Generator, catheter with electrodes, and treatment method for lung passages

Abstract

It provides an interventional procedure that is easily controlled, adapts to the pathophysiological abnormality, treats a large surface area at an appropriate depth, and limits the extent of inflammatory response and remodeling. Systems and methods are provided for treating lung tissue by delivering energy to target tissue using a lung tissue modification system (100), such as an energy delivery catheter (102) system. Examples of lung tissue include epithelium (goblet cells, pseudostratified ciliated columnar epithelial cells, basal cells), lamina propria, submucosa, submucosal glands, basement membrane, smooth muscle, cartilage, and / or nerves. The system may be used to treat various lung diseases or disorders, such as COPD (e.g., chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, primary ciliary dyskinesia (PCD), and / or acute bronchitis.

Description

Technical Field

[0001] Cross - Reference to Related Applications

[0001] This application claims priority to U.S. Patent Application No. 62 / 355,164, "Methods, Apparatuses, and Systems for the Treatment of Pulmonary Disorders," filed on June 27, 2016, and U.S. Patent Application No. 62 / 489,753, "Methods, Apparatuses, and Systems for the Treatment of Pulmonary Disorders," filed on April 25, 2017. The disclosures of both of the above applications are hereby incorporated by reference in their entireties.

Background Art

[0002] I. Anatomical Perspective

[0002] FIG. 1 is an explanatory diagram of the anatomical structure of the lungs. Air enters the lungs L through the trachea T, where the trachea T branches into a plurality of airways that extend throughout the lungs L. The trachea T first branches in the neck CA into the left and right main bronchi MB. These main bronchi MB further divide into lobar bronchi LB, segmental bronchi SB, and sub - segmental bronchi SSB, and end at the alveoli A. The diameter of the airways decreases as they branch. The trachea T can have an inner lumen diameter in the range of about 15 mm to 22 mm, the main bronchi MB can have an inner lumen diameter in the range of about 12 mm to 16 mm, and the lobar bronchi LB can have a lumen diameter in the range of about 9 mm to 12 mm. The size of the subsequent bronchi continues to decrease. The length of the airways also varies for each segment. In some patients, the length of the trachea T is about 12 cm, the length of the main bronchi MB is about 4.8 cm, the length of the lobar bronchi LB is about 1.9 cm, and the length of the subsequent bronchi continues to become shorter. Note that the airway wall becomes thinner and has less support structure as it moves in the distal direction towards the lung tissue.

[0003]

[0003] The airways of the lungs L consist of various layers, each containing one or more types of cells. Figure 2 is a cross-sectional view showing the airway wall W with various layers and structures. The innermost cell layer of the airway wall W is the epithelium, or epithelial layer E, which includes stratified columnar epithelial cells PCEC, goblet cells GC, and basal cells BC. Goblet cells GC are responsible for secreting mucus M, which covers the inner wall of the airway and forms a mucus blanket. Stratified columnar epithelial cells PCEC contain cilia C that extend into the mucus blanket. Cilia C attached to the epithelium E pulsate toward the nose and mouth, pushing mucus M up into the airway and expelling it to the outside.

[0004]

[0004] Basal cells BC are attached to the basement membrane BM, and beneath the basement membrane BM is the submucosa or lamina propria LP. The lamina propria LP contains various types of cells and tissues, such as smooth muscle SM. Smooth muscle is responsible for bronchoconstriction and bronchodilation. The lamina propria LP also contains submucosal glands SG. Submucosal glands SG are involved in most inflammatory responses to pathogens and foreign bodies. Similarly, nerves N are present. Branches of the vagus nerve are located outside the airway wall or run within the airway wall, distributing nerves to mucous glands, airway smooth muscle, connective tissue, and fibroblasts, lymphocytes, mast cells, and various other cell types. Finally, beneath the lamina propria LP is the cartilage layer CL.

[0005]

[0005] Figure 3 is a cross-sectional view of the epithelium E of the airway wall W, showing the types of cell connections within the airway. Pluristratified columnar epithelial cells PCEC and goblet cells GC are connected to each other by tight junctions TJ and adherent junctions AJ. Pluristratified columnar epithelial cells PCEC and goblet cells GC are connected to basal cells BC by adhesion plaques D. Basal cells BC are connected to the basement membrane BM by hemiadhesion plaques H.

[0006] II. Lung Diseases

[0006] Figures 4A and 4B illustrate the bronchial airway B in a healthy state and a diseased state, respectively. Figure 4A shows the bronchial airway B in a healthy state with a normal amount of mucus M and no inflammation. Figure 4B shows the bronchial airway B in a diseased state, particularly chronic obstructive pulmonary disease, such as chronic bronchitis. Chronic bronchitis is characterized by persistent airflow obstruction, chronic cough, and sputum, presenting for at least three months per year for two consecutive years. Figure 4B illustrates both excessive mucus M and inflammation I that leads to airway obstruction. Airway inflammation I is also consistent with thickening of the epithelial layer E.

[0007]

[0007] Various lung disorders and lung diseases can cause airway obstruction. Some of these will be briefly described in this specification.

[0008] A. Chronic obstructive pulmonary disease (COPD)

[0008] Chronic obstructive pulmonary disease (COPD) is a common disease characterized by chronic, irreversible airflow obstruction and persistent inflammation, caused by harmful environmental stimuli such as cigarette smoke and other pollutants. COPD includes a range of diseases with chronic bronchitis that primarily affect the airways. Emphysema, on the other hand, affects the alveoli, or air sacs, that are involved in gas exchange. Some patients will have characteristics of both.

[0009]

[0009] In chronic bronchitis, the structure and function of the airways change. In chronic bronchitis, harmful irritants such as cigarette smoke and pollutants inhaled through the airways are recognized as foreign substances, triggering an inflammatory cascade. Neutrophils, lymphocytes, macrophages, cytokines, and other inflammatory markers are found in the airways of people who have been exposed to radiation for a long time, causing chronic inflammation and airway remodeling. Goblet cells may suffer from hyperplasia, an increase in cell number, or hypertrophy, an increase in goblet cell size. In other words, goblet cells produce more mucus in response to inflammatory stimuli and also to remove inhaled toxins. Excessive mucus further narrows the airway lumen and induces more obstruction. Cilia are damaged by harmful stimuli, so excess mucus remains in the airway lumen, obstructing airflow from proximal to distal during inspiration and from distal to proximal during expiration. Smooth muscles hypertrophy and thicken, causing bronchoconstriction. The submucosal glands also become hyperplastic and thickened, increasing the overall thickness of the airway wall and further narrowing the diameter of the lumen.

[0010]

[0010] In addition to the narrowing of the airway lumen, excessive mucus secretion can also lead to exacerbations or a general deterioration of health. As a result of excessive mucus secretion and ciliary damage, bacteria (e.g., Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, opportunistic Gram-negative bacilli, Mycoplasma pneumoniae, Chlamydia pneumoniae), viruses (rhinovirus, influenza / parainfluenza virus, respiratory syncytial virus, coronavirus, herpes simplex virus, adenovirus) and other organisms (e.g., fungi) can proliferate, causing exacerbations and a range of symptoms. These include worsening cough, congestion, increased sputum production, increased sputum, and / or shortness of breath. Treatment for acute exacerbations may include oral or intravenous administration of steroids, antibiotics, oxygen, endotracheal intubation, and mechanical ventilation.

[0011] B. Asthma

[0011] Asthma is a disease of the airways characterized by airway hyperresponsiveness. In asthma, the epithelium thickens, mucus is excessively secreted due to overproduction from goblet cells and submucosal glands, and the smooth muscle also thickens. As discussed herein, excessive mucus secretion, or excessive mucus, promotes the proliferation of pathogens and leads to infection.

[0012] C. Interstitial pulmonary fibrosis

[0012] Interstitial pulmonary fibrosis is thought to be caused by acute injury to lung tissue that induces chronic and abnormal inflammation. Fibroblasts are activated in response to inflammation, triggering pulmonary fibrosis, scarring, and deterioration of lung function. The survival rate of patients five years after diagnosis is only 20-30%.

[0013] D. Cystic fibrosis (CF)

[0013] Cystic fibrosis (CF) is a systemic disease characterized by pulmonary symptoms and defined by a genetic defect. Mutations in the cystic fibrosis membrane conduction control (CFTR) gene cause significantly viscous secretions that cannot be excreted. Chronic inflammation leads to airway remodeling and excessive secretion via goblet cells and submucosal glands, further triggering intractable airway stenosis and infections.

[0014] D. Bronchiectasis

[0014] Bronchiectasis is a condition in which the airways become dilated, thickened, and even scarred. It is usually caused by damage to the airway walls, impaired mucus clearing in the airways, infections that interfere with both, or other conditions. When this condition occurs, the airways lose their ability to clear mucus, which can lead to recurrent infections. Each infection causes further damage, eventually leading to moderate airflow obstruction. Bronchiectasis can be caused by genetic disorders such as primary ciliary dysplasia syndrome, but it can also be of idiopathic origin.

[0015] Study. Treatment of lung diseases

[0015] In some cases, the most effective treatment for lung disease is lifestyle change, especially quitting smoking. This is especially true in the case of COPD. However, many patients are unable to quit smoking or do not want to. Currently, a variety of treatments are available to alleviate the symptoms of lung disease.

[0016] A. Medications

[0016] COPD can be managed with one or more drug therapies, such as short-acting β-agonists (SABAs), long-acting β-agonists (LABAs), long-acting anticholinergics (LAMAs), steroids, chronic antibiotic therapy, or PDE4 inhibitors such as roflumilast. SABAs and LABAs act on β-receptors in airway smooth muscle to dilate the bronchi. LAMAs act via the anticholinergic pathway, inhibiting acetylcholine release and thus dilating the bronchi. LABAs and LAMAs have been shown to reduce the frequency of shortness of breath and exacerbations and improve quality of life, but have not been shown to reduce mortality. The LAMA tiotropium slows the rate of decline in lung function and prolongs the time to exacerbation. Inhaled corticosteroids directly target inflammation. Inhaled corticosteroids have been shown to reduce exacerbations, but have little effect on lung function or mortality. Combinations of LABAs, LAMAs, and inhaled corticosteroids have already been tested. Inhaled oxygen is known to reduce shortness of breath and improve mortality, but these results are only relevant to progressive diseases defined by strict criteria, requiring chronic administration via nasal cannula or alternative devices.

[0017]

[0017] COPD can also be managed with one or more oral medications, such as PDE4 inhibitors, steroids, and antibiotics. Roflumilast is an oral medication that is a selective long-acting inhibitor of the PDE4 enzyme. Its anti-inflammatory effect is very potent, but it is poorly tolerated due to adverse effects such as diarrhea, weight loss, nausea, loss of appetite, and abdominal pain. Oral steroids such as prednisone can be prescribed to patients to treat acute inflammation during exacerbations. It is known that patients must continue oral steroids for a long period of time if discontinuation of the medication leads to another exacerbation. Oral steroids also have various side effects, including weight gain, insomnia, thyroid dysfunction, and osteoporosis. Long-term administration of azithromycin or antibiotics has been shown to reduce the frequency of COPD exacerbations. Antibiotics can achieve this by eliminating the pathogen causing the exacerbation, or by other mechanisms, including a reduction in mucus secretion, as shown by macrolide antibiotics. Side effects of long-term antibiotic administration include hearing loss and antibiotic resistance.

[0018]

[0018] In many cases, patients do not adhere to prescribed respiratory medications. Inhalation therapy requires deep exhalation as well as synchronization with inhalation, which most patients, especially the elderly, cannot perform. Failure to adhere to the prescribed dosage can lead to problems with cost and / or side effects. In summary, all factors contribute to inappropriate and inconsistent administration.

[0019]

[0019] Asthma is a disease with a wide range of severity in adult patients, from mild to persistent. Mild asthma can be adequately managed by avoiding causative factors and taking short-acting beta-agonists (SABAs). On the other hand, the mainstream treatment for persistent asthma is inhaled glucocorticoids. Clinical trials have shown that regular use of inhaled glucocorticoids reduces the need to carry an inhaler, improves lung function, alleviates symptoms, and prevents exacerbations. Some patients have achieved further benefits by taking leukotriene modifiers or LABAs in addition. Tiotropium may be another option for improving lung function compared to inhaled glucocorticoids alone. In particularly severe cases, temporary or long-term treatment with oral corticosteroids may be necessary.

[0020]

[0020] There is no known cure for interstitial pulmonary fibrosis (IPF). The main treatments are oxygen supplementation as needed and preventive measures such as vaccination. Pirfenidone is an approved antifibrotic agent for IPF that attempts to slow fibroblast lesions, collagen deposition, and inflammatory infiltration of inflammatory cells. Clinical trials have shown that pirfenidone reduces the decrease in vital capacity (a measure of lung function) and demonstrates a reduction in all-cause mortality. Ninetanib is another approved drug for IPF that acts as a receptor blocker for several tyrosine kinases that mediate the synthesis of fibroblast growth factors (e.g., platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor). This slows the rate of disease progression in IPF. No device therapy for IPF has yet been approved.

[0021]

[0021] Treatment for cystic fibrosis has rapidly evolved from chest physiotherapy and oxygen therapy to therapies targeting the underlying defects in the CFTR gene. Ivacaftor is a CFTR enhancer that improves chloride transport via ion channels and is FDA approved for certain CFTR gene mutations. Clinical trials have shown it to improve FEV1 and reduce the frequency of exacerbations. It also improves mucociliary and cough clearance. However, when used alone in patients with the most common delta-F508 deletion, it does not offer significant improvement in outcomes. Other targeted therapies are in clinical trials. Chronic antibiotics, including azithromycin (which has anti-inflammatory effects) and inhaled tobramycin (used to treat Pseudomonas aeruginosa), are commonly prescribed for CF. As with other obstructive diseases, bronchodilators, including LABAs and LAMAs, are well-suited for CF patients. Medications that promote airway secretion clearance include inhaled DNase, which reduces mucus viscosity; inhaled hypertonic saline, which draws moisture from the airways within the mucus; and inhaled N-acetylcysteine, which cleaves disulfide bonds in mucus glycoproteins. Oral steroids are used in exacerbations, but guidelines recommend long-term use of inhaled corthiocosteroids.

[0022]

[0022] Bronchiectasis is an anatomical manifestation of a host injury response that results in excessive dilation of the airway lumen. Treatment is therefore often directed towards the cause of the primary disease. These may, among others, be nontuberculous mycobacterial infections, primary immunodeficiency, allergic bronchopulmonary disease, and aspergillosis. Treatment of acute exacerbations focuses on treating the harmful bacterial pathogen with antibiotics. Macrolide and non-macrolide antibiotics have been shown to reduce the frequency of exacerbations. The use of absorbable antibiotics in the absence of CF is unclear, as is the efficacy of mucolytics. Bronchodilators may be administered to patients showing signs of airway obstruction on vital capacity measurement.

[0023]

[0023] Treatments for primary ciliary dyskinesia syndrome (PCD) aim to improve clearance of secretions and reduce respiratory infections through daily chest physical therapy and prompt treatment of respiratory infections. The role of nebulized DNase and other mucolytics is less clear.

[0024]

[0024] Respiratory infections caused by pathogens in the airway can occur with the above diseases regardless of type and are usually treatable with antibiotics. Unfortunately, drug development in this field has declined and current available treatments are limited. One problem is that there is no single drug that can treat the diverse pathogens seen in patients. Saliva tests can be used to determine commensal pathogens, but in this case, samples need to be obtained by bronchoscopy using special techniques to avoid sample contamination that affects other methods and collection styles. Another problem is that currently available drugs are not always effective because pathogens have developed resistance to these treatments.

[0025] B. Intervention procedures

[0025] Very recently, several groups have developed intervention procedures for COPD. The usefulness of surgical lung volume reduction (LVR) as a treatment has already been demonstrated, but because most patients are frail, morbidity and mortality are very high. Bronchoscopic lung volume reduction (BLVR) can be achieved by using one-way valves, coils, utilization of vapor ablation, or delivery of biologic tissue sealants or polymer-based tissue adhesives to the target lobe. The physiological goal of LVR / BLVR is emphysema and aims to resolve hyperinflation among other patient symptoms. According to some studies, BLVR has been demonstrated to improve lung function and quality of life. Volume reduction therapy has no effect on patients with chronic bronchitis, which is an airway disease rather than an alveolar disease.

[0026]

[0026] Another novel therapy is pulmonary nerve innervation deprivation, which, so to speak, removes the parasympathetic nerves circulating the airways, theoretically neutralizing the reactive airway smooth muscle and inducing chronic bronchiectasis. This produces effects similar to bronchodilators such as LABAs and LAMAs, but can provide long-term effects without the variability usually associated with medication. Because this is a proximal treatment only, the effect is limited to the upper airways, but the higher the resistance in the respiratory system, the lower the position of the airways.

