the present invention, the generator includes a processor in communication with the temperature sensor, the processor comprising: If the temperature rises above the temperature threshold for a thermal tissue effect, at least one energy delivery algorithm is activated. Correct the rhythm.

[0039] In some embodiments, the system is positioned along the catheter and the airway. The airway wall may further include an impedance sensor in contact with the wall to monitor impedance at the airway wall. The impedance sensor provides an indicator of the condition of the airway wall based on impedance. In one example, the condition of the airway wall includes the completion of treatment for a particular cell. In an example, the condition of the airway wall includes the lack of effect of a treatment on certain cells.

[0040] In some embodiments, the generator includes a mechanism for acquiring a cardiac signal from a patient. and identifying a safe period during which non-thermal energy can be delivered to the airway walls of the pulmonary passages based on the cardiac signal. In some embodiments, the safety period is occurs in the ST segment of the cardiac signal. In another embodiment, the safety period occurs in the QT occurs during the interval.

[0041] In some embodiments, the system is adapted to sense a parameter of the airway wall. and the generator further includes at least one sensor configured to modifying at least one energy delivery algorithm based on data obtained from the sensor; The system further includes a processor configured to create a feedback loop.

[0042] In some embodiments, the catheter comprises an expandable catheter that contacts the airway wall of the pulmonary passageway. In some embodiments, the at least two protrusions include: A plurality of wires forming an expandable cage, at least one of the wires having at least one In some embodiments, the catheter includes a shaft and a shaft. In some embodiments, one of the wires does not pass through the expandable cage. At least a portion of each of the wires is insulated from adjacent wires in the plurality of wires. In some embodiments, at least a portion of one of the plurality of wires is an exposed portion of the wire. The active area is insulated from the surrounding airway and focuses energy at specific locations along the airway walls of the lung passages. In some embodiments, multiple wires can be energized simultaneously. In an embodiment, at least a portion of the plurality of wires are individually energizable.

[0043] In some embodiments, at least one electrode has at least two protrusions. In this embodiment, a separate electrode is attached to at least one of the The electrode may be in the form of a coil.

[0044] In some embodiments, the catheter includes a shaft and at least two The prongs include a plurality of wires having ends attached to the shaft and free ends, the prongs being semi-expandable. Form a molded cage.

[0045]

[0045] In some embodiments, the system includes a mechanism for folding at least two protrusions. The catheter further includes a sheath advanceable over the catheter.

[0046] In a second aspect of the present invention, a method for detecting abnormal functioning of the pulmonary passages of a patient is provided. A system for regenerating healthy tissue is provided, the system comprising: a) a small amount of tissue disposed near a distal end of the system; the distal end is positioned within a pulmonary passageway of the patient and includes at least one electrode; a catheter configured such that the poles are capable of transmitting non-thermal energy to an airway wall of the pulmonary passageway; and b) The device is in electrical communication with at least one electrode to maintain collagen matrix structure within the airway wall. While doing so, it removes abnormally functioning cells from the airway walls and regenerates the airway walls with normal healthy tissue. at least one configured to provide a non-thermal energy electrical signal that is transmissible to the wall of the passageway; and a generator having an energy delivery algorithm.

[0047] In some embodiments, the removal comprises cell detachment. For example, cell detachment can be achieved by: This may be achieved by dielectrophoresis. In some embodiments, the removal comprises cell death. For example, cell death may be induced by electroporation or by other mechanisms. Similarly, removal may be achieved by a combination of dielectrophoresis and electroporation, or other mechanisms. It may include combinations.

[0048] In some embodiments, the abnormally functioning cells include epithelial cells rather than basal cells. In one example, the epithelial cells include abnormal or hyperplastic goblet cells. In some embodiments, the abnormally functioning cells comprise submucosal glands. and removal includes causing cell death in the submucosal gland.

[0049] In some embodiments, the electrical signal comprises at least one energy packet. In one example, each pulse has a waveform including: In another example, each pulse is about 500 to 4000V. In some embodiments, at least one energy packet comprises about 500-800 In some embodiments, each pulse is biphasic. .

[0050] In some embodiments, the system is positioned along the catheter and the airway. In some embodiments, the airway wall is in contact with a temperature sensor that monitors the temperature inside and outside the airway wall. In the present invention, the generator includes a processor in communication with the temperature sensor, the processor comprising: If the temperature rises above the temperature threshold for a thermal tissue effect, at least one energy delivery algorithm is activated. Correct the rhythm.

[0051] In some embodiments, the system is disposed along the catheter and configured to irrigate the airway wall. an impedance sensor in contact with the airway wall to monitor impedance at the airway wall; The impedance sensor is an indicator of the condition of the airway wall based on impedance. and communicates.

[0052] In some embodiments, the condition of the airway wall is determined by a lack of efficacy in removing abnormally functioning cells. Including such.

[0053] In some embodiments, the generator includes a mechanism for acquiring a cardiac signal from a patient. and identifying a safe period during which non-thermal energy can be delivered to the airway walls of the pulmonary passages based on the cardiac signal. In some embodiments, the safety period is occurs in the ST segment of the cardiac signal. In another embodiment, the safety period occurs in the QT occurs during the interval.

[0054] In some embodiments, the system is adapted to sense a parameter of the airway wall. and the generator further includes at least one sensor configured to modifying at least one energy delivery algorithm based on data obtained from the sensor; The system further includes a processor configured to create a feedback loop.

[0055] In some embodiments, the catheter comprises an expandable catheter that contacts the airway wall of the pulmonary passageway. The at least two protrusions form an expandable cage. A plurality of wires, at least one of the wires functioning as at least one electrode. .

[0056]

[0056] In some embodiments, the catheter includes a shaft, the shaft comprising an expandable Does not pass through the mold cage.

[0057] In some embodiments, at least a portion of one of the plurality of wires is In some embodiments, the wires are insulated from adjacent wires in the plurality of wires. At least a portion of one of the plurality of wires is insulated leaving an exposed portion of the wire, It creates active regions that focus energy at specific locations along the airway walls of the tract. In some embodiments, multiple wires can be energized simultaneously. At least some of the wires are individually energizable.

[0058] In some embodiments, at least one electrode has at least two protrusions. In this example, the separate electrode is It may be in the shape of a ring.

[0059] In some embodiments, the catheter includes a shaft and at least two The prongs include a plurality of wires having ends attached to the shaft and free ends, the prongs being semi-expandable. Form a molded cage.

[0060]

[0060] In some embodiments, the system includes a mechanism for folding at least two protrusions. The catheter further includes a sheath advanceable over the catheter.

[0061] In a third aspect of the present invention, a method for treating a patient's pulmonary pulmonary syndrome is provided. A system for regenerating healthy tissue is provided, the system comprising: a) a small amount of tissue disposed near a distal end of the system; a distal end for positioning the energy delivery device within a pulmonary passageway of a patient; a catheter configured to deliver thermal energy to an airway wall of the pulmonary passageway; and b) at least The device communicates electrically with one electrode at a time while maintaining the collagen matrix structure in the airway wall. Then, cells involved in the abnormal functioning of the lung passages are removed from the airway walls and the walls are regenerated with normal healthy tissue. at least one of the at least two electrodes configured to provide a non-thermal electrical signal transmissible to an airway wall, and a generator having an energy delivery algorithm.

[0062] In some embodiments, the removal comprises cell detachment. For example, the electrical signal may Dielectrophoresis may cause cell detachment. In some embodiments, the removal is Including cell death.

[0063] In some embodiments, the cells include epithelial cells rather than basal cells. For example, the epithelial cells may comprise abnormal or hyperplastic goblet cells. It may contain ciliated columnar epithelial cells.

[0064] In some embodiments, the cells are lymphocytes, macrophages, eosinophils, fibronectins, Contains fibroblasts, plasma cells, mast cells, white blood cells, or a combination of these. In an embodiment, the cells comprise submucosal glands and removal causes cell death of the submucosal glands. In other embodiments, the cell comprises a pathogen.

[0065] In some embodiments, the electrical signal comprises at least one energy packet. Each energy packet has a waveform including a series of pulses, each of which may include, for example, about 5 Alternatively, each pulse may be about 500 to 4000 V. In some embodiments, at least one energy packet may be about 50 In some embodiments, each pulse has a frequency in the range of 0 to 800 kHz. It's a matter of compatibility.

[0066] In some embodiments, the system is positioned along the catheter and the airway. It further includes a temperature sensor in contact with the wall to monitor the temperature inside and outside the airway wall.

[0067] In some embodiments, the generator includes a process in communication with the temperature sensor. and a processor configured to detect at least one of the following when the temperature rises above a temperature threshold for a thermal tissue effect: Another energy delivery algorithm is modified.

[0068] In some embodiments, the system is positioned along the catheter and the airway. The airway wall may further include an impedance sensor in contact with the wall to monitor impedance at the airway wall. The impedance sensor provides an indicator of the condition of the airway wall based on impedance. It communicates with the data.

[0069] In some embodiments, the condition of the airway wall comprises an ineffective clearance of cells. .

[0070] In some embodiments, the generator includes a mechanism for acquiring a cardiac signal from a patient. and identifying a safe period during which non-thermal energy can be delivered to the airway walls of the pulmonary passages based on the cardiac signal. In some embodiments, the safety period is occurs in the ST segment of the cardiac signal. occurs during the QT interval.

[0071] In some embodiments, the system is adapted to sense a parameter of the airway wall. and the generator further includes at least one sensor configured to modifying at least one energy delivery algorithm based on data obtained from the sensor; The system further includes a processor configured to create a feedback loop.

[0072] In some embodiments, the catheter is an expandable catheter that contacts the airway wall of the pulmonary passageway. In some embodiments, the at least two protrusions include: A plurality of wires forming an expandable cage, at least one of the wires having at least one It functions as an electrode.

[0073] In some embodiments, the catheter includes a shaft, the shaft comprising an expandable Does not pass through the mold cage.

[0074] In some embodiments, at least a portion of one of the plurality of wires is In some embodiments, the wires are insulated from adjacent wires in the plurality of wires. At least a portion of one of the plurality of wires is insulated leaving an exposed portion of the wire, It creates active areas that focus energy at specific locations along the airway wall of the tract.

[0075] In some embodiments, multiple wires can be energized simultaneously. In an embodiment, at least a portion of the plurality of wires are individually energizable.

[0076] In some embodiments, at least one electrode has at least two protrusions. In this embodiment, a separate electrode is attached to at least one of the The electrode may be in the form of a coil.

[0077] In some embodiments, the catheter comprises a shaft and at least two The prongs include a plurality of wires having ends attached to the shaft and free ends, the prongs being semi-expandable. Form a molded cage.

[0078]

[0078] In some embodiments, the system includes a mechanism for folding at least two protrusions. The catheter further includes a sheath advanceable over the catheter.

[0079] In a fourth aspect of the present invention, a system for removing epithelial cells from a body passage is provided. The system includes: a) at least one electrode disposed near a distal end, the distal end being At least one electrode positioned within the body passageway transmits non-thermal energy to a wall of the body passageway. and b) a catheter in electrical communication with at least one electrode; Dielectrophoresis is used to remove epithelial cells from the airway wall and regenerate the wall with normal healthy tissue. At least one energy source configured to provide a transferable non-thermal energy electrical signal. and a generator having a delivery algorithm.

[0080] In some embodiments, the epithelial cells comprise goblet cells. In yet another embodiment, the epithelial cells include multistratified ciliated columnar epithelial cells. , contain goblet cells and pseudostratified ciliated columnar epithelial cells, but not basal cells.

[0081] In some embodiments, the body passageway includes a pulmonary passageway. For example, the body passageway includes , blood vessels, lymphatic vessels, kidney tubules, esophagus, stomach, small intestine, large intestine, appendix, rectum, bladder, ureters, It may be the pharynx, oral cavity, vagina, urethra, or glandular duct.

[0082] In some embodiments, the electrical signal comprises at least one energy packet. In some embodiments, the energy packet has a waveform including a series of pulses. In another embodiment, each pulse is about 500V to 10 kV. In some embodiments, at least one energy The packets have a frequency in the range of approximately 500 to 800 kHz. In this case, each pulse is biphasic.

[0083] In some embodiments, the system is positioned along the catheter and the airway. In some embodiments, the airway wall is in contact with a temperature sensor that monitors the temperature inside and outside the airway wall. In the present invention, the generator includes a processor in communication with the temperature sensor, the processor comprising: If the temperature rises above the temperature threshold for a thermal tissue effect, at least one energy delivery algorithm is activated. Correct the rhythm.

[0084] In some embodiments, the system is positioned along the catheter and the airway. The airway wall may further include an impedance sensor in contact with the wall to monitor impedance at the airway wall. The impedance sensor provides an indicator of the condition of the airway wall based on impedance. In some embodiments, the condition of the airway wall is determined by a lack of efficacy of cell detachment. Includes.

[0085] In some embodiments, the generator includes a mechanism for acquiring a cardiac signal from a patient. and identifying a safe period during which non-thermal energy can be delivered to the airway walls of the pulmonary passages based on the cardiac signal. In some embodiments, the safety period is occurs in the ST segment of the cardiac signal. occurs during the QT interval.

[0086] In some embodiments, the system is adapted to sense a parameter of the airway wall. and the generator further includes at least one sensor configured to modifying at least one energy delivery algorithm based on data obtained from the sensor; The system further includes a processor configured to create a feedback loop.

[0087] In some embodiments, the catheter is an expandable catheter that contacts the airway wall of the pulmonary passageway. In some embodiments, the at least two protrusions include: A plurality of wires forming an expandable cage, at least one of the wires having at least one In some embodiments, the catheter includes a shaft and a shaft. In some embodiments, one of the wires does not pass through the expandable cage. At least a portion of each of the wires is insulated from adjacent wires in the plurality of wires. In some embodiments, at least a portion of one of the plurality of wires is an exposed portion of the wire. The active area is insulated from the surrounding airway and focuses energy at specific locations along the airway walls of the lung passages. produce.

[0088]

[0088] In some embodiments, multiple wires can be energized simultaneously. In some embodiments, at least a portion of the plurality of wires are individually energizable.

[0089] In some embodiments, at least one electrode has at least two protrusions. In this example, the separate electrode is It may be in the shape of a ring.

[0090] In some embodiments, the catheter comprises a shaft and at least two The prongs include a plurality of wires having ends attached to the shaft and free ends, the prongs being semi-expandable. Form a molded cage.

[0091]

[0091] In some embodiments, the system includes a mechanism for folding at least two protrusions. The catheter further includes a sheath advanceable over the catheter.

[0092] In a fifth aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, the system comprising: The system includes: a) delivering energy to a catheter configured to be positioned within a pulmonary passageway; a generator configured to transmit energy to the pulmonary passageway; has at least one energy delivery algorithm and a processor, the processor comprising: providing electrical signals of energy in accordance with at least one energy delivery algorithm; The energy signal has a waveform including at least one energy packet, each energy packet being The energy is delivered to specific cells involved in the excessive secretion of mucus in the lung passages. Selective treatment is given to reduce excess mucus production.

[0093] In some embodiments, each pulse is about 500-4000V.

[0094] In some embodiments, the energy is delivered monopolarly, with each pulse lasting about 20 In another embodiment, the energy is delivered bipolarly, with each The pulse is approximately 500 to 1900 volts.

[0095] In some embodiments, the particular cells include epithelial cells rather than basal cells. .

[0096] In some embodiments, increasing the voltage of the pulse transfers energy to the pulmonary passages. This allows the treatment to be selectively delivered to certain cells located deeper within the wall.

[0097] In some embodiments, at least one energy packet comprises about 500 It has a frequency range of ~800kHz.

[0098] In some embodiments, the energy is for treating the cartilage layer within the pulmonary passageway. In some embodiments, the energy is below a threshold that causes thermal ablation. It is full.

[0099] In some embodiments, the system contacts the walls of the pulmonary passageways and measures the temperature across and within the walls. and further comprising a temperature sensor configured to monitor

[0100]

[0100] In some embodiments, the processor is in communication with the temperature sensor and further The processor then detects whether at least one of the elements is in a state where the temperature rises above a temperature threshold for a thermal tissue effect. In some embodiments, each pulse is biphasic. be.

[0101]

[0101] In some embodiments, the treatment involves removing specific cells.

[0102] In some embodiments, the specific cells include cells of the basement membrane and are selectively treated. Therapies include modifying the cells of the basement membrane and altering the permeability of the basement membrane.

[0103] In some embodiments, the particular cells include submucosal glands and selective treatment In some embodiments, the method includes inducing cell death in the submucosal gland. The cells contain the pathogen and the selective treatment involves causing cell death of the pathogen.

[0104] In some embodiments, the system is adapted to acquire a cardiac signal from the patient. The method further includes: providing a cardiac monitor configured to: Provides a signal.

[0105] In some embodiments, the processor may further comprise: In another embodiment, the processor provides an electrical signal during the QT interval of the cardiac signal. It provides an electrical signal of energy.

[0106]

[0106] In some embodiments, the system contacts the walls of the pulmonary passageway and The impedance sensor further includes an impedance sensor configured to monitor the impedance. The impedance sensor communicates with an impedance-based wall status indicator. In some embodiments, the condition of the airway wall includes completion of a treatment directed to a particular cell. In some embodiments, the condition of the airway wall is determined by the lack of effect of a treatment on certain cells. Includes.

[0107] In some embodiments, the system senses a parameter of a wall of the pulmonary passageway. and the processor further comprises at least one sensor configured to modifying at least one energy delivery algorithm based on data from the two sensors; and create a feedback loop.

[0108]

[0108] In a sixth aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, comprising: The stem a) delivers energy to a catheter configured to be positioned within the pulmonary passageway. and configured to deliver energy to the pulmonary passageway while at least one energy A delivery algorithm and a processor, the processor controlling at least one energy delivery The method includes providing an electrical signal of energy in response to an algorithm, the energy being measured to detect the amount of mucus in the pulmonary passages. The drug reduces mucus hypersecretion by selectively treating specific cells involved in hypersecretion. and b) at least one sensor in communication with the processor, the sensor being , sensing a condition of the pulmonary passageway, and a processor controlling at least one energy delivery based on the condition. At least one parameter of the algorithm is modified.

[0109] In some embodiments, the at least one parameter is a voltage, a frequency , packet period, number of cycles, number of energy packets, idle period, or dead time.

[0110] In some embodiments, the at least one sensor includes a temperature sensor. , the condition includes the temperature at a portion of the wall of the pulmonary passageway.

[0111] In some embodiments, the at least one parameter includes a voltage. The processor reduces the voltage when the temperature reaches a temperature threshold.

[0112] In some embodiments, the processor may be configured to: The supply of electrical energy signals is stopped.

[0113]

[0113] In some embodiments, the system further comprises a catheter. The probe comprises at least one electrode positionable near or against the wall of the pulmonary passage. to transmit energy to the pulmonary passageway, and the at least one sensor includes a temperature sensor; The condition includes a temperature of at least one electrode.

[0114] In some embodiments, at least one sensor is an impedance sensor. In some embodiments, the condition includes an impedance of a portion of a wall of the pulmonary passageway. The processor compares the impedance to an impedance threshold and determines whether the impedance is greater than the threshold. If the impedance threshold is exceeded, the generator issues an alarm.

[0115]

[0115] In some embodiments, the system further comprises a catheter. The probe comprises at least one electrode positionable near or against the wall of the pulmonary passage. and transmitting energy to the pulmonary passageway, and the alarm is provided by at least one of the at least one electrode. The device may include an indication that the device is not properly positioned.

[0116] In some embodiments, the at least one parameter includes a voltage. The processor reduces the voltage when the impedance reaches an impedance threshold.

[0117] In some embodiments, the processor determines whether the impedance is When the threshold energy level is reached, the delivery of the energy electrical signal is discontinued. At least one sensor may be a temperature sensor, an impedance sensor, a surface conductivity sensor, a membrane This includes potential sensors, capacitance sensors, force sensors, or pressure sensors.

[0118] In some embodiments, the system is adapted to acquire a cardiac signal from the patient. The method further includes: providing a cardiac monitor configured to: In some embodiments, the condition of the pulmonary passageway provides a therapeutic signal to specific cells. This includes completion of treatment. In some embodiments, the condition of the pulmonary passages may indicate a lack of effect of a treatment on a particular cell. include.

[0119]

[0119] In a seventh aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, comprising: The stem a) delivers energy to a catheter configured to be positioned within the pulmonary passageway. and configured to deliver energy to the pulmonary passageway while at least two energy A delivery algorithm and a processor, the processor comprising at least two energy delivery Select one of the algorithms and respond to one of at least two energy delivery algorithms. The energy is then applied to the lungs to stimulate the production of electrical energy, which is associated with excessive mucus secretion in the lung passages. a generator that selectively treats certain cells to reduce mucus hypersecretion; and b) and at least one sensor in communication with the processor, the sensor detecting a condition of the pulmonary passageway. and a processor for selecting the other of the at least two energy delivery algorithms. The energy delivery algorithm comprises providing an electrical signal of energy in response to the other of at least two energy delivery algorithms.

[0120] In some embodiments, the at least one sensor includes a temperature sensor. , the condition includes the temperature at a portion of the wall of the pulmonary passageway.

[0121]

[0121] In some embodiments, the system further comprises a catheter. The probe comprises at least one electrode positionable near or against the wall of the pulmonary passage. to transmit energy to the pulmonary passageway, and the at least one sensor includes a temperature sensor; The condition includes a temperature of at least one electrode.

[0122] In some embodiments, at least one sensor is an impedance sensor. In some embodiments, the condition includes an impedance of a portion of a wall of the pulmonary passageway. The processor compares the impedance to an impedance threshold and determines whether the impedance is greater than the threshold. If the impedance threshold is exceeded, the generator will give an alarm. In one embodiment, the at least one parameter includes a voltage, and the processor determines an impedance. When the sensor reaches an impedance threshold, the voltage is reduced.

[0123] In some embodiments, the at least one sensor may be a temperature sensor, an in Impedance sensor, surface conductivity sensor, membrane potential sensor, capacitance sensor, force sensor, or pressure sensor Includes a force sensor.

[0124] In some embodiments, the system is adapted to acquire a cardiac signal from the patient. The method further includes: providing a cardiac monitor configured to: In some embodiments, the condition of the pulmonary passageway provides a therapeutic signal to specific cells. In some embodiments, the status of the pulmonary passageways includes completion of a therapeutic treatment for a particular cell. This includes the lack of effectiveness of treatment.

[0125] In an eighth aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, comprising: The stem a) delivers energy to a catheter configured to be positioned within the pulmonary passageway. and configured to deliver energy to the pulmonary passageway while at least one energy A delivery algorithm and a processor, the processor controlling at least one energy delivery The algorithm delivers electrical energy signals to the airway wall, which then penetrates the airway wall and attacks the abnormal functioning cells. a) a generator for removing the cells; and b) at least one sensor in communication with the processor. the sensor senses a condition of the pulmonary passageway, and the processor determines at least one of the following based on the condition: At least one parameter of the energy delivery algorithm is modified.

[0126]

[0126] In a ninth aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, comprising: The stem a) delivers energy to a catheter configured to be positioned within the pulmonary passageway. and configured to deliver energy to the pulmonary passageway while at least one energy A delivery algorithm and a processor, the processor controlling at least one energy delivery According to an algorithm, an electrical signal of energy is delivered, and the energy is applied to collagen in the airway wall. By removing cells involved in the abnormal functioning of lung passageways from the airway walls while preserving the matrix structure. a) a generator for regenerating the airway wall with normal healthy tissue; and b) a small number of devices in communication with the processor. At least one sensor; The sensor senses a condition of the pulmonary passageway, and the processor controls at least one energy At least one parameter of the drug delivery algorithm is modified.

[0127]

[0127] In a tenth aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, comprising: The system includes: a) providing energy to a catheter configured to be positioned within a pulmonary passageway; and configured to deliver energy to the pulmonary passageway while at least one energy and a processor, the processor controlling at least one energy delivery algorithm. According to the algorithm, an electrical signal of energy is supplied, and the energy is transferred to the wall by dielectrophoresis. a) a generator that removes epithelial cells from the wall and regenerates the wall with normal healthy tissue; and b) a process and at least one sensor in communication with the sensor, the sensor sensing a condition of the pulmonary passageway; The processor determines at least one of the energy delivery algorithms based on the state. Modify one parameter.

[0128] In an eleventh aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, comprising: The system includes: a) providing energy to a catheter configured to be positioned within a pulmonary passageway; and configured to deliver energy to the pulmonary passages while providing at least two energy and a processor, the processor comprising at least two energy delivery algorithms. and selecting one of the energy delivery algorithms and responding to one of at least two energy delivery algorithms. The device delivers an electrical signal of energy to the airway walls, which removes abnormally functioning cells from the airway walls. and b) at least one sensor in communication with the processor, the sensor being , sensing a condition of the pulmonary passageways, and a processor selecting at least two energy delivery algorithms. and selecting the other of the at least two energy delivery algorithms to determine the potential of the energy. Provides a visual signal.

[0129] In a twelfth aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, comprising: The system includes: a) providing energy to a catheter configured to be positioned within a pulmonary passageway; and configured to deliver energy to the pulmonary passages while providing at least two energy and a processor, the processor comprising at least two energy delivery algorithms. and selecting one of the energy delivery algorithms and responding to one of at least two energy delivery algorithms. The energy is delivered to the collagen matrix structure in the airway wall via an electrical impingement technique. Removes cells from the airway walls that are involved in the abnormal functioning of the lung passages, while maintaining normal healthy tissue. a) a generator for regenerating the airway wall; and b) at least one cell in communication with the processor. and a sensor for sensing a condition of the pulmonary passageway, the processor comprising: select another of the energy delivery algorithms, and select at least two other of the energy delivery algorithms. It delivers an electrical signal of energy depending on the direction.

[0130] In a thirteenth aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, comprising: The system includes: a) providing energy to a catheter configured to be positioned within a pulmonary passageway; and configured to deliver energy to the pulmonary passages while providing at least two energy and a processor, the processor comprising at least two energy delivery algorithms. and selecting one of the energy delivery algorithms and responding to one of at least two energy delivery algorithms. The device supplies an electrical signal of energy to the epithelium, which detaches the epithelial cells from the wall by dielectrophoresis. and b) a generator that regenerates the wall with normal healthy tissue; and and at least one sensor, the sensor sensing a condition of the pulmonary passageway, the processor and selecting the other of at least two energy delivery algorithms. An electrical signal of energy is provided in response to another of the algorithms.

[0131] In a fourteenth aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, comprising: The system includes: a) at least one catheter positionable near or against a wall of a pulmonary passageway; a) a catheter having two electrodes for transmitting energy to the pulmonary passageway; and b) a catheter having two electrodes for transmitting energy to the pulmonary passageway. and c) at least one sensor disposed adjacent the pulmonary passageway to sense a condition of the pulmonary passageway and generate a condition value; A generator having a processor configured to issue an alarm when a sensor value exceeds a threshold value. Includes a meter and a transmitter.

[0132] In some embodiments, the at least one sensor is an impedance sensor. and the state value includes the impedance of a portion of the wall of the pulmonary passageway.

[0133] In some embodiments, the alarm is generated by detecting at least one of the electrodes. In another embodiment, the warning includes an indication that one of the sensors is not properly positioned. The information includes an indication that at least one of the at least one electrodes is faulty.

[0134] In a fifteenth aspect of the present invention, there is provided a system for treating a pulmonary passageway of a patient, comprising: The system includes: a) a cardiac monitor configured to acquire a cardiac signal from a patient; and b) a pulmonary passageway. and transmitting an electrical signal of energy to at least one electrode positionable within the lung passageway. and a generator for supplying an electrical signal in synchronization with the cardiac signal. R,

[0135] In some embodiments, the cardiac monitor detects a cardiac signal at a predetermined point. The generator is configured to transmit a cardiac synchronous pulse to the cardiac synchronous pulse generator. In some embodiments, the method includes providing an electrical signal of energy after a predetermined delay from receiving the signal. In some embodiments, the predetermined point is the peak of the R wave of the cardiac signal. The delay is in the range of 50 to 100 milliseconds.

[0136]

[0136] In some embodiments, the generator includes a processor, monitors a plurality of cardiac synchronous pulses, calculates a time interval between successive cardiac synchronous pulses, and If the interval is not constant for a given number of cardiac synchronous pulses, the electrical signal generated by the generator In some embodiments, the predetermined number of cardiac synchronous pulses is five. In an embodiment, the predetermined number of cardiac sync pulses is three. The processor is configured to prevent the delivery of electrical signals by the generator from being interrupted by the cardiac synchronous pulse. In some embodiments, the generator reduces the ST pulses of the cardiac signal. In some embodiments, the generator is configured to transmit an electrical signal at the The transducer is configured to transmit an electrical signal during the QT interval of the cardiac signal. In this embodiment, the generator is configured to not transmit an electrical signal during a T wave of the cardiac signal. In some embodiments, the generator transmits an electrical signal during the retrace period. In some embodiments, the blanking period is configured to be equal to or greater than the R-wave peak of the cardiac signal. The time is 100 to 200 milliseconds after the click.

[0137] In some embodiments, the system includes at least one electrode attached. The catheter further includes a catheter having a catheter inserted therein.

[0138] In some embodiments, the system is configured to image the pulmonary passageways. In some embodiments, the imaging modality further comprises a bronchoscope. nothing.

[0139] In a sixteenth aspect of the present invention, there is provided a method for reducing mucus hypersecretion in the pulmonary passages of a patient. a) an energy delivery body disposed near a distal end of the energy delivery body; the energy delivery body having at least two expandable protrusions for contacting a wall of the pulmonary passageway, each protrusion a) a catheter including at least one electrode; and b) a catheter configured to emit non-thermal energy of any amount. a generator that provides an electrical signal to at least one electrode that transmits toward the wall. The energy dose selectively targets specific cells involved in the hypersecretion of mucus in the airway walls. It reduces the excessive secretion of mucus by the airway walls.

[0140] In some embodiments, the at least two protrusions form an expandable cage. A plurality of wires, at least one of the wires functioning as at least one electrode. .

[0141]

[0141] In some embodiments, the catheter includes a shaft, the shaft being expandable. It does not pass through the dildo.

[0142] In some embodiments, at least a portion of one of the plurality of wires , are insulated from adjacent wires in the plurality of wires. At least a portion of one of the plurality of wires is insulated leaving an exposed portion of the wire, It creates an active area that focuses an amount of energy at a specific location along the airway wall of the passageway.

[0143]

[0143] In some embodiments, multiple wires can be energized simultaneously. In an embodiment, at least a portion of the plurality of wires are individually energizable.

[0144]

[0144] In some embodiments, at least one electrode has at least two protrusions. In this embodiment, the separate electrode is a coil-shaped It may be in the form of

[0145] In some embodiments, the catheter comprises a shaft and at least two The prongs include a plurality of wires having ends attached to the shaft and free ends, the wires being semi-expandable. Form a dildo cage.

[0146] In some embodiments, the system includes a folding mechanism for folding at least two protrusions. The catheter further includes a sheath advanceable over the catheter.

[0147] In some embodiments, selective treatment involves the selection of specific cells from the airway wall. The particular cells may include epithelial cells rather than basal cells. In one embodiment, the epithelial cells include abnormal or hyperplastic goblet cells. In another embodiment, the epithelial cells include abnormal hyperstratified goblet cells. Contains ciliated columnar epithelial cells.

[0148] In some embodiments, the removal comprises cell detachment. Thus, elimination includes cell death.

[0149] In some embodiments, the specific cells include cells of the basement membrane and are selectively treated. Therapies include modifying the cells of the basement membrane and altering the permeability of the basement membrane.

[0150] In some embodiments, the particular cells include submucosal glands and selective treatment This includes causing cell death in the submucosal gland.

[0151] In some embodiments, the particular cells include a pathogen and the selective treatment is , including causing cell death of the pathogen.

[0152] In some embodiments, selective treatment selectively modifies specific cells. These include altering mucus production by

[0153] In some embodiments, the electrical signal comprises at least one energy packet. In one example, each pulse has a waveform including a series of energy packets. , approximately 500V to 10kV.

[0154]

[0154] In some embodiments, the system is disposed along the energy delivery body. The airway wall further includes a temperature sensor in contact with the airway wall to monitor the temperature inside and outside the airway wall.

[0155] In some embodiments, the generator includes a processor that communicates with the temperature sensor. and a processor, the processor detecting at least one of the temperature thresholds for a thermal tissue effect when the temperature rises above a thermal tissue effect threshold. The energy delivery algorithm is also modified.

[0156]

[0156] In some embodiments, the system is disposed along the energy delivery body. and an impedance sensor in contact with the airway wall to monitor the impedance at the airway wall. The impedance sensor further includes an impedance sensor that indicates the condition of the airway wall based on impedance. Communicates with the indicator.

[0157] In some embodiments, the generator is operable to obtain a cardiac signal from a patient. and analyzing cardiac signals to identify safe periods during which non-thermal energy can be delivered to the airway walls of the pulmonary passages. and a processor configured to:

[0158] In some embodiments, the system is adapted to sense a parameter of the airway wall. and the generator further includes at least one sensor configured as follows: Modify the electrical signal based on data from the sensor, creating a feedback loop. The device further includes a processor configured to:

[0159] In a seventeenth aspect of the present invention, there is provided a method for reducing mucus hypersecretion in the pulmonary passages of a patient. The present invention provides a method for measuring a pulmonary function, the method comprising: a) positioning at least one electrode within a pulmonary passageway; At least one electrode is positioned near or against a portion of the airway wall of the pulmonary passageway. and b) energizing at least one electrode to deliver non-thermal energy to a portion of the airway wall. The non-thermal energy reaches specific cells involved in the hypersecretion of mucus in the airway walls. Selective treatments are administered to reduce the excessive secretion of mucus by the airway walls.

[0160] In some embodiments, selective treatment involves the selection of specific cells from the airway wall. In one example, the particular cells include epithelial cells rather than basal cells. In one example, the epithelial cells include abnormal or hyperplastic goblet cells. Contains ciliated columnar epithelial cells.

[0161] In some embodiments, the removal comprises cell detachment. For example, the removal comprises induction In some embodiments, the removal may include cell detachment by electrophoresis. include.

[0162] In some embodiments, the specific cells include cells of the basement membrane and are selectively treated. Therapies include modifying the cells of the basement membrane and altering the permeability of the basement membrane.

[0163] In another embodiment, the particular cells include submucosal glands and the selective treatment is This includes causing cell death in the submucosal gland.

[0164] In yet another embodiment, the particular cell comprises a pathogen and the selective treatment comprises: This involves causing cell death in pathogens.

[0165] In some embodiments, selective treatment selectively modifies specific cells. These include altering mucus production by

[0166]

[0166] In some embodiments, at least one electrode comprises a plurality of electrodes forming an expandable cage. Positioning at least one electrode in the pulmonary passageway expands the expandable cage. wherein at least one of the plurality of wires contacts an airway wall of the pulmonary passageway. In some embodiments, the multiple wires function as monopolar electrodes and the method includes: In some embodiments, the method further includes positioning a return electrode adjacent the plurality of wires. The ears function as bipolar electrodes.

[0167] In some embodiments, at least one electrode comprises at least two electrodes. and the energizing includes energizing at least two electrodes that function as a bipolar pair.

[0168] In some embodiments, the non-thermal energy has any amount of energy and the method The method further comprises the steps of: re-energizing at least one electrode to generate non-thermal energy having a different energy amount; The method further comprises delivering a

[0169]

[0169] In some embodiments, the reenergization step includes detecting a portion of the airway wall. In some embodiments, the sensed condition includes temperature. In an embodiment, the sensed condition includes impedance.

[0170]

[0170] In some embodiments, the method includes reenergizing at least one electrode. and selectively treating different cells in a portion of the airway wall. In some embodiments, the application of electricity to specific cells is effective to treat epithelial cells as well as submucosal cells. Contains different cells including cells.

[0171] In some embodiments, the application of current to at least one electrode is The method includes administering electrical current to at least one electrode in synchronization with the cardiac cycle. In morphology, synchronization involves the outer T wave of the cardiac cycle.

[0172] In some embodiments, The method includes repositioning at least one electrode within the pulmonary passageway, the at least one electrode contacting the pulmonary passageway. and positioning the airway wall adjacent or against a different portion of the airway wall of the tract. energizing at least one electrode to deliver energy to a different portion of the airway wall. In some embodiments, the portion and the distinct portion are adjacent to one another.

[0173] In some embodiments, the method further comprises connecting at least one electrode to a different At least one electrode is disposed adjacent to a portion of the airway wall of a different pulmonary passageway. and energizing at least one electrode to a different It further includes delivering energy to a portion of an airway wall of the pulmonary passageway.

[0174] In some embodiments, the non-thermal energy comprises at least one energy part. The energy packets are delivered by an electrical signal having a waveform that includes a series of pulses. In some embodiments, each pulse is about 500 to 4000 V. In some embodiments, each energy packet is a frequency in the range of about 500 to 800 kHz. Has a number.

[0175]

[0175] These and other embodiments are described in the following description in conjunction with the accompanying drawings. This is explained in further detail in

[0176] Incorporation by Reference

[0176] All publications, patents and patent applications mentioned herein are the property of their respective owners. All publications, patents, or patent applications are specifically and individually indicated to be incorporated by reference. No. 6,313,997, filed on Oct. 23, 2003, and is incorporated by reference herein to the same extent as if fully set forth herein. [Brief description of the drawings]

[0177]

[0177] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will now be described with reference to illustrative embodiments in which the principles of the invention are utilized. The following detailed description may be obtained by reference to the accompanying drawings, in which:

[0178] [Figure 1]

[0178] An explanatory diagram of the anatomical structure of the lungs. [Diagram 2]

[0179] FIG. 1 is a cross-sectional view illustrating an airway wall having various layers and structures. [Diagram 3]

[0180] FIG. 1 is a cross-sectional view of the epithelium of an airway wall showing various cell connections within the airway. [Figure 4A]

[0181] 1 shows the bronchial airways in a healthy state. [Figure 4B]

[0181] Bronchial airways in a diseased state are shown. [Diagram 5]

[0182] 1 illustrates one embodiment of a pulmonary tissue modification system for use in treating a patient. [Figure 6]

[0183] FIG. 6 is a detailed view of the embodiment of the therapeutic energy delivery catheter shown in FIG. 5. [Figure 7]

[0184] FIG. 1 is a schematic diagram of one embodiment of a lung tissue modification system. [Figure 8A]

[0185] 1 shows a bronchoscope inserted into a patient's mouth / oral cavity. [Figure 8B]

[0185] A bronchoscope is shown inserted into the patient's nose / nasal cavity. [Figure 9]

[0186] 1 shows the positioning of the distal end of the catheter within the main bronchus for the purpose of treating the airway. [Figure 10]

[0186] Shown is the positioning of the distal end of the catheter within the main bronchus for the purpose of airway treatment. [Figure 11]

[0186] Shown is the positioning of the distal end of the catheter within the main bronchus for the purpose of airway treatment. [Figure 12]

[0187] 1 is a flow chart illustrating the methods described herein in a stepwise approach to treating a patient. [Figure 13]

[0188] 1 illustrates one embodiment of a waveform of a signal provided by an energy delivery algorithm. [Figure 14]

[0189] 13 shows example waveforms for another energy delivery algorithm. [Figure 15]

[0190] 13 shows example waveforms for another energy delivery algorithm. [Figure 16]

[0191] 13 shows example waveforms for another energy delivery algorithm. [Figure 17]

[0192] 13 illustrates an embodiment in which the delivered energy detaches cells from the airway wall, causing the cells to be removed. [Figure 18]

[0193] 13 illustrates an embodiment in which the delivered energy kills cells and ultimately removes them from the airway wall. [Figure 19]

[0194] 13A-B show schematic diagrams of epithelial cell removal by dielectrophoretic effects. [Figure 20]

[0195] 1 is a graph illustrating a portion of a sample electrocardiogram (ECG) tracing of a human heart highlighting a desired period for delivery of energy pulses to the pulmonary passageways via an energy delivery body. [Figure 21]

[0196] 1 is a flow chart illustrating an embodiment of a method for synchronizing the delivery of energy with the cardiac cycle. [Figure 22]

[0197] 1 illustrates how to access lung tissue, such as the parenchyma, via the nose or mouth. [Figure 23A]

[0198] 1 shows exemplary images of pulmonary passageways obtained using confocal laser endomicroscopy (CLE). [Figure 23B]

[0198] Exemplary images of pulmonary passageways obtained using optical coherence tomography (OCT) are shown. [Figure 24]

[0199] 1 illustrates an embodiment of an energy delivery catheter comprising a single energy delivery body having electrodes formed from multiple ribbons or wires forming a helical cage. [Diagram 25]

[0200] 1 illustrates an embodiment in which the energy delivery catheter includes two energy delivery bodies. [Figure 26]

[0201] 1 illustrates an embodiment of an energy delivery catheter including a single energy delivery body mounted on a shaft extending through the energy delivery body. [Figure 27]

[0202] 13 shows an embodiment in which both energy deliveries are carried on a single shaft. [Figure 28A]

[0203] 13 shows an embodiment in which the energy of one energy delivery body upon expansion is unconstrained at one end, forming a half-cage shape. [Figure 28B]

[0204] 13 shows an embodiment in which both energy delivery bodies have braided metal wires configured to form a semi-cage shape upon expansion. [Figure 29]

[0205] 1 shows a braided wire cage energy delivery device with energizable wires in which some of the wires are insulated with a portion of the insulation removed that defines an activation area. [Diagram 30]

[0206] 13 shows another embodiment in which a tube is cut with a laser and both ends are constrained via the tube itself to form a collapsible cage. [Diagram 31]

[0207] 1 shows an embodiment of an energy transfer device in which an insulated wire and one or more separate additional electrodes (coil-like) are coupled to the insulated cage wire to form an active area. [Diagram 32]

[0208] 1 illustrates an embodiment of an energy delivery body including multiple tines. [Diagram 33]

[0209] 1 illustrates an embodiment of an energy delivery body that includes one or more protrusions. [Diagram 34]

[0210] 1 illustrates an embodiment of an energy delivery body that includes one or more protrusions, each protrusion being formed from a non-conductive material and carrying, supporting and / or otherwise coupled to a separate electrode. [Diagram 35]

[0211] 1 illustrates an embodiment of a catheter having two energy delivery bodies, each having the shape of an expandable coil. [Diagram 36]

[0212] 1 illustrates an embodiment of an energy delivery body that includes a coil having a width and a length, where the length of the coil preforms a generally circular pattern. [Figure 37]

[0213] 1 illustrates one embodiment of an energy delivery body that includes a rod having electrodes, the length of the rod preforming a generally circular pattern. [Figure 38]

[0214] 1 illustrates an embodiment of a catheter having a sheath that retracts proximally to expose one or more prongs. [Figure 38A]

[0215] FIG. 39 is a cross-sectional view taken along line AA in FIG. 38. [Figure 39]

[0216] An embodiment of a prong having two electrodes therebetween attached to an insulating substrate as a means of maintaining distance between the electrodes is shown. [Diagram 40]

[0217] 37 illustrates an embodiment of a prong having a narrower insulating substrate than shown in FIG. 36. [Diagram 41]

[0218] 13 shows an embodiment of a prong having a narrower insulating substrate and two or more electrodes. [Diagram 42]

[0219] 1 shows multiple electrodes mounted on an insulating substrate. [Diagram 43]

[0220] Illustrated in Figures 36-37 is an insulating substrate having a spiral electrode. [Diagram 44]

[0221] As shown in FIG. 38, an insulating substrate having a spiral electrode is shown. [Figure 45A]

[0222] The expandable member is shown expanding until a desired interface is formed between the prongs and the bronchial wall. [Figure 45B]

[0222] The expandable member is shown expanding until a desired interface is formed between the prong and the bronchial wall. [Diagram 46]

[0223] 1 shows an embodiment of an energy delivery catheter having four energy deliveries operable in a bipolar / multiplexed fashion. [Figure 47]

[0224] 1 illustrates unipolar energy delivery, supplying energy between an energy delivery body and a dispersive (counter) electrode that is applied externally to the patient's skin. [Figure 48]

[0225] 1 shows an example of a catheter removably connected to a bronchoscope. [Figure 49A-C]

[0226] 1 shows the introduction of a catheter having two energy deliveries through a bronchoscope. [Figure 50]

[0227] FIG. 1 is a schematic diagram of a single target segment within the main bronchus of the lung. [Figure 51]

[0228] FIG. 1 is a schematic diagram of two target segments positioned adjacent to each other such that the overall target, or treatment area, is generally adjacent. [Figure 52]

[0229] FIG. 1 is a schematic diagram of two target areas in a patient. [Figure 53]

[0230] FIG. 1 is a schematic side view of a portion of an energy delivery body having a braided cage. [Figure 54]

[0231] 51 is a schematic cross-sectional view of the energy delivery body of FIG. 50 positioned in a lung passage having an airway wall. [Figure 55]

[0232] FIG. 13 is a schematic diagram of the effect of continuous circumferential treatment of an airway along the length of an energy transfer body. [Figure 56]

[0233] FIG. 1 is a schematic illustration of discontinuous tissue effects in a pulmonary passageway. [Figure 57A]

[0234] Histological illustration (Laboratory 6, Animal 1-10085) shows a cross-section from an untreated airway. [Figure 57B]

[0234] Histological illustration (Lab 6, Animal 1-10085) is a cross-section from a treated airway. [Figure 58A]

[0235] Another histological illustration is shown (Laboratory 6, Animal 1-10085), a cross-section from an untreated airway. [Figure 58B]

[0235] Another histological example is shown (Lab 6, Animal 1-10085), a cross section from a treated airway. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0179]

[0236] Specific embodiments of the device, delivery system, and method are described below with reference to the drawings. However, the detailed description may not necessarily refer to any component, feature, or step as essential to the invention. It doesn’t mean there is.

[0180] I. Overview

[0237] Mucus secretion in the bronchial airways protects the lining and helps fight off infection. Mucus production is important for the lungs' defense against bacteria, particles, and chemical stimuli. The normal secretion level varies depending on the type of stimulus, such as a strong food. Mucus in the epithelial layer of the bronchial airways traps particles, and ciliated cells transport mucus to the lower respiratory tract. As a result, the mucus is eventually removed by coughing or swallowing. Mucus also contains antibacterial agents that aid in the defenses against pathogens and harmless inhaled proteins. Proteins are thus removed from the airways, limiting their contact with other immune components. In the lining of the mouth, mucus is produced by goblet cells, which complex it with water in secretory granules. In the larger airways, mucus is also produced by mucus glands. When exposed to infection or intoxication, the airway epithelium upregulates mucus secretion capacity to induce coughing. After that, the airway epithelium recovers and returns to normal, and the goblet cells disappear. , coughing is reduced.

[0181]

[0238] However, in many cases of lung injury and lung disease, the body does not recover. Instead, they chronically produce excess mucus, which accumulates in the lungs. This can lead to chronic coughing. This causes symptoms such as difficulty breathing, fatigue, chest pain, and discomfort. Excessive mucus secretion is the cause of many medical conditions. CF-associated bronchiectasis and non-CF bronchiectasis It is the main clinical and pathological feature of chronic obstructive pulmonary disease and asthma.

[0182]

[0239] All of the above diseases involve impaired innate lung defenses and activated host inflammatory responses. In addition to Toll-like receptor (TLR) signaling, abnormal levels of antimicrobial peptides, Activator, salivary lysozyme, sputum secretory leukocyte protease inhibitor, macrophage, mucin Triggers transcription and NF-KB (nuclear factor kappa B light chain enhancer of activated B cells) pathways. Increased production and decreased clearance induce exacerbations and increased airway epithelial damage. The goblet cell population expands, and mucin production is upregulated. Similarly, inflammation increases during exacerbations, proteases are activated, and It destroys the elastic fibers that allow air and CO2 to enter and leave the alveoli. The airway epithelium produces more mucus to clear the airways of inflammatory cells, which can progress the disease. Pathogens penetrate the mucus but cannot be expelled. As the cycle progresses, the overproduction of mucus , resulting in pathological conditions that increase the risk of infection, hospitalization, and morbidity.

[0183]

[0240] Airway wall structure is affected / remodeled to interrupt or prevent the disease progression cycle. to restore the architecture, functionality, and / or activity to a relatively normal state and a lung tissue modification system useful for affecting one or more cellular structures within the airway wall. Lung tissue modification systems deliver energy, typically characterized by high voltage pulses. In some embodiments, the energy delivery is clinically significant. This allows for the modification or removal of target tissue without causing an inflammatory response. A certain degree of inflammatory healing reaction is acceptable. This allows for a healthy recovery within a few days of the procedure. New tissue can then be regenerated.

[0184]

[0241] In one method, energy output from the lung tissue modification system induces cell proliferation in the epithelial layer E. Abnormal dysfunctional ciliated pseudostratified epithelial cells PCEC and hyperplastic goblet cells G C are detached from the basal cells BC, drawn into the airway lumen, and excreted. The BC cells were left behind in the basement membrane BM, and normal goblet cells GC and normal multistratified ciliated columnar epithelial cells PCEC were This triggers reverse remodeling of the disease and reduces mucus hypersecretion. Newly regenerated goblet cells (GC) have very low mucus production. Newly regenerated multi-layered ciliated columnar epithelial cells The PCECs regenerate normally functioning cilia (C), allowing mucus (M) to be expelled more easily. The patient then has a mucus volume increase. The reduction in volume was immediately felt, and coughing and airway obstruction were also reduced. Over the next few weeks, the exacerbations decreased and the patient's condition improved. It is expected that the quality of life will improve.

[0185]

[0242] In some embodiments, due to the relative strength of cell-cell bonds, the energy , between the basal cells BC and the more superficial goblet-shaped GC and multi-stratified ciliated columnar epithelial cells PCEC. Induces epithelial separation. The basal cells BC are connected to the basement membrane BM by hemidesmosomes H (see Figure 3). In addition, the basal cells BC communicate with the goblet cells GC and the multilayered basal cells BC via the desmosomes D (see Figure 3). The ciliated columnar epithelial cells (PCECs) are connected to the lung tissue engineering system. The electrode configuration was designed to disrupt connections by focal adhesion D but leave hemidesmosomes H intact. This removes the surface cells, leaving the basal cells (BC) largely intact, and The regeneration process is initiated by the destruction of the basement membrane (BM) and the resulting necrosis. or faster than would normally be expected in a thermal ablation procedure. Destruction and necrosis are caused by, among others, T cells, macrophages, IL-13, IL-4, monocytes, pro- This leads to the activation of inflammatory pathways including inflammatory enzymes, cytokines, and chemokines. The disclosed method results in little or no destruction of the basement membrane BM and little or no acute inflammation. This allows for the regeneration of healthy new target tissue within days of the procedure. In the embodiment, the energy output from the lung tissue modification system causes other changes or further changes in the airway wall W. It is understood that the method can induce various changes to regenerate healthy target tissue.

[0186]

[0243] FIG. 5 illustrates one embodiment of a lung tissue modification system 100 for use in treating a patient P. In this embodiment, the system 100 includes a therapeutic The catheter 102 includes an energy delivery catheter 102 having at least one The energy delivery body 108 is an elongated shaft 102 having a handle 110 at its proximal end. 06. The generator 104 is coupled to the catheter 102 and the energy delivery body 10 5, the catheter 102 provides electrical energy to, for example, The catheter can be inserted into the bronchial passages of the patient P in a variety of ways, for example through the lumen of the bronchoscope 112. This can be done.

[0187]

[0244] FIG. 6 is a detailed view of an embodiment of the therapeutic energy delivery catheter 102 shown in FIG. In this embodiment, the energy delivery body 108 includes a single unipolar delivery electrode, The type, number, and arrangement may vary, and the present specification describes variations below. In an embodiment, the energy delivery body 108 forms a helical cage that functions as an electrode. a plurality of wires restrained by a proximal end restraint 122 and a distal end restraint 124; 1. In another embodiment, the wire or ribbon is straight rather than helical. In yet another embodiment, the cage is shaped like a straight cage (i.e., configured to form a straight cage). In some embodiments, the energy delivery body 108 is formed by cutting a tube with a laser. In this embodiment, the energy delivery body 108 is self-expanding and delivered to the target area in a folded state. For example, when the sheath 126 is placed on the energy supply body 108, it is configured in a folded state. In FIG. 6, the catheter shaft 106 (within the sheath 126) can be The catheter 102 is inserted into the proximal end restraint portion 122 and is inserted into the distal end restraint portion 124 without restraining the distal end restraint portion 124. The sheath 126 is disposed over the energy delivery body 108 and is free to move relative to the shaft 106. When advanced, the distal end restraint 124 moves forward, thereby causing the energy delivery body 1 Stretch / fold 08, then restrain.