[0027]

[0027] As a treatment method for airway diseases, various thermal ablation techniques are also described, but all of these have problems and issues related to the control of ablation and / or the targeting of specific cell types. Spray cryotherapy is a therapy in which liquid nitrogen is directly sprayed onto the bronchial wall in order to excise superficial airway cells and produce a regenerative effect on the bronchial wall. The operator (e.g., a physician) usually performs a "spray coating" on the wall, so the application range, dose, and / or depth of treatment tend to be left to the operator unless there is an appropriate controller. Also, in skip regions where nitrogen is not directly sprayed, the treatment is likely to be incomplete. Furthermore, due to the lack of accurate depth control, especially since the wall thickness of the airway wall can vary, there is a possibility of inadvertently damaging tissues that are not treatment targets, such as the lamina propria mucosa and cartilage. High-frequency and microwave ablation techniques are also described, but in this case, energy is delivered to various locations in the airway wall to excise the diseased tissue. Due to uncontrolled heat conduction, the inability to measure the actual tissue temperature that controls energy delivery, the risk of repeated treatment, and the variable wall thickness of the bronchus, there is a possibility of inadvertently damaging tissues that are not treatment targets. In addition, in order to apply energy diversely, repositioning of the catheter is required, and there is even a possibility that the treatment will be incomplete. All of these thermal ablation techniques non-selectively ablate various layers of the airway wall, so often an undesirable ablation is performed on non-target tissues rather than the epithelium. When tissues that are not treatment targets of the epithelium are damaged, an inflammatory cascade occurs, inducing inflammation and leading to exacerbation and remodeling. As a result, the airway lumen is further narrowed. Therefore, there is a need for continuous improvement in intervention procedures and their control that target specific depths and structures suitable for physiological diseases while limiting the degree of inflammatory reaction and remodeling.

[0028]

[0028] Asthmatx has previously developed a radiofrequency ablation system for performing bronchial thermoplasty. The operator inserts a catheter into the airway and activates electrodes to heat the airway tissue and cauterize the smooth muscle. Due to the acute inflammation caused by the heat generated during the procedure, many patients suffer from acute exacerbations. In the AIR2 clinical trial, when the "Asthma Quality of Life Questionnaire" was applied, patients did not show clinically significant improvement at 12 months compared to the placebo group. However, the treatment group experienced fewer exacerbations and fewer visits to the emergency room. Although this procedure has received FDA approval, it has side effects and is designated as an "investigational procedure" by insurance companies, so it is not yet widely used.

[0029]

[0029] Therefore, there is still an unmet need for interventions that are easy to control, adapt to pathophysiological abnormalities, can treat a large surface area at an appropriate depth, and can limit the degree of inflammatory response and remodeling. The present invention aims to satisfy at least some of these objectives. [Overview of the project]

[0030]

[0030] Described herein are apparatus, systems and methods used for the treatment or manipulation of lung tissue, and / or for the treatment of lung diseases or lung disorders, including COPD (e.g., chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, primary ciliary dysfunction syndrome (PCD), acute bronchitis, and / or other lung diseases or lung disorders. One or more features of any of these embodiments may be combined with one or more features of one or more other embodiments to constitute a novel embodiment to which the claims belong. Examples of lung cells, but not limited to, include epithelium (goblet cells, stratified ciliated columnar epithelial cells, basal cells), lamina propria, submucosa, submucosal glands, basement membrane, smooth muscle, cartilage, nerves, pathogens present near or within tissue, or combinations thereof.

[0031]

[0031] The methods, apparatus, and systems disclosed herein involve treating lung tissue by delivering energy, generally characterized by high-voltage pulses, to target tissue using a lung tissue modification system (e.g., an energy delivery catheter system). In some embodiments, energy delivery removes target tissue without causing any clinically significant inflammatory healing response, while in other embodiments, some degree of inflammatory healing response is acceptable. Furthermore, new, healthy target tissue is regenerated within a few days of the procedure. In other embodiments, energy delivery removes pathogens present in the airways by destruction or other means without causing substantial impact or damage to other airway structures.

[0032]

[0032] In a first embodiment, a system is provided for reducing excessive mucus secretion in a patient's pulmonary passages, the system comprising: a) a catheter comprising at least one electrode located near its distal end, the distal end positioned within the patient's pulmonary passages, and configured so that at least one electrode can deliver non-thermal energy to the airway walls of the pulmonary passages; and b) a generator having at least one energy delivery algorithm configured to communicate with at least one electrode and supply an electrical signal of non-thermal energy that can be delivered to the airway walls, thereby selectively treating specific cells associated with excessive mucus secretion in the airway walls to reduce excessive mucus secretion in the airway walls.

[0033]

[0033] In some embodiments, selective treatment includes selectively removing specific cells from the airway wall. In some embodiments, removal includes cell exfoliation. For example, cell exfoliation may be performed by dielectrophoresis. In some embodiments, removal includes cell death. For example, cell death may be performed by electroporation, or by other mechanisms. Similarly, removal may include a combination of dielectrophoresis and electroporation, or other mechanisms.

[0034]

[0034] In some embodiments, certain cells include epithelial cells rather than basal cells. For example, the epithelial cells may include abnormal or hyperplastic goblet cells. Alternatively, the epithelial cells may include abnormal pluristratified ciliated columnar epithelial cells.

[0035]

[0035] In some embodiments, the specific cells include cells of the basement membrane, and selective treatment includes modifying the cells of the basement membrane and altering the permeability of the basement membrane. In some embodiments, the specific cells include cells of the submucosa, and selective treatment includes inducing cell death of the submucosa. In some embodiments, the specific cells include pathogens, and selective treatment includes inducing cell death of the pathogens. In some embodiments, selective treatment includes selectively modifying specific cells to alter mucus production.

[0036]

[0036] In some embodiments, the electrical signal has a waveform that includes at least one energy packet, each energy packet containing a series of pulses. In one example, each pulse is approximately 500V to 10kV. In another example, each pulse is approximately 500V to 4000V.

[0037]

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

[0038]

[0038] In some embodiments, the system further includes a temperature sensor positioned along the catheter and in contact with the airway wall to monitor the temperature inside and outside the airway wall. In some embodiments, the generator includes a processor that communicates with the temperature sensor, and the processor modifies at least one energy delivery algorithm if the temperature rises above a temperature threshold for the thermal tissue effect.

[0039]

[0039] In some embodiments, the system further includes an impedance sensor positioned along a catheter and in contact with the airway wall to monitor the impedance in the airway wall, the impedance sensor communicating with an indicator that indicates the state of the airway wall based on the impedance. In one example, the state of the airway wall includes the completion of treatment for a particular cell. In another example, the state of the airway wall includes the lack of effect of treatment for a particular cell.

[0040]

[0040] In some embodiments, the generator further includes a mechanism for acquiring a patient's cardiac signal and a processor configured to identify a safe period in which non-thermal energy can be transferred to the airway walls of the lung passages based on the cardiac signal. In some embodiments, the safe period occurs in the ST portion of the cardiac signal. In other embodiments, the safe period occurs during the QT interval of the cardiac signal.

[0041]

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

[0042]

[0042] In some embodiments, the catheter has at least two expandable projections that contact the airway wall of the lung passage. In some embodiments, at least two projections have a plurality of wires that form an expandable cage, and at least one of the wires functions as at least one electrode. In some embodiments, the catheter includes a shaft, which does not pass through the expandable cage. In some embodiments, at least a portion of one of the plurality of 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 insulated, leaving the exposed portion of the wire, creating an active region that concentrates energy at a specific location along the airway wall of the lung passage. In some embodiments, the plurality of wires can be energized simultaneously. In other embodiments, at least a portion of the plurality of wires can be energized individually.

[0043]

[0043] In some embodiments, at least one electrode includes a separate electrode attached to at least one of at least two protrusions. In this embodiment, the separate electrode may be coil-shaped.

[0044]

[0044] In some embodiments, the catheter includes a shaft, and at least two projections comprise a plurality of wires having ends attached to the shaft and free ends, forming a semi-expandable cage.

[0045]

[0045] In some embodiments, the system further includes a sheath that can advance on the catheter to fold at least two projections.

[0046]

[0046] In a second aspect of the present invention, a system is provided for regenerating normal healthy tissue in the lung passage of a patient that is abnormally functioning, the system comprising: a) a catheter comprising at least one electrode positioned near its distal end, the distal end of which is located within the patient's lung passage, and the at least one electrode configured to transmit non-thermal energy to the airway wall of the lung passage; and b) a generator having at least one energy delivery algorithm configured to communicate with the at least one electrode and supply an electrical signal of non-thermal energy that can be transmitted to the airway wall, thereby removing abnormally functioning cells from the airway wall and regenerating the airway wall with normal healthy tissue, while maintaining the collagen matrix structure within the airway wall.

[0047]

[0047] In some embodiments, removal includes cell detachment. For example, cell detachment may be performed by dielectrophoresis. In some embodiments, removal includes cell death. For example, cell death may be performed by electroporation, or by other mechanisms. Similarly, removal may include a combination of dielectrophoresis and electroporation, or other mechanisms.

[0048]

[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 another example, the epithelial cells include abnormal pluristratified ciliated columnar epithelial cells. In some embodiments, the abnormally functioning cells include submucosal gland cells, and removal includes causing cell death of the submucosal gland.

[0049]

[0049] In some embodiments, the electrical signal has a waveform comprising at least one energy packet, each energy packet comprising a series of pulses. In one example, each pulse is approximately 500V to 10kV. In another example, each pulse is approximately 500 to 4000V. In some embodiments, at least one energy packet has a frequency in the range of approximately 500 to 800kHz. In some embodiments, each pulse is biphasic.

[0050]

[0050] In some embodiments, the system further includes a temperature sensor positioned along the catheter and in contact with the airway wall to monitor the temperature inside and outside the airway wall. In some embodiments, the generator includes a processor that communicates with the temperature sensor, and the processor modifies at least one energy delivery algorithm if the temperature rises above a temperature threshold for the thermal tissue effect.

[0051]

[0051] In some embodiments, the system further includes an impedance sensor positioned along the catheter and in contact with the airway wall to monitor the impedance in the airway wall, the impedance sensor communicating with an indicator that indicates the state of the airway wall based on the impedance.

[0052]

[0052] In some embodiments, the condition of the airway wall includes the lack of effect in removing abnormally functioning cells.

[0053]

[0053] In some embodiments, the generator further includes a mechanism for acquiring a patient's cardiac signal and a processor configured to identify a safe period in which non-thermal energy can be transferred to the airway walls of the lung passages based on the cardiac signal. In some embodiments, the safe period occurs in the ST portion of the cardiac signal. In other embodiments, the safe period occurs during the QT interval of the cardiac signal.

[0054]

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

[0055]

[0055] In some embodiments, the catheter has at least two expandable projections that contact the airway wall of the lung passage. In one example, at least two projections have a plurality of wires that form an expandable cage, and at least one of the wires functions as at least one electrode.

[0056]

[0056] In some embodiments, the catheter includes a shaft, and the shaft does not pass through the expandable cage.

[0057]

[0057] In some embodiments, at least a portion of one of the plurality of 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 insulated, leaving the exposed portion of the wire, creating an active region that concentrates energy at a specific location along the airway wall of the lung passage. In some embodiments, the plurality of wires can be energized simultaneously. In other embodiments, at least a portion of the plurality of wires can be energized individually.

[0058]

[0058] In some embodiments, at least one electrode includes a separate electrode attached to at least one of the at least two protrusions. In this example, the separate electrode may be coil-shaped.

[0059]

[0059] In some embodiments, the catheter includes a shaft, and at least two projections comprise a plurality of wires having ends attached to the shaft and free ends, forming a semi-expandable cage.

[0060]

[0060] In some embodiments, the system further includes a sheath that can advance on the catheter to fold at least two projections.

[0061]

[0061] In a third aspect of the present invention, a system is provided for regenerating normal healthy tissue in the lung passage of a patient with abnormal function, the system comprising: a) a catheter comprising at least one electrode positioned near its distal end, the distal end of which is located within the patient's lung passage, and an energy deliverer configured to deliver non-thermal energy to the airway wall of the lung passage; and b) a generator having at least one energy delivery algorithm configured to electrical communicate with the at least one electrode and supply an electrical signal of non-thermal energy that can be delivered to the airway wall, thereby removing cells involved in the abnormal function of the lung passage from the airway wall and regenerating the airway wall with normal healthy tissue, while maintaining the collagen matrix structure within the airway wall.

[0062]

[0062] In some embodiments, removal includes cell detachment. For example, an electrical signal may induce cell detachment by dielectrophoresis. In some embodiments, removal includes cell death.

[0063]

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

[0064]

[0064] In some embodiments, the cells include lymphocytes, macrophages, eosinophils, fibroblasts, plasma cells, mast cells, leukocytes, or a combination thereof. In some embodiments, the cells include submucosal gland cells, and removal includes causing cell death of the submucosal gland cells. In other embodiments, the cells include pathogens.

[0065]

[0065] In some embodiments, the electrical signal has a waveform comprising at least one energy packet, each energy packet comprising a series of pulses. For example, each pulse may be about 500V to 10kV. Alternatively, each pulse may be about 500 to 4000V. In some embodiments, at least one energy packet has a frequency in the range of about 500 to 800kHz. In some embodiments, each pulse is biphasic.

[0066]

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

[0067]

[0067] In some embodiments, the generator includes a processor that communicates with a temperature sensor, and the processor modifies at least one energy delivery algorithm if the temperature rises above a temperature threshold for the thermal structure effect.

[0068]

[0068] In some embodiments, the system further includes an impedance sensor positioned along the catheter and in contact with the airway wall to monitor the impedance in the airway wall, the impedance sensor communicating with an indicator that indicates the state of the airway wall based on the impedance.

[0069]

[0069] In some embodiments, the condition of the airway wall includes a lack of effect on cell removal.

[0070]

[0070] In some embodiments, the generator further includes a mechanism for acquiring a patient's cardiac signal and a processor configured to identify a safe period in which non-thermal energy can be transferred to the airway walls of the lung passages based on the cardiac signal. In some embodiments, the safe period occurs in the ST portion of the cardiac signal. In some embodiments, the safe period occurs during the QT interval of the cardiac signal.

[0071]

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

[0072]

[0072] In some embodiments, the catheter has at least two expandable projections that contact the airway wall of the lung passage. In some embodiments, at least two projections have a plurality of wires that form an expandable cage, and at least one of the wires functions as at least one electrode.

[0073]

[0073] In some embodiments, the catheter includes a shaft, and the shaft does not pass through the expandable cage.

[0074]

[0074] In some embodiments, at least a portion of one of the plurality of 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 insulated, leaving the exposed portion of the wire, creating an active region that concentrates energy at a specific location along the airway wall of the lung passage.

[0075]

[0075] In some embodiments, multiple wires can be energized simultaneously. In other embodiments, at least some of the multiple wires can be energized individually.

[0076]

[0076] In some embodiments, at least one electrode includes a separate electrode attached to at least one of at least two protrusions. In this embodiment, the separate electrode may be coil-shaped.

[0077]

[0077] In some embodiments, the catheter includes a shaft, and at least two projections comprise a plurality of wires having ends attached to the shaft and free ends, forming a semi-expandable cage.

[0078]

[0078] In some embodiments, the system further includes a sheath that can advance on the catheter to fold at least two projections.

[0079]

[0079] A fourth aspect of the present invention provides a system for removing epithelial cells from a body passage, the system comprising: a) a catheter comprising at least one electrode positioned near its distal end, the distal end positioned within a body passage, and the at least one electrode configured to transmit non-thermal energy to the wall of the body passage; and b) a generator having at least one energy delivery algorithm configured to communicate with the at least one electrode and supply an electrical signal of non-thermal energy that can be transmitted to the airway wall, causing epithelial cells to detach from the wall by dielectrophoresis and the wall to regenerate with normal healthy tissue.

[0080]

[0080] In some embodiments, the epithelial cells include goblet cells. In other embodiments, the epithelial cells include stratified ciliated columnar epithelial cells. In yet another embodiment, the epithelial cells include goblet cells and stratified ciliated columnar epithelial cells, rather than basal cells.

[0081]

[0081] In some embodiments, the body passages include the lung passages. For example, the body passages may be blood vessels, lymphatic vessels, renal tubules, esophagus, stomach, small intestine, large intestine, appendix, rectum, bladder, ureter, pharynx, oral cavity, vagina, urethra, or glandular tubules.

[0082]

[0082] In some embodiments, the electrical signal has a waveform comprising at least one energy packet, each energy packet comprising a series of pulses. In some embodiments, each pulse is approximately 500V to 10kV. In other embodiments, each pulse is approximately 500 to 4000V. In some embodiments, at least one energy packet has a frequency in the range of approximately 500 to 800kHz. In some embodiments, each pulse is biphasic.

[0083]

[0083] In some embodiments, the system further includes a temperature sensor positioned along the catheter and in contact with the airway wall to monitor the temperature inside and outside the airway wall. In some embodiments, the generator includes a processor that communicates with the temperature sensor, and the processor modifies at least one energy delivery algorithm if the temperature rises above a temperature threshold for the thermal tissue effect.

[0084]

[0084] In some embodiments, the system further includes an impedance sensor positioned along the catheter and in contact with the airway wall to monitor the impedance in the airway wall, the impedance sensor communicating with an indicator that indicates the state of the airway wall based on the impedance. In some embodiments, the state of the airway wall includes the absence of a cell exfoliation effect.

[0085]

[0085] In some embodiments, the generator further includes a mechanism for acquiring a patient's cardiac signal and a processor configured to identify a safe period in which non-thermal energy can be transferred to the airway walls of the lung passages based on the cardiac signal. In some embodiments, the safe period occurs in the ST portion of the cardiac signal. In some embodiments, the safe period occurs during the QT interval of the cardiac signal.