[0188]

[0245] The catheter 102 includes a handle 110 at its proximal end. In some embodiments, In this case, the handle 110 can be removed by, for example, pressing a handle removal button 130. In this embodiment, the handle 110 includes an energy delivery device operation knob 132. By moving the knob 132, the cage electrode expands or contracts / folds. The handle 110 further includes a bronchoscope working port snap for coupling with a bronchoscope 112. 134 and a cable plug-in port 136 that couples to the generator 104 .

[0189]

[0246] Referring back to FIG. 5, in this embodiment, a therapeutic energy delivery catheter The generator 102 is coupled to a dispersive (counter) electrode 140 that is applied externally to the skin of the patient P. In this embodiment, the distal end of the catheter 102 can be connected to the catheter 104. supplying energy between an energy delivery body 108 disposed near the distal end and a return electrode 140; As further described herein, bipolar energy delivery can be achieved. It will be appreciated that other positioning arrangements may be used instead. The generator 104 may include a user interface 150, one or more energy transfer algorithms, Rhythm 152, processor 154, data storage / retrieval unit 156 (memory and / or data The energy storage subsystem 158 includes a In some embodiments, the energy storage / Delivery using one or more capacitors, but as state-of-the-art technology develops, any suitable The device may further include one or more communication ports.

[0190]

[0247] In some embodiments, the generator 104 includes three subsystems: It should be understood that: 1) high energy storage system; 2) high voltage and medium frequency switching amplifier; 3) system control, firmware, and user interface. The system controller allows for synchronization of pulse energy output to the patient's cardiac rhythm. The generator is equipped with a cardiac synchronous trigger monitor that detects the heart rate and the heart rate. It supplies power to multiple DC (direct current) sources. The generator controller controls the energy supply. Instructs the DC power source to charge the high energy capacitor storage battery before delivery. When starting energy delivery, the generator controller, high energy storage bank, two-phase The two pulse amplifiers operate simultaneously to produce a high voltage, medium frequency output.

[0191]

[0248] The processor 154 may be, for example, a general purpose processor, a field programmable gate FPGAs, Application Specific Integrated Circuits (ASICs), Digital Signal Processors The processor 154 may be a digital signal processor (DSP), etc. or other modules, processes and / or functions related to the system 100, and / or The system 100 may be configured to implement a network.

[0192]

[0249] In this specification, the term "module" refers to, for example, a memory, a processor, This includes the sensors, electrical traces, optical connectors, and software (which runs on the hardware). It means any assembly and / or set of operatively connected electrical elements. For example, a module that runs on a processor may be a hardware-based module (e.g., F PGA, ASIC, DSP) and / or software-based modules (e.g. memory The program may be any combination of a program, a program code, or a module of computer code stored in a memory.

[0193]

[0250] The data storage / retrieval unit 156 may be, for example, a random access memory (RAM), Memory buffers, hard drives, databases, erasable programmable read-only memories (EPROM), Electrically Erasable Read-Only Memory (EEPROM), Read-Only Memory (RO The data storage / retrieval unit 156 may be a processor, a memory, a flash memory, etc. Instructions that cause 154 to execute modules, processes and / or functions associated with the system 100 can be stored.

[0194]

[0251] In some embodiments, the data storage / retrieval unit 156 includes various A persistent computer readable medium storing instructions or computer code corresponding to the operation of the computer implementation. This includes computer storage products having a non-transitory processor-readable medium. The computer-readable medium (or processor-readable medium) may be a transitory propagating signal (e.g., a signal transmitted over a space or cable). It is considered persistent because it does not involve propagating electromagnetic waves that carry information on a transmission medium such as a cable. The media and computer code (also referred to as Code) are designed and constructed for a specific purpose. Examples of non-transitory computer readable media include hard disks. , floppy disks, magnetic tapes and other magnetic storage media, compact disks / digital Video discs (CD / DVD), compact disc read-only memory (CD-ROM) M), optical storage media such as holographic devices, magneto-optical recording media such as optical disks, carrier waves Signal Processing Modules, ASICs, Programmable Logic Devices (PLDs), Read-Only Program code, such as memory (ROM) and random access memory (RAM) devices Specially configured hardware devices configured to store and execute the code, Other embodiments described herein include, but are not limited to, those described herein. The present invention relates to a computer program product capable of storing the instructions and / or computer code described herein. do.

[0195]

[0252] Examples of computer code include microcode or microinstructions, e.g. The machine instructions generated by the compiler, the code that generates the web service, the interpreter Examples of files that contain high-level instructions that are executed by a computer using a For example, but not limited to, imperative programming languages ​​(e.g., C, Fort ran, functional programming languages ​​(Haskell, Erlang, etc.), logic programming languages ​​(e.g., Prolog), object-oriented programming languages ​​( (e.g., Java, C++, etc.) or other suitable programming languages ​​and / or development tools. Exemplary computer code may be used to implement embodiments. This includes, but is not limited to, encoded codes and compressed codes.

[0196]

[0253] In some embodiments, the system 100 may be, for example, a local area network (LAN). LAN, wide area network (WAN), virtual network, electrical communication Wired networks, such as communication networks, data networks, and / or the Internet The network may be implemented as any of a variety of networks, including wireless and / or digital networks. In some embodiments, communication may be performed using any suitable type and / or method. Secure communications (e.g., Secure Sockets Layer (SSL)) and / or apply encryption In other embodiments, any or all communications may be unsecured. This is also fine.

[0197]

[0254] The user interface 150 allows for the input of patient data, treatment algorithms (i.e. The energy delivery algorithm 152) is selected, the energy delivery is started, and the storage / retrieval unit 15 6 to view records stored by the operator or otherwise communicate with the generator 104. The device may include a touch screen and / or physical buttons that allow the user to control the device.

[0198]

[0255] Any of the systems disclosed herein allow for operator-defined input. The user interface 150 may be configured to: ,Energy delivery pulse, power, target temperature, operation during energy delivery or at other times For example, the various operating modes may include , system startup and self-test, operator input, algorithm selection, pre-treatment system status state and feedback, energy delivery, display and feedback after energy delivery, treatment data data management and / or downloads, software updates, or any combination thereof. It is possible to do so.

[0199]

[0256] In some embodiments, the system 100 includes an external cardiac monitor 170, etc. The device also includes a mechanism for acquiring an electrocardiogram (ECG). An example of a cardiac monitor is the AccuSync. In some embodiments, the compound is available from Medical Research, Inc. Thus, an external cardiac monitor 170 is operably connected to the generator 104. An ECG is acquired continuously using an internal monitor 170. External electrodes 172 are attached to the patient P. An ECG may be acquired. The generator 104 analyzes one or more cardiac cycles and generates an energy Identify the beginning of a period during which it is safe to apply energy to the patient P, thereby timing the energy delivery to the pericardial In some embodiments, this period is when the energy pulse is delivered at the T wave. The pulse is delivered within milliseconds of the R wave to avoid the risk of arrhythmias that may occur if the pulse is delivered too close to the R wave. Such cardiac synchronization is typically used when applying unipolar energy delivery, but may also be used in other cases. Let it be understood that it is possible.

[0200]

[0257] In some embodiments, the processor 154 may implement an energy delivery algorithm. Modify and / or switch the system, monitor the energy supply and any sensor data, and provide feedback In some embodiments, the processor responds to the monitoring data via a group. 154 is a block diagram of a system for measuring one or more measurement system parameters (e.g., electrical current), one or more measurement tissue parameters, and parameters (e.g., impedance) and / or combinations thereof. The control loop is configured to execute one or more algorithms that implement a back control loop.

[0201]

[0258] The data storage / retrieval unit 156 stores data related to the delivered therapy. Optionally, connect a device (e.g., a laptop or thumb drive) to the communications port. In some embodiments, the device can download the data. For example, instructions stored in data storage / retrieval unit 156 and executable by processor 154. In some embodiments, the device has local software that directs the download of information. In the embodiment, an operator controls a computer device via a user interface 150. , tablets, mobile devices, servers, workstations, cloud computing devices, including but not limited to, computing devices / systems; You can choose to download data to your system via wired and / or As mentioned above, data can be downloaded through a communication port that allows wireless connection. , and data uploads such as custom algorithm uploads and software updates. It is possible.

[0202]

[0259] As described above, the various energy delivery algorithms 152 are The data can be programmed or stored in the memory or data storage / retrieval unit 156. Alternatively, the energy delivery algorithm can be preprogrammed. These algorithms may be added to the data storage / retrieval unit and executed by the processor 154. Each of the algorithms 152 is executable by a processor 154. In some embodiments, the catheter 102 may be, for example, For example, determination of temperature, impedance, resistance, capacitance, conductivity, permittivity, and / or conductivity. The sensor data includes one or more sensors 160 used to determine the Used for therapy monitoring and / or direct feedback via processor 154, The cardiogram delivery algorithm 152 can be modified. For example, impedance measurements can be It is used to determine the initial dose to be applied as well as the need for further treatment. can be.

[0203]

[0260] Any of the systems disclosed herein may be used to measure temperature, impedance, duration of treatment, or depending on inputs such as the time aspects of the energy delivery pulse, therapeutic potential and / or system state. and automated treatment delivery algorithms that can dynamically determine when to adjust and / or discontinue treatment plans. Good too.

[0204]

[0261] In some embodiments, as shown in FIG. This is done using a commercially available system, such as a bronchoscope 112 connected to an imaging screen 180. An imaging device may be incorporated into the catheter 102. The imaging device may be mechanically attached to the catheter 102 using a suitable mechanism. The devices may be electrically, operably, and / or communicatively coupled.

[0205]

[0262] 7 is a schematic diagram of one embodiment of a lung tissue modification system 100. In the illustrated embodiment, the catheter 102 is configured for unipolar energy delivery. Thus, the dispersive (neutral) electrode or return electrode 140 is attached to the skin of the patient while operatively connected to the injector 104 for return of the energy delivered through the catheter 102. The energy delivery catheter 102 is a path for delivering energy to one or more energy delivery bodies 108 ( poles), one or more sensors 160, one or more imaging modalities 162, one or more buttons 164, and / or a positioning mechanism 166 (e.g., a lever and a handle with a pull wire) and / or dials, telescoping tubes, sheaths, etc., but are not limited to these. One or more energy delivery bodies 108 contact tissue. In one embodiment, the foot switch 168 is operably connected to the generator 104 to It is used to initiate delivery of

[0206]

[0263] As previously mentioned, the user interface 150 allows for input of patient data, energy Selection of the delivery algorithm 152, initiation of energy delivery, and storage / retrieval unit 156 storing A timer that allows an operator to view records or perform other communications with the generator 104. The processor 154 may include an energy Manages and executes delivery algorithms, monitors energy supply and sensor data, and provides feedback The data storage / retrieval unit 156 stores and responds to monitoring data via a Connect a device (e.g., laptop or thumb drive) to communication port 167. When connected, data can be downloaded from the data storage / retrieval unit 156.

[0207]

[0264] The catheter 102 is connected to a generator 104 and / or a separate imaging screen 105. 80. The imaging device 162 is incorporated into the catheter 102. Alternatively or additionally, the catheter 102 may be used , a separate imaging device or imaging device 169, such as a commercially available system (i.e., a bronchoscope, etc. A separate imaging device 169 may be attached to the catheter 1 using a suitable mechanism. 02 may be mechanically, operably, and / or communicatively coupled to

[0208]

[0265] According to FIG. 8A, a bronchoscope 112 is inserted into the oral cavity OC of a patient P. Methods of access include the use of the nose or other orifices, such as the nasal cavity (Figure 8B). Alternatively, a suitable artificial opening may be used (not shown, e.g., a stoma, tracheal Use of the bronchoscope 112 allows for direct visualization of the target tissue. Using the working channel of the bronchoscope 112, in accordance with the devices and systems disclosed herein, The catheter 102 is delivered, and the placement of the catheter can be confirmed with the naked eye. 1, the catheter 102 is shown being introduced into the trachea T ​​and main bronchus MB at its distal end. , the catheter 102 may be inserted into the femoral bronchus LB, the distal segmental bronchus SB or the subsegmental bronchus SB, as required. It may be inserted into the bronchial SSB.

[0209]

[0266] 9-11 show a catheter 102 with a distal end inserted into the main bronchus for the purpose of airway treatment. In some embodiments, the catheter 102 is shown positioned within the MB. The prongs include an atraumatic tip 125 so that the prongs can be advanced through the airway without damaging the airway wall W. FIG. 9 shows the energy delivery body 108 in the main bronchus MB while the sheath 126 is covering the energy delivery body 108. The catheter 102 is shown advancing through the catheter 102. The positioning of the catheter 102 can be monitored using various imaging techniques. For example, a bronchoscope 112 may be used to guide the patient to the target site in real time. Direct visual guidance may be provided and the catheter 102 may be used before, during, and after treatment. The correct positioning of the sheath 126 may be observed. FIG. 1, the cap 108 is shown exposed. Of course, in some embodiments, In this embodiment, the energy delivery body 108 is self-expanding, so that the sheath 126 extends beyond the energy delivery body 108. In this embodiment, the sheath 126 is withdrawn to hold the energy Releasing the delivery body 108 allows the energy delivery body to self-expand. The energy delivery body 108 may be moved, for example, by retracting the sheath 126 and then moving the knob 132. 11 illustrates an expandable cage-type energy delivery device 108. The energy delivery body 108 contacts the airway wall W. Further imaging verifies positioning. and / or additional measurements (e.g., depth) may be taken.

[0210]

[0267] Once the energy delivery body 108 is positioned at the desired location, the therapeutic energy is delivered to the The therapeutic energy is delivered to the airway wall W by the energy delivery device 108. The energy is applied according to a delivery algorithm.

[0211]

[0268] In some embodiments, the user interface 1 of the generator 104 50 allows the user to select a desired treatment algorithm 152. In this case, the algorithm 152 may be configured to measure the temperature of the catheter 102 using one or more sensors. The generator 104 automatically selects the desired value based on the information obtained by A variety of energy delivery algorithms may be used here. In some embodiments, the algorithm 152 generates a series of packets with a rest period between each packet. generating a signal having a waveform including energy packets, each energy packet being a series of high voltage packets; In some embodiments, each high voltage pulse comprises a pulse of about 500 V to 10 kV. Alternatively, it is about 500 V to about 5000 V, and all values ​​within this range are applicable. In some embodiments, the frequency of the delivered energy is from about 10 kHz to about 10 MHz. Or, it is within the range of about 100kHz to about 1MHz, and all values ​​within this range are applicable. The algorithm 152 delivers energy to the airway wall with minimal tissue heating and Alternatively, the desired treatment may be delivered without any tissue heating. The device measures electrode and / or tissue temperature during treatment to determine whether the tissue stored energy is clinically significant. Ensure that the temperature sensor is not sufficient to induce tissue heating. or monitor the temperature of the electrode. If a certain threshold temperature is exceeded (e.g. 65°C), the generator The controller can then change its algorithm to automatically stop delivering energy or reach a set threshold. If the temperature exceeds a certain threshold (vertical 65°C), the generator The modulator shortens the pulse width or lengthens the time between pulses and / or packets. , a prescribed stepwise approach that considers percentages of parameters, or other methods. This is an example of a process that can be implemented.

[0212]

[0269] Conventional radiofrequency ablation (RFA) uses high-frequency waves of 350 to 550 kHz. The application of electrical current kills cells and heats the tissue, resulting in thermal necrosis of cells. Many RFA devices have been developed for the treatment of solid tumors, kidneys, nerves, etc. Cross wave ablation is a type of thermal ablation method that uses alternating current of 300MHz to 300GHz. This also causes thermal necrosis of cells. The energy source is solid, due to the size of the cauterization zone and the uniform heating. It is used to treat tumors. In general, thermal ablation denatures proteins in tissues, causing significant inflammation. They cause reactions, are difficult to control, and often cause damage to non-target tissue. In certain cases of treatment (e.g., tumor therapy), inflammation may be tolerated, but the focus is on the lung airways. If left untreated, inflammation can lead to serious complications (e.g., exacerbation). Although it is unclear how denaturation affects clinical morbidity, intact, undenatured proteins , the host response to various challenges to the immune system, regardless of their effects on pathogens, tumors, etc. These limitations are likely to increase the risk of infection. This is less desirable.

[0213]

[0270] Conversely, algorithm 152 delivers non-thermal energy to the airway wall W to reduce inflammation. In some embodiments, the algorithm 152 to affect tissue to a predetermined depth and / or to target specific cells within the airway wall. In some embodiments, the generator is adapted to use a unique algorithm. Each setting has a target cell depth reflected by the setting. For example, The algorithm primarily affects pathogens present in the mucus layer, and a different setting / algorithm Rhythm targets the epithelium, while other settings / algorithms target mainly the epithelium, basement membrane, and submucosa. and / or smooth muscle. Yet another setting / algorithm targets primarily epithelium, basement membrane, Targeting the submucosa, smooth muscle, submucosal glands and / or nerves. In this embodiment, the treatment is performed at the same location, but in other embodiments, the operator may perform the treatment at different locations. A specific cell type may be selected for treatment. The settings utilized by the operator depend on the patient's condition. The effect of the present invention may depend on the physiological nature of the condition.

[0214]

[0271] The biological mechanisms and cellular processes by which energy removes cells are discussed in the following sections. The energy is delivered to the airway wall W at the target location to treat healthy tissue. For example, it regenerates normal goblet cells (GC) and normal multistratified ciliated columnar epithelial cells (PCEC) and treats diseases. Induce reverse remodeling of the goblet cells to reduce mucus hypersecretion. The productivity is very low. Newly regenerated multi-layered ciliated columnar epithelial cells (PCEC) have normally functioning cilia C. The normal healthy tissue will regenerate and expel mucus M more easily within a few days of treatment. This dramatically reduces symptoms such as coughing and excessive mucus production in patients, resulting in As a result, exacerbations are reduced and quality of life is improved.

[0215]

[0272] FIG. 12 illustrates the methods described herein using a stepwise approach to treating a patient. 1 is a flow chart illustrating an example of a method for providing therapeutic energy to a patient, the patient being able to receive therapeutic energy from ... In some embodiments, the method may be performed by a catheter or a generator. One or more steps disclosed in the specification may be optional. The guideline includes an evaluation of the patient's anatomy and / or suitability for the procedure to determine whether or not the procedure should be performed. In some embodiments, the evaluation is optional and may involve the following steps: First, access the airway (300) (if necessary). (Only if necessary). Then, any appropriate pre-treatment imaging, sputum sampling, etc., as necessary and / or desired may be performed. Pre-procedure imaging may include non-invasive CT scans, bronchoscopy, and / or biopsies. Inspection, confocal laser endoscopy (CLE), optical coherence tomography (OCT), or any Appropriate techniques, as well as any measurements (e.g., depth) are included. Sputum sampling is performed using nasal mucosa. Brushing, nasal washing, bronchial brushing, bronchial washing, and / or bronchoalveolar lavage Then, the necessity of treatment for the patient is judged. If the judgment is "No" (302), Then, proceed to the end (322). If the answer is "Yes" (303), access is terminated if necessary. In some embodiments, the treatment is administered one or more days after the pre-treatment assessment. In this embodiment, access is requested (304).

[0216]

[0273] In some embodiments, treatment is administered immediately following the pre-treatment assessment. In this embodiment, a second access is not necessary. 05 is to introduce a catheter. As mentioned above, there are various ways to introduce a catheter. By way of example, the catheter is delivered through a working channel of a bronchoscope. In step 306, the catheter is positioned at the target site. The bronchoscope provides real-time direct visual guidance to the target site and the catheter It is also used to observe the correct positioning of the catheter so that it is in contact with the airway wall. Then, additional imaging (307) is performed to determine the location of the one or more energy delivery devices. , positioning can be verified and / or additional measurements (e.g., depth) can be made. In the next step 308, the operator also selects the desired energy delivery algorithm 15 2 can be selected. This is based on the target treatment depth, as explained in detail above. Alternatively, the generator can provide predefined algorithms that are suitable for most patients. In this embodiment, the next step 309 is configured to apply the algorithm: Execute or apply the energy delivery algorithm, as described herein, using the foot pedal or After energy application, the operator presses the energy application button (310 ) can be evaluated. Additional imaging with or without measurements and / or Messages sent by the transducer (e.g., regarding energy delivery, which may result in incomplete treatment) If the treatment is not permitted (311), the operator The controller returns to step 306 to locate the target site. If treatment is acceptable (312 ), the operator proceeds to the next step. The next step in the procedure is to treat more treatment areas. If the answer is "No" (313), the operator Then, proceed to the final imaging (315) and proceed with the remaining steps until the end (322). If "s" (314), the operator repositions (316) to the next target site and continues the treatment step. Once all treatments are complete, the operator may take any final scans (315). Continue to step 3, where the operator reviews the images to ensure all target areas have been satisfactorily treated. If the answer is "No" (317), the operator is prompted to "Retry to next target area" Return to Positioning (316) for additional treatment. If Yes (318), the operator The data can be compared to any pre-treatment biopsies and / or sputum samples (301) taken. At a later date, decide whether to obtain one or more immediate biopsies and / or sputum samples (319). Follow-up images and / or biopsies and / or sputum samples are obtained (320) and other images, biopsies, and and / or sputum samples to assist in the assessment and / or documentation of treatment outcomes. The operator then administers substances or activators to assist the normative healing process (3 21), which may further reduce the possibility of treatment problems or complications. This can further reduce the severity and frequency of exacerbations, especially in the short term. Some examples are isotonic saline gels, medicated films, antibacterial, antiviral, antifungal, As a result of exposing tissue to high energy fields, the treated tissue becomes The procedure is then completed (322). The patient should continue to follow his / her doctor's instructions and should the disease or disorder recur and / or persist. The entire procedure can be repeated.

[0217]

[0274] Therefore, the desired clinical effect was not achieved or was achieved but symptoms recurred after treatment. In certain embodiments, it may be desirable to repeat the procedure. In some embodiments, rather than simply re-treating a specific area, different parts of the lung anatomy may be re-treated. It may also be preferable to target 10 minutes. Repeated treatment in the same tissue area as the treatment or in a tissue area clearly different from the initial intervention This may be done.

[0218]

[0275] Various embodiments have been described above, which have been presented by way of example and not limitation. It should be understood that the above methods may be implemented by performing certain events in a particular order. In addition, certain events may be reordered. They may be run simultaneously in parallel processes if possible, or they may be run sequentially as described above. Good too.

[0219] II. Energy Delivery Algorithm

[0276] As previously mentioned, the one or more energy delivery algorithms 152 The energy delivery device 104 may be programmed to deliver energy to the patient P, and may be preprogrammed. The one or more energy delivery algorithms 152 may be configured to reduce or avoid inflammation. The electrical signal that provides non-thermal energy that is delivered to the airway wall W as a target is specified. The algorithm 152 may be configured to affect tissue to a predetermined depth and / or within the airway wall. The depth and / or targeting can be tailored to target specific cells. The parameters of the energy signal defined by the energy delivery algorithm 152, the catheter 1 02 (particularly the one or more energy delivery bodies 108), and / or the unipolar or bipolar energy delivery body 108. In one example, bipolar energy delivery is dependent on the choice of unipolar energy delivery. In a bipolar configuration, the positive and negative electrodes are in contact with each other. Close enough together to provide therapeutic effect at both poles and between poles. Compared to monopolar, therapeutic effect is The effect can be spread over a larger surface area, and the therapeutic effect can be achieved even with low voltage. Similarly, lower voltages reduce the penetration depth and affect epithelial cells rather than submucosal cells. In addition, cardiac synchronization can be achieved if the applied voltage is low enough to avoid stimulation of the cardiomyocytes. It will no longer be necessary.

[0220]

[0277] Of course, a variety of energy delivery algorithms 152 may be used. In some embodiments, the algorithm 152 includes a series of energy packets. The present invention defines a signal having a waveform, with each energy packet including a series of high voltage pulses. In one embodiment, the algorithm 152 may include, for example, a packet count, a number of pulses in a packet, , the duration of the applied energy, including the frequency of each pulse, and the energy amplitude (e.g., voltage). Specify which signal parameters are used. A period of pause may be inserted between packets. The test may be gated to the cardiac cycle and vary with the patient's heart rate. Sensor Information and Automatic Shutdown A feedback loop based on specifications, etc. may also be included.

[0221]

[0278] FIG. 13 illustrates an example of a waveform 400 of a signal defined by the energy delivery algorithm 152. Here, two packets, a first packet 402 and a second packet 4, packets 402, 404 are shown separated by a quiet period 406. In this embodiment, each packet 402, 404 includes a first biphasic pulse ( a first positive peak 408 and a first negative peak 410) and a second biphasic pulse (including a second positive peak The first and second biphasic pulses include a first negative peak 408' and a second negative peak 410'. are separated by a dead time 412 (i.e., pause) between each pulse. Since the biphasic pulse is symmetrical, the set voltage 416 is Here, the two-phase symmetrical wave is also a square wave, and the magnitude and time of the positive voltage wave are the same as those of the negative voltage wave. The magnitude of the pressure wave is approximately equal to the amplitude of the pressure wave. A positive voltage wave causes depolarization of cells, which are normally negatively charged. The cell becomes temporarily positive. A negative voltage wave causes cell hyperpolarization, where the cell potential is negative. .

[0222]

[0279] In some embodiments, each high voltage pulse or set voltage 416 may Between about 500V and 10kV, including all values ​​and subranges, especially between about 500V and 4000V V. In some embodiments, each high voltage pulse generally penetrates the airway wall W. Approximately 1000V to 2500V, it is used to treat specific cells such as epithelial cells somewhat shallowly. In some embodiments, each high voltage pulse generally penetrates the airway W. The voltage is about 2600V to 4000V, which is the voltage that affects cells located slightly deeper, such as submucosal cells or smooth muscle cells. The set voltage 416 is a method of supplying energy. varies depending on whether the device is in monopolar or bipolar mode. The energy is delivered in a monopolar manner, with each high voltage pulse being approximately 2000V to 3500V, more specifically Typically, it is 2500V. For bipolar delivery, lower voltages are used due to the smaller directional electric field. In some embodiments, the energy is delivered in a bipolar manner, with each pulse delivering approximately 1 00V to 1900V, specifically 100V to 999V, more specifically about 500V to 80 0V, for example 500V, 550V, 600V, 650V, 700V, 750V, 8 It is 00V.

[0223]

[0280] In some embodiments, the set voltage 416 can be any value and all values ​​in between. The voltage range is from about 50 V to about 4 kV, or from about 500 V to about 4 kV. In the embodiment, the set voltage 416 is in the range of about 500V to about 500V, including all values ​​and subranges therebetween. It outputs kV.

[0224]

[0281] The number of pulses per unit time is called the frequency. The signal has a frequency between 100 kHz and 1 MHz. In some embodiments, the signal is It has a frequency of about 100 to 500 kHz that usually penetrates the airway W, and is transmitted to submucosal cells or smooth muscle cells. Therapy or action is directed at specific cells located somewhat deeper, such as the cytoplasm. In terms of shape, it usually has a frequency of about 600 kHz to 1 MHz that penetrates the airway wall W, and It provides a shallow treatment or effect on specific cells such as cells. At frequencies below 100 Hz, undesirable muscle stimulation may occur. In this case, the signal has a frequency of 500 to 800 kHz, for example, 500 kHz, 550 kHz, Has frequencies of 600kHz, 650kHz, 700kHz, 750kHz, and 800kHz In particular, in some embodiments, the signal has a frequency of 600 kHz. Therefore, cardiac synchronization is usually aimed at reducing or avoiding undesirable myocardial stimulation. In some embodiments, the biphasic pulse reduces undesirable muscle stimulation, particularly myocardial stimulation. Components that minimize signal artifacts would be even more useful. Higher frequencies may be used.

[0225]

[0282] In some embodiments, the time between packets, or idle period 406, is: Set between about 0.1 seconds and about 5 seconds, including all values ​​and subranges therebetween. In this embodiment, the pause period 406 is from about 0.001 seconds to about 0.5 seconds, including all values ​​and subranges therebetween. In some embodiments, the idle period 406 is about 1 second. In some embodiments, the signal is synchronized to the heart rhythm, sending each packet during a heart beat. In another embodiment utilizing cardiac synchronization, The rest period between packets is affected by cardiac synchronization as explained in a later section. Therefore, the hiatus period 406 will also change.

[0226]

[0283] The cycle count 420 is the number of pulses in each packet. See FIG. Then, the first packet 402 has a cycle count 420 of 2 (i.e., two double In some embodiments having a phasic pulse, the cycle count 420 is It is set from 1 to 100 for each packet, including all values ​​and subranges of In an embodiment, the cycle number 420 is a maximum of 5 parts, including all values ​​and subranges therebetween. pulses, max. 10 pulses, max. 25 pulses, max. 40 pulses, max. 60 pulses, max. 80 pulses pulses, up to 100 pulses, up to 1000 pulses, or up to 2000 pulses.

[0227]

[0284] The packet period is determined by the number of cycles. The more cycles, the shorter the packet period. In some embodiments, the packet period is longer and the amount of energy delivered is greater. The interval is about 50 to 100 microseconds, e.g. 50 microseconds, 60 microseconds, 70 microseconds The time may be 100, 80, 90, or 100 microseconds.

[0228]

[0285] The number of packets delivered or packet count during treatment is the sum of all values ​​and samples in between. 1 packet, 2 packets, 3 packets, 4 packets, 5 packets, 10 packets including the range packets, 15 packets, 20 packets, max. 5 packets, max. 10 packets, max. 15 packets packets, up to 20 packets, up to 100 packets, or up to 1000 packets. In some embodiments, the number of packets delivered is 5, with each packet containing 100 microseconds. 100 Hz, and a set voltage of 2500 V. The number of packets delivered is 5 to 10, and each packet lasts for 100 microseconds. and a set voltage of 2500V. This improves the uniformity of the treatment effect. In some embodiments, the number of packets delivered is less than 20, and each packet contains 100 It has a packet duration of microseconds and a set voltage of 2500V. Avoid impacting the bone layer CL. In some embodiments, the set voltage is 2500V, The total energy delivery period is 0.5-100 milliseconds, which is optimal for therapeutic effect.

[0229]

[0286] In some embodiments, the dead time 412 is the time between all values ​​and sub-values. In another embodiment, the dead time 41 is set to about 0 to about 500 nanoseconds, inclusive. 2 is approximately 0 to 10 microseconds, approximately 0 to approximately 100 microseconds, including all values ​​and subranges therebetween In some embodiments, the dead time 412 is about 0 to about 100 microseconds. is 0.2 to 0.3 microseconds.

[0230]

[0287] The specific settings for the desired modification of the target tissue depend on each other and on the electrode design. Accordingly, the embodiments described herein provide specific example waveforms to achieve the desired tissue effect. The use of multiple waveforms and / or characteristics in any combination to achieve the desired results is within the scope of the present invention. A first exemplary combination of parameters for the energy signal is The frequency is 600 kHz, the voltage is 3000 V, and the number of packets is 10. A second exemplary combination of data is a frequency of 600 kHz, a voltage of 2500 V, and a packet count of 1000 Hz. 5. A third exemplary parameter combination for the energy signal is a frequency of 600k Hz, voltage 2300V, packet number 20. In the first example, the high voltage caused damage to the epithelium and The therapeutic effect of the submucosal tissue was enhanced. In the second example, the voltage was lower and the number of packets was smaller. In the third case, the number of packets was large and the voltage was low, resulting in less therapeutic effect on the epithelium and submucosa. The therapeutic effect on the epithelium was enhanced and the therapeutic effect on the submucosa was reduced because of the low The low voltage does not penetrate deep enough to have a similar therapeutic effect on the submucosal glands compared to the high voltage. This confirms that.

[0231]

[0288] FIG. 14 illustrates an example waveform 40 of a signal prescribed by another energy delivery algorithm 152. Here, two packets are shown: the first packet 402 and the second packet 403. 404, where packets 402, 404 are separated by a quiet period 406. In this embodiment, each packet 402, 404 includes a first biphasic pulse (first positive pulse). a first biphasic pulse (including a first positive peak 408 and a first negative peak 410) and a second biphasic pulse (including a second positive peak 4 The first and second biphasic pulses each have a first negative peak 410' and a second negative peak 411'. The pulses are separated by dead time 412 between them. In this embodiment, waveform 400 is Asymmetric, the set voltage is different for the positive and negative peaks. Asymmetric waveforms are more consistent because the negative amplitude maintains the same charge cell membrane charge potential for a longer period of time. In this embodiment, the first positive peak 408 is located just before the first negative peak The set voltage 416 is greater than the set voltage 416' of the circuit 410. In some embodiments, the asymmetry further includes pulses with different pulse widths. Because biphasic waveforms are asymmetric, a voltage in one direction (i.e., positive or negative) will The voltage is larger than that of the depolarization curve, while the pulse length is calculated to be smaller than that of the depolarization curve. The area under the hyperpolarization curve is equal to the area under the depolarization curve. Alternatively, the areas under the depolarization and hyperpolarization curves are not equal. This is also fine.

[0232]

[0289] FIG. 15 illustrates an example waveform 40 of a signal prescribed by another energy delivery algorithm 152. 0. Similarly, two packets, a first packet 402 and a second packet 404 4, where packets 402, 404 are separated by a quiet period 406. In this embodiment, each packet 402, 404 includes a first monophasic pulse 430 and a second monophasic pulse 432. The first and second monophasic pulses 430, 432 have a monophasic pulse 432 between each pulse. The monophasic waveforms are separated by dead times 412. However, adjacent muscle groups are , are stimulated more strongly by monophasic waveforms than by biphasic waveforms.

[0233]

[0290] FIG. 16 illustrates an example waveform 40 of a signal prescribed by another energy delivery algorithm 152. 0. Similarly, two packets, a first packet 402 and a second packet 404 4, where packets 402, 404 are separated by a quiet period 406. In this embodiment, each packet 402, 404 includes three biphasic pulses 440, 442, Additionally, the pulses 440, 442, and 444 are sinusoidal in shape rather than square wave. Yes. Sine waves have the advantage of being symmetrical. Symmetry helps reduce unwanted muscle stimulation.

[0234]

[0291] A button 164 on the catheter 102 or operably connected to the generator 104 Energy delivery can be achieved by actuation of various mechanisms, such as a foot switch 168 mounted on the Such actuation typically provides the same amount of energy. The amount of energy delivered The amount of energy delivered to the airway wall W is determined by the number of packets and the packet voltage. Maintaining temperatures within and outside the wall (W) below the threshold for thermal ablation, particularly the threshold for thermal ablation of the basement membrane (BM) Additionally, the amount of energy may be increased over time to further reduce or eliminate heat buildup during the treatment procedure. The amount of energy may gradually increase or decrease. Instead of inducing a thermal effect, the amount of energy may eventually Provides levels that trigger the biological mechanisms and cellular effects that result in the regeneration of healthy tissue do.

[0235] III. Biological Mechanisms and Cellular Effects

[0292] As mentioned above, the algorithm aims to stimulate biological mechanisms while reducing or avoiding inflammation. Energy is provided to the airway wall W at a level that induces rhythmic and cellular effects. The mechanisms and cellular processes described herein include, but are not limited to, the following examples: .

[0236]

[0293] The energy delivered to the airway wall W ultimately leads to the regeneration of healthy lung airway tissue. These effects include cell detachment from the airway wall (W). The detached cells may be carried away naturally or in a deliberate manner) or cell death (e.g. Other cell effects include the elimination of specific cell types through cell proliferation, lysis, and apoptosis. The results include cell reprogramming or conditioning cells for improved drug uptake. It is conceivable that specific cell types may be modified without being eliminated, for example.

[0237]

[0294] In some embodiments, the specific cells are isolated by cell isolation from the airway wall W. FIG. 17 shows how energy (arrow 200) is delivered by one or more energy delivery bodies. 1 illustrates an embodiment in which energy 200 is delivered to the airway wall W using a basal The target cell depth was set to affect the epithelial layer E without extending beyond the membrane BM. The energy 200 is generated by specific epithelial cells, here multi-stratified ciliated columnar epithelial cells (PCECs) and The goblet cells (GC) and basal cells (BC) were separated from the remaining epithelial layer (e.g., basal cells) and / or basement membrane (BM). The isolated cells are then free to move within the lung passages and participate in the natural elimination process. The tissue is then removed by a catheter insertion or by an intervention such as suction.

[0238]

[0295] In another embodiment, specific cells are eliminated and affected by cell death. The cells die by lysis or apoptosis, ultimately leading to removal of the cells from the airway wall W. FIG. 18 illustrates an embodiment in which energy 202 is delivered to an airway wall W by one or more energy delivery bodies. Nergi202 is designed to affect the epithelial layer E without spreading beyond the basement membrane BM. However, in this embodiment, the energy 02 kills certain epithelial cells, in this case the multistratified ciliated columnar epithelial cells PCEC and goblet cells GC. The endothelial cells are configured to destroy the endothelial cells (see dashed line) and retain other cells (eg, basement cells BC). The mechanisms that lead to cell death are diverse. For example, in some embodiments, cells Death occurs by disruption of the cell membrane. In this embodiment, the delivered energy is delivered to the cell membrane at the site of cell death. Disrupts the lipid bilayer of the cell membrane so that it cannot maintain its barrier function. Without it, cells would need sodium, potassium, calcium, and adenosine triphosphate (ATP ) cannot maintain an adequate intracellular concentration. As a result, cells lose homeostasis and die. In some embodiments, cell death occurs by destruction of organelles. In this state, the delivered energy permanently disrupts the function of the organelle. These organelles include the endoplasmic reticulum, Golgi apparatus, mitochondria, nuclei, and nucleoli. If they cannot function properly, the cell will die. In one example, both the cell membrane and organelles are delivered. It can be understood that the energy is targeted to the cell membrane or organelles. If a policy only has a partial effect on the public, the cumulative effect on both objectives will be the final would result in cell death.

[0239]

[0296] After cell death, the inflammatory cascade begins. Cell fragments and intracellular contents are transported to the leukocytes. and macrophages to enter the affected area of ​​the airway wall W. Over a period of hours to days Thus, dead cells are removed from the area by phagocytosis. Unlike thermal ablation, which is the process by which cells phagocytose, it is restricted to cellular debris and not to collagen in the extracellular matrix. The present invention is not limited to the matrix components.

[0240]

[0297] In some embodiments, specific cells are not ablated, but rather the target cells are For example, in some embodiments, In the cytoplasmic gastrocnemius (GC), the ability to secrete accumulated mucus or to produce mucus is altered. The function of the cilia of PCECs was restored, allowing them to better excrete mucus into the airways. In another embodiment, the multi-stratified ciliated columnar epithelial cells (PCECs) and goblet cells are GC was unchanged, but deeper structures were primarily affected, with reduced smooth muscle hypertrophy and chronic inflammation. It has effects such as neutralizing inflammatory cells and eosinophils.

[0241]

[0298] Regardless of whether cell removal or cell modification is performed, the airway wall W regenerates, In one example, epithelial cells are regenerated to their pre-treatment state, whereas smooth muscle (SM), Deeper cells, including eosinophils, submucosal gland SGs, and chronic inflammatory cells, are permanently reduced.

[0242]

[0299] As previously mentioned, the present invention may be adapted to affect tissue to a predetermined depth and / or to affect the airway wall. The algorithm can be tailored to target specific cell types within the Various algorithms are used to separate the mucus layer (M), epithelial layer (E), basement membrane (BM), lamina propria (LP), and smooth muscle cells (SM). , submucosa, submucosal gland SG, nerve N, or a combination thereof. In one embodiment, the algorithm penetrates from the epithelial layer E of the airway wall W to the basement membrane BM. In this embodiment, various cell types are targeted. For example, energy leaves basal cells (BC) and multistratified ciliated columnar epithelial cells (PCEC) and goblet cells. The present invention may be configured to target cellular GCs and cause the elimination of these cells. In this study, the airway wall W is composed of dysfunctional multi-layered ciliated cylinders that cause hypersecretion of mucus. The delivered energy is abnormally multi-stratified ciliated casts. The epithelial cells PCEC and goblet cells GC are removed by cell death or detachment, and the basal cells BC are , leaving the basement membrane (BM) intact. The multistratified ciliated columnar epithelial cells (PCEC) and goblet cells (GC) Recall that the nuclei are connected by tight junctions (TJ) and adherens junctions (AJ). Ciliated columnar epithelial cells PCEC and goblet cells GC are connected to basal cells BC by focal adhesions D. In some embodiments, the energy is applied to the tight junctions TJ and the adherens junctions AJ. Then, the adhesion focal spot D is punched out, and the multistratified ciliated columnar epithelial cells PCEC and goblet cells GC are removed. Similarly, the energy is directed to maintain the hemidesmosomes H that connect the basal cells BC to the basement membrane 126. Thus, the basal cells BC remain intact.

[0243]

[0300] Elimination of multistratified ciliated columnar epithelial cells (PCEC) and goblet cells (GC) is mediated by multiple mechanisms. This can reduce mucus production and secretion. For example, this removal is unique to mucins. This weakens the signaling mechanisms that lead to the expression of proteins that inhibit mucus production. In particular, Muc5ac is a protein found in the mucin of airway goblet cells GC and is involved in the expression of MU It is encoded by the C5AC gene. Various ligands and transcription factors involved in Muc5ac expression Interleukin-13 is a transcription factor that binds to the interleukin-4Rα subunit. It binds to receptors containing Stat6, activates Janus kinase 1 (Jak1), and promotes Stat6 activation. MUC5AC and the Muc5ac promoter share a common Stat6 binding site. Although it does not have a transcription factor receptor 5 (SAM-C domain-containing Ets transcription factor), Stat6 activation is mediated by SPDEF (SAM-C domain-containing Ets transcription factor). This leads to increased expression of the α-terminal endogenous β-terminal endothelial cell, which upregulates multiple genes involved in mucosal metaplasia and Foxa2. As a result, Muc5ac is negatively regulated. Ligands including transforming growth factor α, amphiregulin, and neuregulin act on mitochondria. It binds to ErbB receptors, activating MAP kinase (MAPK). Hyperoxia-inducible factor 1 (HIF-1) also activates ErbB receptors downstream. The C5AC and Muc5ac promoters contain conserved HIF-1 binding sites. C3 and β2-adrenergic receptor signaling also enhances Muc5ac production. Sox2 Transcription factors such as Notch, E2f4, and Math primarily regulate expression.

[0244]

[0301] Multi-stratified ciliated columnar epithelial cells (PCEC) and goblet cells (GC) were removed by cell death or detachment. When mucus is produced, the signaling pathway that leads to Muc5ac expression is attenuated. This reduces mucus in the airways and is a common cause of COPD (chronic bronchitis, emphysema), asthma, and interstitial pneumonia. Those with interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, acute bronchitis, or other lung disease or disorder This could be considered a beneficial effect for patients.

[0245]

[0302] Removal of epithelial cells also reduces mucus secretion through a variety of mechanisms. In addition, when the mucus-producing goblet cells (GCs) are removed, there are no cells left to secrete mucus into the airways. Secretion is triggered by the molecular mechanism of mucin exocytosis. Secretory granules bind the closed conformation of syntaxin anchored to the plasma membrane, Munc1 Correlation between effector proteins acting as tethers to 8 and granule-associated Rab proteins ATP binds to the Gq-linked P2Y2 purine receptor and docks at the plasma membrane. It binds to the phospholipase C (P2Y2R) receptor and activates phospholipase C (PLC), which then initiates secretion. This results in the production of the second messengers diacylglycerol (DAG) and inositol. DAG activates Munc1314 to synthesize IP3. SNAP-23 (synaptosome-associated protein 23) is a stimulatory protein that opens the synaptosome and pulls the granules and plasma membrane together. SNARE 23) and VAMP (vesicle-associated membrane protein) It forms a soluble N-ethylmaleimide-sensitive factor-binding protein (FBP) receptor complex. IP3 is a calcium receptor that acts on the endoplasmic reticulum (ER). release and activate synaptotagmin to facilitate final coiling of the SNARE complex. This induces the cellular proliferation of the inflammatory process, resulting in membrane fusion and release of mucin.

[0246]

[0303] Signaling mechanisms that induce mucin exocytosis upon removal of epithelial cells This weakens the mucus production, resulting in less mucus in the airways. COPD (chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis This may be of benefit to patients suffering from chronic obstructive pulmonary disease, acute bronchitis, and other lung diseases or disorders.

[0247]

[0304] In some embodiments, the basal cells BC remaining on the basement membrane BM are normal It is possible to regenerate goblet cells (GC) and normal multistratified ciliated columnar epithelial cells (PCEC), thereby In some embodiments, reverse remodeling of the disease is triggered and mucus hypersecretion is reduced. In this study, PCECs, which are multilayered ciliated columnar epithelial cells, further migrate from the peripheral regions of the airway wall W. Goblet cells (GCs) normally act as energy receptors and proliferate to help regenerate healthy tissue in the target area. The regeneration occurs at a lower level compared to the mild, moderate, or severe goblet cell hyperplasia present prior to addition. Newly regenerated goblet cells (GC) have very low mucus production. Newly regenerated multi-layered ciliated columnar epithelial cells (PCE) C regenerates normally functioning cilia C, allowing mucus M to be expelled more easily. This allows Healthy tissue regenerated within days of the procedure, and patients experienced a dramatic reduction in symptoms such as coughing and excessive mucus production. resulting in fewer exacerbations and improved quality of life.

[0248]

[0305] In other embodiments, the energy is removed, such as by cell death or detachment. The abnormal goblet cells (CG) are targeted, leaving the multi-layered ciliated columnar epithelial cells (PCEC) and basal cells (BC) alone. The removal of abnormal goblet cells (CG) may be achieved by the above-mentioned mechanism, which is to suppress mucus production. and / or reduced mucus secretion. Similarly, energy may be lost by cell death or detachment, etc. The target is the abnormal multi-layered ciliated columnar epithelial cells (PCEC) that are removed by the endothelial cell transplantation. Similarly, the energy may be removed by cell death or detachment, etc. The target is the abnormal basal cells (BC) that are removed, and the multi-layered ciliated columnar epithelial cells (PCEC) and goblet cells (GC) Regardless of the combination of the above cell removal methods, the remaining cells may be , which may be further modified or acted upon by the delivered energy or by subsequent delivered energy. For example, the remaining abnormal goblet cells (CG) may remain intact and modified to suppress mucus production and / or This results in a reduction in mucus secretion. The cell population may be partially ablated, and specific cell A portion of the cells of the vesicle type are ablated by the delivered energy, and the remainder are modified as needed.

[0249]

[0306] In another embodiment, the algorithm comprises: In this embodiment, the change in the epithelial layer E is generated. occurs as described above. In addition, the basement membrane (BM) remodels the airway wall (W) to a healthy state. In some embodiments, the delivered energy is used to aid in During this time, changes occur in the basement membrane (BM), and the thickness of the basement membrane (BM) stabilizes or decreases. Thickening of the membrane BM is one of the hallmarks of many lung diseases, including chronic bronchitis and asthma. The delivered energy may then be targeted to the basement membrane BM to stop or reverse such thickening. In some embodiments, such changes in the basement membrane BM may affect cells such as neutrophils and It affects the ability of inflammatory molecules, such as cytokines, to pass through the basement membrane (BM), thus This assists in the regeneration of healthy airway walls (W).

[0250]

[0307] In some embodiments, the algorithm penetrates the epithelial layer E of the airway wall W. , which is configured to generate energy beyond the basilar membrane BM. The constituent layers of the pulmonary wall W change position depending on the anatomical variations along the pulmonary passageway. For example, The location of the smooth muscle layer SM varies along the length of the pulmonary passageway, ranging from adjacent to the basement membrane BM to a fixed Therefore, for a particular pulmonary passage segment, the airway wall W is selected For example, the delivery energy can be titrated to target specific locations of the smooth muscle layer (SM). The algorithm can be selected or adjusted to affect the smooth muscle hypertrophy. Many lung diseases, including bronchitis, asthma, and several other airway diseases that result in airway hyperresponsiveness In some embodiments, the delivered energy induces cell death of smooth muscle cells. This reduces airway hyperresponsiveness and provides the desired bronchodilatory effect.

[0251]

[0308] In some embodiments, the algorithm is adapted to affect submucosal gland SG. The submucosal glands overproduce and oversecrete mucus in the affected airways. In some embodiments, the delivered energy induces cell death in the submucosal gland SG. Reduction in glandular SG reduces mucus in the airways and improves patient outcomes.

[0252]

[0309] In some embodiments, the delivered energy is adapted to impact the lamina propria LP. The lamina propria LP has loose connective tissue. The connective tissue and matrix structure of P has a very high compressibility and elasticity. The loose structure allows for the presence of many cell types. The cell populations in the lamina propria LP are diverse, including fibroblasts, lymphocytes, and plasma cells. These include macrophages, eosinophilic leukocytes and mast cells. Patients with airway disease often Chronic inflammation, specifically increased lymphocyte and macrophage populations. In the method, the delivered energy is directed to inflammatory cells, particularly lymphocytes, macrophages and / or eosinophils. Such energy is released by the extracellular matrix, which reduces the amount of cellular globulin and thereby reduces inflammation. Cells are removed from the lamina propria LP by cell death, etc., while maintaining the matrix. By maintaining the matrix structure, stem cells and / or other cells can repopulate the matrix. Healthy tissue can be formed. This is because the layer of the airway wall W, which contains the extracellular matrix, What are fibrosis or other scarring mechanisms that result in permanent changes, such as melting or disintegration of layers? In contrast, the cartilage layer CL is not damaged, thus maintaining the structural integrity of the airway. , collapse can be prevented.

[0253]

[0310] Therefore, one or more algorithms may be used to provide energy to the airway wall W. The energy may penetrate to a certain depth in the airway wall W and affect one or more layers of the wall W. The energy acts on various layers extending from the surface to a particular depth. Alternatively, the energy may be applied to surrounding layers. The cells may be configured to act on cells at a particular depth without affecting the The effects of the cell culture may include cell death or cell removal by detachment, or the alteration of specific cell functions. One example is a cellular modification that changes only some of the cells of the same type or in the same layer. is affected by the delivered energy. Optionally, Either of these can be used to deliver additional energy to target larger cells of the same type or in the same layer. They may operate on parts or wholes, or may utilize either the same or different algorithms. The effect can be amplified by providing additional energy using the removes cells from the modified cells. Also, applying the same or a different algorithm, Additional energy is delivered to affect different portions or different depths of the airway wall.

[0254]

[0311] The actual mechanism for removing or modifying the cells is described, for example, in algorithm 152. , energy delivery device 108, patient anatomy, etc. In this method, cells are removed (eg, separated) by dielectrophoresis.

[0255]

[0312] Dielectrophoresis describes the movement of particles under the influence of a non-uniform applied electric field. The motion is determined by the magnitude and polarity of the charge induced in the particle by the applied electric field. The dipole moment induced in the grains is due to the generation of equal and opposite charges at the grain boundaries. The induced projection is not uniformly distributed over the entire particle surface, so the macroscopic The applied electric field is non-uniform, so the local electric field and the forces on both sides of the particle Therefore, depending on the relative polarizability of the particle with respect to the surrounding medium, the inner electrode and the high electric field towards the outer electrode and low field region (positive dielectrophoresis) or towards the outer electrode and low field region (negative dielectrophoresis) The dielectrophoretic force is a function of the cell volume and polarization, the surrounding medium It is a function of the electrical conductivity and permittivity, as well as the frequency and spatial gradient of the magnitude of the generated electric field.

[0256]

[0313] In some embodiments, multi-stratified ciliated columnar epithelial cells PCEC and goblet cells GC The removal of abnormal epithelial cells such as the endothelial cell 104 is achieved by one or more energies delivered by the energy delivery device 108. 1 is a result of dielectrophoresis induced by a laser pulse. The epithelial layer E was separated by dielectrophoresis, and abnormal multistratified ciliated columnar epithelial cells (PCEC) and The goblet cells GC are detached from the fixed basal cells BC and removed from the airway wall W. The basal cells BC are semicircular. The basal cell BC is connected to the basement membrane BM by focal adhesion H, and the basal cell BC is connected to the goblet cell GC via focal adhesion D. Note that the electrodes are connected to the ciliated epithelial cells (ECs). Instead of separating the connections by adhesion spot D, hemidesmosome H remains intact. The superficial cells are removed, while the basal cells (BC) remain largely intact and regenerate the epithelium. Get ready.