[0086]

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

[0087]

[0087] In some embodiments, the catheter has at least two expandable projections that contact the airway wall of the lung passage. In some embodiments, at least two projections have a plurality of wires that form an expandable cage, and at least one of the wires functions as at least one electrode. In some embodiments, the catheter includes a shaft, which does not pass through the expandable cage. In some embodiments, at least a portion of one of the plurality of 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 insulated, leaving the exposed portion of the wire, creating an active region that concentrates energy at a specific location along the airway wall of the lung passage.

[0088]

[0088] In some embodiments, multiple wires can be energized simultaneously. In some embodiments, at least some of the multiple wires can be energized individually.

[0089]

[0089] In some embodiments, at least one electrode includes a separate electrode attached to at least one of at least two protrusions. In this example, the separate electrode may be coil-shaped.

[0090]

[0090] In some embodiments, the catheter includes a shaft, and at least two projections comprise a plurality of wires having ends attached to the shaft and free ends, forming a semi-expandable cage.

[0091]

[0091] In some embodiments, the system further includes a sheath that can advance on the catheter to fold at least two projections.

[0092]

[0092] A fifth aspect of the present invention provides a system for treating a patient's pulmonary passages, the system comprising a) a generator configured to supply energy to a catheter configured to be positioned within the pulmonary passages so that the energy is delivered to the pulmonary passages, the generator comprising at least one energy delivery algorithm and a processor, the processor supplying an electrical signal of energy according to the at least one energy delivery algorithm, each electrical signal having a waveform comprising at least one energy packet, each energy packet comprising a series of pulses, the energy selectively treating specific cells associated with excessive mucus secretion in the pulmonary passages to reduce excessive mucus secretion.

[0093]

[0093] In some embodiments, each pulse is approximately 500 to 4000V.

[0094]

[0094] In some embodiments, the energy is delivered unipolarly, with each pulse being approximately 2000 to 3500 volts. In other embodiments, the energy is delivered bipolarly, with each pulse being approximately 500 to 1900 volts.

[0095]

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

[0096]

[0096] In some embodiments, as the pulse voltage increases, the energy selectively treats specific cells located deeper within the walls of the lung passages.

[0097]

[0097] In some embodiments, at least one energy packet has a frequency in the range of about 500 to 800 kHz.

[0098]

[0098] In some embodiments, the energy is below a threshold for treating the cartilage layer within the lung passages. In some embodiments, the energy is below a threshold for causing thermal ablation.

[0099]

[0099] In some embodiments, the system further includes a temperature sensor configured to contact the wall of the lung passage and monitor the temperature inside and outside the wall.

[0100]

[0100] In some embodiments, the processor communicates with a temperature sensor, and further modifies at least one energy delivery algorithm if the temperature rises above a temperature threshold for the thermal structure effect. In some embodiments, each pulse is biphasic.

[0101]

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

[0102]

[0102] In some embodiments, the specific cells include basement membrane cells, and the selective treatment includes modifying the basement membrane cells and altering the permeability of the basement membrane.

[0103]

[0103] In some embodiments, the specific cells include a submucosal gland, and the selective treatment includes inducing cell death of the submucosal gland. In some embodiments, the specific cells include a pathogen, and the selective treatment includes inducing cell death of the pathogen.

[0104]

[0104] In some embodiments, the system further includes a cardiac monitor configured to acquire the patient's cardiac signals, and a processor supplies an electrical signal of energy in synchronization with the cardiac signals.

[0105]

[0105] In some embodiments, the processor supplies an electrical energy signal during the ST portion of the cardiac signal. In other embodiments, the processor supplies an electrical energy signal during the QT interval of the cardiac signal.

[0106]

[0106] In some embodiments, the system further includes an impedance sensor configured to contact the wall of the lung passage and monitor the impedance in the wall, the impedance sensor communicating with an indicator that indicates the state of the wall based on the impedance. In some embodiments, the state of the airway wall includes the completion of treatment for a particular cell. In some embodiments, the state of the airway wall includes the absence of the effect of treatment on a particular cell.

[0107]

[0107] In some embodiments, the system further includes at least one sensor configured to sense parameters of the lung passage walls, and a processor modifies at least one energy delivery algorithm based on data obtained from at least one sensor, creating a feedback loop.

[0108]

[0108] In a sixth aspect of the present invention, a system is provided for treating a patient's pulmonary passage, the system comprising: a) a generator configured to supply energy to a catheter positioned within the pulmonary passage, thereby enabling the energy to be delivered to the pulmonary passage; and a processor comprising at least one energy delivery algorithm, the processor supplying an electrical signal of energy according to the at least one energy delivery algorithm, the energy selectively treating specific cells associated with excessive mucus secretion in the pulmonary passage to reduce excessive mucus secretion; and b) at least one sensor communicating with the processor, the sensor sensing the state of the pulmonary passage, and the processor modifying at least one parameter of the at least one energy delivery algorithm based on the state.

[0109]

[0109] In some embodiments, at least one parameter includes voltage, frequency, packet duration, number of cycles, number of energy packets, pause period, or dead time.

[0110]

[0110] In some embodiments, at least one sensor includes a temperature sensor, the state includes the temperature of a portion of the wall of the lung passage.

[0111]

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

[0112]

[0112] In some embodiments, the processor stops supplying electrical signals of energy when the temperature reaches a temperature threshold.

[0113]

[0113] In some embodiments, the system further includes a catheter having at least one electrode that can be positioned near or relative to the wall of the lung passage to transmit energy to the lung passage, and at least one sensor including a temperature sensor, the state including the temperature of at least one electrode.

[0114]

[0114] In some embodiments, at least one sensor includes an impedance sensor, and the state includes the impedance of a portion of the wall of the lung passage. In some embodiments, a processor compares the impedance to an impedance threshold, and if the impedance exceeds the impedance threshold, an alarm is issued by a generator.

[0115]

[0115] In some embodiments, the system further includes a catheter having at least one electrode that can be positioned near or relative to the wall of the lung passage to transmit energy to the lung passage, and the alarm includes an indication that at least one of the at least one electrode is not properly positioned.

[0116]

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

[0117]

[0117] In some embodiments, the processor stops supplying the electrical signal of energy when the impedance reaches an impedance threshold. In some embodiments, at least one sensor includes a temperature sensor, an impedance sensor, a surface conduction sensor, a film potential sensor, a capacitance sensor, a force sensor, or a pressure sensor.

[0118]

[0118] In some embodiments, the system further includes a cardiac monitor configured to acquire the patient's cardiac signals, and a processor supplies electrical signals of energy in synchronization with the cardiac signals. In some embodiments, the state of the lung passages includes the completion of treatment for specific cells. In some embodiments, the state of the lung passages includes a lack of therapeutic effect on specific cells.

[0119]

[0119] A seventh aspect of the present invention provides a system for treating a patient's pulmonary passages, the system comprising: a) a generator configured to supply energy to a catheter positioned within the pulmonary passages, the system comprising at least two energy delivery algorithms and a processor, the processor of which selects one of the at least two energy delivery algorithms and supplies an electrical signal of energy according to the other of the at least two energy delivery algorithms, the energy being used to selectively treat specific cells associated with excessive mucus secretion in the pulmonary passages to reduce excessive mucus secretion; and b) at least one sensor communicating with the processor, the sensor sensing the state of the pulmonary passages, the processor of which selects the other of the at least two energy delivery algorithms and supplies an electrical signal of energy according to the other of the at least two energy delivery algorithms.

[0120]

[0120] In some embodiments, at least one sensor includes a temperature sensor, the state includes the temperature of a portion of the wall of the lung passage.

[0121]

[0121] In some embodiments, the system further includes a catheter having at least one electrode that can be positioned near or relative to the wall of the lung passage to transmit energy to the lung passage, and at least one sensor including a temperature sensor, the state including the temperature of at least one electrode.

[0122]

[0122] In some embodiments, at least one sensor includes an impedance sensor, and the state includes the impedance of a portion of the wall of the lung passage. In some embodiments, the processor compares the impedance to an impedance threshold, and if the impedance exceeds the impedance threshold, the generator issues an alarm. In some embodiments, at least one parameter includes a voltage, and the processor reduces the voltage when the impedance reaches the impedance threshold.

[0123]

[0123] In some embodiments, at least one sensor includes a temperature sensor, an impedance sensor, a surface conduction sensor, a membrane potential sensor, a capacitance sensor, a force sensor, or a pressure sensor.

[0124]

[0124] In some embodiments, the system further includes a cardiac monitor configured to acquire the patient's cardiac signal, and a processor supplies an electrical signal of energy in synchronization with the cardiac signal. In some embodiments, the state of the lung passage includes the completion of treatment for a particular cell. In some embodiments, the state of the lung passage includes the absence of a therapeutic effect for a particular cell.

[0125]

[0125] In an eighth aspect of the present invention, a system is provided for treating a patient's pulmonary passage, the system comprising: a) a generator configured to supply energy to a catheter configured to be positioned within the pulmonary passage, thereby enabling the energy to be delivered to the pulmonary passage; and b) a generator comprising at least one energy delivery algorithm and a processor, the processor supplying an electrical signal of energy according to the at least one energy delivery algorithm, the energy removing abnormally functioning cells from the airway wall; and at least one sensor communicating with the processor, the sensor sensing the state of the pulmonary passage, and the processor modifying at least one parameter of the at least one energy delivery algorithm based on the state.

[0126]

[0126] In a ninth aspect of the present invention, a system for treating a patient's pulmonary passage is provided, the system comprising: a) a generator configured to supply energy to a catheter positioned within the pulmonary passage, thereby enabling the energy to be delivered to the pulmonary passage; and b) a generator configured to supply energy to a catheter configured to be positioned within the pulmonary passage, the generator having at least one energy delivery algorithm and a processor, the processor supplying an electrical signal of energy according to at least one energy delivery algorithm, the energy causing the airway wall to regenerate with normal healthy tissue by removing cells involved in abnormal function of the pulmonary passage from the airway wall while maintaining the collagen matrix structure within the airway wall; and b) at least one sensor communicating with the processor. The sensor detects the state of the lung passages, and the processor modifies at least one parameter of at least one energy delivery algorithm based on the state.

[0127]

[0127] In a tenth aspect of the present invention, a system is provided for treating a patient's pulmonary passage, the system comprising: a) a generator configured to supply energy to a catheter configured to be positioned within the pulmonary passage, thereby enabling the energy to be delivered to the pulmonary passage; and b) a generator comprising at least one energy delivery algorithm and a processor, the processor supplying an electrical signal of energy according to at least one energy delivery algorithm, the energy causing epithelial cells to detach from the wall by dielectrophoresis and regenerate the wall with normal healthy tissue; and at least one sensor communicating with the processor, the sensor sensing the state of the pulmonary passage, and the processor modifying at least one parameter of the at least one energy delivery algorithm based on the state.

[0128]

[0128] In an eleventh aspect of the present invention, a system is provided for treating a patient's pulmonary passages, the system comprising a) a generator configured to supply energy to a catheter configured to be positioned within the pulmonary passages, the system comprising at least two energy delivery algorithms and a processor, the processor of which selects one of the at least two energy delivery algorithms and supplies an electrical signal of energy according to one of the at least two energy delivery algorithms, the energy removing abnormally functioning cells from the airway wall, and b) at least one sensor communicating with the processor, the sensor sensing the state of the pulmonary passages, the processor of which selects the other of the at least two energy delivery algorithms and supplies an electrical signal of energy according to the other of the at least two energy delivery algorithms.

[0129]

[0129] In a twelfth aspect of the present invention, a system is provided for treating a patient's pulmonary passage, the system comprising: a) a generator configured to supply energy to a catheter configured to be positioned within the pulmonary passage, thereby enabling the energy to be delivered to the pulmonary passage; and a processor configured to supply energy to at least two energy delivery algorithms, the processor selecting one of the at least two energy delivery algorithms and supplying an electrical signal of energy according to one of the at least two energy delivery algorithms, the energy causing the airway wall to regenerate with normal healthy tissue by removing cells involved in the abnormal function of the pulmonary passage from the airway wall while maintaining the collagen matrix structure within the airway wall; and b) at least one sensor communicating with the processor, the sensor sensing the state of the pulmonary passage; and the processor selecting the other of the at least two energy delivery algorithms and supplying an electrical signal of energy according to the other of the at least two energy delivery algorithms.

[0130]

[0130] In a thirteenth aspect of the present invention, a system is provided for treating a patient's pulmonary passage, the system comprising: a) a generator configured to supply energy to a catheter configured to be positioned within the pulmonary passage, the system comprising at least two energy delivery algorithms and a processor, the processor of which selects one of the at least two energy delivery algorithms and supplies an electrical signal of energy according to one of the at least two energy delivery algorithms, the energy causing epithelial cells to detach from the wall by dielectrophoresis and regenerate the wall with normal healthy tissue; and b) at least one sensor communicating with the processor, the sensor sensing the state of the pulmonary passage, the processor of which selects the other of the at least two energy delivery algorithms and supplies an electrical signal of energy according to the other of the at least two energy delivery algorithms.

[0131]

[0131] In a fourteenth aspect of the present invention, a system for treating a patient's pulmonary passage is provided, the system comprising: a) a catheter having at least one electrode that can be positioned near or relative to the wall of the pulmonary passage to transmit energy to the pulmonary passage; b) at least one sensor positioned along the catheter to sense the state of the pulmonary passage and generate a state value; and c) a generator having a processor configured to issue an alarm if the sensor value exceeds a threshold.

[0132]

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

[0133]

[0133] In some embodiments, the alarm includes an indication that at least one of the at least one electrodes is not properly positioned. In other embodiments, the alarm includes an indication that at least one of the at least one electrodes is faulty.

[0134]

[0134] In a fifteenth aspect of the present invention, a system for treating a patient's pulmonary passage is provided, the system comprising: a) a cardiac monitor configured to acquire the patient's cardiac signals; and b) a generator that supplies an electrical signal of energy transferable to the pulmonary passage to at least one electrode that can be positioned within the pulmonary passage, wherein the generator supplies the electrical signal in synchronization with the cardiac signals.

[0135]

[0135] In some embodiments, the cardiac monitor is configured to send a cardiac synchronization pulse to a generator at a predetermined point in the cardiac signal, and the generator supplies an electrical signal of energy after a predetermined delay from the reception of the cardiac synchronization pulse. In some embodiments, the predetermined point is the peak of the R wave in the cardiac signal. In some embodiments, the predetermined delay is in the range of 50 to 100 milliseconds.

[0136]

[0136] In some embodiments, the generator includes a processor which monitors a number of cardiac synchronization pulses, calculates the time interval between consecutive cardiac synchronization pulses, and prevents the generator from supplying an electrical signal if the time interval is not constant for a predetermined number of cardiac synchronization pulses. In some embodiments, the predetermined number of cardiac synchronization pulses is 5. In other embodiments, the predetermined number of cardiac synchronization pulses is 3. In some embodiments, the processor reduces the predetermined number of cardiac synchronization pulses if the generator has already prevented it from supplying an electrical signal. In some embodiments, the generator is configured to transmit an electrical signal during the ST portion of the cardiac signal. In some embodiments, the generator is configured to transmit an electrical signal during the QT interval of the cardiac signal. In some embodiments, the generator is configured not to transmit an electrical signal during the T wave of the cardiac signal. In some embodiments, the generator is configured not to transmit an electrical signal during the retrace period. In some embodiments, the retrace period is 100 to 200 milliseconds after the R wave peak of the cardiac signal.

[0137]

[0137] In some embodiments, the system further includes a catheter to which at least one electrode is attached.

[0138]

[0138] In some embodiments, the system further includes an imaging device configured to image the lung passages. In some embodiments, the imaging device includes a bronchoscope.

[0139]

[0139] In a sixteenth aspect of the present invention, a system is provided for reducing excessive mucus secretion in a patient's pulmonary passages, the system comprising a catheter comprising an energy delivery body positioned near its distal end, the energy delivery body having at least two expandable projections that contact the wall of the pulmonary passage, each projection comprising at least one electrode, and b) a generator that supplies an electrical signal to at least one electrode that transmits an arbitrary amount of non-thermal energy toward the wall, the amount of energy being such that it selectively treats specific cells associated with excessive mucus secretion of the airway wall to reduce excessive mucus secretion by the airway wall.

[0140]

[0140] In some embodiments, at least two projections have a plurality of wires that form an expandable cage, and at least one of the wires functions as at least one electrode.

[0141]

[0141] In some embodiments, the catheter includes a shaft, and the shaft does not pass through the expandable cage.

[0142]

[0142] In some embodiments, at least a portion of one of the plurality of 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 insulated, leaving the exposed portion of the wire, creating an active region that concentrates an amount of energy at a specific location along the airway wall of the lung passage.

[0143]

[0143] In some embodiments, multiple wires can be energized simultaneously. In other embodiments, at least some of the multiple wires can be energized individually.

[0144]

[0144] In some embodiments, at least one electrode includes a separate electrode attached to at least two protrusions. In this embodiment, the separate electrode may be coil-shaped.

[0145]

[0145] In some embodiments, the catheter includes a shaft, and at least two projections comprise a plurality of wires having ends attached to the shaft and free ends, forming a semi-expandable cage.

[0146]

[0146] In some embodiments, the system further includes a sheath that can advance on the catheter to fold at least two projections.

[0147]

[0147] In some embodiments, selective treatment involves selectively removing specific cells from the airway wall. The specific cells may include epithelial cells rather than basal cells. In one example, the epithelial cells include abnormal or hyperplastic goblet cells. In another example, the epithelial cells include abnormal pluristratified ciliated columnar epithelial cells.