[0257]

[0314] FIG. 19 illustrates a schematic of epithelial cell removal by dielectrophoretic effects, where: A distal portion of an embodiment of the catheter 102 having an energy delivery body 108 is inserted into the pulmonary passageway. As can be seen from the electric field lines shown by dashed lines, the energy 204 is The shape of the energy delivery body 108 and its application externally to the skin of the patient P may be varied. Depending on the positioning of the return electrode 140, the electric field becomes non-uniform. The drug delivery device 108 is positively charged. This is the strongest / most concentrated pole of the electric field. The return electrode 140 is negatively charged and is the weakest pole of the electric field. The periphery is made up of epithelial cells from the airway wall (e.g., multistratified ciliated columnar epithelial cells PCEC and goblet cells G). C) Induce the separation and displacement of epithelial cells (see downward arrows). or removed by a intended mechanism.

[0258]

[0315] In some embodiments, cells are transfected using electroporation or other mechanisms. Reversible electroporation is a method in which a short high-voltage pulse is applied to the cell membrane to remove or modify the This is a non-thermal technique that generates a strong electric field that increases the electrical conductivity of the cell membrane, forming holes in the cell membrane (e.g., the plasma membrane). These pores allow the introduction of chemicals, DNA, and / or other drugs into the cells. Thus, in some embodiments, reversible electroporation can be used to, for example, Modifying cells within the tract wall W and, for example, increasing the uptake of drugs or agents. The IRE technique uses short high-voltage pulses to generate strong electric fields that increase the cell membrane voltage, essentially It induces necrosis of cells by forming holes in cell membranes (e.g., plasma membranes) without substantial protein denaturation. Thus, in some embodiments, the method is a non-thermal ablation method that induces cell death. To remove the endothelial cell, irreversible electroporation can be used. In this study, a combination of mechanisms, such as a combination of dielectrophoresis and electroporation, was used to Remove or modify.

[0259]

[0316] Instead of or in addition to affecting the tissue cells of the airway wall W, the delivered energy may act on pathogens present inside or near the airway wall W. For example, bacteria (e.g. Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, Opportunistic Gram-negative rods bacteria, mycoplasma pneumoniae), viruses (rhinovirus, influenza / parainfluenza influenza virus, respiratory syncytial virus, coronavirus, herpes simplex virus, adenovirus viruses), and other organisms (e.g. fungi).

[0260]

[0317] In some embodiments, the lung tissue modification system 100 additionally or alternatively Pathogens typically found within the lumen of the patient's airway (e.g., within the mucus layer M) or within the tissue layer of the airway wall W. In some embodiments, the effect is to control, reduce, and / or eliminate the infection. Thus, the energy output from the system 100 is directed to the mucus layer M and the airways present in or near the airways. This affects all pathogens that may be present. The mucus layer M becomes less viscous and therefore This makes it easier for the patient to expel the bacteria via coughing. The antibodies may be killed or programmed to inhibit (kill) the virus, thereby reducing or eliminating the infection.

[0261]

[0318] In some embodiments, the stem 100 is capable of detecting antibodies or Develop other symbiotic and supportive immune responses to enhance future immunity and resistance to that pathogen in the future. The system 100 substantially non-thermally affects pathogens. The cell fragments still contain the protein. As proteins are released into the local environment and circulation, the immune system must respond to these challenges. , develop new ways of recognizing and responding to threats, and in the future, protect hosts from those challenges or pathogens. Increase defense.

[0262]

[0319] As mentioned before, the energy signal parameters may vary depending on different effects such as different penetration depths. In one example, the system 100 is operated to induce the mucus layer M and any resident In one example, separation of the epithelial layer E occurs. In one example, the system 100 may be configured to perform a segmentation of the epithelial layer E via a single energy delivery algorithm. Separation occurs, pathogens are affected, and / or deeper structures are affected. In one example, the generator can be configured to use a variety of stored energy delivery algorithms. The user can then use these algorithms to tailor the treatment to an individual patient. Two or more of the following may be applied to address the needs of each individual patient: , may be administered in a single treatment session or in multiple treatment sessions.

[0263]

[0320] In one example, smooth muscle cells (SM), submucosal glands (SG), and / or deeper cells including nerves (N). It is desirable to affect the patient's pathology due to the mucus excess caused by the epithelium E. is more complex than secretion, and therefore the procedure is intended to affect deeper structures Airway smooth muscle cells (SM) are known to contribute to bronchial hyperresponsiveness, and submucosal gland (S) G may contribute to severe mucus hypersecretion, and N nerves regulate the secretion of submucosal glands (SG) and airway smooth muscles (SM). Or, it may be a combination of asthma and chronic obstructive pulmonary disease (COPD) (e.g., asthma-COPD). Patients with complex pathologies such as PD overlap syndrome may experience some mechanism (e.g., mucus hypersecretion, may benefit from procedures targeting smooth muscle hypertrophy, ciliary dysfunction, and / or , etc.) and / or the target tissue. The energy dose is designed to affect structures deep within the epithelium E. can be titrated repeatedly (e.g., based on sensor and / or other feedback). In one example, as the energy dose increased, the submucosal gland SG became lighter. It undergoes partial membrane dissolution to a degree or significant loss of structural integrity. However, the lamina propria LP, a cell layer located between the epithelium E and the submucosal gland SG, remains unchanged. The thermal energy source induces significant changes in the structure of the extracellular matrix, This leads to fibrosis.

[0264]

[0321] In addition to submucosal gland SGs, smooth muscle SMs disappeared from focal changes in a dose-dependent manner. , causing the removal of epithelium E over a period of days to weeks. The cartilage layer CL, the deepest structure, was not affected by the energy and showed no signs of inflammation or necrosis. It acts as an insulating barrier.

[0265] IV. Sensors

[0322] In some embodiments, one or more system or tissue parameters are measured. To achieve this, one or more sensors 160 are included in the system 100. 0 is a temperature sensor, impedance sensor, resistance sensor, surface conductance sensor, membrane Potential sensors, capacitance sensors, and / or force / pressure sensors, or a combination thereof Thus, the parameters measured by the sensor 160 include, to name a few, The sensors 160 may include impedance, membrane potential or capacitance, and / or temperature. , inter alia, (a) obtaining baseline measurements; and (b) measuring parameters during the delivery of energy. and / or (c) measuring a parameter after energy delivery. can be.

[0266]

[0323] The sensor 160 is disposed on the energy delivery body 108 adjacent to the energy delivery body 108. or at any suitable location along the distal portion of the catheter 102. Temperature sensors can monitor the temperature of the electrodes and / or the electrode / tissue interface. The impedance sensor can monitor the impedance of the tissue across the two electrodes. Conductance sensors monitor the transfer of electrical energy across any two electrodes. The force / pressure sensor can monitor the amount of force or pressure that the electrodes exert on the tissue. can.

[0267]

[0324] This sensor information can be used to, by way of non-limiting example, determine the proper deployment of the energy supplier 108. to determine the amount of energy required to drive the treatment algorithm 152 and / or to control the energy delivery for safety reasons. The sensor 160 can be used as feedback to the system to stop the It is also used to sense when treatment has been achieved. The system 152 also uses the detected data to optimize the treatment so that the targeted tissue treatment is achieved. The treatment algorithm 152 can be automatically titrated. One or more parameters and / or aspects of the system are iteratively modified based on the sensor data. For example, in some embodiments, the power and / or energy duration may be can be increased or decreased based on sensor data.

[0268] A. Impedance sensor 1. Ensuring proper positioning of the energy delivery device

[0325] In some embodiments, the energy delivery device 108 is appropriately inserted into the airways of the lungs. One or more impedance sensors are used to determine whether the device is deployed. In some embodiments, a brief, low voltage signal is used to determine their positioning and airway. The energy delivery body 108 is delivered to the energy delivery body 108 during deployment / expansion within the target area. Measured current feedback received by generator 104 from the impedance sensor Based on the clock, the generator's processor 154 is configured to calculate the impedance. The calculation is performed using a constant voltage and an actual current. The calculated impedance is then , an impedance that is considered acceptable for a properly inserted and deployed energy delivery body 108. The calculated impedance is compared to the allowable impedance range. If not, the generator 104 may display a particular message and / or notify the operator. For example, if the energy delivery device 108 is still attached to the bronchoscope 112, the device emits a specific sound to warn the user. If so, the generator 104 measures a very high impedance that is outside the acceptable range. In such a case, the generator may be turned on when the operator activates the energy transfer body 108. Messages (e.g., At this point the message may change. (e.g., Ready).

[0269]

[0326] Other types of sensors, such as temperature, force or pressure sensors, may be paired with the electrodes prior to the start of treatment. This can be used in addition or alternatively to confirm contact with the tissue. Adequate contact between the electrode and the tissue is a key factor for effective treatment. Firm and consistent contact is desired to adequately bind the material and achieve the desired tissue effect. It is.

[0270] 2. Ensuring catheter functionality

[0327] In some embodiments, the catheter 102 is functional or potentially defective. One or more impedance sensors are used to determine whether a defect exists. In the form of a short-term low-voltage signal (e.g., 1-5 packets in duration and approximately 500 V) during their positioning and deployment / expansion within the target area. The measured current feed received by the generator 104 is delivered to the delivery body. Based on the back, the generator processor 154 calculates the impedance. The calculation is performed using the set voltage and the actual current. The calculated impedance is This is compared to impedance values ​​considered acceptable for a properly functioning catheter. If the calculated impedance is outside the range of acceptable impedances, the generator The detector 104 may optionally display a particular message and / or alert the operator. For example, if the catheter is defective, the impedance will be very high and In this embodiment, the generator 14 generates a message (e.g., "catheter exchange" Once replaced, the generator 104 will operate at a much lower output within acceptable limits. Detects impedance and displays a different message (e.g., "Position Catheter"). Impedance measurements can therefore be used to detect dysfunctional catheters. This can be used to avoid safety hazards.

[0271] 3. Energy algorithm correction

[0328] In some embodiments, which energy delivery algorithm 152 to apply and / or to define the need to apply additional energy to the target location. Impedance measurements can be performed before and after application of the gi. In some embodiments, Pre-treatment impedance measurements can be used to determine settings for various signal parameters. In another embodiment, a method for determining whether to adjust the energy delivery algorithm can be used. A sensor can be used to determine the

[0272]

[0329] In some embodiments, the impedance measurement is performed as follows. Once positioned at the target area within the pulmonary passageway, a short duration low voltage signal is delivered to a generator (e.g., The energy is delivered to the energy delivery body 108 via the generator 104. Based on the measured current feedback received by the generator 104, A calculation is performed using the set voltage and the actual current to calculate the impedance. The impedance measured is considered acceptable for the impedance measured. The measured impedance value is then compared to the measured energy delivery value. The parameters that can be adjusted are: , voltage, frequency, pause period, number of cycles, dead time, number of packets or The feedback control rule includes, but is not limited to, the combinations thereof. The system adjusts the performance of the energy delivery based on one or more measured system or tissue parameters. The parameter can be configured to be modified.

[0273]

[0330] In some embodiments, one or more sensors are used to monitor electrical properties of the tissue. An impedance sensor is used. The impedance value can be considered an indicator of tissue condition. In some embodiments, to provide the impedance spectrum, The impedance is measured at different frequencies. This spectrum shows the frequency dependence of the impedance. Characterize the components that are dependent on or ineffective. Tissues have both resistant and reactive components. These are the components of complex impedance. Reactance is the capacitance of tissue and inductance is the The frequency dependent component of the impedance, including the impedance of the tissue, changes in the overall Not only does the impedance change, but the resistive or reactive components of the complex impedance also change. The measurement of complex impedance involves the conduction of a low-voltage sensing signal between two electrodes. The signal may include, but is not limited to, a sinusoid. Changes in impedance may reflect the condition of the treated tissue, and therefore may be useful in determining whether treatment is effective. indicates that the treatment will affect tissue and not affect tissue, or that treatment is complete. The impedance value also varies depending on the contact conditions between the sensor and the airway tissue. In addition, the sensor may be used to determine the contact condition between the electrode and the tissue.

[0274]

[0331] In one example, the generator 104 may detect a need for additional energy delivery at a target location. Optionally, the generator 104 may instruct the user that a particular message will not be and / or which energy delivery algorithm 154 has been selected or A specific sound is emitted to alert the operator regarding the completion of treatment at the target location. The generator 104 automatically selects the appropriate algorithm for the particular measured impedance. or cut off delivery of the energy signal when it is determined that treatment is complete. Additionally, impedance or other sensors can be used to measure safety. The above concerns may lead to the determination that treatment should automatically be discontinued.

[0275] B. Temperature Sensor

[0332] In some embodiments, one or more temperature sensors are used to measure electrical conductivity during treatment. The temperature of the electrodes and / or tissue is measured to determine whether the energy deposited in the tissue is causing clinically significant tissue heating. In some embodiments, the measurement is performed at or near the electrode. The measured temperature is also used to determine the contact condition between the electrodes and the tissue prior to treatment. This is a level that is sufficient to generate heat but insufficient to cause substantial thermal damage. This can be achieved by applying energy with a bell. The electrodes are pressed against the airway wall. Depending on whether it is suspended in the airway, moving within the airway lumen, or floating, the temperature may change. They differ in steady-state value or its variability.

[0276]

[0333] In some embodiments, the tissue is contacted and the tissue exceeds a predetermined safety threshold. To prevent heating, one or more of the energy delivery bodies 108 may be provided along a surface thereof. Thus, one or more temperature sensors are positioned to monitor the temperature of the tissue during treatment. A temperature sensor can be used. In one embodiment, the temperature is measured at a threshold value (e.g., 40° C. , 45℃, 50℃, 60℃, 65℃) The change may be to reduce the measured temperature or to reduce the temperature below a preset threshold. Energy delivery parameters (e.g., algorithm modifications). Adjustments may include rest periods or dead periods. These include, but are not limited to, increasing the time or decreasing the number of packets. is determined by a predetermined stepwise approach that considers the percentages of the parameters, or by other methods. This is an example of a process that can be implemented.

[0277]

[0334] In other embodiments, one or more temperature sensors measure the temperature of the tissue and / or the electrodes. When a certain threshold temperature is exceeded (e.g., 65° C.), the generator 104 starts the algorithm. For example, the safety threshold is set to 65°C and the energy supply is automatically stopped. A feedback signal from one or more temperature sensors that the generator 104 is exceeding a temperature safety threshold. If a feedback is received, therapy is automatically stopped.

[0278] C. Sensor for monitoring electrode contact

[0335] In some embodiments, multiple sensors (e.g., temperature, impedance , force, pressure, etc.) in various directions, such as in a circumferential direction, on the surface of one or more energy delivery bodies 108. In such a configuration, the sensor is used to detect the energy delivery from one or more energy delivery bodies. Whether or not there is sufficient contact between the surface of 108 and the bronchial airway wall surface, e.g., proper circumferential and Non-circumferential (e.g., non-uniform temperature, impedance, etc.) are stable (e.g., continuously changing temperature, impedance, force, etc.) and / or The sensor indicates that contact is not sufficient, such as by detecting a force or vibration. Adjust the level of expansion of the bronchus to better match the internal diameter of the bronchus being treated. Select catheters 102 having energy delivery bodies 108 of different sizes. In an embodiment, the generator 104 interprets the degree, quality, and / or stability of the contact. providing feedback to the operator to aid in proper positioning of the energy delivery body; For example, the operator may select one or more energy sensors that are not in contact with the circumferential direction. When in the process of positioning the lubricant delivery device, the user interface of the generator 104 150 may display a message such as "poor contact."

[0279]

[0336] In some embodiments, a force or pressure sensor is used to measure the energy delivery and a wall of the airway, thereby detecting and measuring a contact force between the energy delivery body and the tissue. The contact state of the object can be determined.

[0280]

[0337] Any of the embodiments of the system 100 disclosed herein may be used to monitor the application of treatment. One or more sensors may be incorporated to provide visibility.

[0281] V. Cardiac Synchronization

[0338] In some embodiments, the energy signal is synchronized with the patient's cardiac cycle to detect cardiac instability. Therefore, the patient's cardiac cycle is usually monitored using an electrocardiogram (ECG). Referring to FIG. 20, a typical ECG tracing 600 includes a P wave 60 representing an atrial depolarization. 2. QRS complex 604 representing ventricular depolarization and atrial repolarization, and T wave 60 representing ventricular repolarization. 6 repeat cycles to safely deliver energy into the airways in close proximity to the heart In addition, synchronization between energy delivery and the patient's cardiac cycle is employed to reduce the risk of cardiac arrhythmias. The supplied energy increases myocardial cell membrane permeability to allow ion transport, High-voltage energy should not be injected into the myocardium as it may induce cardiac arrhythmias, especially ventricular fibrillation. To avoid cardiac arrhythmias, electrical energy The drug is delivered to the airways in a manner that is outside the "vulnerable period" of the myocardium. Within the ventricle, periods of weakness of the ventricular muscle are indicated on the ECG by full T waves 606. For the myocardium, the vulnerable period coincides with the middle and end of the T wave 606. When the energy pulse is delivered close to the ventricle, the vulnerable period occurs a few milliseconds earlier than the heartbeat. Therefore, the entire T wave can be considered to be within the ventricular vulnerable period.

[0282]

[0339] The remainder of the cardiac cycle are the P waves 602 and the QRS complexes 604, which together Also includes periods during which the atrial or ventricular muscles are refractory to high-voltage energy stimulation. If the energy pulse is delivered during the muscle's refractory period, the probability of arrhythmia can be minimized. The ST segment 608 (the interval between ventricular depolarization and repolarization) and T The Q interval 610 (the interval that includes the end of the first cardiac cycle and the midpoint of the second cardiac cycle) is This is the period during which energy is generated. No induction of cardiac arrhythmia due to the depolarized state of the myocardium (refractory period) FIG. 20 shows an example of a cardiac cycle during which energy may be safely applied. Includes shaded boxes indicating representative parts.

[0283]

[0340] FIG. 21 illustrates a method for synchronizing the delivery of energy with the cardiac cycle, according to some embodiments. 1 is a flow chart illustrating an embodiment of a method for detecting an electrocardiogram (ECG). CG) is operably connected to a communication port 167 on the energy generating generator 104. External cardiac monitor 170 (AccuSync Medical Research Co. The pulse rate is obtained by a suitable monitor, such as a cardiac monitor available from rporation. Here, the cardiac monitor 170 continuously acquires an ECG and The cardiac cycle is analyzed to identify the beginning of the period in which it is safe to apply energy. In some embodiments, the cardiac monitor 170 detects this event / onset (e.g., For example, when an R wave is detected in an ECG tracing, low-voltage transistor-transistor logic ( START Step 650. In the embodiment, the processor 154 of the energy generating generator 104 has a communication port 167. 6. Monitor (at step 652) to determine if a cardiac sync pulse is detected. If a TL pulse is not detected by the generator 104 (step 654), the user The user is notified using the interface 150 (step 656). For example, The interface 150 may display a bright red heart and / or any other suitable visual indicator. The cardiac synchronous pulse is detected by the generator 104 (step 65 8), the user is notified using the user interface 150 (step 660). For example, a solid red heart changes to a flashing yellow heart, and the heart sync pulses. It lights up when a signal is detected.

[0284]

[0341] The external cardiac monitor 170 may send erroneous TTL pulses, so , the patient's heart rate is not within the normal expected range and is unstable; and / or However, if the patient has an extended QRS complex that is far from or different from the patient's basic heart rhythm, The next step is to check the heart rate and TT because the neurator should not continue the treatment. Establishing the reliability of the L-pulse (i.e., cardiac synchronous pulse) (step 662 In one embodiment, the processor 154 of the generator 104 is used to generate a TTL pulse. It monitors the data and measures the time between each beat, called Δt1, Δt2, Δt3, Δt4, and Δt5. These values ​​are generated as a rolling buffer containing the last five Δt calculations. These five values ​​can then be stored in the data storage module 156 of the calculator 104. The average of the two values ​​can be calculated and called Δt-ave. The above TTL pulses can be used to calculate the next Δt (e.g. Δt6, Δt7, etc.). This can also be stored in the data storage module 156. For example, two TTL Pulses can be used.

[0285]

[0342] These are then calculated using the algorithm module 152 of the generator 104. The value of is compared to a set of criteria that, if met, indicates that the patient's heart rhythm is normal / consistent. It provides confidence that the TTL pulse is reliable and that the You can check your heart rate and see that it is between 40 and 150 beats per minute (bpm). In this example, Verify that the heart rate is not unstable by comparing Δt6 and Δt7 with Δt-ave. In one embodiment, to continue, Δt6 and / or Δt7 can be In this example, both criteria must be met to ensure reliability. However, in other embodiments, both criteria Once authenticity is confirmed, the user interface 150 may not be required. The user may be notified that it is safe to continue using the device (step 666). For example, a blinking yellow heart on the user interface 150 may be changed to a blinking green heart. The user interface 150 can then be used to set the high energy Instruct the user to charge a storage unit (e.g., one or more capacitors). In the example, user interface 150 displays a softkey labeled "Charge." The charge button allows the user to press the charge button to charge the high energy storage unit. If the button is not pressed (step 668), the processor 154 detects the heart rate and TTL signals. Keep checking the reliability.

[0286]

[0343] When processor 154 recognizes that the charge button has been pressed (step 670 ), the processor 154 continues to check the reliability of the heart rate and the TTL signal (step 6 72). During that time, a predefined / predetermined amount of time (e.g., about 30, 40, 50, 60 , or up to 120 seconds, including all values ​​and subranges therebetween) has elapsed. Once the reliability of the rate and TTL has been verified (step 674), the system enters charging mode. The system is in a state where the heart rate is checked and the reliability of the cardiac sync pulse is established. Return (step 662). If the timeout has not been reached (step 676), the reliability The user interface 150 notifies the user (at step 680) until (Step 678). User interface 150 indicates that the softkey is labeled "Ready." The system 100 can be modified so that the foot switch 168 is Waiting to be pressed.

[0287]

[0344] While the system 100 waits for the foot switch 168 to be pressed (step 34 8), which monitors the heart rate and keeps checking the self-confidence (672). If the foot switch 168 is not pressed within a certain period (e.g., about 30, 40, 50, 60, or Predefine another timeout for the range (up to 120 seconds, including all values ​​and subranges in between) As shown, when the timeout is reached (step 674), the system The system stops being ready to deliver energy, checks the heart rate and triggers the TTL power The system returns to a state where the user has established trust with the footswitch (step 662). When the switch is pressed (step 684), the energy supply can be started (step 68 6). However, generator 104 waits until the next cardiac pulse is detected. , can be configured to more reliably deliver energy after an R wave is detected. In one embodiment, the energy is applied approximately 50 milliseconds after the leading edge of the TTL pulse is detected. However, this value is in the range of approximately 0 to 300 milliseconds. Then, the first energy packet can be delivered (step 686). The processor 104 checks to determine if all packets have been delivered ( If not, processor 154 monitors the heart rate (step 690). ) It continues to check the reliability of the TTL pulse and ends when the reliability of the cardiac synchronous pulse is re-established. Energy delivery can continue (step 662).

[0288]

[0345] In one example, a TTL pulse immediately following the energy delivery may be used to measure the high voltage energy delivered. It is better to ignore it because it is a false trigger caused by a process. The sensor 154 is energized for approximately 400 ms after it is powered up or before the last TTL pulse. You can ignore the TTL pulse for about 450 ms after the edge. The L pulse can be ignored for about 50 ms to about 1 second, including all values ​​and subranges in between. When the processor detects the next TTL pulse, it calculates the next Δt and applies it to the previously defined period. The result can then be compared (step 690) to a standard (i.e., based on a rolling average). Due to the possibility of a transient delay in the heart rate after energy delivery, the following Δt may deviate from the norm: If it is, it is simply ignored. Then the next Δt is calculated and compared to the previously defined criteria. If the criteria is met (step 700), the next packet is delivered. If all packets have not been delivered, the system updates the heart rate (step 686). The heart continues to monitor and check the reliability of the cardiac synchronous pulses as previously described (step 690). If reliability is established (step 700), the cycle continues. If not (step 702), the heart may turn yellow and flash or light up red. Therefore, the user is notified (step 704).

[0289]

[0346] If the system 100 is unable to determine acceptable reliability or within a certain period of time (e.g. for example, about 10, 20, 30, 40, 50, or 60 seconds) until the TTL pulse is no longer detected. If so, a timeout is reached (step 706). At this point, the cycle ends and the user is notified (step 708). The remaining packets are not delivered. The process then returns to the beginning (step 650). If the system can determine acceptable reliability within the set time limit (step 7), 00), does not time out (step 688), and continues to monitor heart rate continuously as described above. If the reliability is confirmed (step 700), Then, the next energy packet is delivered (step 686). Once the treatment is complete, step 710, the user is notified of the completion of the treatment. (Step 708). When the current associated with any delivery of the high energy packets exceeds a set value (e.g. If the load current exceeds 100 amps (e.g., approximately 45 amps) (step 686), the cycle may also be terminated. (step 708).

[0290]

[0347] In some embodiments, the components for obtaining the electrocardiogram 170 include a The cardiac monitor is limited to acquiring up to 5-lead ECG. In some cases, it may be beneficial to incorporate additional leads into the system. This eliminates the need to use the communications port 167 to receive the cardiac synchronous pulse. Rather, the processor 154 detects the R waves directly and evaluates the completeness of the entire QRS complex. The present invention can be configured to

[0291]

[0348] In some embodiments, the processor 154 calculates Δt-ave The system may be configured to use more than four Δt's or less than four Δt's for the purpose of the present invention. In some embodiments, the processor 154 calculates Δt-ave using 3 to 10 Δt's. In addition, the processor 154 may be configured to calculate For example, a processor may be configured to use Δt other than Δt6 and Δt7. The processor 154 may be configured to use the subsequent Δt. It may be configured to allow heart rates in excess of the above-mentioned 40-150 bpm. For example, , the processor 154 may select a value between 30 and 160 bp, including all values ​​and subranges therebetween. The processor 154 may be configured to allow for a range of heart rates of Δt 6 or Δt7 may be configured to be greater or smaller than ±10%. For example, the processor 154 may calculate Δt6 or other data points including a rolling average. The present invention may be configured to allow the deviation to be within ±50% of 3%. The illustrated example of user interface 150 is merely an example and is not intended to be limiting of the present invention. .

[0292]

[0349] The generator may therefore be configured to continuously monitor the patient's heart rate. If a cardiac arrhythmia is induced, therapy can be automatically stopped and an alarm sounded.