[0148]

[0148] In some embodiments, removal includes cell exfoliation. In other embodiments, removal includes cell death.

[0149]

[0149] In some embodiments, the specific cells include basement membrane cells, and the selective treatment includes modifying the basement membrane cells and altering the permeability of the basement membrane.

[0150]

[0150] In some embodiments, the specific cells include a submucosal gland, and the selective treatment includes inducing cell death of the submucosal gland.

[0151]

[0151] In some embodiments, the specific cells include a pathogen, and the selective treatment includes inducing cell death of the pathogen.

[0152]

[0152] In some embodiments, selective treatment includes selectively modifying specific cells to alter mucus production.

[0153]

[0153] In some embodiments, the electrical signal has a waveform that includes at least one energy packet, each energy packet containing a series of pulses. In one example, each pulse is approximately 500V to 10kV.

[0154]

[0154] In some embodiments, the system further includes temperature sensors positioned along the energy delivery body and in contact with the airway wall to monitor the temperature inside and outside the airway wall.

[0155]

[0155] In some embodiments, the generator includes a processor that communicates with a temperature sensor, and the processor modifies at least one energy delivery algorithm if the temperature rises above a temperature threshold for the thermal structure effect.

[0156]

[0156] In some embodiments, the system further includes an impedance sensor positioned along an energy delivery body and in contact with the airway wall to monitor the impedance in the airway wall, the impedance sensor communicating with an indicator that indicates the state of the airway wall based on the impedance.

[0157]

[0157] In some embodiments, the generator further includes a mechanism for acquiring a patient's cardiac signal and a processor configured to analyze the cardiac signal and identify a safe period in which non-thermal energy can be transferred to the airway walls of the lung passages.

[0158]

[0158] In some embodiments, the system further includes at least one sensor configured to sense parameters of the airway wall, and the generator further includes a processor configured to modify an electrical signal based on data obtained from the at least one sensor and to create a feedback loop.

[0159]

[0159] A 17th aspect of the present invention provides a method for reducing excessive mucus secretion in a patient's pulmonary passages, the method comprising: a) positioning at least one electrode within the pulmonary passage such that at least one electrode is positioned near or against a portion of the airway wall of the pulmonary passage; and b) energizing at least one electrode to deliver non-thermal energy to a portion of the airway wall, the non-thermal energy selectively treating specific cells associated with excessive mucus secretion in the airway wall to reduce excessive mucus secretion by the airway wall.

[0160]

[0160] In some embodiments, selective treatment involves selectively removing specific cells from the airway wall. In one example, the specific cells include epithelial cells rather than basal cells. In another example, the epithelial cells include abnormal or hyperplastic goblet cells. In yet another example, the epithelial cells include abnormal pluristratified ciliated columnar epithelial cells.

[0161]

[0161] In some embodiments, removal includes cell detachment. For example, removal may include cell detachment by dielectrophoresis. In some embodiments, removal includes cell death.

[0162]

[0162] In some embodiments, the specific cells include basement membrane cells, and the selective treatment includes modifying the basement membrane cells and altering the permeability of the basement membrane.

[0163]

[0163] In another embodiment, the specific cells include a submucosal gland, and the selective treatment includes inducing cell death of the submucosal gland.

[0164]

[0164] In another embodiment, the specific cells include a pathogen, and the selective treatment includes inducing cell death of the pathogen.

[0165]

[0165] In some embodiments, selective treatment includes selectively modifying specific cells to alter mucus production.

[0166]

[0166] In some embodiments, at least one electrode has a plurality of wires forming an expandable cage, and positioning of at least one electrode in the lung passage includes expanding the expandable cage so that at least one of the plurality of wires comes into contact with the airway wall of the lung passage. In some embodiments, the plurality of wires function as a unipolar electrode, and the method further includes positioning a counter electrode plate near the patient. In some embodiments, the plurality of wires function as a bipolar electrode.

[0167]

[0167] In some embodiments, at least one electrode comprises at least two electrodes, and current application comprises current application to at least two electrodes that function as a bipolar pair.

[0168]

[0168] In some embodiments, the non-thermal energy has an arbitrary amount of energy, and the method further includes re-energizing at least one electrode to deliver non-thermal energy having a different amount of energy.

[0169]

[0169] In some embodiments, the re-energizing step is performed in accordance with a condition sensed from a portion of the airway wall. In some embodiments, the sensed condition includes temperature. In other embodiments, the sensed condition includes impedance.

[0170]

[0170] In some embodiments, the method further includes re-energizing at least one electrode to selectively treat different cells in a portion of the airway wall. In some embodiments, the energizing of specific cells includes different cells, including epithelial cells as well as submucosal cells.

[0171]

[0171] In some embodiments, energizing at least one electrode includes energizing at least one electrode in synchronization with the patient's cardiac cycle. In some embodiments, the synchronization includes the outside of the T wave of the cardiac cycle.

[0172]

[0172] In some embodiments, The method further includes repositioning at least one electrode within the lung passage so that at least one electrode is positioned near or against a different portion of the airway wall of the lung passage, and energizing at least one electrode to deliver energy to the different portion of the airway wall. In some embodiments, the portion and the different portion are adjacent to each other.

[0173]

[0173] In some embodiments, the method further includes positioning at least one electrode in different lung passages of a patient such that at least one electrode is located near or relative to a portion of the airway wall of the different lung passages, and energizing at least one electrode to deliver energy to a portion of the airway wall of the different lung passages.

[0174]

[0174] In some embodiments, non-thermal energy is supplied by an electrical signal having a waveform comprising at least one energy packet, each energy packet comprising a series of pulses. In some embodiments, each pulse is about 500 to 4000 V. In some embodiments, each energy packet has a frequency in the range of about 500 to 800 kHz.

[0175]

[0175] These embodiments and other embodiments will be described in further detail in the following description relating to the attached drawings.

[0176] Embedding by reference

[0176] All publications, patents and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is incorporated by reference specifically and individually. [Brief explanation of the drawing]

[0177]

[0177] Novel features of the present invention are described in detail in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by referring to the following detailed description illustrating exemplary embodiments in which the principles of the present invention are utilized, as well as to the appended drawings.

[0178] [Figure 1]

[0178] This is an explanatory diagram of the anatomical structure of the lungs. [Figure 2]

[0179] This is a cross-sectional view showing the airway wall, which has various layers and structures. [Figure 3]

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

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

[0181] Shows the bronchial airway in a diseased state. [Figure 5]

[0182] This document illustrates one embodiment of a lung tissue reshaping system used in the treatment of patients. [Figure 6]

[0183] Figure 5 is a detailed diagram of an embodiment of a therapeutic energy delivery catheter. [Figure 7]

[0184] This is a schematic diagram of one embodiment of a lung tissue remodeling system. [Figure 8A]

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

[0185] Shows a bronchoscope inserted into the patient's nose / nasal cavity. [Figure 9]

[0186] This shows the positioning of the distal end of a catheter within the main bronchus for the purpose of airway treatment. [Figure 10]

[0186] This shows the positioning of the distal end of a catheter within the main bronchus for the purpose of airway treatment. [Figure 11]

[0186] This shows the positioning of the distal end of a catheter within the main bronchus for the purpose of airway treatment. [Figure 12]

[0187] This is a flowchart illustrating the method described herein in a stepwise approach to treating a patient. [Figure 13]

[0188] This shows one embodiment of the waveform of the signal supplied by the energy delivery algorithm. [Figure 14]

[0189] Here are some waveform examples for a different energy delivery algorithm. [Figure 15]

[0190] Here are some waveform examples for a different energy delivery algorithm. [Figure 16]

[0191] Here are some waveform examples for a different energy delivery algorithm. [Figure 17]

[0192] This describes an embodiment in which the delivered energy separates the cells from the airway wall and causes the cells to be removed. [Figure 18]

[0193] This embodiment demonstrates how delivered energy kills cells, ultimately removing them from the airway wall. [Figure 19]

[0194] This diagram schematically illustrates the removal of epithelial cells by dielectrophoresis. [Figure 20]

[0195] This graph illustrates a portion of a sample electrocardiogram (ECG) trace from a human heart, highlighting the desirable timeframe for the delivery of energy pulses to the lung pathways via energy delivery devices. [Figure 21]

[0196] This flowchart shows one embodiment of a method for synchronizing energy supply with the cardiac cycle. [Figure 22]

[0197] This describes how to access lung tissue, such as parenchymal tissue, through the nose or mouth. [Figure 23A]

[0198] This image shows an example of a lung passage obtained using confocal laser endoscopy (CLE). [Figure 23B]

[0198] An example image of a lung passage obtained using optical coherence tomography (OCT) is shown. [Figure 24]

[0199] This document describes one embodiment of an energy delivery catheter, comprising a single energy delivery body having electrodes formed from multiple ribbons or wires that form a spiral cage. [Figure 25]

[0200] An embodiment is shown in which an energy delivery catheter includes two energy delivery bodies. [Figure 26]

[0201] An embodiment of an energy delivery catheter including a single energy delivery body is shown, wherein the energy delivery body is mounted on a shaft extending through the energy delivery body. [Figure 27]

[0202] This describes an embodiment in which both energy carriers are supported on a single shaft. [Figure 28A]

[0203] This embodiment shows how, during expansion, the energy of one energy carrier is not confined at one end, forming a semi-cage shape. [Figure 28B]

[0204] The present embodiment shows both energy carriers having braided metal wires configured to form a semi-cage shape when expanded. [Figure 29]

[0205] This shows a braided wire cage type energy delivery body that includes energizable wires, with some wires insulated while a portion of the insulator defining the activation region has been removed. [Figure 30]

[0206] Another embodiment is shown in which a tube is cut with a laser and both ends are constrained through the tube itself to form a folding cage. [Figure 31]

[0207] This describes an embodiment of an energy transfer device in which an insulated wire and one or more separate additional electrodes (coil-shaped) are connected to an insulated cage wire to form an active region. [Figure 32]

[0208] An embodiment of an energy delivery body including multiple tines is shown. [Figure 33]

[0209] An embodiment of an energy delivery body including one or more protrusions is shown. [Figure 34]

[0210] The present invention illustrates an embodiment of an energy delivery body comprising one or more protrusions, each formed from a non-conductive material, which either support and / or otherwise bind separate electrodes. [Figure 35]

[0211] This document describes one embodiment of a catheter having two energy delivery bodies, each of which has the shape of an expanded coil. [Figure 36]

[0212] An embodiment of an energy delivery body including a coil having width and length is shown, where the length of the coil is pre-formed into a substantially circular pattern. [Figure 37]

[0213] An embodiment of an energy delivery body including a rod having electrodes is shown, the length of which the rod is pre-formed in a substantially circular pattern. [Figure 38]

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

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

[0216] An embodiment of a prong is shown having two electrodes mounted on an insulating substrate between them as a means of maintaining the distance between electrodes. [Figure 40]

[0217] Figure 36 shows an embodiment of the prong having a narrower insulating substrate than shown in the illustration. [Figure 41]

[0218] Furthermore, an embodiment of the prong having a narrower insulating substrate and two or more electrodes is shown. [Figure 42]

[0219] This shows multiple electrodes mounted on an insulating substrate. [Figure 43]

[0220] Figures 36-37 show an insulating substrate having a helical electrode. [Figure 44]

[0221] Figure 38 shows an insulating substrate having a helical electrode. [Figure 45A]

[0222] This demonstrates expanding the expandable member until the desired interface is formed between the prong and the bronchial wall. [Figure 45B]

[0222] This shows expanding the expandable member until a desired interface is formed between the prong and the bronchial wall. [Figure 46]

[0223] An embodiment of an energy delivery catheter having four energy delivery bodies capable of operating in a bipolar / multiplex mode is shown. [Figure 47]

[0224] This illustrates unipolar energy delivery, which supplies energy between an energy delivery device and dispersed (paired) electrodes applied externally to the patient's skin. [Figure 48]

[0225] An example of a catheter detachably connected to a bronchoscope is shown. [Figure 49A-C]

[0226] This shows the introduction of a catheter with two energy delivery bodies through a bronchoscope. [Figure 50]

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

[0228] This is a schematic diagram of two target segments positioned adjacent to each other, such that the overall goals or treatment areas are generally adjacent. [Figure 52]

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

[0230] This is a schematic side view of a part of an energy delivery body having a woven cage. [Figure 54]

[0231] Figure 50 is a schematic cross-sectional view of an energy delivery device positioned within a lung passage with an airway wall. [Figure 55]

[0232] This is a schematic diagram illustrating the effect of continuous, circumferential treatment of the airway along the length of the energy transporter. [Figure 56]

[0233] This is a schematic diagram of the discontinuous tissue effect in the lung passages. [Figure 57A]

[0234] Histological examples are shown (Laboratory 6, Animal 1-10085), cross-sectional views from an untreated airway. [Figure 57B]

[0234] A histological example is shown (Laboratory 6, Animal 1-10085), a cross-sectional view from a treated airway. [Figure 58A]

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

[0235] Another histological example is shown (Laboratory 6, Animal 1-10085), a cross-section from a treated airway. [Modes for carrying out the invention]

[0179]

[0236] Specific embodiments of the apparatus, delivery system, and method are described below with reference to the drawings. However, detailed descriptions do not imply that any particular component, feature, or process is essential to the present invention.

[0180] I. Overview

[0237] Mucus secretion in the bronchial airways plays a crucial role in lung defense by protecting the inner lining and helping to eliminate infections. The amount of mucus secreted varies depending on the type of irritant, such as bacteria, particles, or chemical irritants. Normal secretion levels increase or decrease depending on the temporary state of the environment. In the epithelial layer of the bronchial airways, mucus traps particles, and ciliated cells allow the mucus to exit the lower airways. As a result, the mucus is eventually removed by coughing or swallowing. Mucus also contains antimicrobial agents that aid in defense functions. Pathogens and harmless inhaled proteins are thus eliminated from the airways, limiting contact with other immune components. In the bronchial airways, mucus is produced by goblet cells. Goblet cells produce mucin, which is released into the airway lumen by forming complexes with water in secretory granules. In larger airways, mucus is also produced by mucous glands. When exposed to the risk of infection or poisoning, the airway epithelium upregulates its mucus-secreting capacity, causing coughing and sputum production. Subsequently, the airway epithelium recovers and returns to a normal state, goblet cells disappear, and the cough subsides.

[0181]

[0238] However, in some cases of lung damage and lung disease, the body does not recover and chronically produces excessive mucus, which accumulates in the lungs. This causes symptoms such as chronic cough, shortness of breath, fatigue, chest pain, and discomfort. Excessive mucus secretion is associated with many conditions and is a major clinical and pathological feature in bronchiectasis associated with cystic fibrosis (CF), non-CF bronchiectasis, chronic obstructive pulmonary disease, and asthma.

[0182]

[0239] All of the above diseases involve impaired congenital lung defenses and activation of the host inflammatory response. In addition to Toll-like receptor (TLR) signaling, abnormal levels of antimicrobial peptides, surfactants, salivary lysozyme, sputum-secreting leukocyte protease inhibitors, and macrophages trigger mucin transcription and the NF-KB (nuclear factor κB light chain enhancer for activated B cells) pathway. Increased mucus production and decreased clearance induce exacerbations and increased airway epithelial damage. Ciliary activity is interrupted, and mucin production is upregulated. Goblet cell populations expand. Epithelial cell proliferation increases, accompanied by differentiation into goblet cells. Similarly, inflammation increases during exacerbations, proteases are activated, and elastic fibers that allow air and CO2 to enter and exit the alveoli are destroyed. In response to the injury, the airway epithelium produces even more mucus to clear the airways of inflammatory cells. This drives the disease forward. Pathogens enter the mucus but cannot be eliminated. Thus, another exacerbation cycle begins in the airways. As the worsening cycle progresses, excessive mucus production leads to pathological conditions that increase the risk of infection, hospitalization, and illness.

[0183]

[0240] To interrupt or prevent the disease progression cycle, the airways are treated with lung tissue modification systems that affect one or more cellular structures within the airway wall so that the airway wall structures recover from a diseased / remodeling state to a relatively normal state of architecture, function, and / or activity. Lung tissue modification systems treat lung tissue via energy delivery, typically characterized by high-voltage pulses. In some embodiments, energy delivery allows for modification or removal of target tissue without causing a clinically significant inflammatory response. In other embodiments, however, some degree of inflammatory healing response is acceptable. This allows for the regeneration of healthy new tissue within days of treatment.

[0184]

[0241] In one method, energy output from the lung tissue modification system induces separation in the epithelial layer E. Abnormally dysfunctional ciliated pseudolaminar epithelial cells (PCEC) and hyperplastic goblet cells (GC) are separated from basal cells (BC), drawn into the airway lumen, and expelled. As a result, basal cells (BC) remain in the basement membrane (BM), and normal goblet cells (GC) and normal stratified ciliated columnar epithelial cells (PCEC) are regenerated. This triggers reverse remodeling of the disease, reducing excessive mucus secretion. The newly regenerated goblet cells (GC) have very low mucus productivity. The newly regenerated stratified ciliated columnar epithelial cells (PCEC) regenerate normally functioning cilia (C), making it easier to expel mucus (M). Patients immediately notice a reduction in mucus volume, and cough and airway obstruction are also reduced. Subsequently, a decrease in exacerbations and an improvement in quality of life can be expected within a few weeks.

[0185]

[0242] In some embodiments, due to the relative strength of cell-cell junctions, energy induces epithelial separation between basal cells BC and goblet cells GC and stratified ciliated columnar epithelial cells PCEC, which are closer to the surface. Basal cells BC are linked to the basement membrane BM by hemiadhesion plaques H (see Figure 3). Furthermore, basal cells BC are linked to goblet cells GC and stratified ciliated columnar epithelial cells PCEC via adhesion plaques D (see Figure 3). The energy parameters and electrode configuration of the lung tissue modification system may be designed to separate the linkage by adhesion plaques D while leaving hemiadhesion plaques H intact. This removes surface cells, leaving basal cells BC nearly intact and ready for epithelial regeneration. The regeneration process is faster than what is typically expected with trauma or cauterization treatments that destroy the basement membrane BM and cause necrosis. For example, basement membrane destruction and necrosis, such as in thermal ablation, lead to the activation of inflammatory pathways, particularly those involving T cells, macrophages, IL-13, IL-4, monocytes, proteases, cytokines, and chemokines. In the method disclosed herein, the basement membrane BM is hardly destroyed, and acute inflammation occurs with little to no effect. This allows for the regeneration of healthy new target tissue within a few days after the procedure. In other embodiments, it is understood that energy output from the lung tissue modification system can induce other or further changes in the airway wall W, thereby regenerating healthy target tissue.

[0186]

[0243] Figure 5 shows one embodiment of a lung tissue modification system 100 used to treat patient P. In this embodiment, the system 100 includes a therapeutic energy delivery catheter 102 connectable to a generator 104. The catheter 102 comprises an elongated shaft 106 having at least one energy delivery body 108 near its distal end and a handle 110 at its proximal end. The generator 104 is connected to the catheter 102 and provides electrical energy to the energy delivery body 108. As illustrated in Figure 5, the catheter 102 can be inserted into the bronchial passage of patient P by various means, such as through the lumen of a bronchoscope 112.

[0187]

[0244] Figure 6 is a detailed view of an embodiment of the therapeutic energy delivery catheter 102 shown in Figure 5. In this embodiment, the energy delivery body 108 includes a single unipolar delivery electrode, but the type, number, and arrangement may be changed, and examples of such changes are described below. In this embodiment, the energy delivery body 108 includes a plurality of wires or ribbons 120 constrained by a proximal end constrainer 122 and a distal end constrainer 124 that form a helical cage that functions as an electrode. In other embodiments, the wires or ribbons are linear rather than helical (i.e., configured to form a linear cage). In yet another embodiment, the energy delivery body 108 is formed by laser cutting a tube. In some embodiments, the energy delivery body 108 is self-expanding and delivered to the target area in a folded state. For example, by placing a sheath 126 on top of the energy delivery body 108, it can be configured in a folded state. In Figure 6, the catheter shaft 106 (within the sheath 126) terminates at the proximal restraint 122 and moves freely relative to the shaft 106 of the catheter 102 with minimal restraint at the distal restraint 124. When the sheath 126 is advanced, covering the energy delivery body 108, the distal restraint 124 moves forward, thereby stretching / folding and subsequently restraining the energy delivery body 108.

[0188]

[0245] The catheter 102 includes a handle 110 at its proximal end. In some embodiments, the handle 110 can be removed, for example, by pressing a handle release button 130. In this embodiment, the handle 110 includes an energy delivery device operating knob 132, and the movement of the knob 132 causes the cage electrode to expand or contract / fold. In this example, the handle 110 further includes a bronchoscopic work port snap 134 for connecting to a bronchoscope 112 and a cable plug-in port 136 for connecting to a generator 104.

[0189]

[0246] Referring back to Figure 5, in this embodiment, the therapeutic energy delivery catheter 102 can be connected to the generator 104 together with a dispersed (pair) electrode 140 applied externally to the patient P's skin. Thus, in this embodiment, energy is supplied between the energy delivery body 108, located near the distal end of the catheter 102, and the counter electrode plate 140, thereby achieving unipolar energy delivery. It is understood that bipolar energy delivery and other positioning methods may be used instead, as will be further described herein. In this embodiment, the generator 104 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage / retrieval unit 156 (such as memory and / or a database), and an energy storage subsystem 158. The subsystem 158 is responsible for generating and storing the energy to be delivered. In some embodiments, one or more capacitors are used for energy storage / delivery, but as modern technology develops, any suitable element may be used. Furthermore, one or more communication ports are included.

[0190]

[0247] It should be understood that in some embodiments, the generator 104 comprises three subsystems: 1) a high-energy storage system, 2) a high-voltage, medium-frequency switching amplifier, and 3) system control, firmware, and user interface. The system controller includes a cardiac synchronization trigger monitor that enables the pulse energy output to be synchronized with the patient's cardiac rhythm. The generator takes in an AC (alternating current) mains power supply and powers multiple DC (direct current) power supplies. The generator controller instructs the DC power supplies to charge the high-energy capacitor battery before energy delivery. When initiating therapeutic energy delivery, the generator controller, high-energy storage bank, and biphase pulse amplifier operate simultaneously to generate a high-voltage, medium-frequency output.

[0191]

[0248] The processor 154 may be, for example, a general-purpose processor, a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), or a digital signal processor (DSP). The processor 154 may be configured to execute application processes and / or other modules, processes and / or functions related to system 100, and / or networks related to system 100.

[0192]

[0249] In this specification, the term “module” means any assembly and / or set of electrically connected components, including, for example, memory, processors, electrical traces, optical connectors, and software (executed in hardware). For example, a module executed by a processor may be any combination of hardware-based modules (e.g., FPGAs, ASICs, DSPs) and / or software-based modules (e.g., modules of computer code stored in memory).

[0193]

[0250] The data storage / retrieval unit 156 may be, for example, a random access memory (RAM), a memory buffer, a hard drive, a database, an erasable programmable read-only memory (EPROM), an electrically erasable read-only memory (EEPROM), a read-only memory (ROM), or flash memory. The data storage / retrieval unit 156 can store instructions that cause the processor 154 to execute modules, processes, and / or functions related to the system 100.

[0194]

[0251] In some embodiments, the data storage / retrieval unit 156 includes a computer storage product having a persistent computer-readable medium (also called a persistent processor-readable medium) for storing instructions and computer code corresponding to various computer implementations. The computer-readable medium (or processor-readable medium) is considered persistent because it does not contain transient propagating signals (e.g., propagating electromagnetic waves that carry information in space or on a transmission medium such as a cable). The medium and computer code (also called code) may be designed and constructed for a specific purpose. Examples of persistent computer-readable mediums include, but are not limited to, magnetic storage media such as hard disks, floppy disks, and magnetic tapes; optical storage media such as compact disks / digital video discs (CDs / DVDs), compact disk read-only memory (CD-ROMs), and holographic devices; magneto-optical recording media such as optical disks; and specially configured hardware devices configured to store and execute program code, such as carrier signal processing modules, ASICs, programmable logic devices (PLDs), read-only memory (ROMs), and random access memory (RAM) devices. Other embodiments described herein relate, for example, to computer program products capable of storing instructions and / or computer code described herein.

[0195]

[0252] Examples of computer code include, but are not limited to, microcode or microinstructions, such as machine instructions generated by a compiler, code that generates web services, and files containing high-level instructions that are executed by a computer using an interpreter. For example, embodiments may be implemented using imperative programming languages ​​(e.g., C, Fortran), functional programming languages ​​(e.g., Haskell, Erlang), logic programming languages ​​(e.g., Prolog), object-oriented programming languages ​​(e.g., Java, C++), other suitable programming languages, and / or development tools. Examples of computer code also include, but are not limited to, control signals, encryption code, and compression code.

[0196]

[0253] In some embodiments, the system 100 may be communicably connected to any variety of networks implemented as wired and / or wireless networks, such as a local area network (LAN), wide area network (WAN), virtual network, telecommunications network, data network, and / or the Internet. In some embodiments, communications may be protected by applying secure communications of an appropriate type and / or method (e.g., Secure Sockets Layer (SSL)) and / or encryption. In other embodiments, any or all communications may not be protected.

[0197]

[0254] The user interface 150 may include a touchscreen and / or physical buttons that allow the operator to input patient data, select a treatment algorithm (i.e., an energy delivery algorithm 152), initiate energy delivery, view records stored in the memory / retrieval unit 156, or otherwise communicate with the generator 104.

[0198]

[0255] Any of the systems disclosed herein may include a user interface 150 configured to accept operator-defined inputs. Operator-defined inputs may include energy delivery pulses, power, target temperature, operating mode, or a combination thereof, during or at any other point in time. For example, various operating modes may include system startup and self-test, operator input, algorithm selection, pre-treatment system state and feedback, energy delivery, post-energy delivery display and feedback, treatment data management and / or download, software updates, or a combination thereof.

[0199]

[0256] In some embodiments, the system 100 also includes a mechanism for acquiring an electrocardiogram (ECG), such as an external cardiac monitor 170. Examples of cardiac monitors are available, for example, from AccuSync Medical Research. In some embodiments, the external cardiac monitor 170 is operably connected to the generator 104. Here, the ECG is acquired continuously using the cardiac monitor 170. Alternatively, the ECG may be acquired by attaching an external electrode 172 to the patient P. The generator 104 analyzes one or more cardiac cycles to identify the starting point of a period in which it is safe to apply energy to the patient P, thereby synchronizing the energy delivery with the cardiac cycle. In some embodiments, this period is within milliseconds of the R wave to avoid the risk of arrhythmias that may occur if the energy pulse is delivered on the T wave. It will be understood that such cardiac synchronization is typically used when applying unipolar energy delivery, but may be used in other cases.

[0200]

[0257] In some embodiments, the processor 154 modifies and / or switches energy delivery algorithms, monitors energy supply and arbitrary sensor data, and responds to monitored data via a feedback loop. In some embodiments, the processor 154 is configured to execute one or more algorithms that perform a feedback control loop based on one or more measurement system parameters (e.g., current), one or more measurement tissue parameters (e.g., impedance), and / or a combination thereof.

[0201]

[0258] The data storage / retrieval unit 156 stores data related to the delivered treatment. Optionally, a device (e.g., a laptop or thumb drive) can be connected to the communication port to download this data. In some embodiments, the device has local software that instructs the download of information, such as instructions stored in the data storage / retrieval unit 156 and executable by the processor 154. In some embodiments, the operator can select data downloads targeting devices and / or systems such as (but not limited to) computer devices, tablets, mobile devices, servers, workstations, and cloud computing devices / systems via the user interface 150. Data downloads are possible via the communication port, which allows for wired and / or wireless connections, as described above, and data uploads, such as custom algorithm uploads and software updates, are also possible.

[0202]

[0259] As described above, various energy delivery algorithms 152 can be programmed into the generator 104, or they can be pre-programmed, such as by storing them in memory or the data storage / retrieval unit 156. Alternatively, the energy delivery algorithms may be added to the data storage / retrieval unit and executed by the processor 154. Each of these algorithms 152 is executable by the processor 154. Examples of algorithms are described in more detail below. In some embodiments, the catheter 102 includes one or more sensors 160 used, for example, to determine temperature, impedance, resistance, capacitance, conductivity, dielectric constant, and / or conductivity. Sensor data can be used for treatment planning, treatment monitoring, and / or direct feedback via the processor 154 to modify the energy delivery algorithm 152. For example, impedance measurement is used not only to determine the initial dose to be applied, but also to determine the need for further treatment.

[0203]

[0260] Any of the systems disclosed herein may include an automated treatment delivery algorithm that can dynamically determine whether to adjust and / or discontinue the treatment plan in response to inputs such as temperature, impedance, treatment duration or temporal aspects of energy delivery pulses, therapeutic capacity and / or system status.

[0204]

[0261] In some embodiments, imaging can be performed using a commercially available system, such as a bronchoscope 112 connected to a separate imaging screen 180, as illustrated in Figure 5. The imaging device may be incorporated into the catheter 102 or used together with the catheter 102. The imaging device may be mechanically, operably, and / or communicatively connected to the catheter 102 using an appropriate mechanism.

[0205]

[0262] Figure 7 is a schematic diagram of one embodiment of the lung tissue modification system 100. In this embodiment, the catheter 102 is configured for unipolar energy delivery. As shown, a dispersed (neutral) electrode or counter electrode plate 140 is operably connected to the generator 104 while fixed to the patient's skin and serves as the return path for energy delivered through the catheter 102. The energy delivery catheter 102 includes one or more energy delivery bodies 108 (including electrodes), one or more sensors 160, one or more imaging devices 162, one or more buttons 164, and / or positioning mechanisms 166 (e.g., levers and / or dials on a handle with a pull wire, nesting tubes, sheaths, etc.). One or more energy delivery bodies 108 are in contact with the tissue. In some embodiments, a foot switch 168 is operably connected to the generator 104 and used to initiate energy delivery.

[0206]

[0263] As described above, the user interface 150 may include a touchscreen and / or physical buttons that allow the operator to input patient data, select an energy delivery algorithm 152, start energy delivery, view records stored in the memory / retrieval unit 156, or perform other communications with the generator 104. The processor 154 manages and executes the energy delivery algorithm, monitors energy supply and sensor data, and responds to monitoring data via a feedback loop. The data memory / retrieval unit 156 stores treatment-related data. When a device (e.g., a laptop or thumb drive) is connected to the communication port 167, data can be downloaded from the data memory / retrieval unit 156.

[0207]

[0264] The catheter 102 is operably connected to the generator 104 and / or a separate imaging screen 180. The imaging device 162 may be incorporated into the catheter 102 or used together with the catheter 102. Alternatively, or in addition to, a separate imaging device or imaging apparatus 169, such as a commercially available system (i.e., a bronchoscope), may be used. The separate imaging apparatus 169 may be mechanically, operably, and / or communicatively connected to the catheter 102 using an appropriate mechanism.

[0208]

[0265] As shown in Figure 8A, the bronchoscope 112 is inserted into the oral cavity (OC) of patient P. Methods of accessing the airway also include the use of other openings, such as the nose or nasal cavity (NC) (Figure 8B). Alternatively, an appropriate artificial opening may be used (not shown; e.g., stoma, tracheostomy). The use of the bronchoscope 112 allows for direct visualization of the target tissue. Using the working channel of the bronchoscope 112, the catheter 102 can be advanced according to the apparatus and systems disclosed herein, and the placement of the catheter can be visually confirmed. Figures 8A and 8B illustrate the introduction of the catheter 102 into the distal trachea (T) and main bronchus (MB), but the catheter 102 may also be inserted into the femoral bronchus (LB), distal segmental bronchus (SB), or subsegmental bronchus (SSB) as needed.

[0209]

[0266] Figures 9-11 show the distal end of the catheter 102 positioned within the main bronchus MB for airway treatment. In some embodiments, the catheter 102 has a non-traumatic tip 125 or so that it can advance through the airway without damaging the airway wall W. Figure 9 illustrates the catheter 102 advancing within the main bronchus MB while the sheath 126 covers the energy delivery body 108. Positioning of the catheter 102 may be assisted by various imaging techniques. For example, a bronchoscope 112 may be used to provide real-time direct visual guidance to the target site, and the precise positioning of the catheter 102 may be observed before, during, and after treatment. Figure 10 illustrates the case where the sheath 126 is withdrawn to expose the energy delivery body 108. Naturally, in some embodiments, the energy delivery body 108 is self-expanding, so the sheath 126 holds the energy delivery body 108 in a folded state. In this embodiment, when the sheath 126 is withdrawn and the energy delivery body 108 is released, the energy delivery body can self-expand. In other embodiments, the energy delivery body 108 is expanded by other mechanisms, such as the movement of a knob 132, after the sheath 126 is withdrawn. Figure 11 illustrates an expandable cage-type energy delivery body 108, which contacts the airway wall W. Positioning may be verified by further imaging and / or additional measurements (e.g., depth) may be performed.

[0210]

[0267] Once the energy delivery body 108 is positioned in the desired location, therapeutic energy is supplied to the airway wall W by the energy delivery body 108. The therapeutic energy is applied according to at least one energy delivery algorithm.

[0211]

[0268] In some embodiments, the user interface 150 of the generator 104 allows the selection of a desired treatment algorithm 152. In other embodiments, the algorithm 152 is automatically selected by the generator 104 based on information obtained by one or more sensors attached to the catheter 102. Details are described below. Here, a variety of energy delivery algorithms may be used. In some embodiments, the algorithm 152 generates a signal having a waveform that includes a series of energy packets with a pause period between each packet, and each energy packet includes a series of high-voltage pulses. In some embodiments, each high-voltage pulse is approximately 500V to 10kV, or approximately 500V to approximately 5000V, and all values ​​within this range can be applied. In some embodiments, the frequency of the supplied energy is in the range of approximately 10kHz to approximately 10MHz, or approximately 100kHz to approximately 1MHz, and all values ​​within this range can be applied. The algorithm 152 delivers energy to the airway wall to perform the desired treatment with minimal tissue heating, or without any tissue heating. In some embodiments, a temperature sensor measures the electrode and / or tissue temperature during treatment to ensure that the accumulated energy in the tissue is not sufficient to induce clinically significant tissue heating. For example, the temperature sensor monitors the temperature of the tissue and / or electrode. If a predetermined threshold temperature is exceeded (e.g., 65°C), the generator modifies its algorithm to automatically stop the energy supply or lower the temperature below the set threshold. Furthermore, if the temperature exceeds a predetermined threshold (e.g., 65°C), the generator reduces the pulse width or extends the time between pulses and / or packets. The above is an example of a process that can be implemented by a predetermined stepwise approach that considers the percentage of parameters, or by other means.