[0293] V. Imaging

[0350] Imaging can be utilized to: (a) detect diseased target tissue; (b) identifying the area to be treated; and (c) determining the effectiveness of energy delivery to the treatment area. (d) assess whether areas were missed or inadequately treated; (e) perform a pre- and post-treatment Imaging measures the target treatment depth and uses that depth to determine a specific energy delivery algorithm (f) identifying a target cell type or cell interface to achieve a tissue effect to that depth; Using the intra-treatment imaging and its location or depth to select a particular energy delivery algorithm; (g) obtaining a tissue effect on a target cell type or cell interface; and / or (g) the presence or absence of inflamed tissue. Regardless, post-treatment imaging will identify the presence of pathogens.

[0294]

[0351] In some embodiments, confocal laser endomicroscopy (CLE), optical coherence tomography (OCM), Optical Coherence Tomography (OCT), Ultrasound, Static or Dynamic CT, X-ray, Magnetic Resonance Imaging (MRI) , and / or other imaging modalities may be used. The lung tissue modification system 1 may be incorporated into another device to provide a separate device / system or 00 (functionally and / or structurally) incorporated / integrated into the imaging device (singular or (multiple) are areas of thickened epithelium, goblet cell hyperplasia, and Localization and identification of various sections of tissue, including submucosal glands, smooth muscle, and / or other abnormalities In some embodiments, the method can be used to measure the target treatment depth and / or access the target treatment depth. Used to select a treatment algorithm 152 sufficient to treat to the target treatment depth At least one energy delivery device can then be positioned at the site of abnormal airway wall tissue. The imaging device (single or multiple imaging devices) can be used to determine the location of the target tissue and deliver energy to affect the target tissue. (plural) describes where the treatment was or was not administered before, during, during, and / or after the treatment. This can be used to determine whether the energy has properly impacted the airway wall. If an area is missed or an area is determined to be insufficiently affected, appropriate measures should be taken. Energy delivery is repeated, followed by imaging modality(s), until treatment is achieved. Additionally, imaging information can be used to identify specific cell types and / or desired treatments. This allows the determination of whether or not a therapeutic depth has been applied, depending on the anatomical characteristics of a wide variety of patients. Allows customization of energy delivery algorithms for treating structures.

[0295]

[0352] In some embodiments, in combination with the use of a fluorescent agent (e.g., fluorescein), Combined imaging is performed to enhance the recognition of pathogens that may be present in the airways. Directly tag specific pathogens (e.g., bacteria) or target cells associated with various infectious conditions. One may choose to indirectly tag cells (e.g., neutrophils). In embodiments, such imaging methods / approaches include: gaining access to the airway; Delivering a fluorescent agent into the airway; exciting the fluorescent agent by delivering an excitation signal to the airway. and evaluating the presence or absence of fluorescence in response to an excitation signal.

[0296] A. Imaging for access

[0353] In general, the methods, devices, and systems disclosed herein are directed to treating a natural opening. through a passageway (e.g., mouth or nose), an artificially created opening (e.g., tracheotomy, surgically The created stoma, and / or appropriate intraoperative and / or postoperative opening, and / or airway Through an artificially created opening in the lung and / or other area of ​​tissue, the lung tissue or target Access areas (e.g., trachea, main bronchi, lobar bronchi, segmental bronchi, accessory bronchi, parenchymal tissue) The type of procedure available depends on the patient's age, comorbidities, and need for other concomitant procedures. The type of surgery required depends on factors such as the need for surgery and / or previous surgery.

[0297]

[0354] Methods for accessing the airways and / or other lung tissue (e.g., parenchyma) include nasal or via the mouth to the trachea and / or more distal bronchi. 8A to 8B, the bronchoscope 112 is used to is inserted into the oral cavity (OC) or other natural orifice, such as the nose or nasal cavity (NC). Other lung tissues such as the parenchyma can be accessed via the nose or mouth as shown in Figure 22. As shown, the distal end of the catheter 102 passes through the trachea T, the main bronchus MB, and the trachea T. The bronchus is advanced into the lobar bronchus LB, which crosses from the pulmonary passage to the surrounding lung tissue LT. This is accomplished using an instrument or catheter that has a guidance system that allows for lateral guidance.

[0298]

[0355] In some instances, direct visualization may not be necessary and / or desired. The therapeutic catheter can be delivered directly to the airways via the nose or mouth.

[0299]

[0356] In other embodiments, the method comprises administering to the patient a therapeutically effective amount of the agent that provides access to the airways and / or lung tissue (e.g., parenchymal tissue). Access is accomplished through other instruments inserted into the chest. In this study, one or more of a variety of imaging modalities ( For example, a bronchoscope 112 may be used. The drug may be delivered via the mouth to allow for direct visualization and delivery of the drug. Alternatively, The imaging modality may be through a separate working channel of the bronchoscope 112, through the nose, or through the mouth. In some embodiments, the imaging device (e.g., , direct visualization, CLE, and / or OCT) to the system generator 10 4 or a catheter 102 together with an appropriate mechanism for connecting to a commercially available console. 23A and 23B are images obtained using CLE and OCT, respectively. These images are based on CT scans using airway wall thickness (AWT) measurements. Based on visualization of cellular structures, we aimed to guide delivery to a predefined location previously identified on the screen. The present invention can be used to target treatment and / or assess the effectiveness of treatment.

[0300] B. Imaging for treatment planning

[0357] Methods relating to imaging include using pre-imaging to plan treatment Imaging is used to detect diseased target tissue, identify areas to be treated, and and / or to determine an appropriate energy delivery algorithm to achieve a desired treatment depth. For example, a CT scan can be obtained pre- or intra-operatively, from which the AW The T or Pi10 (theoretical airway wall thickness for an airway with an inner circumference of 10 mm) measurement is obtained. The target area is These metrics can be used to identify CLE or OCT can be used to measure the target treatment depth. The desired treatment depth is determined by the airway lumen LM It can be based on the thickness t of the epithelium E as measured from N to the basement membrane BM. Goblet cells G C or the distance d to a target cell type such as smooth muscle (not shown), and / or Any other structures determined to be relevant. FIG. 23B provides an exemplary OCT image of a diseased airway. The thickness of the airway, t', is measured from the airway lumen LMN to the outer edge of the airway EDG. These measurements can then be used to determine the specific energy delivery. A depth algorithm 152 can be selected to achieve tissue effects to that depth. For example, the generator 104 may provide a user interface 102 that allows for selection of a desired treatment depth. 50 (e.g., a touch screen) so that the operator can select the desired depth. The system 100 then selects the appropriate energy delivery algorithm to achieve that depth. 152 can be configured to automatically select the target treatment site. Other anatomical assessments can be performed to assess the presence or absence of pulmonary edema. For example, CLE can be used to assess the presence or absence of pulmonary edema. The size and / or density of goblet cell GCs, together with the distance d from the goblet cell GC to the goblet cell GC, are evaluated to determine whether treatment is appropriate. Both location and target depth can be targeted. These methods allow treatment to be tailored to each patient. This allows for customization to be tailored to suit your needs.

[0301]

[0358] In some embodiments, the use of the bronchoscope 112 allows for the sputum sample to be analyzed. If one or more pathogens are found, this information will be used to The information is used to determine the appropriate energy delivery algorithm to achieve the desired treatment depth as a result of the initial data. Improved tissue imaging may be achieved by determining the algorithm 152 in some cases. As with the combination of pathogen identification and treatment, only the mucus layer M where the pathogens multiply is treated. In other cases, it may be desirable to limit the depth of the airway obstruction, while in other cases, it may affect deeper airway structures. In order to plan treatment, it is necessary to determine whether or not an infection of the tracheobronchial tree is present. If infection is thought to be present, a sputum sample may be obtained and evaluated to determine if The generator does not substantially affect other layers, including pathogens causing infection or other lung tissue. It can be programmed to affect the mucus layer of the airways without causing any discomfort. The method of conducting the study is also used to evaluate the effectiveness of the treatment. Additional sputum samples, as well as biopsies, may be taken before or after the energy delivery procedure to These samples and biopsies can be compared to the planned samples and to each other. These data, combined with clinical examination of the patient, can be used to determine the effectiveness of the procedure. The data can be used to further optimize treatment.

[0302]

[0359] The method of performing one or more tissue biopsies may be useful in evaluating treatment regimens and / or efficacy of treatment. To plan treatment, a biopsy is performed and the patient's suitability ( For example, excessive mucus production, goblet cell density, goblet cell hypertrophy, epithelial thickness, inflammation, basement membrane thickening, submucosal Determine inflammation, submucosal eosinophilia, submucosal gland thickening) (e.g., smooth muscle hypertrophy, or other parameters) meters) and / or the degree of airway obstruction (e.g., thickness of the epithelium and / or other layers). By measuring one or more of the parameters, the generator can determine the effect on tissue at a particular depth. The energy delivery algorithm can be customized for each patient. For example, the voltage can be increased for patients with a thicker epithelium. Additional biopsies may be taken immediately or after the energy delivery procedure to assess the efficacy of the treatment. These biopsies can be compared with the planning biopsies and with each other. For example, the effectiveness of treatment can be judged by whether a post-treatment biopsy changes from a planned biopsy. If no lesions were detected, the area was not treated or inadequate treatment was performed to affect the tissue. Sufficient energy was applied, but post-treatment biopsies showed a decrease in epithelial thickness and / or structure. If a regeneration of healthy epithelium is demonstrated, the efficacy of energy delivery can be verified. By performing multiple biopsies along the airway, a sufficient percentage of the total surface area can be treated. These data, combined with clinical examination of the patients, can be used to further evaluate whether The data can be used to further optimize treatment.

[0303] C. Intra-treatment imaging

[0360] The use of the bronchoscope 112 allows for direct visualization of the target tissue as well as catheter 10. 2 and visual confirmation of the positioning. Direct visualization may not be necessary and the catheter 102 is delivered directly to the airway. Alternatively, various imaging modalities (e.g., C In one example, the bronchoscope 112 may include a catheter 1 The catheter is delivered via the mouth to allow for direct visualization and delivery of the catheter. The imaging modality may be through a separate working channel of the bronchoscope 112, through the nose, or through the mouth. In some embodiments, the imaging technique (e.g., Imaging techniques (e.g., direct visualization, CLE, and / or OCT) are used to determine the system generator or The catheter is equipped with an appropriate mechanism for connection to any of the commercially available consoles. can be.

[0304] D. Post-treatment imaging

[0361] In some embodiments, the methods relating to imaging include intraoperative and / or postoperative procedural imaging. Using imaging to evaluate the effectiveness of the procedure (e.g., using an imaging diagnostic device 169 In some embodiments, during the procedure, the operator may Use the CT scan to assess the target treatment area and determine if the area was missed or inadequately treated. For example, if an area is poorly processed, the operator can determine whether The operator can then observe that the target depth was not achieved. Remeasure the size, select the appropriate treatment algorithm 152, and treat again at the same location. In some embodiments, the generator 104 may be based on the desired depth. If there are no different preset algorithms, then use the same energy delivery algorithm Imaging can also be used to monitor the healing process and correlate tissue changes with clinical outcomes. It is used after the procedure to visualize the changes in the tissue as the healing process progresses and to assess the effectiveness of the procedure. These data will make it easier to assess the efficacy of the drug. This may lead to doctors deciding to take additional steps to affect the tissue. There is a gender.

[0305] VII. Catheter Embodiments

[0362] Various energy delivery catheter 102 embodiments are contemplated. The above features and characteristics may be used in any combination to achieve a desired tissue effect. Typically, such a catheter 102 is a pulmonary catheter having a lumen diameter of about 3 to 20 mm. The energy delivery body 108 is sized and configured to treat the passageway. near, against, in contact with, or exerting a pressure or force on wall W In some embodiments, the energy delivery body 108 expands within the lung passageway lumen. It expands to a diameter of up to 22 mm, in particular 3 to 20 mm or 3 to 22 mm.

[0306]

[0363] FIG. 24 shows a single energy delivery body 108 that is made up of at least two prongs. 1 illustrates an embodiment of an energy delivery catheter 102 that contacts the luminal wall of a pulmonary passageway. There may be a single protrusion, but the protrusion extends radially outwardly so as to contact the wall of the pulmonary passageway. Typically, two protruding segments are used to apply substantially opposing forces to the catheter and support the catheter between them. In this embodiment, at least two projections form a helical cage. A plurality of ribbons or wires constrained by a proximal end constraint 122 and a distal end constraint 124. In this embodiment, the proximal end restraint 122 is attached to the shaft 106. 1, the shaft 106 does not penetrate the energy delivery body 108. This allows the energy transfer body 108 to be folded without adding any additional dimensions to the energy transfer body 108. The lubricant delivery device 108 is delivered to the target area in a folded configuration. For example, this can be accomplished by positioning a sheath 126 over the energy supply 108. In FIG. 24, the catheter shaft 106 terminates in a proximal restraint 122. , the distal end restraint portion 124 is substantially unrestrained and freely moved relative to the shaft 106 of the catheter 102. Advancement of the sheath 126 over the energy delivery body 108 causes the distal end restraint 124 moves forward, thereby stretching / folding the energy delivery body 108 The retraction of the sheath 126 allows the energy delivery body 108 to self-expand, etc. In other embodiments, the wire or ribbon 120 is not helical. It is linear (i.e., configured to form a linear cage). In this example, the energy delivery body 108 is formed by laser cutting a tube.

[0307]

[0364] In some embodiments, the energy delivery body 108 includes multiple electrodes 107. Each wire 120 acts as a separate electrode 107 and has its neighbor as a return electrode. or fired separately using a dispersive electrode attached to the patient as a return electrode. In one example, each wire 120 of the energy delivery body 108 may be connected to each other. 0, and a separate conductor wire can be used to direct energy to the generator 10. 4 to the wire 120 of the energy delivery body 108. The wires 120 may be electrically connected to each other to form one or more wire sets. The algorithm 152 of the generator 104 may be implemented as ) to another wire, as well as the wire between the active and return (ground) states. It is possible to perform a swap of the functions of the

[0308]

[0365] FIG. 25 illustrates an energy delivery catheter 102 that includes two energy delivery bodies, i.e., The energy delivery body 108 includes a first energy delivery body 108 and a second energy delivery body 108′, 8' shows an embodiment that functions similarly to the embodiment of FIG. 24. In this embodiment, the first The energy delivery body 108 is disposed along the distal end of the first shaft 106 and the second The energy delivery body 108' is disposed along the distal end of the second shaft 106'. The shafts 106, 106' can be passed through the sheath 126 together such that In some embodiments, the shafts 106, 106' are aligned parallel to each other. In this embodiment, the shafts 106, 106 25, the second energy delivery body 108 is generally located distal to the first energy delivery body 108. The energy delivery bodies 108, 108' may be arranged so as to be staggered from one another, such as by disposing two energy delivery bodies 108'. In such a configuration, the energy delivery bodies 108, 108' are arranged The energy bodies 108, 108' may be separated by any suitable distance. Since the energy bodies 108, 108' are aligned with respect to the For example, in this embodiment, the energy transfer bodies 108, 108' The second shaft 106' is arranged so as not to impede the expansion of the first energy transmission body 108. Instead, the second shaft 106' is configured to have a cage-shaped axial extension between the wires 120. In some embodiments, the shaft 106, 10 In particular, the shafts 106, 10 6' can slide in the longitudinal direction parallel to each other. The arms 106, 106' can be rotated to increase or decrease the distance between the energy delivery bodies 108, 108'. Once the desired distance is achieved, the shafts 106, 106' , are fixed in place to maintain a desired distance between the energy delivery bodies 108, 108'. .

[0309]

[0366] In the embodiment shown in FIG. 25, each energy delivery body 108, 108' is The energy delivery body 108 is a spiral cage made up of electrodes 107 in the form of ears 120. 08' can be operated in bipolar and / or monopolar modes. The wire or ribbon 120 is straight rather than helical (i.e., does not form a straight cage). In some embodiments, the energy delivery bodies 108, 108' are configured to In this embodiment, the first shaft 106 is formed by cutting a tube with a laser. , terminates at a first proximal end constraint 122 of the first electrode body 108 and a first distal end constraint 12 The second shaft 106' is connected to the second electrode body 104, leaving the second shaft 106' essentially unconstrained. 8' and terminates at a second proximal end restraint 122' and essentially restrains at a second distal end restraint 124'. Advance the sheath 126 over the energy delivery bodies 108, 108' This allows the distal end restraints 124, 124' to move forward, thereby The energy delivery bodies 108, 108' are folded, stretched and constrained. Retraction of 6 exposes the energy delivery bodies 108, 108' for expansion and delivery of energy. Can.

[0310]

[0367] FIG. 26 illustrates a monopolar electrode 107 formed by multiple ribbons or wires 120. 1 is an embodiment of an energy delivery catheter 102 having a single energy delivery body 108 comprising: 1 shows an embodiment in which the energy delivery body 108 has a plurality of electrodes extending therethrough. The energy delivery body 108 is attached to the shaft 106. The energy delivery body 108 also has a proximal end restraint 122 and the distal end restraint 124. In this configuration, the energy Either the proximal end restraint 122 or the distal end restraint 124 is engaged so that the delivery body 108 is folded. One end slides freely on shaft 106, and the other end is fixedly attached to shaft 106. Upon delivery of the energy delivery body 108 to the target treatment area, the sheath 126 may be, for example, , the lever of the catheter handle 110 operably connected to the sheath 126 The sheath 126 is withdrawn by the operator via the rider or plunger. This removes the constraints that are keeping the energy delivery body 108 collapsed, resulting in the energy This allows the wire 120 of the delivery body 108 to contact the bronchial wall.

[0311]

[0368] In some embodiments, the folded configuration of the energy delivery body 108 is This can be achieved by a mechanism that limits the expansion without using 126. For example, In some embodiments, the pull wire is connected to the proximal end restraint 12 of the energy delivery body 108. 2 and attached to a lever, slider, or plunger of the catheter handle 110. The catheter extends along the lumen along with a shaft 126 which is operably connected thereto. In this embodiment, the distal end restraint 124 is fixedly attached to the shaft 106 and the proximal end restraint 12 2 is configured to slide freely on shaft 106. The pull wire During the compression, the proximal end restraint 122 causes the energy delivery body 108 to fold. The pull wire is maintained in this position by being restrained within the handle 110. Relief of pulling forces, such as by reducing or removing the constraints in the handle 110, can be achieved. The release allows the pull wire to move, thus self-expanding the energy delivery body 108. As the catheter expands due to its tensile properties, the proximal end restraint 122 is freed and the distal end restraint 124 is freed. Move closer.

[0312]

[0369] In another embodiment, the proximal restraint 122 is fixed to the shaft 106 and the distal restraint 122 is fixed to the shaft 106. The end restraint portion 124 can slide freely on the shaft 106. The rod (or tube to achieve higher column strength) is attached to the distal end restraint 124. Attached to and extending along the lumen along the inner shaft 106 is a catheter handle 110. A push rod is operatively connected to a mechanism such as a lever, slider, or plunger. When the catheter 102 is pushed and subsequently restrained within the handle 110 of the catheter 102, the distal restraint 12 4 moves away from the proximal end restraint 122, thereby displacing the energy delivery body 108 When the energy delivery body 108 self-expands, the release of the push rod causes the energy Alternatively, the push rod can be retracted to allow the delivery body 108 to expand. Pulling distal end restraint 124 toward proximal end restraint 122, thereby increasing energy delivery The body 108 is expandable.

[0313]

[0370] In the embodiment shown in FIG. 26, the energy delivery body 108 includes a proximal end constraint. The braid is configured to be restrained by both the distal end restraint portion 122 and the distal end restraint portion 124 to form a cage. The energy delivery body 108 is formed by a metal tube. The energy delivery body 108 is controlled (i.e., folded) as described above. When the energy delivery body 108 includes a braided metal tube, Each wire in the braided tube is bounded by the wires adjacent to it, as well as by the braid itself. This support and interwoven structure is supported by the interwoven nature of the Ensuring minimal variation in the spacing between the wires, known as the set hole or aperture size Moreover, this support and interweaving configuration allows the braided tube to be made from very small wires. This makes it possible to construct a cage having a large radial stability and yet still have a large radial stability of the cage. This maintains the relatively small profile of the energy delivery body 108 in the folded / constrained state. , while optimizing the size of the opening of the braided tube when the electrode is deployed / expanded, It is now possible to use wires (e.g. 12, 16, 18, 20, 22, 24, etc.) In this embodiment, the spacing between the wires is fairly narrow and spans 360 degrees of the lumen of the lung passageway. This essentially results in continuous therapy.

[0314]

[0371] FIG. 27 shows that both energy transfer bodies 108, 108' are mounted on a single shaft 106. In order to collapse the energy delivery bodies 108, 108', a first The first proximal end restraint 122 of the energy delivery body 108 is secured to the catheter shaft 106. The other end restraints 122', 124, and 124' are attached to the catheter. The catheter can slide freely on the shaft 106. The energy delivery body 108 The energy delivery bodies 108, 108' are delivered together with a sheath 126 that constrains the energy delivery bodies 108, 108'. Upon delivery of the catheter to the target area, the sheath 126 may be moved, for example, by a lever or slider or a caliper. The catheter is pulled by an operator via a mechanism such as a plunger in the handle 110. Retraction of the sheath 126 collapses the energy delivery bodies 108, 108'. 3, thereby removing the constraints that are keeping the surfaces of the energy delivery bodies 108, 108′ from Further, in some embodiments, the first distal The end restraint 124 and the second proximal end restraint 122" are connected to each other via a coupler 800. The coupler 800 is made of an electrically insulating material (e.g., polyether block amide (Pe bax® tubing, polyimide tubing, etc.) and An insulating gap 802 is provided between 8, 108' to achieve electrical discontinuity therebetween. In some embodiments, the gap 802 is between 1 and 20 mm. This prevents arcing within the catheter shaft 106.

[0315]

[0372] In some embodiments, the folded configuration of the energy delivery bodies 108, 108' This can be achieved by limiting their expansion without the use of a sheath 126. For example, in one embodiment, the distal end of the pull wire (not shown) can be connected to a second distal end restraint. The proximal ends of the pull wires are attached to the bundle 124' and are connected to a mechanism (e.g., a lever) of the handle 110. The first proximal end restraint 122 is attached to the catheter. The other end restraints 124, 122', 124' are fixedly attached to the shaft 106. The energy delivery device 100 slides freely on the catheter shaft 106. 8, 108' is in a folded configuration prior to beginning positioning through the bronchoscope, Suppose we ask the operator to expand / extend these. This expansion / extension is done by of the handle 110 pulling the distal end restraint 124' towards the first proximal end restraint 122 By an operator actuating a mechanism (e.g., a lever, plunger, or slider) This allows the energy delivery bodies 108, 108' to be deployed / expanded efficiently. In this configuration, each is separately attached to each energy delivery body 108, 108'. The expansion can be achieved by using two pull wires. In this embodiment, the operator can separately control the expansion levels of the energy delivery bodies 108, 108'. It is possible.

[0316]

[0373] In some embodiments, one or more of the energy delivery bodies 108, 108′ may It is unconstrained at both ends, rather one end is unconstrained creating a half cage shape. FIG. 28A shows one energy delivery body 108' being constrained at one end during expansion. 1 shows an embodiment in which the fibers are not bundled but form a half-cage shape. The energy delivery bodies 108, 108' are made of braided metal wire. The distal most energy delivery body 108' is restrained by both the second proximal end restraint 122' and the second distal end restraint 124'; and The distal most energy delivery body 108' is configured to form a closed braided cage shape. , typically expandable so that at least its widest expanded diameter contacts the wall W of the lung passageway. The proximal most or first energy delivery body 108 is restrained at a first proximal end restraint 122. , and is configured to form approximately a half-open cage or semi-cage when expanded, as shown. The proximal energy delivery body 108 typically has a diameter at least as wide as the wall of the pulmonary passage W. The shaft 106 is expandable to contact the first and second proximal end restraints 12. 2, 122'. The half-cage shape of the proximal energy delivery body 108 is , its widest expanded diameter is not when the proximal energy delivery body 108 is in its entirety. This allows the distal most energy delivery body 108' to be closer to that of the distal most energy delivery body 108' than would be possible without the distal most energy delivery body 108'. Reducing this distance between the transmission bodies 108, 108' reduces the distance between the energy bodies 108, 108' In addition to the above, the therapeutic effect between the energy transmitters 108, 108' is enabled. Considering the effect between 108 and 108', this ultimately produces a greater surface treatment effect. Additionally, the half-cage shape helps to avoid arcing.

[0317]

[0374] The configuration shown in FIG. 28A uses a sheath (not shown) as described in detail above. and both energy delivery bodies 108, 108' are self-expandable. In one embodiment, the second energy delivery body 108' is folded prior to delivery into the bronchoscope. Once positioned at the desired target area, the device is placed in a closed position and connected to a second distal restraint. 124') which is deployed / expanded via a pull wire (not shown) connected to the handle 1 To the mechanism in 10. The full cage (energy supplier 108') and the half cage (energy supplier 108) This combination can be used for bipolar or unipolar energy delivery. When made of braided metal wires, each wire is paralleled by the wires adjacent to it. The braid is supported by the interwoven nature of the braid itself. is the minimum variation in spacing between wires, otherwise known as the braid hole or aperture size. Moreover, this support and interweaving arrangement can be achieved with very small wires. This allows the braid to be constructed from a single wire and still have significant radial stability of the cage. , the opening size of the braid when the energy delivery body 108, 108' is deployed or expanded. Folding or constraining the small profile of the energy delivery body 108, 108' while optimizing Many wires (e.g. 12, 16, 18, 20, 22, 24, etc.) can be connected while maintaining the same state. In this embodiment, the spacing between the wires is quite small, allowing Providing 360 degree treatment within the aisle.

[0318]

[0375] FIG. 28B shows that both energy delivery bodies 108, 108′ have a proximal end restraint 122. , 122' shows an embodiment in which the braided metal wire is fixed to the shaft 106. In an embodiment, both energy suppliers 108, 108' are configured to form a half cage. A sheath of this configuration (not shown) is used for delivery as described above. and the energy delivery bodies 108, 108' are self-expanding. This configuration of 108, 108' may be used for bipolar and / or unipolar energy delivery. can be done.