[0212]

[0269] Conventional radiofrequency ablation (RFA) uses high-frequency alternating current in the 350-550 kHz range to kill cells and cause thermal necrosis of cells by generating heat in the tissue. Many RFA devices have been developed for the treatment of cardiac arrhythmias, solid tumors, and renal nerves. Microwave ablation is a type of thermal ablation that uses alternating current in the 300 MHz-300 GHz range, and this also causes thermal necrosis of cells. Due to the size of the ablation zone and uniform heating, the energy source is used in the treatment of solid tumors. In general, thermal ablation denatures proteins in tissue, causing a significant inflammatory response, is difficult to control, and often damages non-target tissues. In certain treatments (e.g., tumor treatment), inflammation is within acceptable limits, but when the focus is on the pulmonary airways, inflammation can lead to serious complications (e.g., exacerbation). It is unclear how protein denaturation affects clinical morbidity, but intact, undenatured proteins are likely to enhance the host's response to various attacks on the immune system, regardless of their impact on pathogens or tumors. Because of these limitations, thermal cauterization, especially of the airways, is not particularly desirable.

[0213]

[0270] Conversely, algorithm 152 can deliver non-thermal energy to the airway wall W, thereby reducing or avoiding inflammation. In some embodiments, algorithm 152 is modified to affect tissue to a predetermined depth and / or target specific cells within the airway wall. In some embodiments, the generator has unique algorithm settings, where the target cell depth is reflected in each setting. For example, one setting / algorithm primarily affects pathogens present in the mucus layer, another setting / algorithm targets epithelium, yet another setting / algorithm primarily targets epithelium, basement membrane, submucosa, and / or smooth muscle. Yet another setting / algorithm primarily targets epithelium, basement membrane, submucosa, smooth muscle, submucosal glands, and / or nerves. In some embodiments, treatment is performed in the same location, but in other embodiments, the operator may choose to treat specific cell types in different locations. The settings utilized by the operator may depend on the physiological nature of the patient's condition.

[0214]

[0271] The biological mechanisms and cellular processes by which Energi removes cells will be described in more detail in later sections. Energi treats the airway wall W at the target location and regenerates healthy tissue. For example, it regenerates normal goblet cells GC and normal stratified ciliated columnar epithelial cells PCEC, inducing reverse remodeling of the disease and reducing excessive mucus secretion. Newly regenerated goblet cells GC have very low mucus productivity. Newly regenerated stratified ciliated columnar epithelial cells PCEC regenerate normally functioning cilia C, making it easier to expel mucus M. Thus, normal healthy tissue is regenerated within a few days of treatment. This dramatically reduces the patient's symptoms such as cough and excessive mucus secretion, resulting in fewer exacerbations and an improved quality of life.

[0215]

[0272] Figure 12 is a flowchart illustrating the method described herein by a stepwise approach to treating a patient. This method can be performed by a practitioner, a therapeutic energy delivery catheter, or a generator, as needed. In some embodiments, one or more steps disclosed herein may be optional. A first set of steps may be used to assess the patient's anatomical structure and / or suitability of the procedure for determining whether the procedure is appropriate. In some embodiments, the assessment is optional and may include one or more of the following steps: First, access the airway (if necessary) (300) (if necessary); then, perform any appropriate pre-procedure imaging, sputum sampling, and / or biopsy as needed and / or desired (301). Pre-procedure imaging may include non-invasive CT scans, bronchoscopy, confocal laser endoscopy (CLE), optical coherence tomography (OCT), or any appropriate technique, as well as any measurements (e.g., depth). Sputum sampling includes nasal mucosal brushing, nasal lavage, bronchial brushing, bronchial lavage, and / or bronchoalveolar lavage. The need for treatment for the patient is then determined. If the determination is "No" (302), proceed to termination (322). If the determination is "Yes" (303), access is obtained if necessary (304). In some embodiments, the procedure is performed at least one day after the pre-treatment assessment. In this embodiment, access is required (304).

[0216]

[0273] In some embodiments, the treatment is performed immediately after the pre-treatment assessment. In this embodiment, no further access is required. In this embodiment, the next step 305 of the treatment is to introduce the catheter. As described above, the catheter may be introduced in various ways, but exemplarily, the catheter is transported through the working channel of the bronchoscope. In the next step 306, the catheter is positioned at the target site. Also, as an example, the bronchoscope is used to provide real-time direct visual guidance to the target site and to observe the precise positioning of the catheter. This involves positioning one or more energy deliverers so as to be in contact with the airway wall. Then, additional imaging (307) can be used to verify the positioning and / or to create additional measurements (e.g., depth). In the next step 308, the operator can also select a desired energy delivery algorithm 152. As described in detail above, this includes an example based on the target treatment depth. Alternatively, the generator is configured to apply a predefined algorithm suitable for most patients. In this embodiment, the next step 309 is to execute or apply the energy delivery algorithm, which is used here via a foot pedal or other mechanism described herein. After energy application, the operator can evaluate the energy application (310). This may include performing additional imaging, with or without measurement, and / or responding to messages transmitted by the generator (e.g., errors in energy delivery that may result in incomplete treatment). If treatment is not acceptable (311), the operator returns to the target site positioning step 306. If treatment is acceptable (312), the operator proceeds to the next step. The next step in the procedure is to determine whether more treatment sites need to be treated. If "No" (313), the operator then proceeds to the final imaging (315) and completes the remaining steps (322). If "Yes" (314), the operator repositions to the next target site (316) and repeats the treatment steps.Once all treatment is complete, the operator proceeds to an optional final imaging (315), where the operator can review the imaging to confirm that all target areas have been satisfactorily treated. If “No” (317), the operator returns to “repositioning to the next target site” (316) to perform additional treatment. If “Yes” (318), the operator decides whether to take one or more immediate biopsies and / or sputum samples (319) for comparison with any pre-treatment biopsies and / or sputum samples (301) obtained. Follow-up images and / or biopsies and / or sputum samples may be obtained at a later date (320) and compared with other images, biopsies and / or sputum samples to aid in the evaluation and / or documentation of the treatment outcome. The operator may then administer substances or activators to support the normative healing process (321), thereby further reducing the possibility of treatment problems or complications. This may also further reduce the degree and frequency of exacerbations, particularly in the short term. Some examples of these drugs include isotonic saline gels, medicated films, antibacterial agents, antiviral agents, antifungal agents, and anti-inflammatory agents. As a result of exposing the tissue to a high-energy field, the treated tissue can be modified to improve drug uptake. The procedure is then completed (322). The patient continues to follow the doctor's instructions, and if the disease or disorder recurs and / or persists, the entire procedure may be repeated.

[0217]

[0274] Therefore, in certain embodiments where the desired clinical effect was not obtained or was obtained but symptoms recurred after treatment, it is desirable to repeat the procedure. In these embodiments, it may be preferable not only to re-treat a specific area, but also to target a different part of the anatomical structure of the lung. Thus, the system 100 may be used to re-treat the same tissue portion as the original treatment site, or a tissue portion that is clearly different from the initial intervention.

[0218]

[0275] While various embodiments have been described above, please understand that these are presented as examples only and not limitations. If the above method is considered to perform specific events in a specific order, the order of those events may be changed. Furthermore, the specific events may be executed simultaneously in parallel processes if possible, or they may be executed sequentially as described above.

[0219] II. Energy Delivery Algorithms

[0276] As described above, one or more energy delivery algorithms 152 may be programmed into the generator 104 to deliver energy to the patient P, or they may be pre-programmed. One or more energy delivery algorithms 152 specify an electrical signal that supplies non-thermal energy to be delivered to the airway wall W for the purpose of reducing or avoiding inflammation. Generally, the algorithms 152 are adjusted to affect tissue to a predetermined depth and / or target specific cells within the airway wall. The depth and / or targeting depends on the parameters of the energy signal defined by one or more energy delivery algorithms 152, the design of the catheter 102 (particularly one or more energy delivery bodies 108), and / or the choice of unipolar or bipolar energy delivery. In one example, bipolar energy delivery can achieve therapeutic effects at lower voltages compared to unipolar energy delivery. In a bipolar configuration, the positive and negative electrodes are close enough to each other to produce therapeutic effects both at the electrodes and between the electrodes. Compared to unipolar, the therapeutic effect can be spread over a larger surface area and can produce therapeutic effects at lower voltages. Similarly, low voltage can reduce penetration depth, affecting epithelial cells rather than submucosal cells. In addition, if the supply voltage is low enough to avoid stimulating cardiomyocytes, cardiac synchronization becomes unnecessary.

[0220]

[0277] Naturally, various energy delivery algorithms 152 may be used. In some embodiments, algorithm 152 defines a signal having a waveform comprising a series of energy packets, each energy packet comprising a series of high-voltage pulses. In such embodiments, algorithm 152 specifies signal parameters such as the duration and energy amplitude (e.g., voltage) of the applied energy, including, for example, the number of packets, the number of pulses in each packet, and the frequency of each pulse. There may be a fixed pause between packets, and the packets may be gated to the cardiac cycle and vary according to the patient's heart rate. A feedback loop based on sensor information and automatic shutdown specifications may also be included.

[0221]

[0278] Figure 13 shows one embodiment of the signal waveform 400 defined by the energy delivery algorithm 152. Here, two packets, namely a first packet 402 and a second packet 404, are shown, separated by a pause period 406. In this embodiment, each packet 402, 404 has a first two-phase pulse (including a first positive peak 408 and a first negative peak 410) and a second two-phase pulse (including a second positive peak 408' and a second negative peak 410'). The first and second two-phase pulses are separated by a dead time 412 (i.e., a pause) between each pulse. In this embodiment, since the two-phase pulses are symmetric, the set voltage 416 is the same for the positive and negative peaks. Here, the two-phase symmetric wave is also a square wave, and the magnitude and time of the positive voltage wave are approximately equal to the magnitude of the negative voltage wave. The positive voltage wave causes depolarization of cells, which are normally negatively charged, to temporarily become positive. Negative voltage waves cause cellular hyperpolarization, where the cell potential is negative.

[0222]

[0279] In some embodiments, each high-voltage pulse or set voltage 416 is between approximately 500V and 10kV, particularly between approximately 500V and 4000V, encompassing all values ​​and subranges in between. In some embodiments, each high-voltage pulse is generally between approximately 1000V and 2500V, penetrating the airway wall W, and treating or acting on specific cells, such as epithelial cells, at a relatively shallow level. In some embodiments, each high-voltage pulse is generally between approximately 2600V and 4000V, penetrating the airway W, and treating or acting on specific cells located at a slightly deeper level, such as submucosal cells or smooth muscle cells. The set voltage 416 varies depending on whether the energy delivery method is unipolar or bipolar. In some embodiments, energy is delivered unipolarly, and each high-voltage pulse is between approximately 2000V and 3500V, more specifically 2500V. In the case of bipolar delivery, lower voltages are used due to the small directed electric field. In some embodiments, energy is delivered in a bipolar manner, with each pulse being approximately 100V to 1900V, specifically 100V to 999V, and more specifically approximately 500V to 800V, such as 500V, 550V, 600V, 650V, 700V, 750V, and 800V.

[0223]

[0280] In some embodiments, the set voltage 416 is approximately 50V to approximately 4kV, or approximately 500V to approximately 4kV, including all values ​​and subranges in between. In other embodiments, the set voltage 416 is approximately 500V to approximately 5kV, including all values ​​and subranges in between.

[0224]

[0281] The number of pulses per unit time is called frequency. In some embodiments, the signal has a frequency of 100 kHz to 1 MHz. In some embodiments, the signal has a frequency of approximately 100 to 500 kHz, which typically penetrates the airway W, and treats or acts on specific cells located somewhat deeper, such as submucosal cells or smooth muscle cells. In some embodiments, the signal has a frequency of approximately 600 kHz to 1 MHz, which typically penetrates the airway wall W, and treats or acts on specific cells somewhat shallowly, such as epithelial cells. Frequencies below 300 kHz may result in undesirable muscle stimulation. Therefore, in some embodiments, the signal has a frequency of 500 to 800 kHz, for example, 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, and 800 kHz. In particular, in some embodiments, the signal has a frequency of 600 kHz. In addition, cardiac synchronization is usually aimed at reducing or avoiding undesirable myocardial stimulation. In some embodiments, biphasic pulses are aimed at reducing undesirable muscle stimulation, especially myocardial stimulation. Higher frequencies may be used if there are components that minimize signal artifacts.

[0225]

[0282] In some embodiments, the time between packets, i.e., the pause period 406, is set to approximately 0.1 seconds to approximately 5 seconds, encompassing all values ​​and subranges within that period. In other embodiments, the pause period 406 is approximately 0.001 seconds to approximately 10 seconds, encompassing all values ​​and subranges within that period. In some embodiments, the pause period 406 is approximately 1 second. Specifically, in some embodiments, the signal is synchronized to the heart rhythm, and each packet is delivered between heartbeats, so the pause period coincides with the heartbeat. In other embodiments utilizing cardiac synchronization, the pause period between packets is affected by cardiac synchronization, as described in later sections, so the pause period 406 also changes.

[0226]

[0283] Cycle count 420 is the number of pulses within each packet. Referring to FIG. 13, in some embodiments where the first packet 402 has a cycle count 420 of 2 (i.e., having two biphasic pulses), the cycle count 420 is set to 1 to 100 for each packet, including all values and sub-ranges therebetween. In some embodiments, the cycle count 420 is up to 5 pulses, up to 10 pulses, up to 25 pulses, up to 40 pulses, up to 60 pulses, up to 80 pulses, up to 100 pulses, up to 1000 pulses, or up to 2000 pulses, including all values and sub-ranges therebetween.

[0227]

[0284] The packet period is determined by the cycle count. The more the cycle count, the longer the packet period and the more the supply energy amount. In some embodiments, the packet period is about 50 to 100 microseconds, such as 50 microseconds, 60 microseconds, 70 microseconds, 80 microseconds, 90 microseconds, or 100 microseconds.

[0228]

[0285] The number of delivery packets or packet count during treatment is 1 packet, 2 packets, 3 packets, 4 packets, 5 packets, 10 packets, 15 packets, 20 packets, up to 5 packets, up to 10 packets, up to 15 packets, up to 20 packets, up to 100 packets, or up to 1000 packets, including all values and sub-ranges therebetween. In some embodiments, the number of delivery packets is 5, and each packet has a packet duration of 100 microseconds and a set voltage of 2500V. In some embodiments, the number of delivery packets is 5 to 10, and each packet has a packet duration of 100 microseconds and a set voltage of 2500V. Thereby, the uniformity of the treatment effect is improved. In some embodiments, the number of delivery packets is less than 20, and each packet has a packet duration of 1 microsecond and a set voltage of 2500V. Thereby, the influence on the cartilage layer CL is avoided. In some embodiments, the set voltage is 2500V, and the total energy delivery period is 0.5 to 100 milliseconds, which is optimal for the treatment effect.

[0229]

[0286] In some embodiments, the dead time 412 is set to be about 0 to about 500 nanoseconds, including all values and sub-ranges therebetween. In other embodiments, the dead time 412 is about 0 to 10 microseconds, about 0 to about 100 microseconds, about 0 to about 100 milliseconds, including all values and sub-ranges therebetween. In some embodiments, the dead time 412 is 0.2 to 0.3 microseconds.

[0230]

[0287] Specific settings aimed at desired changes in the target tissue depend on each other and on the electrode design. Thus, the embodiments described herein show exemplary waveforms, and using multiple waveforms and / or characteristics in any combination to obtain a desired tissue effect is within the scope of the present invention. A first exemplary combination of parameters for the energy signal is a frequency of 600 kHz, a voltage of 3000 V, and a number of packets of 10. A second exemplary combination of parameters for the energy signal is a frequency of 600 kHz, a voltage of 2500 V, and a number of packets of 5. A third combination of exemplary parameters for the energy signal is a frequency of 600 kHz, a voltage of 2300 V, and a number of packets of 20. In the first example, due to the high voltage, the therapeutic effect on the epithelium and submucosal tissue was enhanced. In the second example, due to the low voltage and the small number of packets, the therapeutic effect on the epithelium and submucosal tissue was small. In the third example, due to the large number of packets and the low voltage, the therapeutic effect on the epithelium was enhanced and the therapeutic effect on the submucosal tissue was reduced. This supports that a low voltage cannot penetrate as deeply as a high voltage to have a similar therapeutic effect on the submucosal gland.

[0231]

[0288] Figure 14 shows an example of a signal waveform 400 defined by another energy delivery algorithm 152. Here, two packets, namely a first packet 402 and a second packet 404, are shown, separated by a pause period 406. In this embodiment, each packet 402, 404 has a first two-phase pulse (including a first positive peak 408 and a first negative peak 410) and a second two-phase pulse (including a second positive peak 408' and a second negative peak 410'). The first and second two-phase pulses are separated by a dead time 412 between each pulse. In this embodiment, since the waveform 400 is asymmetric, the set voltages are different for the positive and negative peaks. Asymmetric waveforms result in a more consistent therapeutic effect because the dominant positive or negative amplitude maintains the same charge cell membrane charge potential for a longer period. In this embodiment, the first positive peak 408 has a set voltage 416 that is greater than the set voltage 416' of the first negative peak 410. In some embodiments, the asymmetry further includes pulses with different pulse widths. In some embodiments, because the two-phase waveform is asymmetric, the voltage in one direction (i.e., positive or negative) is greater than the voltage in the other direction, while calculating the pulse length results in a smaller area under the depolarization curve, equal to the area under the hyperpolarization curve. Alternatively, the areas under the depolarization and hyperpolarization curves do not have to be equal.