[0319]

[0376] In some embodiments, the entire surface of one or more energy delivery bodies 108 , energized by an energy signal for delivery to the target tissue. In other embodiments, the active surface area of ​​the energy delivery body 108 is provided and the remaining portion In some embodiments, this is done by removing the end caps leaving one or more active regions. This is accomplished by partially insulating one or more portions of the energy delivery body 108. For example, FIG. 29 shows a wafer with a portion of the insulator removed to define active area 820. A current carrying wire 12 (acting as one or more electrodes) with a portion of the ear 120 being insulated. 0. In some embodiments, the insulating The border is removed from the outer (tissue-contacting) surface of the wire 120. This technique is used, for example, to If the measured impedance through the pole wire 120 is affected by the amount of exposed metal, and is useful when it is desired that the measured impedance represent the interface between the electrode and the tissue. In another embodiment, both the outer and inner surfaces of the electrode wire 120 are free of insulation. One method for manufacturing an energy delivery body 108 having this configuration is The method involves creating a braid using insulated wire and then removing the braid using appropriate means (e.g., laser, machine). 8. The method includes removing insulation using a single Although an active area 820 is shown, multiple active areas can be used to generate any treatment pattern. Also contemplated are the non-braided energy delivery bodies 108 described herein. Similar techniques can be used for the fabrication of these embodiments. Insulation may be applied or removed as part of any desired process to achieve various treatment patterns. In one embodiment, an active area(s) 820 configuration can be defined.

[0320]

[0377] FIG. 30 shows a metal (e.g., Nitinol) tube 830 being laser cut into two pieces. Another embodiment forms a folded cage 832 whose ends are constrained via the tube 830 itself. The cage 832 is then self-adjusting during use to function as the energy delivery body 108. It can be expanded and shaped so that it can self-expand or push A / pull mechanism can be used to expand / collapse the basket 832 for delivery and treatment. In some embodiments, one end 834 of the cage 832 can be removed, as shown in FIG. A free end 836 is then formed. An insulating material (e.g., a polymer tube) is then inserted into the free end 836. 6 and applied to a portion of the cage 832. In this case, the insulation is applied to the proximal and distal portions of the cage and one or more conductive / insulating wires are provided between them. In another embodiment, the cage 832 is cut away from the active area 820, as shown in FIG. The ear 120 is insulated and has one or more separate additional electrodes 840 (shown as coils) The insulated cage wire is then connected to form the active area 820. This assembly is then The energy delivery body 108 is secured to the terminal 102 and has a plurality of predetermined active areas 832. It can be operated as a unipolar electrode.

[0321]

[0378] 32 shows another embodiment of the energy delivery body 108. In this embodiment 31. The body 108 includes a plurality of teeth 840, similar to the free end 836 of FIG. 0 can expand outward to contact the lung passageway wall. In the embodiment, one or more tines 840 are insulated with insulating material 842. Electrodes 107 positioned along each tine 840, such as near the ends, remove the insulating material 842. The insulating layer can be created by exposing the underlying activatable elements or wires through a thin insulating layer. Alternatively, as shown in FIG. 32, a separate electrode 107 may be attached to an insulating material 842. In some embodiments, the tines 840 are formed from polymer-coated wire. The wires can act as structural support for the tines 840 to self-expand. and can be energized to deliver therapeutic energy and / or used to sense temperature. In some embodiments, the teeth 840 are sealed for delivery. The catheter is collapsible via the sheath 126 and expands when the sheath 126 is retracted to contact the tissue. All electrodes can be fired simultaneously in a unipolar fashion, and independently in a unipolar fashion. and / or any putter required to produce the desired therapeutic effect. The electrodes can be fired between each other using the same length of wire. The length of the electrodes is 3mm, 5mm, 1cm, 2cm. In FIG. 32, the range is about 3 mm to about 5 cm, such as 3 cm, 4 cm, or 5 cm. Although depicted as the same size, the dimensions (eg, length, width) vary.

[0322]

[0379] 33 shows another embodiment of the energy delivery body 108. In this embodiment Rather than a cage weave, the energy delivery body 108 includes one or more protrusions 850. Each protrusion 850 acts as an electrode and extends semicircularly from the longitudinal axis or shaft 106 of the catheter 102. It is formed by a wire or ribbon 120 that is bent radially outward. Each protrusion 850 is electrically insulated from each other protrusion. The protrusions 850 are made of stainless steel. The electrodes may be constructed from a variety of suitable materials such as copper, spring steel, or other alloys to act as electrodes. Each protrusion 850 may be an energy delivery body, for example a round wire or a ribbon. 108 over at least a portion of the proximal and distal ends thereof. It is insulated with insulating segments 852 such as polyether block amide, polyimide, etc. The exposed portions 854 of the wire or ribbon can then act as electrodes on each protrusion 850. In one embodiment, the exposed portion 854 of the protrusion 850 is completely free of the insulator 852. In other embodiments, the insulator 852 is a protruding part that does not contact tissue and is completely insulated. The side surface of the protrusion 850 (e.g., the inner surface facing the shaft 106 of the catheter 102) is left In one embodiment, each protrusion 850 is independently The two prongs 850 act as neutral electrodes (pair) and the two prongs 850 act as active electrodes. The inactive and active electrodes may be positioned adjacent to each other. Neutral electrodes (counter electrodes) positioned at 180 degrees from each other can be electrically connected to each other. In this embodiment, the two pairs of protrusions 850 are Only two conductors (power lines) are required to connect to the generator 104. The pair of protrusions 850 used in the polar method can be further multiplied to determine the role of active electrode versus neutral electrode. Any combination or rotation of the generator 104 can be achieved. The IEEE 802.11b standard is designed to have enough channels (i.e., 1 to 4 channels) to support one of the following methods: This embodiment of the energy delivery body 108 can be configured as follows: It can be delivered in a folded configuration and can be attached to tissue via a pullback wire and mechanism in the handle. It is extended to touch.

[0323]

[0380] FIG. 34 illustrates another embodiment of an energy delivery body 108 that includes one or more protrusions 850. 1, each protrusion 850 extends from the longitudinal axis or shaft 106 of the catheter 102. However, in this embodiment, each protrusion 850 is bent radially outward. It is formed from a non-conductive material and carries, supports, and / or otherwise supports a separate electrode 107. Each electrode 107 is coupled to the generator 104 via a conductor that connects the electrode 107 to the generator 104. The protrusion 850 may be attached to the handle, such as via a pull wire and mechanism in the handle. In this embodiment, each electrode 107 is positioned relative to the tissue when expanded. 107 is positioned on or adjacent to each protrusion 850. In this case, an insulator is provided to electrically insulate the electrode 107 from the projection 850 itself. If the protrusions 850 are made of a polymer or other non-conductive material, no additional insulation is necessary. In some embodiments, the protrusions 850 are made of round wire or ribbon. As shown, it is configured to form a straight cage. Alternative embodiments (not shown) In the embodiment, the protrusions 850 are arranged in a spiral shape. 7 also applies to other embodiments, such as where the cage is made of a braided material. As in the above embodiment, the electrodes 107 may be energized in various combinations. Each protrusion 850 may be electrically connected to one another or may be electrically insulated from one another. To increase the surface area of ​​the electrodes 107, each may be made of, for example, a metal coil. or in the form of a slotted (e.g., laser cut) tube. These configurations allow for a larger spatial range and also allow the cage protrusions 850 to move freely. Maintain flexibility of electrode 107 to allow bending and straightening. As with 33, the surface of the protrusion 850 is completely exposed or exposed over the area that does not contact tissue. It can be insulated.

[0324]

[0381] FIG. 35 illustrates another embodiment of a catheter 102 having at least one energy delivery body. 1 shows an embodiment in which each energy delivery body acts as an electrode itself. or act as a carrier for separate electrodes mounted thereon. In this embodiment, the catheter includes an expandable coil that can be either The terminal 102 is adjacent to two energy transmitters, namely the second energy transmitter 108'. Each of the energy delivery bodies 108, 108' includes a first energy delivery body 108 disposed in a first direction. The distal end 870 of the second energy delivery body 108' has the shape of an expandable coil. , coupled to or formed on the inner member 872 and the first energy delivery body 1 The proximal end 874 of the tubing 808 is coupled to an outer member 876. The outer member 876 is connected to the inner member 872. 10, and can be rotated relative to the energy delivery body 108, 108' to fold and / or expand the energy delivery body 108, 108'. The coupler 878 attaches the energy delivery bodies 108, 108' together and couples the energy delivery bodies 108, 108' together as desired. If so, there is insulation between them. The energy delivery bodies 108, 108' may be monopolar and / or bipolar. The energy delivery bodies 108, 108' can be sized as described herein. The length of each extension coil may be about 5 mm to about 10 mm. The range is about 20 mm.

[0325]

[0382] FIG. 36 shows a narrow area along the wall of a lung passageway, or along a partial inner circumference of a lung passageway. 1 illustrates an energy delivery body 108 configured for more limited application of therapeutic energy. In this embodiment, the energy delivery body 108 is a coil that limits the length of the active area. Where a very localized tissue effect is desired or where the tissue effect is in contact with tissue, Such an embodiment can be used when the scope of the invention extends beyond the sexual domain. In the embodiment, the energy delivery body 108 includes a coil 880 having a width and a length. The 80 length can be pre-formed into a semi-circular or circular pattern as shown. The treatment length L1 is determined by the width of the coil 880 when the coil 880 contacts the pulmonary passageway wall W. This configuration can be operated in a unipolar configuration as shown. However, Two or more coils 880 may be used to allow for bipolar and / or multiplexed energy delivery. Similarly, FIG. 37 illustrates a rod 882 (shape) having a width and a length. 10 shows an embodiment of an energy delivery body 108 including a rod 882 having a length of The rod 882 is preformed in a semicircular or circular pattern. The one or more electrodes 107 are embedded within the rod 882. The treatment length L1 is in contact with the lung passageway wall W. This embodiment is provided by the width of one or more electrodes 107 that are connected to each other. Unipolar activation between a diffuse (neutral) electrode, bipolar activation between individual electrodes, and / or any of the electrodes These devices are designed to allow multiple activation between combinations of It is further envisioned that two or more of the above arrangements may be used. When preformed into a semicircular or circular shape, the sheath 126 is used to hold the energy delivery body 1 08 can be folded and constrained for self-expansion and / or pulled / pushed The wires can be used to extend the energy delivery body 108. These methods for expanding and / or collapsing the can be.

[0326]

[0383] The energy delivery body 108 provides greater control over the force exerted on the bronchial wall. In this embodiment, the energy delivery body 108 is optimized for the situation in which it is desired to is delivered to the bronchial lumen via a three-step process. First, as shown in FIG. The sheath 126 is retracted proximally, thereby removing one or more prongs that act as prongs. This embodiment exposes a central lumen 900 as shown in cross-section in FIG. It includes four prongs 900 arranged symmetrically around 2. One, two, three, four, There may be any number of prongs 900, including five, six or more. 0 includes at least one electrode 107. FIG. 39 shows a structure in which the electrodes 107 are spaced apart from each other to maintain the distance therebetween. As a means for this, the device is attached to an insulating substrate 904, such as a polymer substrate (e.g., ribbon, strip). A prong having two electrodes 107 having an elongated shape (like a wire) attached thereto. 9 shows an embodiment of 900. The electrodes 107 may have a circular or square / rectangular cross section. Typically, the electrodes 107 are fixed to the insulating substrate 904 so that they are substantially parallel to each other. The manufacturing methods for attaching the pole 107 to the insulating substrate 904 include co-extrusion, deposition, adhesive-based bonding, etc. Insulating substrate 9 can be used, but is not limited to, thermal bonding. The width of 04 can be changed.

[0327]

[0384] FIG. 40 illustrates an embodiment of a prong 900 having a narrower insulating substrate 904 than that shown in FIG. Similarly, FIG. 41 shows an embodiment with a narrower insulating substrate 904 and more than two electrodes 1 41 shows an embodiment of a prong 900 having five electrodes 107. However, you can choose one, two, three, four, five, six, seven, eight, or more. There can be any number of electrodes 107. FIG. 42 shows a polymer substrate (e.g. ribbon, strip) 1 shows a plurality of electrodes 107 mounted on the The wires are positioned generally parallel to one another leaving gaps between each wire.

[0328]

[0385] In some embodiments, the insulating substrate 904 having the electrodes 107 is stripped. The electrodes 107 are configured as a loop (FIGS. 39-42). Thus, the electrodes 107 are arranged along the length of the airway. In another embodiment, the electrodes 107 are deployed as linear strips that are positioned The insulating substrate 904 is configured as a spiral, and the electrodes are deployed in a spiral shape. As shown in 39-40, an insulating substrate 9 having an electrode 107 configured as a spiral FIG. 44 shows an insulator having an electrode 107 as shown in FIG. 41 configured as a spiral. The edge substrate 904 is shown.

[0329]

[0386] In some embodiments, a push button, as described above with respect to other embodiments, A pull mechanism can be used to deploy the strip or ribbon. In the case of a spiral, a rotation The electrode 107 is connected to an energy source controlled by a generator. Depending on the application algorithm, they can be electrically connected to each other or isolated from each other. or there can be electrical interconnections of different interconnection patterns between the electrodes.

[0330]

[0387] Once one or more prongs 900 are exposed, the second step of the three-step process is expansion. Advancing the expandable member 910 out of the lumen 902 while in an unstrained state The third step includes introducing an expandable member 910, such as a balloon, by 45A-45B, the expandable member 9 is expanded, such as by inflating a balloon. 01 between the prong 900 (and thus the electrode 107) and the bronchial wall W. The prongs 900 are inserted until the desired interface is achieved. The tensionable member 910 is positioned while already positioned under the prong 900. In this configuration, the retraction of the sheath 126 In this case, both the expandable member 910 and the prongs 900 are exposed at the same time, thus allowing the expandable The step of advancing the member 910 out of the lumen 902 is eliminated. The material 910 is then inserted into the prong 900 until the desired interface between the prong 900 and the bronchial wall S is achieved. The size (e.g., length, width) of the prongs 900 may be the same. The number of prongs 900 can vary from 1 (for a monopolar configuration) to 100 (for a monopolar and / or The application of energy to the electrodes 107 is controlled by an energy delivery device (e.g., The number of iterations varies widely depending on the algorithm (generator, etc.).

[0331]

[0388] FIG. 46 illustrates a configuration in which more than two energy delivery bodies 108 ( The energy delivery catheter 102 has four energy delivery bodies 108 (shown). In this embodiment, the energy delivery body 108 is made of braided metal wire. The wires function as electrodes. The energy transfer body 108 is made up of two electrodes, one of which is neutral. The power provided by the external generator 104 between any pair of energy transfer bodies 108 The active energy delivery body 108 can be bipolarly actuated by cycling The combination between the neutral energy delivery body 108 and the In this embodiment, energy is transferred to two energy transfer bodies 108 while one energy transfer body 108 functions as a neutral electrode. The active energy delivery body 108 and the intermediate energy delivery body 108 may be applied. Combination of active energy delivery body 108 and neutral energy delivery body 108 Switching / circulating energy between the activated energy delivery body 108 and the non-activated energy delivery body 108 The selection of the energy delivery agent 108 is performed by the energy delivery algorithm 152 of the generator 104. The algorithm 152 determines the predetermined technique, the image data, and the desired region. and other factors that determine the depth of treatment. can be used and distributed.

[0332]

[0389] FIG. 47 illustrates an energy delivery catheter 10 having a multi-energy delivery body design. 2 illustrates another embodiment of the energy delivery body 108. In this embodiment, the energy delivery body 108 is monopolar and and / or bipolar multi-mode. Monopolar energy delivery can be achieved by using the distal end 920 of the catheter 102. and one or more energy delivery bodies 108 positioned near the skin of the patient P and externally applied to the skin of the patient P. This is accomplished by delivering energy between the dispersive (counter) electrode 922 and the 108, switching / circulating energy between the active energy delivery body 108 and the dispersive electrodes 922 The ring, and the selection between the activated energy delivery body 108 and the non-activated energy delivery body 108, This is accomplished via the energy delivery algorithm 152 of the generator 102. The algorithm 152 uses a given technique, image data, and other parameters to determine the desired area and depth of treatment. Energy can be applied and distributed among the energy delivery bodies 108 based on the factors.

[0333]

[0390] The drawings in this specification are drawn to approximately the same size (e.g., length, diameter) for illustrative purposes. Although the energy delivery body 108 is depicted as having a circular shape, the configuration is not limited thereto. In some embodiments, the energy delivery device accounts for the tapering of the airway lumen and adjusts the energy field Varying the size of the implant to better localize and / or enhance tissue treatment For example, the desired catheter positioning may be such that the distal energy delivery device is located within the lobar bronchus ( The proximal energy delivery device is located in the main bronchus (diameter approximately 12 mm to 20 mm). 16mm), the distal energy delivery body extends to about 12mm. and the proximal energy delivery body is designed to expand to about 16 mm. The energy delivery bodies also come in different sizes to better localize the energy field. For example, if unipolar energy delivery is desired, a dispersive (neutral) electrode (Figure 4) may be used for positioning. 7) positioned outside the patient, such as by a catheter or another device. It is beneficial to incorporate the therapeutic energy into the It is closer to the drug delivery system. Lower voltages can be applied to generate the same electric field. This can reduce the risk of inducing muscle contractions or arrhythmias. The bodies also come in different sizes to enhance their ability to separate tissue. In this embodiment, the active portion of the energy delivery device is that area in contact with the airway. For example, two equal sized energy delivery bodies are positioned in the same sized airway, approximately If expanded in the same way, the contact area of ​​two different energy delivery bodies may be approximately the same. However, it is possible that two identically sized energy delivery devices may be delivered to airways of different sizes. If not positioned and / or expanded in the same way, the active portion of each energy delivery body The distribution is significantly different. One electrode is constructed to have a larger contact area than the other. In some cases, non-uniform electric fields polarize cells, resulting in tissue separation efforts. The energy delivery device also biases the energy field perpendicular to the epithelium. The catheter is configured to apply a shear force to the epithelium or along the epithelium.

[0334]

[0391] FIG. 48 illustrates an exemplary bronchoscope 112 configured for removably connecting to the bronchoscope 112. 1 shows a catheter 102. In this embodiment, the handle 110 of the catheter 102 is Removably connectable to an external port 952 of the working channel of the bronchoscope 112 (e.g., The docking mechanism 950 includes a docking mechanism that is a snap-fit ​​mechanism. This allows the operator to control both the bronchoscope 112 and the catheter 102 during the procedure. In another embodiment, the handle 110 can be attached to the bronchoscope 112. Various bronchoscope attachments and and / or can be connected to accessories (e.g., valves, not shown). The handle 110 may be adapted to connect to an external port or valve of a working channel of a bronchoscope 112 . In such a case, the stability of the catheter 102 is and an attachment located on the external port 952 of the working channel of the bronchoscope 112. This is achieved by friction between the bearing and the component (e.g. a valve).

[0335]

[0392] In some embodiments, the distal end 954 of the catheter handle 110 and the The length between the proximal end 956 of the energy delivery body 108 and the working channel The working length of the bronchoscope 112 is determined based on the distance between the proximal end of the working channel and the distal end of the working channel. The length of the catheter handle 110 is adjusted to be substantially equal to the length of the channel. When connected (e.g., snapped) to the external port 952 of the working channel of the bronchoscope 112 In the targeted region of the pulmonary passageway, an energy transmitter(s) 108 is introduced into the pulmonary passageway. The step of positioning the one or more energy delivery bodies 108 at the bronchoscope 112 may include moving the bronchoscope 112. , thereby achieving this by moving the catheter 102 there. One or more energy delivery bodies 108 are successfully positioned within the target area, and this position is Once visually assessed and confirmed by the operator (e.g., using visual bronchoscopy), The one or more energy delivery bodies are operably connected to the one or more energy delivery bodies 108. A mechanism within the catheter handle 110 that is operable to connect one or more energy delivery bodies 108 (or by a lever, slider, plunger, or button) that is operably connected to the the catheter (by means of a catheter wire or other mechanism) and deploy / expand it or position it so that it can contact tissue. The device is then ready for energy delivery.

[0336]

[0393] In some embodiments, the distal end 954 of the catheter handle 110 and the The length between the distal-most end 958 of the one or more energy delivery bodies 108 is equal to or greater than the length of the working channel 954. Based on the distance between the proximal end and the distal end of the working channel 960, the working channel of the bronchoscope 112 The catheter handle 110 is adjusted so that it is substantially equal to the length of the tracheal channel. When connected (e.g., snapped) to the external port 952 of the endoscope working channel, one or more The energy delivery device 108 has not yet been introduced into the bronchial lumen (FIG. 49A), and the bronchoscope 112 One or more energy delivery bodies 108 are positioned within the channel to introduce the energy delivery bodies 108 into the bronchial lumen. The process of removing the handle 112 (FIG. 49B) removes the main mechanisms (e.g., levers, sliders, and plates) of the handle 112. This can be accomplished via a button (or a controller). The target is successfully positioned within the region and this position is visually assessed and confirmed by the operator. When the secondary mechanism of the handle 112 (e.g., Via a lever, slider, plunger, button) the electrodes are expanded or deployed, or It is now in position to contact the tissue (FIG. 49C) and is ready for energy delivery. A secondary handle mechanism (e.g., lever, slider, plunger, button) controls the catheter sheath. One or more To deploy / expand the energy delivery body 108, the operator moves the secondary mechanism proximally. , thereby moving the catheter sheath proximally, thereby displacing one or more energy delivery bodies 1 08 and allow them to expand. In another configuration, a secondary handle mechanism (e.g. , lever, slider, plunger, button) to pull or push wire / tube The one or more energy transmitters are operably connected (e.g., glued or welded) to the proximal end of the To deploy or expand the body 108, the operator moves and pulls the secondary mechanism proximally. Pull the wire or tube toward the distal end or pull distally to push the push wire / tube toward the distal end. In both embodiments, depending on the particular configuration of the catheter and its deployment mechanism, Next, actions performed by the operator using the handle mechanism result in one or more energy deliveries. In yet another configuration, one or more pull wires or The system has one or more secondary handle mechanisms connected to push wires or tubes. In this scenario, the expansion of one or more energy delivery bodies 108 occurs at different times and with different magnitudes. The levels can be controlled independently by actuating different secondary handle mechanisms. do.

[0337]

[0394] In some embodiments, the distal end of the catheter handle and one or more energy The length between the proximal end of the lubricant delivery body 108 and the proximal end of the lubricant delivery body 108 is substantially longer than the length of the working channel. When one or more energy delivery bodies 108 are introduced into the pulmonary passageways, the handle The bronchoscope is not in contact with the external port of the working channel of the bronchoscope. The step of positioning the drug delivery device 108 may be performed by moving the bronchoscope or by using a catheter. This is accomplished by moving the catheter itself. In this case, the catheter is The catheter handle is held by the operator to allow for holding the bronchoscope. Long enough to be able to be held or placed on or near the patient. The energy delivery body 108 above is successfully positioned within the target area, and this position is Once visually assessed and confirmed by a human bronchoscopy technician (e.g., using visual bronchoscopy), The energy delivery body 108 may be operably connected to one or more energy delivery bodies 108. Mechanisms in the catheter handle that are in contact with the catheter (e.g., levers, sliders, plungers, buttons) This positions it for deployment or contact with tissue and ready for energy delivery.

[0338]

[0395] The present invention may be combined in part or in whole with other embodiments. According to the described embodiment, the handle of the catheter is connected to an external port of the bronchoscope working channel. The docking mechanism may be removably connected (e.g., snapped) to the In one embodiment, the handle is attached to an external port of the bronchoscope working channel. In yet another embodiment, the valve may be connected to various fittings and / or accessories (e.g., valves). The handle may be fitted with any mechanism that snaps into the external port of the bronchoscope working channel. and the stability of the device depends on the friction between the catheter shaft and the accessories (e.g., the valve). This is accomplished by attaching it to the external port of the working channel of the bronchoscope.

[0339] VIII. Treatment Patterns

[0396] A patient P may have a single target area or multiple target areas for treatment. are adjacent regions of the pulmonary passageway that are targeted for treatment. A single pulmonary passageway may have multiple target regions. Similarly, target regions may be positioned along separate pulmonary passageways. Each target region may include: The target segment may include one or more target segments. The target segment is the portion of the pulmonary passageway that can be treated by a single treatment. 102 , along the pulmonary airway wall W where the wall tissue is being treated by one or more electrodes 108 Different embodiments of the catheter 102 are adapted to accommodate different sections of the pulmonary passageways. Therefore, the size of the target segment may be determined by the catheter 102 / system. In addition, the catheter 102 is moved continuously along the pulmonary passageway. The target region can be moved to produce multiple adjacent target segments, and the adjacent target segments are Cover.

[0340]

[0397] Accordingly, a method for treating a patient's airway may include (a) administering a single treatment at a target segment. (b) performing two or more treatments at adjacent target segments so that the entire treatment area is generally contiguous; and / or (c) administering two or more treatments spaced apart from one another. FIG. 50 is a schematic diagram of a single target segment 1000 within the main bronchus MB of the lung. In the embodiment, the target segment 1000 positions one or more energy delivery bodies 108 of the catheter 102. The treatment is performed by positioning the entire eye and delivering therapeutic energy thereto. Two targets 1002 positioned adjacent to each other such that the target or treatment area 1002 is generally adjacent. FIG. 1 is a schematic diagram of a target segment 1000a, 1000b. 100b positions the catheter 102 to first treat the first target segment 1000a. and then repositioning the catheter 102 to treat the second target segment 1000b. Of course, various target segments can be treated by using different catheters 10. The target segments 1000a, 1000b may be treated in any order. It will also be appreciated that in some embodiments, the target segments may overlap. Thus, both figures, Figs. 50-52, show a single target area within a pulmonary passageway. FIG. 1 is a schematic diagram of two target regions 1004, 1006 within a patient. The first target area 1004 is positioned within the main bronchus MB, and the second target area 1006 is positioned within the pulmonary bronchus. The first target region 1004 is positioned within the lobar bronchus LB. and the second target area 1006 is covered by a target segment 1010, where The target segments 1008 and 1010 are spatially separated from each other. 1010, position the catheter 102 to first treat the first target segment 1008. and then repositioning the catheter 102 to treat the second target segment 1010. Of course, different target segments can be treated with different catheters. The target segments 1008, 1010 can be treated in any order. These diagrams may be used alone or in combination with each other to achieve the desired result. It will be appreciated that the present invention provides exemplary treatment patterns that may be used.

[0341]

[0398] Within the target segment, the lung passageway tissue is subjected to different treatment patterns at any given cross-section. For example, some embodiments may include a method for determining whether a target segment is Other embodiments include treating the entire circumference of the airway over a given length of the target segment. The present invention includes treating one or more discrete portions of the circumference of the airway over a wide area.

[0342]

[0399] FIG. 53 is a schematic side view of a portion of an energy delivery body 108 made of a braided cage. The braid is made up of individual wires 120 that deliver energy. Between the wires are holes 1050. Depending on the degree of expansion (indicated by diameter 1052), the pore size changes. 53 positioned within a lung passageway having an airway wall W. Thus, the energy transfer body 108 is shown as multiple cross sections of a wire. 20 is positioned relative to the lumen of the lung passage (i.e., along the inner surface of the airway wall W). In some embodiments, continuous circumferential treatment (shading, 1054) of the airway W. Similarly, in some embodiments, the length 1 of the energy delivery body 108 is Continuous circumferential treatment along 056 is also achieved. The effect of this is shown in FIG.

[0343]

[0400] In some embodiments, to achieve substantially continuous circumferential treatment over a given length, In order to achieve this, at least the applied electric field (V / cm) and the electrode design are taken into consideration. is applied in a monopolar manner, the electric field is applied to the energy delivery body 108 substantially dispersive (neutral) ) Electrodes are positioned elsewhere on or inside the patient's body. Changing the magnitude of the field and / or The distribution depends on the applied voltage and the geometric relationship of the wires 120. See examples in Figures 53-55. The energy delivery body 108, which is in contact with the circumference and length of the tissue to be treated, is then The wires 120 are arranged close to each other, forming a metal braid. The electric field between each wire 120 provides the desired tissue effect continuously around the entire circumferential area of ​​the contact portion 1054. In this example, diameter 1052 is sufficient to completely fold it for shipping. Diameter ranges from 2-3mm when collapsed to 10mm, 12mm when fully expanded. It is designed to expand to 15mm, 18mm, 20mm, or 22mm. All values ​​in the range are applicable. Depending on the degree of expansion, the size of the hole diameter 1050 is It produces a continuous tissue effect with pore sizes that vary but generally range up to at least 10 mm2. When the pore size becomes significantly larger, the applied The same field can result in discontinuous tissue effects (shown as shading 1056). In an embodiment, the energy delivery body is made up of four wires 120, each of which has a total length of provides tissue effects that contribute to a discontinuous tissue effect in a time-dependent manner, which is essential for providing clinical benefit. This can speed up the rate of healing while still affecting a sufficient amount of tissue for the injury to occur. The sequelae can also be achieved by decreasing the applied electric field.

[0344]

[0401] Some embodiments include from about 25 to about 50%, from about 50% to about 50%, inclusive of all values. The energy delivery device includes a treatment area ranging from about 75% to about 100% of the surrounding area. All values ​​within this range are applicable. Some embodiments are Sufficient to treat a wide range of patient anatomies while minimizing the number of individual treatments From about 5 mm to about 20 mm, including all values ​​and subranges therebetween, allowing for flexibility Includes treatment length of range.

[0345] IX. General Embodiments

[0402] The present invention may be combined in part or in whole with other embodiments. In some embodiments of the present invention, a pulmonary tissue modification system for performing a pulmonary procedure comprises: An energy generating generator, an energy delivery catheter, an accessory, and one or more imaging modalities Includes vessels.

[0346]

[0403] In some embodiments, two energy sensors are attached near the distal end. The bipolar catheter containing the delivery body is connected to an energy producing generator outside the body. The distal end of the catheter is passed through the mouth or nose using a bronchoscope or other direct visualization system. The energy delivery bodies are deployed so that they contact the airway walls, The operator then operates the foot switch, Any suitable interface, such as a button on the generator, a button on the catheter, or a remote control, may be used. A generator is operated via the interface to generate a pulmonary circulation adjacent to and / or between the electrodes. In some embodiments, the operator can deliver energy to the tissue. The energy delivery vehicle can then be moved to another portion of the affected airway to deliver another treatment, or the energy delivery vehicle can be moved to another portion of the airway to deliver another treatment. One may choose to treat the entire surface of the airway or multiple portions of the airway. In some embodiments, multiple treatments may be administered to the same portion of the airway, depending on the desired depth of penetration. In some embodiments, two or more different An energy delivery algorithm may be employed.

[0347]

[0404] In some embodiments, a single energy A monopolar catheter having a delivery body is connected to an energy generating generator outside the body. The distal end of the catheter is visualized orally or via the use of a bronchoscope or other direct visualization system. The electrode is passed through the nose and into the bronchial tree. It is deployed and expanded so that it contacts the airway wall. and / or otherwise positioned. A dispersive (neutral) electrode or return electrode is positioned on the patient's other surface ( an external location (e.g., the patient's skin) and connected to a generator The operator then uses, for example, a forceps to deliver energy to the airway tissue via the electrodes. The jet can be operated via the hand switch, the generator button, the catheter button, or a remote control. The operator can then direct the energy delivery object to another portion of the affected airway. Therapy can be delivered to the entire surface of a portion of the airway or to multiple areas of the airway. In some embodiments, two or more The monopolar energy delivery device may be incorporated into one or more catheters to reposition the catheter. Depending on the desired penetration depth, multiple locations can be treated without disrupting the airway. In some embodiments, multiple treatments can be administered to the same area of ​​the skin. To achieve this effect, two or more different energy delivery algorithms may be employed. In some embodiments, a user interface on the generator is used to In one embodiment, the desired treatment algorithm can be selected. The generator automatically selects the desired output based on information provided by one or more sensors. It is possible.

[0348]

[0405] In some embodiments, a plurality of energy sensors are attached near the distal end. The catheter containing the delivery body is connected to an energy generating generator outside the body. The distal end of the catheter is then inserted through the mouth or nose using a bronchoscope or other direct visualization system. The energy delivery bodies are passed into the bronchial tree. The energy delivery bodies are deployed and expanded so that they contact the airway walls. The operator is then positioned, for example, by a foot switch, Energy is delivered to the airway tissue via the injector button, catheter button, or energy delivery device. The generator can be activated via a remote control to deliver the gi. In embodiments, energy delivery may be performed using any suitable method to affect the desired target tissue. The energy delivery devices may be multiplexed across any one or more of the energy delivery devices in any pattern. In some embodiments, a dispersive (neutral) electrode is attached to another surface of the patient, such as the patient's skin. and can be connected to a generator to allow monopolar energy delivery to any energy delivery object. Depending on the desired depth of penetration, multiple treatments can be administered to the same portion of the airway. In some embodiments, two or more different The following energy delivery algorithms can be adopted: The face is used to select a desired treatment algorithm or to select the algorithm. is automatically selected by the generator based on the information.

[0349]

[0406] In some embodiments, the target therapeutic area is a region of interest that is a pathogenic cell and / or a deeper are identified and used to select treatment algorithms that are sufficient to affect the affected tissue. The electrode system is then deployed at the site of the pathogenic cells and / or abnormal airway wall tissue and energized. The imaging device(s) can be delivered to affect the target tissue. may be used before, during, during, and / or after treatment to determine where treatment was administered or It can be determined whether the energy was adequately absorbed and / or whether the energy adequately impacted the airway wall. If it is determined that a therapeutic area was missed or that the target therapeutic area was not adequately affected, Energy delivery is repeated, followed by imaging as described herein, until a desired treatment is achieved. Additionally, the imaging information can be used to identify specific cell types and / or desired treatments. It is possible to determine whether depth has been applied, which is a feature of many different patient anatomy. This allows for customization of energy delivery algorithms to treat structures.

[0350]

[0407] In some embodiments, any of the devices and / or systems described herein The system is generally used to plan, guide and / or examine airway access and, optionally, treatment. and / or post-procedure imaging for the purpose of identifying affected airways and / or other pulmonary In some embodiments, the method can be used in a method for treating tissue (e.g., parenchymal tissue). The method includes treating a sufficient treatment area with each energy application, treating a sufficient entire treatment area, and Treatment is based on: The imaging and / or sensor information and the like may be used to customize the image. A combination of.

[0351] X. Example

[0408] The following examples further illustrate embodiments of the systems and methods disclosed herein. are illustrative and should not be construed as limiting their scope in any way. .

[0352]

[0409] Example 1: Circumferential treatment and tissue effects with a bipolar system

[0353]

[0410] A non-thermal energy delivery device has been developed having a bipolar expandable energy delivery body. The energy delivery bodies are mounted on a catheter shaft that has a mechanism for expanding and contracting both energy delivery bodies. Two energy delivery systems, each containing a centrically mounted Nitinol, braided, and extended electrodes. (See, e.g., FIG. 27). The diameter of the expanded energy delivery body ranged from about 5 mm to The energy deliveries were substantially equal in length, each about 3 cm. spaced approximately 2.5 cm from end to end along the longitudinal axis of the catheter shaft. The effects of pulsed high-voltage energy on the epithelial and submucosal layers in the airways were evaluated. To evaluate the effect of endothelial cell proliferation, the device was introduced into the left and / or right bronchus of live anesthetized pigs and energy was delivered in both directions. The pulse frequency was about 300 kHz, the pulse amplitude was about 4000 V, and the total energy was about 100 Hz. The energy supply duration is approximately 415 microseconds (83 microseconds per packet, 5 packets) (To).

[0354]

[0411] After the procedure, the animals were collected and euthanized about 24 hours later. The airways were then incised and the The airways were then sectioned at approximately 5 mm increments and cut in the usual manner. Processed for histology. Sections of both treated and untreated areas were processed for comparison purposes. Slides were prepared with hematoxylin-eosin (H&E) staining.

[0355]

[0412] FIG. 57A shows a normal portion of a healthy and untreated airway, and FIG. A normal section of a treated airway 24 hours after delivery is shown. In an untreated airway (Figure 57A), Pseudostratified columnar epithelial cells PCEC and goblet cells GC and submucosal gland SG, connective tissue CT, smooth muscle The ciliated epithelium E with intact submucosal structures including the SM and cartilage CL can be observed. In the treated airways (Fig. 57B), the upper airway was composed of pseudostratified columnar epithelial cells PCEC and goblet cells GC. The epithelium E was substantially removed or destroyed, leaving only cellular debris and basement membrane. Most notably, the submucosal gland cells (SGs) are mostly The smooth muscle SM and connective tissue layer CT are also absent, and the extracellular glandular structures are destroyed. It shows signs of cell damage and destruction while bone CL remains unaffected.

[0356]

[0413] Example 2: Circumferential treatment and tissue effects with a monopolar system

[0357]

[0414] A non-thermal energy delivery device has been developed having a unipolar expandable energy delivery body. The device includes a catheter shaft having a mechanism for expanding and contracting the energy delivery body. A single energy transmitter containing Nitinol, braided, and extended electrodes concentrically mounted on a bolster. The expanded energy delivery diameter ranged from about 5 mm to The range was approximately 20 mm from the epithelium to the submucosal layer of the airway. To evaluate the effect of energy, the device was introduced into the left and / or right bronchi of live anesthetized pigs. The pulse frequency was approximately 300 kHz and the pulse amplitude was approximately 100 Hz. Approximately 4000V, total energy supply duration approximately 415 microseconds (83 mA per packet) The time was 1000 ms, 5 packets.

[0358]

[0415] After the procedure, the animals were collected and euthanized about 24 hours later. The airways were then incised and the The airways were then sectioned at approximately 5 mm increments and cut in the usual manner. Processed for histology. Sections of both treated and untreated areas were processed for comparison purposes. Slides were prepared with hematoxylin-eosin (H&E) staining.

[0359]

[0416] FIG. 58A shows a normal portion of a healthy and untreated airway, and FIG. A normal section of a treated airway 24 hours after delivery is shown. In an untreated airway (Figure 58A), Pseudostratified columnar epithelial cells PCEC and goblet cells GC and submucosal gland SG, connective tissue CT, cartilage C The ciliated epithelium E with intact submucosal structures including L and smooth muscle SM can be observed. In treated airways (Figure 58B), epithelial E and goblet cells GC were substantially removed or destroyed. Only cellular debris and the basement membrane BM remained. Furthermore, the submucosa was not affected. Most notably, submucosal gland cell SGs are absent in some areas. In this example, extracellular structures including smooth muscle SM and connective tissue layer CT were hardly affected. The cartilage CL was not affected. The therapeutic effect was observed when the electrodes were in contact with the airway. Tissue changes were observed where the catheter was in use, whether using a bipolar or monopolar system. be.

[0360]

[0417] As used herein, the terms "about" and / or "approximately" refer to a numerical value and / or When used in conjunction with a number or range, the numerical values ​​and / or recited numerical values ​​and / or ranges generally are not to be construed as limiting the scope of the invention. In one example, the terms "about" and "approximately" refer to a range that is within or near the recited value. Within 10%. For example, in one example, "about 100 [units]" means ±10% of 100. The terms "about" and "approximately" can mean within (for example, 90 to 110). The words can be used interchangeably.

[0361]

[0418] Although preferred embodiments of the present invention have been shown and described herein, such implementations may be used without departing from the spirit and scope of the present invention. It will be apparent to those skilled in the art that the embodiments are provided by way of example only. Numerous variations, changes, and substitutions are contemplated without departing from the invention. Various alternatives to the embodiments of the invention described herein may be used in practicing the invention. The following appended claims define the scope of the invention and All methods and structures within the scope of these claims and their equivalents are hereby incorporated by reference. It is considered. The present invention provides, for example, the following items. (Item 1) 1. A system for reducing mucus hypersecretion in a pulmonary passageway of a patient, comprising: a catheter including at least one electrode disposed near a distal end, the distal end configured to be positioned within a pulmonary passageway of a patient, the at least one electrode configured to deliver non-thermal energy to an airway wall of the pulmonary passageway; a generator having at least one energy delivery algorithm in electrical communication with the at least one electrode and configured to provide an electrical signal of the non-thermal energy transmittable to the airway wall to selectively treat specific cells associated with mucus hypersecretion in the airway wall to reduce mucus hypersecretion in the airway wall; Including, the system. (Item 2) 2. The system of item 1, wherein the selective treatment comprises selectively removing the specific cells from the airway wall. (Item 3) 3. The system of item 2, wherein the removal comprises cell detachment. (Item 4) 4. The system of item 3, wherein cell detachment is performed by dielectrophoresis. (Item 5) 3. The system according to item 2, wherein the removal comprises cell death. (Item 6) 6. The system of any of items 1, 2, 3, 4 or 5, wherein the specific cells include epithelial cells but not basal cells. (Item 7) 7. The system of claim 6, wherein the epithelial cells comprise abnormal or hyperplastic goblet cells. (Item 8) 7. The system of claim 6, wherein the epithelial cells comprise abnormally multistratified ciliated columnar epithelial cells. (Item 9) The system of item 1, wherein the specific cells include cells of a basement membrane, and the selective treatment includes modifying the cells of the basement membrane and altering the permeability of the basement membrane. (Item 10) 6. The system of any of items 1, 2 or 5, wherein the specific cells include submucosal gland cells, and the selective treatment includes causing cell death of the submucosal gland cells. (Item 11) 6. The system of any of items 1, 2 or 5, wherein the specific cells comprise a pathogen and the selective treatment comprises causing cell death of the pathogen. (Item 12) The system described in item 1, wherein the selective treatment comprises selectively modifying the specific cells to alter mucus production. (Item 13) 13. The system of any of items 1 to 12, wherein the electrical signal has a waveform including at least one energy packet, each energy packet including a series of pulses. (Item 14) Item 13. The system of item 12, wherein each pulse is about 500V to 10 kV. (Item 15) 14. The system according to item 12 or 13, wherein each pulse is about 500 to 4000 V. (Item 16) 15. The system of any of items 12, 13 or 14, wherein the at least one energy packet has a frequency in the range of approximately 500 to 800 kHz. (Item 17) 16. The system of any of items 12, 13, 14 or 15, wherein each pulse is biphasic. (Item 18) 18. The system of any of items 1 to 17, further comprising a temperature sensor positioned along the catheter and in contact with the airway wall to monitor the temperature inside and outside the airway wall. (Item 19) 20. The system of claim 17, wherein the generator includes a processor in communication with the temperature sensor, the processor modifying the at least one energy delivery algorithm if the temperature rises above a temperature threshold for a thermal tissue effect. (Item 20) 20. The system of any of items 1 to 19, further comprising an impedance sensor positioned along the catheter and in contact with the airway wall to monitor impedance at the airway wall, the impedance sensor in communication with an indicator that indicates a condition of the airway wall based on the impedance. (Item 21) 20. The system of claim 19, wherein the state of the airway wall includes completion of treatment for the specific cells. (Item 22) 20. The system of item 19, wherein the condition of the airway wall comprises a lack of effect of treatment on the particular cells. (Item 23) 23. The system of claim 1, wherein the generator further comprises a mechanism for acquiring a cardiac signal of the patient; and a processor configured to identify a safe period during which the non-thermal energy may be delivered to the airway wall of the pulmonary passage based on the cardiac signal. (Item 24) 23. The system of claim 22, wherein the safe period occurs in the ST segment of the cardiac signal. (Item 25) 23. The system of claim 22, wherein the safety period occurs during a QT interval of the cardiac signal. (Item 26) 26. The system of claim 1, further comprising at least one sensor configured to sense a parameter of the airway wall, the generator further comprising a processor configured to modify the at least one energy delivery algorithm based on data obtained from the at least one sensor, creating a feedback loop. (Item 27) 27. The system of claim 1, wherein the catheter has at least two expandable protrusions that contact the airway wall of the lung passage. (Item 28) 27. The system of claim 26, wherein the at least two prongs have a plurality of wires forming an expandable cage, at least one of the wires functioning as the at least one electrode. (Item 29) 28. The system of claim 27, wherein the catheter includes a shaft, the shaft not passing through the expandable cage. (Item 30) 29. The system of any of items 27 to 28, wherein at least a portion of one of the plurality of wires is insulated from adjacent wires in the plurality of wires. (Item 31) 30. The system of claim 29, wherein at least a portion of one of the plurality of wires is insulated leaving an exposed portion of the wire to create an active region that focuses the energy at a specific location along an airway wall of the lung passage. (Item 32) 31. The system of any of items 27 to 30, wherein the multiple wires are simultaneously energizable. (Item 33) 31. The system of any of items 27 to 30, wherein at least a portion of the plurality of wires are individually energizable. (Item 34) 27. The system of claim 26, wherein the at least one electrode comprises a separate electrode attached to at least one of the at least two protrusions. (Item 35) Item 34. The system of item 33, wherein the separate electrode is coil-shaped. (Item 36) 27. The system of claim 26, wherein the catheter includes a shaft, and the at least two prongs comprise a plurality of wires having an end attached to the shaft and a free end, forming a semi-expandable cage. (Item 37) 36. The system of any of items 26 to 35, further comprising a sheath advanceable over the catheter to collapse the at least two protrusions. (Item 38) 1. A system for regenerating normal healthy tissue in an abnormally functioning pulmonary passageway of a patient, comprising: a catheter including at least one electrode disposed near a distal end, the distal end configured to be positioned within a pulmonary passageway of a patient, the at least one electrode configured to deliver non-thermal energy to an airway wall of the pulmonary passageway; a generator in electrical communication with the at least one electrode and having at least one energy delivery algorithm configured to provide an electrical signal of the non-thermal energy transmittable to the airway wall, the electrical signal removing abnormally functioning cells from the airway wall and regenerating the airway wall with normal healthy tissue while maintaining a collagen matrix structure within the airway wall; Including, the system. (Item 39) Item 39. The system of item 38, wherein the removal comprises cell detachment. (Item 40) 40. The system of claim 39, wherein the electrical signal induces cell detachment by dielectrophoresis. (Item 41) Item 39. The system of item 38, wherein the removal comprises cell death. (Item 42) 42. The system of any of items 38, 39, 40 or 41, wherein the abnormally functioning cells comprise epithelial cells but not basal cells. (Item 43) 43. The system of claim 42, wherein the epithelial cells comprise abnormal or hyperplastic goblet cells. (Item 44) 43. The system of claim 42, wherein the epithelial cells comprise abnormally multistratified ciliated columnar epithelial cells. (Item 45) 42. The system of claim 38 or 41, wherein the abnormally functioning cells comprise submucosal glands and the ablation comprises causing cell death of the submucosal glands. (Item 46) 46. ​​The system of any of items 38 to 45, wherein the electrical signal has a waveform including at least one energy packet, each energy packet including a series of pulses. (Item 47) Item 47. The system of item 46, wherein each pulse is about 500V to 10 kV. (Item 48) 48. The system according to item 46 or 47, wherein each pulse is about 500 to 4000 V. (Item 49) 49. The system of any one of items 46, 47, and 48, wherein the at least one energy packet has a frequency in the range of approximately 500 to 800 kHz. (Item 50) 50. The system of any of items 46, 47, 48 or 49, wherein each pulse is biphasic. (Item 51) 51. The system of any of items 38 to 50, further comprising a temperature sensor positioned along the catheter and in contact with the airway wall to monitor the temperature inside and outside the airway wall. (Item 52) 52. The system of claim 51, wherein the generator includes a processor in communication with the temperature sensor, the processor modifying the at least one energy delivery algorithm if the temperature rises above a temperature threshold for a thermal tissue effect. (Item 53) 53. The system of any of items 38 to 52, further comprising an impedance sensor positioned along the energy catheter and in contact with the airway wall to monitor impedance at the airway wall, the impedance sensor in communication with an indicator that indicates a condition of the airway wall based on the impedance. (Item 54) 54. The system of claim 53, wherein the condition of the airway wall comprises an ineffective removal of the abnormally functioning cells. (Item 55) 55. The system of claim 38, wherein the generator further comprises a mechanism for acquiring a cardiac signal of the patient; and a processor configured to identify a safe period during which the non-thermal energy may be delivered to the airway wall of the pulmonary passage based on the cardiac signal. (Item 56) 56. The system of claim 55, wherein the safe period occurs in the ST segment of the cardiac signal. (Item 57) 56. The system of claim 55, wherein the safety period occurs during a QT interval of the cardiac signal. (Item 58) 58. The system of claim 38, further comprising at least one sensor configured to sense a parameter of the airway wall, the generator further comprising a processor configured to modify the at least one energy delivery algorithm based on data obtained from the at least one sensor, creating a feedback loop. (Item 59) 59. The system of claim 38, wherein the catheter has at least two expandable protrusions that contact the airway wall of the lung passage. (Item 60) 60. The system of claim 59, wherein the at least two protrusions have a plurality of wires forming an expandable cage, at least one of the wires functioning as the at least one electrode. (Item 61) Item 61. The system of item 60, wherein the catheter includes a shaft, the shaft not passing through the expandable cage. (Item 62) 62. The system of any of items 59 to 61, wherein at least a portion of one of the plurality of wires is insulated from adjacent wires in the plurality of wires. (Item 63) Item 63. The system of item 62, wherein at least a portion of one of the plurality of wires is insulated leaving an exposed portion of the wire to create an active region that focuses the energy at a specific location along the airway wall of the lung passage. (Item 64) 64. The system of any of items 59 to 63, wherein the multiple wires are simultaneously energizable. (Item 65) 64. The system of any of items 59 to 63, wherein at least a portion of the plurality of wires are individually energizable. (Item 66) 60. The system of claim 59, wherein the at least one electrode comprises a separate electrode attached to at least one of the at least two protrusions. (Item 67) Item 67. The system of item 66, wherein the separate electrode is coil-shaped. (Item 68) 60. The system of claim 59, wherein the catheter includes a shaft, and the at least two prongs comprise a plurality of wires having an end attached to the shaft and a free end, forming a semi-expandable cage. (Item 69) 69. The system of any of items 59 to 68, further comprising a sheath advanceable over the catheter to collapse the at least two prongs. (Item 70) 1. A system for regenerating normal healthy tissue in an abnormally functioning pulmonary passageway of a patient, comprising: a catheter including at least one electrode disposed near a distal end, the distal end configured to be positioned within a pulmonary passageway of a patient, the energy delivery entity configured to deliver non-thermal energy to an airway wall of the pulmonary passageway; a generator in electrical communication with the at least one electrode and having at least one energy delivery algorithm configured to provide an electrical signal of the non-thermal energy transmittable to the airway wall, the electrical signal removing from the airway wall cells involved in the abnormal functioning of the pulmonary passageway and regenerating the airway wall with normal healthy tissue while maintaining a collagen matrix structure within the airway wall; Including, the system. (Item 71) Item 71. The system of item 70, wherein the removal comprises cell detachment. (Item 72) 72. The system of claim 71, wherein the electrical signal induces cell detachment by dielectrophoresis. (Item 73) Item 71. The system of item 70, wherein the removal comprises cell death. (Item 74) 74. The system of any of paragraphs 70, 71, 72, or 73, wherein the cells comprise epithelial cells but not basal cells. (Item 75) 75. The system of claim 74, wherein the epithelial cells comprise abnormal or hyperplastic goblet cells. (Item 76) 75. The system of claim 74, wherein the epithelial cells comprise abnormally multistratified ciliated columnar epithelial cells. (Item 77) 74. The system of claim 70 or 73, wherein the cells comprise lymphocytes, macrophages, eosinophils, fibroblasts, plasma cells, mast cells, leukocytes, or combinations thereof. (Item 78) 74. The system of claim 70 or 73, wherein the cells comprise submucosal gland cells and the removing comprises causing cell death of the submucosal gland cells. (Item 79) 74. The system of claim 70 or 73, wherein the cell comprises a pathogen. (Item 80) 80. The system of any of items 70 to 79, wherein the electrical signal has a waveform including at least one energy packet, each energy packet including a series of pulses. (Item 81) 81. The system of item 80, wherein each pulse is about 500V to 10 kV. (Item 82) 82. The system of claim 80 or 81, wherein each pulse is about 500 to 4000 V. (Item 83) 83. The system of any of items 80, 81, or 82, wherein the at least one energy packet has a frequency in the range of approximately 500 to 800 kHz. (Item 84) 84. The system of any of items 80, 81, 82, or 83, wherein each pulse is biphasic. (Item 85) 85. The system of any of items 70 to 84, further comprising a temperature sensor positioned along the catheter and in contact with the airway wall to monitor the temperature inside and outside the airway wall. (Item 86) 86. The system of claim 85, wherein the generator includes a processor in communication with the temperature sensor, the processor modifying the at least one energy delivery algorithm if the temperature rises above a temperature threshold for a thermal tissue effect. (Item 87) 87. The system of any of items 70 to 86, further comprising an impedance sensor positioned along the catheter and in contact with the airway wall to monitor impedance at the airway wall, the impedance sensor in communication with an indicator that indicates a condition of the airway wall based on the impedance. (Item 88) 88. The system of claim 87, wherein the condition of the airway wall comprises an ineffectiveness in removing the cells. (Item 89) 89. The system of claim 70, wherein the generator further comprises a mechanism for acquiring a cardiac signal of the patie...

Claims

[Claim 1] The invention described in the specification.

Images