[0232]

[0289] Figure 15 shows an example of a signal waveform 400 defined by another energy delivery algorithm 152. Similarly, two packets, namely a first packet 402 and a second packet 404, are shown, separated by a pause period 406. In this embodiment, each packet 402, 404 has a first single-phase pulse 430 and a second single-phase pulse 432. The first and second single-phase pulses 430, 432 are separated by a dead time 412 between each pulse. A single-phase waveform yields a more desirable therapeutic effect because the same charge cell membrane potential is maintained for a longer period. However, adjacent muscle groups are stimulated more strongly by a single-phase waveform than by a two-phase waveform.

[0233]

[0290] Figure 16 shows an example of a signal waveform 400 defined by another energy delivery algorithm 152. Similarly, two packets, namely the first packet 402 and the second packet 404, are shown, separated by a pause period 406. In this embodiment, each packet 402, 404 contains three two-phase pulses 440, 442, and 444. Furthermore, pulses 440, 442, and 444 are sinusoidal rather than square. Sinusoidal waves have the advantage of being symmetrical. Symmetry helps reduce unwanted muscle stimulation.

[0234]

[0291] Energy delivery can be performed by the activation of various mechanisms, such as a button 164 on the catheter 102 or a foot switch 168 operably connected to the generator 104. Such activation typically provides an equal amount of energy. The amount of energy is determined by the number of delivery packets and the packet voltage. Each amount of energy supplied to the airway wall W maintains the temperature inside and outside the wall W below the threshold for thermal ablation, particularly the threshold for thermal ablation of the basement membrane BM. Furthermore, the amount of energy may be gradually increased or decreased over time to further reduce or eliminate heat buildup during the treatment procedure. The amount of energy is provided at a level that induces biological and cellular effects, which ultimately lead to the regeneration of healthy tissue, rather than inducing thermal effects.

[0235] III. Biological Mechanisms and Cellular Effects

[0292] As described above, the algorithm delivers energy to the airway wall W at a level that induces biological mechanisms and cellular effects while reducing or avoiding inflammation. Exemplary biological mechanisms and cellular processes are described herein, but are not limited to these examples.

[0236]

[0293] The energy supplied to the airway wall W ultimately triggers various cellular effects that lead to the regeneration of healthy lung airway tissue. Examples of cellular effects include the removal of specific cell types through cell separation from the airway wall W (which may be carried away naturally or intentionally) or cell death (e.g., lysis and apoptosis). Other cellular effects may include the modification of specific cell types without removal, such as cell reprogramming or cell modification aimed at uptake of improving agents.

[0237]

[0294] In some embodiments, specific cells are removed by cell separation from the airway wall W. Figure 17 shows an embodiment in which energy (arrow 200) is supplied to the airway wall W by one or more energy deliverers. In this embodiment, the energy 200 has a target cell depth set to affect the epithelial layer E without spreading beyond the basement membrane BM. The energy 200 is configured to separate specific epithelial cells, in this case stratified ciliated columnar epithelial cells PCEC and goblet cells GC, from the remaining epithelial layer (e.g., basal cells BC) and / or the basement membrane BM. The separated cells are free to move within the lung passage and are removed by natural elimination processes or by interventional methods such as aspiration.

[0238]

[0295] In other embodiments, specific cells are removed by cell death, and affected cells are killed by lysis or apoptosis, ultimately removing them from the airway wall W. Figure 18 shows an embodiment in which energy 202 is delivered to the airway wall W by one or more energy deliverers, and the energy 202 has a target cell depth set so that it affects the epithelial layer E without spreading beyond the basement membrane BM. However, in this embodiment, the energy 202 is configured to kill specific epithelial cells, here polystratified ciliated columnar epithelial cells PCEC and goblet cells GC (see dashed line), while retaining other cells (e.g., basal cells BC). The mechanisms that lead to cell death are diverse. For example, in some embodiments, cell death occurs by disruption of the cell membrane. In this embodiment, the delivered energy disrupts the lipid bilayer of the cell membrane so that the cell membrane cannot maintain its barrier function. Without the plasma membrane, the cell cannot properly maintain intracellular concentrations of sodium, potassium, calcium, and adenosine triphosphate (ATP). As a result, the cell loses homeostasis and dies. In some embodiments, cell death occurs through the destruction of organelles. In these embodiments, delivered energy permanently impairs the function of organelles, including the endoplasmic reticulum, Golgi apparatus, mitochondria, nucleus, and nucleolus. If these organelles are unable to function properly, the cell dies. In one example, it can be understood that both the cell membrane and organelles are targets of delivered energy. Therefore, if delivered energy has only a partial effect on the cell membrane or organelles, the cumulative effect on both targets will ultimately lead to cell death.

[0239]

[0296] Following cell death, an inflammatory cascade occurs. Cell fragments and intracellular contents signal leukocytes and macrophages to enter the affected area of ​​the airway wall. Over several hours to several days, dead cells are removed from the area by phagocytosis. Unlike thermal ablation, which damages the extracellular matrix, phagocytosis is limited to cellular debris and not to collagen or matrix components of the extracellular matrix.

[0240]

[0297] In some embodiments, specific cells are not removed; rather, target cells are modified or affected, such as through reprogramming. For example, in some embodiments, the ability to secrete or produce accumulated mucus is altered in goblet cells (GC). Alternatively, modification restores the function of cilia C in stratified ciliated columnar epithelial cells (PCEC), allowing for better mucus expulsion into the airway. In other embodiments, stratified ciliated columnar epithelial cells (PCEC) and goblet cells (GC) remain unchanged, but deeper structures are primarily affected, resulting in effects such as reduced smooth muscle hypertrophy and neutralization of chronic inflammatory cells and eosinophils.

[0241]

[0298] Regardless of whether cell removal or cell modification is performed, the airway wall W regenerates and restores normal function. In one case, epithelial cells regenerate to their pre-treatment state, but deep-layer cells, including smooth muscle SM, eosinophils, submucosal gland SG, and chronic inflammatory cells, are permanently reduced.

[0242]

[0299] As described above, algorithms can be adjusted to affect a predetermined depth of tissue and / or target specific cell types within the airway wall. For example, various algorithms may specifically target the mucus layer M, epithelial layer E, basement membrane BM, lamina propria LP, smooth muscle cells SM, submucosa, submucosal glands SG, nerves N, or combinations thereof. In one embodiment, the algorithm is configured to generate energy that penetrates from the epithelial layer E to the basement membrane BM of the airway wall W. In this embodiment, various cell types are targeted. For example, the energy may be configured to remove stratified ciliated columnar epithelial cells PCEC and goblet cells GC, leaving basal cells BC intact. In this embodiment, the airway wall W has dysfunctional stratified ciliated columnar epithelial cells PCEC and hyperplastic goblet cells GC, which cause excessive mucus secretion. The delivered energy removes the abnormal stratified ciliated columnar epithelial cells PCEC and goblet cells GC by cell death or detachment, while leaving the basal cells BC intact along the basement membrane BM. It should be noted that stratified ciliated columnar epithelial cells (PCECs) and goblet cells (GCs) are linked by tight junctions (TJs) and adherent junctions (AJs). Furthermore, stratified ciliated columnar epithelial cells (PCECs) and goblet cells (GCs) are linked to basal cells (BCs) by adhesion plaques (Ds). In some embodiments, the energy punches through the tight junctions (TJs) and adherent junctions (AJs), as well as the adhesion plaques (Ds), removing the stratified ciliated columnar epithelial cells (PCECs) and goblet cells (GCs). Similarly, the energy may be configured to retain hemiadhesion plaques (Hs) linking basal cells (BCs) to the basement membrane (126). Thus, basal cells (BCs) remain intact.

[0243]

[0300] Removal of pseudostratified ciliated columnar epithelial cells (PCECs) and goblet cells (GCs) can reduce mucus production and secretion through various mechanisms. For example, this removal weakens the signaling mechanisms that lead to the expression of proteins found in mucin, thereby reducing mucus production. In particular, Muc5ac is a protein found in the mucin of airway goblet cells (GCs) and is encoded by the MUC5AC gene. Various ligands and transcription factors are involved in Muc5ac expression. Interleukin-13 binds to a receptor containing the interleukin-4Rα subunit, activating Januskina 1 (Jak1) and causing phosphorylation of Stat6. Although MUC5AC and the Muc5ac promoter do not share a common Stat6 binding site, Stat6 activation leads to increased expression of SPDEF (SAM peak domain-containing Ets transcription factor), upregulating several genes involved in mucosal metaplasia and inhibiting Foxa2 expression. As a result, Muc5ac is negatively regulated. Ligands including epidermal growth factor, transforming growth factor α, amphiregulin, and neuregulin bind to the ErbB receptor, which activates mitogen-activated protein kinase (MAPK). Oxygen-inducible factor 1 (HIF-1) is also activated downstream of the ErbB receptor. The HIF-1 binding site is conserved in the proximal MUC5AC and Muc5ac promoters. Signaling at complement C3 and β2-adrenergic receptors also amplifies Muc5ac production. Transcription factors such as Sox2, Notch, E2f4, and Math primarily regulate expression.

[0244]

[0301] When pseudostratified ciliated columnar epithelial cells (PCECs) and goblet cells (GCs) are removed by cell death or exfoliation, the signaling mechanism that leads to Muc5ac expression is weakened. As a result, mucus is not produced, and airway mucus decreases. This may be beneficial for patients with COPD (chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, acute bronchitis, or other lung diseases or lung disorders.

[0245]

[0302] The removal of epithelial cells also reduces mucus secretion through various mechanisms. In particular, the removal of mucus-producing goblet cells (GCs) leaves no cells that secrete mucus into the airways. Mucus secretion is triggered by the molecular mechanism of mucin exocytosis. Mucin-containing secretory granules dock to the plasma membrane through the interaction of an effector protein, which acts as a tether to Munc18, which binds the closed conformation of syntaxin fixed to the plasma membrane, and a granule-binding Rab protein. Secretion is triggered when ATP binds to the P2Y2 purinergic receptor (P2Y2R) bound to Gq, activating phospholipase C (PLC), resulting in the production of the secondary messengers diacylglycerol (DAG) and inositol triphosphate (IP3). DAG can activate Munc1314 to open syntaxin, forming a 4-helix SNARE (soluble N-ethylmaleimide-sensitive factor-binding protein receptor) complex with SNAP-23 (synaptosome-associated protein 23) and VAMP (vesicle-associated membrane protein), which pulls the granules and plasma membrane together. IP3 induces calcium release from the IP3 receptor (IP3R) in the endoplasmic reticulum (ER), activating synaptotagmin to induce the final coil formation of the SNARE complex, resulting in membrane fusion and mucin release.

[0246]

[0303] Removing epithelial cells weakens the signaling mechanism that causes mucin exocytosis. As a result, less mucus is secreted, and the amount of mucus in the airways decreases. This may be beneficial for patients with COPD (chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, acute bronchitis, and other lung diseases or lung disorders.

[0247]

[0304] In some embodiments, basal cells BC left on the basement membrane BM can regenerate normal goblet cells GC and normal stratified ciliated columnar epithelial cells PCEC, thereby triggering reverse remodeling of the disease and reducing mucus overproduction. In some embodiments, stratified ciliated columnar epithelial cells PCEC further proliferate by migrating from the surrounding region of the airway wall W, assisting in the regeneration of healthy tissue in the target region. Goblet cells GC typically regenerate at a lower level compared to the mild, moderate, or severe goblet cell hyperplasia present before energy application. Newly regenerated goblet cells GC have very low mucus productivity. Newly regenerated stratified ciliated columnar epithelial cells PCEC regenerate normally functioning cilia C, making mucus M easier to expel. As a result, normal healthy tissue is regenerated within days of treatment, dramatically reducing symptoms such as cough and mucus overproduction in the patient, resulting in fewer exacerbations and an improved quality of life.

[0248]

[0305] In other embodiments, the energy may be configured to target abnormal goblet cells (CG) that are removed by cell death or shedding, leaving goblet cells (PCEC) and basal cells (BC) intact. The removal of abnormal goblet cells (CG) results in a decrease in mucus production and / or secretion through the above mechanism. Similarly, the energy may be configured to target abnormal goblet cells (PCEC) that are removed by cell death or shedding, leaving goblet cells (CG) and basal cells (BC) intact. Similarly, the energy may be configured to target abnormal basal cells (BC) that are removed by cell death or shedding, leaving goblet cells (PCEC) and goblet cells (GC). Regardless of how the above cell removals are combined, the remaining cells are further modified or affected by the delivered energy, or by subsequent delivered energy. For example, the remaining abnormal goblet cells (CG) are modified intact, resulting in a decrease in mucus production and / or secretion. The cell population may be partially removed, with some cells of a specific cell type being removed by delivery energy and the remainder being modified as needed.

[0249]

[0306] In other embodiments, the algorithm is configured to generate energy that penetrates the epithelial layer E of the airway wall W to the basement membrane BM. In this embodiment, the change in the epithelial layer E occurs as described above. Further, the basement membrane BM is affected by the delivered energy to assist in remodeling the airway wall W to a healthy state. In some embodiments, a change occurs in the basement membrane BM, and the membrane thickness of the basement membrane BM stabilizes or decreases. The thickening of the basement membrane BM is one of the characteristics of many lung diseases including chronic bronchitis and asthma. Therefore, the delivered energy may target the basement membrane BM for the purpose of halting or reversing such thickening. In some embodiments, such a change in the basement membrane BM affects the permeability of cells such as neutrophils and inflammatory molecules such as cytokines to the basement membrane BM, and thus assists in the regeneration of the healthy airway wall W.

[0250]

[0307] In some embodiments, the algorithm is configured to generate energy that penetrates the epithelial layer E of the airway wall W and exceeds the basement membrane BM. The constituent layers of the airway wall W behind the basement membrane BM change their positions according to the fluctuations of the anatomical structure along the lung passage. For example, the position of the smooth muscle layer SM changes along the length of the lung passage, but is in the range from the adjacent position to the basement membrane BM to below the lamina propria LP. Therefore, for a specific lung passage segment, a layer selected from the airway wall W is targeted and the delivered energy is titrated. For example, the algorithm can be selected or adjusted to affect a specific position of the smooth muscle layer SM. Smooth muscle hypertrophy is a characteristic of many lung diseases including chronic bronchitis, asthma, and several other airway diseases that cause airway hyperresponsiveness. In some embodiments, the delivered energy induces cell death of smooth muscle cells. Thereby, airway hypersensitivity is reduced and a desirable bronchodilation effect is obtained.

[0251]

[0308] In some embodiments, the algorithm is selected or adjusted to affect submucosal gland sigma (SGs). Submucosal glands overproduce and oversecrete mucus in the affected airway. In some embodiments, the delivered energy induces cell death in submucosal SGs. A reduction in submucosal SGs leads to a decrease in airway mucus and an improved patient outcome.

[0252]

[0309] In some embodiments, the algorithm is selected or adjusted so that the delivered energy affects the lamina propria (LP). The lamina propria has loose connective tissue. The connective tissue and matrix structure of the mucosal lamina propria possess very high compressibility and elasticity, thereby enabling the expansion of the lung passages. Furthermore, the loose structure allows for the presence of many cell types. The cell populations of the lamina propria are diverse and include, for example, fibroblasts, lymphocytes, plasma cells, macrophages, eosinophilic leukocytes, and mast cells. Patients suffering from airway diseases often have chronic inflammation, specifically an increase in the populations of lymphocytes and macrophages. In some embodiments, the delivered energy reduces the amount of inflammatory cells, particularly lymphocytes, macrophages, and / or eosinophils, thereby reducing inflammation. Such energy removes cells from the lamina propria by means of cell death, etc., while maintaining the extracellular matrix. By maintaining the matrix structure, stem cells and / or other cells can regrow the matrix and form healthy tissue. This is in contrast to fibrosis or other scar formation mechanisms in which the layers of the airway wall W, including the extracellular matrix, are permanently altered, for example, by the lysis or breakdown of the layers. In addition, since the cartilage layer CL is not damaged, the structural integrity of the airway can be maintained and its collapse can be prevented.

[0253]

[0310] Therefore, one or more algorithms may be used to deliver energy and affect one or more layers of the airway wall W. The energy penetrates to a specific depth in the airway wall W and acts on various layers extending from the surface of the wall W to a specific depth. Alternatively, the energy may be configured to act on cells at a specific depth without affecting the surrounding layers. Effects on cells include cell death or cell removal by cell detachment, or cell modification that alters a specific function of the cell. In one example, only a portion of cells of the same type or within the same layer are affected by the delivered energy. Optionally, additional energy may be delivered using either the same or different algorithms to act on a larger portion or all of the cells of the same type or within the same layer. Alternatively, additional energy can be supplied using either the same or different algorithms to increase the effect. For example, the additional energy removes cells from modified cells. Furthermore, the same or different algorithms may be applied to deliver additional energy to affect different portions or depths of the airway wall.

[0254]

[0311] The actual mechanism for removing or modifying cells depends, for example, on algorithm 152, energy delivery device 108, patient anatomical structure, etc. In some embodiments, cells are removed (e.g., separated) by dielectrophoresis.

[0255]

[0312] Dielectrophoresis describes the movement of particles under the influence of a non-uniformly applied electric field. Dielectrophoretic motion is determined by the magnitude and polarity of the charge induced within the particle by the applied electric field. The dipole moment induced within the particle can be represented by the generation of equal and opposite charges at the particle boundary. Since the induced projection is not uniformly distributed across the entire particle surface, macroscopic dipoles are formed. Because the applied electric field is non-uniform, the local electric field and the forces generated on both sides of the particle are different. Therefore, depending on the relative polarizability of the particle with respect to the surrounding medium, it is induced to move towards the inner electrode and high electric field region (positive dielectrophoresis) or towards the outer electrode and low electric field region (negative dielectrophoresis). Dielectrophoretic force is a function of cell volume and polarization, conductivity and dielectric constant of the surrounding medium, and the frequency and spatial gradient of the magnitude of the generated electric field.

[0256]

[0313] In some embodiments, the removal of abnormal epithelial cells such as stratified ciliated columnar epithelial cells (PCEC) and goblet cells (GC) is the result of dielectrophoresis induced by one or more energy pulses delivered by energy deliverer 108. In particular, in some embodiments, the epithelial layer E is separated by the action of dielectrophoresis, and the abnormal stratified ciliated columnar epithelial cells (PCEC) and goblet cells (GC) are separated from fixed basal cells (BC) and removed from the airway wall (W). Note that basal cells (BC) are linked to the basement membrane (BM) by semi-adhesion plaques (H), and basal cells (BC) are linked to goblet cells (GC) and ciliated epithelial cells (EC) via adhesion plaques (D). With respect to energy parameters and electrode configuration, instead of separating the linkage by adhesion plaques (D), the semi-adhesion plaques (H) are left intact. As a result, surface cells are removed, and basal cells (BC) remain largely undamaged, preparing to regenerate the epithelium.

[0257]

[0314] Figure 19 schematically illustrates the removal of epithelial cells by the dielectrophoretic effect. Here, the distal portion of the embodiment of the catheter 102 having the energy delivery body 108 is located within the lung passage. As can be seen from the dashed electric field lines, energy 204 is delivered from the energy delivery body 108. Due to the shape of the energy delivery body 108 and the positioning of the counter electrode plate 140 applied externally to the patient P's skin, the electric field is non-uniform. In this embodiment, the energy delivery body 108 is positively charged, which is the strongest / most concentrated pole of the electric field. The counter electrode plate 140 is negatively charged and is the weakest pole of the electric field. As a result, the non-uniform electric field induces the separation and displacement of epithelial cells (e.g., polystratified ciliated columnar epithelial cells PCEC and goblet cells GC) from the airway wall W (see downward arrows). The epithelial cells are then removed spontaneously or by intended mechanisms.

[0258]

[0315] In some embodiments, cells are removed or modified by electroporation or other mechanisms. Reversible electroporation is a non-thermal technique in which short, high-voltage pulses generate a strong electric field that increases the cell membrane voltage, forming pores in the cell membrane (e.g., the plasma membrane). These pores allow for the introduction of chemicals, DNA, and / or other drugs into the cells. Thus, in some embodiments, reversible electroporation is used to modify cells, for example, within the airway wall W, and to increase the uptake of drugs or agents. Irreversible electroporation (IRE) is a non-thermal cauterization technique in which short, high-voltage pulses generate a strong electric field that increases the cell membrane voltage, forming pores in the cell membrane (e.g., the plasma membrane) without substantial protein denaturation, thereby inducing cell necrosis. Thus, in some embodiments, irreversible electroporation can be used to remove cells by cell death. In some embodiments, cells are removed or modified by a combination of mechanisms, such as a combination of dielectrophoresis and electroporation.

[0259]

[0316] Instead of affecting the tissue cells of the airway wall W, or in addition to that, the delivered energy may act on pathogens present inside or near the airway wall W. The types of pathogens are not particularly limited and include, for example, bacteria (e.g., Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, opportunistic Gram-negative bacilli, Mycoplasma pneumoniae), viruses (rhinovirus, influenza / parainfluenza virus, respiratory syncytial virus, coronavirus, herpes simplex virus, adenovirus), and other organisms (e.g., fungi).

[0260]

[0317] In some embodiments, the lung tissue modification system 100 additionally or alternatively affects pathogens found within the lumen of the patient's airway (e.g., within the mucus layer M) or within the tissue layers of the airway wall W to manage, reduce, and / or eliminate infection. In some embodiments, the energy output from the system 100 affects the mucus layer M and any pathogens that may be present in or near the airway. The mucus layer M becomes less viscous, thus facilitating expulsion by the patient through coughing. Pathogens may be killed or programmed to die (e.g., by apoptosis), thereby reducing or eliminating infection.

[0261]

[0318] In some embodiments, Stem 100 helps patients develop antibodies or other symbiotic and supportive immune responses against a target pathogen, thereby improving future immunity and future resistance to that pathogen. Since System 100 affects the pathogen substantially non-thermally, resulting in cell death, the cell fragments still contain proteins. As intact proteins are released into the local environment and circulation, the immune system develops new ways of monitoring, recognizing, and responding to these challenges, thereby enhancing host defense against those challenges or pathogens in the future.

[0262]

[0319] As mentioned above, energy signal parameters are manipulated to produce different effects, such as different penetration depths. In one example, system 100 can be configured to affect only the mucous layer M and any commensal pathogens. In one example, separation of the epithelial layer E occurs. In another example, system 100 can be configured so that separation of the epithelial layer E occurs via a single energy delivery algorithm, the pathogen is affected, and / or deeper structures are affected. In one example, the generator may have a variety of stored energy delivery algorithms, and the user can apply two or more of these algorithms to tailor the treatment to an individual patient. This is done in a single treatment session or multiple treatment sessions to address the individual patient's needs.

[0263]

[0320] In one example, it is desirable to affect deeper cells, including smooth muscle cells (SM), submucosal glandular cells (SG), and / or nerves (N). The patient's pathology is more complex than mucus hypersecretion caused by epithelial E, and therefore the procedure is intended to affect deeper structures. Airway smooth muscle cells (SM) are known to contribute to bronchial hyperresponsiveness, submucosal glandular cells (SG) can contribute to severe mucus hypersecretion, and nerves (N) innervate both submucosal glandular cells (SG) and airway smooth muscle (SM). Alternatively, patients with complex conditions such as asthma and chronic obstructive pulmonary disease (COPD) (e.g., asthma-COPD overlap syndrome) may benefit from procedures targeting certain mechanisms (e.g., mucus hypersecretion, smooth muscle hypertrophy, ciliary dysfunction, and / or) and / or target tissues. The energy dose can be titrated to affect deeper structures of epithelial E (e.g., it can be iteratively modified based on sensors and / or other feedback). In one example, as the energy dose increases, the submucosal glandular cells (SG) undergo mild partial membrane lysis. Alternatively, structural integrity is significantly lost. Uniquely, and unlike thermal energy, the lamina propria LP, the cell layer located between the epithelium E and the submucosal gland SG, remains unchanged. Thermal energy sources cause significant structural changes in the extracellular matrix, leading to fibrosis.

[0264]

[0321] In addition to the submucosal gland SG, the smooth muscle SM, depending on the dose, causes decongestion of the epithelium E over several days to several weeks, ranging from focal changes to complete disappearance. The cartilage layer CL, the deepest structure within the airway wall, is unaffected by energy, shows no signs of inflammation or necrosis, and acts as an insulating barrier.

[0265] IV. Sensors

[0322] In some embodiments, one or more sensors 160 are included in the system 100 to measure one or more system or tissue parameters. Exemplary sensors 160 include temperature sensors, impedance sensors, resistance sensors, surface conductance sensors, membrane potential sensors, capacitance sensors, and / or force / pressure sensors, or combinations thereof. Thus, parameters measured by the sensors 160 may include, to name a few, impedance, membrane potential or capacitance, and / or temperature. The sensors 160 are used, among other things, to (a) obtain a reference measurement, (b) measure parameters during energy delivery, and / or (c) measure parameters after energy delivery.

[0266]

[0323] The sensor 160 can be positioned on the energy delivery body 108, adjacent to the energy delivery body 108, or at any suitable position along the distal portion of the catheter 102. A temperature sensor can monitor the temperature of the electrode and / or the electrode / tissue interface. An impedance sensor can monitor the impedance of the tissue across the two electrodes. A conductance sensor can monitor the transmission of electrical energy across any two electrodes. A force / pressure sensor can monitor the amount of force or pressure that the electrode exerts on the tissue.

[0267]

[0324] This sensor information can be used, in non-limiting examples, as feedback to the system to determine the appropriate deployment of the energy supply unit 108, drive the treatment algorithm 152, and / or stop the energy supply for safety reasons. Sensor 160 is also used to sense when appropriate treatment has been achieved. Algorithm 152 in generator 104 can also use the detected data to automatically titrate the treatment algorithm 152 so that target tissue treatment is achieved. In other words, one or more parameters and / or aspects of the treatment algorithm can be iteratively modified based on sensor data. For example, in some embodiments, power and / or energy duration can be increased or decreased based on sensor data.

[0268] A. Impedance sensor 1. Ensuring the appropriate location of the energy delivery device.

[0325] In some embodiments, one or more impedance sensors are used to determine whether the energy deliverer 108 is properly inserted and deployed in the airway of the lung. In some embodiments, a short-duration low-voltage signal is delivered to the energy deliverer 108 during their positioning and deployment / expansion within the target area of ​​the airway. Based on the measured current feedback received by the generator 104 from one or more impedance sensors, the generator's processor 154 performs calculations using the set voltage and actual current to calculate the impedance. The calculated impedance is then compared to an impedance value considered acceptable for a properly inserted and deployed energy deliverer 108. If the calculated impedance is outside the acceptable impedance range, the generator 104 displays a specific message and / or emits a specific sound to warn the operator. For example, if the energy deliverer 108 is still inside the bronchoscope 112, the generator 104 may measure a very high impedance that is outside the acceptable range. In such a case, the generator may display a message (e.g., confirm electrode position) until the operator repositions the energy deliverer 108 into the airway where the impedance is significantly lower and within the acceptable range. At this point, the message may change (for example, "Ready").

[0269]

[0326] Other types of sensors, such as temperature, force, or pressure sensors, can be used additionally or alternatively to confirm contact between the electrode and tissue before the start of treatment. Adequate contact between the electrode and the airway wall is a crucial element for effective treatment. A firm and consistent contact is desirable to adequately transfer energy from the electrode to the tissue and achieve the desired tissue effect.

[0270] 2. Ensuring the function of the catheter

[0327] In some embodiments, one or more impedance sensors are used to determine whether the catheter 102 is functional or potentially defective. In this embodiment, a short-duration low-voltage signal (e.g., a signal with a duration of 1 to 5 packets and a voltage of approximately 500V) is delivered to the energy deliverer during their positioning and deployment / expansion within the target area. Based on the measured current feedback received by the generator 104, the generator's processor 154 performs calculations using the set voltage and actual current to calculate the impedance. The calculated impedance is compared to an impedance value considered acceptable for a properly functioning catheter. If the calculated impedance is outside the acceptable impedance range, the generator 104 optionally displays a specific message and / or emits a specific sound to warn the operator. For example, if the catheter is defective, the impedance will be very high. In this embodiment, the generator 14 displays a message (e.g., "Catheter Replacement"). Once replaced, the generator 104 can detect a much lower impedance within the acceptable range and display another message (e.g., "Position Catheter"). Thus, impedance measurement can be used to avoid safety issues by detecting a malfunctioning catheter.

[0271] 3. Modification of the energy algorithm

[0328] In some embodiments, impedance measurements can be taken before and after energy application to define which energy delivery algorithm 152 to apply and / or whether additional energy needs to be applied to the target location. In some embodiments, pre-treatment impedance measurements can be used to determine the settings for various signal parameters. In other embodiments, sensors can be used to determine whether or not the energy delivery algorithm should be adjusted.

[0272]

[0329] In some embodiments, impedance measurement is performed as follows: Once positioned in a target region within the lung passage, a short-term low-voltage signal is delivered to the energy deliverer 108 via a generator (e.g., generator 104). Based on the measured current feedback received by generator 104, generator 104 performs calculations using the set voltage and actual current to calculate the impedance. The calculated impedance is compared to an impedance value considered acceptable for the measured impedance. The energy delivery algorithm 152 is then modified or adjusted based on the measured impedance. Parameters that can be adjusted include, but are not limited to, voltage, frequency, pause period, number of cycles, dead time, number of packets or packets, or a combination thereof. Thus, the feedback control loop can be configured to modify the parameters of energy delivery based on one or more measured system or tissue parameters.

[0273]

[0330] In some embodiments, one or more impedance sensors are used to monitor the electrical properties of tissue. The impedance value can be considered an indicator of the tissue state. In some embodiments, impedance is measured at different frequencies to provide an impedance spectrum. This spectrum characterizes the frequency-dependent or inactive components of the impedance. Tissue has both resistive and reactive components. These are the components of complex impedance. Reactance is a frequency-dependent component of impedance, including the capacitance and inductance of the tissue. As the state of the tissue changes, not only does the overall impedance change, but the resistive or reactive components of the complex impedance also change. Measuring complex impedance involves conducting a low-voltage sensing signal between two electrodes. The signal may, but is not limited to, a sine wave. Changes in complex impedance, including changes in resistance or reactance, may reflect the state of the treated tissue, thus indicating whether the treatment is affecting the tissue, not affecting the tissue, or whether the treatment is complete. The impedance value also changes depending on the contact state between the sensor and the airway tissue. In this way, the sensor can also be used to determine the contact state between the electrode and the tissue.

[0274]

[0331] For example, the generator 104 instructs the user that no further energy delivery is required at the target location. Optionally, the generator 104 displays a specific message and / or emits a specific sound to warn the operator which energy delivery algorithm 154 has been selected or that treatment is complete at that target location. Thus, the generator 104 can be configured to automatically select an appropriate algorithm for a given measurement impedance or to cut off the transmission of the energy signal when it is determined that treatment is complete. Furthermore, impedance or other sensors can be used to determine that treatment should be automatically terminated due to safety concerns.

[0275] B. Temperature sensor

[0332] In some embodiments, one or more temperature sensors are used to measure the temperature of the electrode and / or tissue during treatment to ensure that the energy accumulated in the tissue does not cause clinically significant tissue heating. In some embodiments, the temperature measured at or near the electrode is also used to determine the contact conditions between the electrode and the tissue before treatment. This can be achieved by applying energy at a level sufficient to generate heat but insufficient to cause substantial thermal damage. Depending on whether the electrode is pressed against the airway wall, moving within the airway lumen, or floating, the temperature will differ in its steady-state value or variability.

[0276]

[0333] In some embodiments, one or more temperature sensors are positioned along the surface of one or more energy delivery bodies 108 to contact the tissue and prevent the tissue from being heated beyond a predetermined safety threshold. Thus, one or more temperature sensors can be used to monitor the tissue temperature during treatment. In one embodiment, a temperature change that meets a predetermined criterion, such as the temperature rising above a threshold value (e.g., 40°C, 45°C, 50°C, 60°C, 65°C), triggers an energy supply parameter (e.g., modification of the algorithm) to lower the measured temperature or lower the temperature below a preset threshold. Adjustments include, but are not limited to, increasing the pause or dead time, or decreasing the number of packets. Adjustments are an example of a process that can be achieved by a predetermined stepwise approach that considers the percentage of the parameter, or by other means.

[0277]

[0334] In another embodiment, one or more temperature sensors monitor the temperature of the tissue and / or electrodes, and if a predetermined threshold temperature is exceeded (e.g., 65°C), the generator 104 modifies its algorithm to automatically stop the energy supply. For example, if the safety threshold is set to 65°C and the generator 104 receives feedback from one or more temperature sensors that the temperature safety threshold has been exceeded, the treatment is automatically stopped.

[0278] C. Sensor that monitors electrode contact

[0335] In some embodiments, multiple sensors (e.g., temperature, impedance, force, pressure, etc.) are placed at various locations, such as circumferentially, on the surface of one or more energy deliverers 108. In such configurations, the sensors can be used to indicate whether the contact between the surface of one or more energy deliverers 108 and the surface of the bronchial airway wall is sufficient, for example, properly circumferential and / or stable. If the sensors indicate insufficient contact, such as not being circumferential (e.g., uneven temperature, impedance, force, etc.) and / or being stable (e.g., continuously changing temperature, impedance, force, etc.), the level of expansion of one or more energy deliverers is adjusted, or a catheter 102 having energy deliverers 108 of different sizes that better match the inner diameter of the bronchus being treated is selected. In some embodiments, the generator 104 is configured to interpret the degree, quality, and / or stability of contact and provide feedback to the operator to help with the proper positioning of the energy deliverers. For example, when the operator is in the process of positioning one or more energy deliverers that are not in circumferential contact, the user interface 150 of the generator 104 may display a message such as "poor contact".

[0279]

[0336] In some embodiments, force or pressure sensors can be used to detect and measure the contact force between the energy delivery body and the airway wall, thereby determining the contact state between the energy delivery body and the tissue.

[0280]

[0337] Any embodiment of System 100 disclosed herein may incorporate one or more sensors to monitor the application of treatment.

[0281] V. Cardiac Synchronization

[0338] In some embodiments, energy signals are synchronized with the patient's cardiac cycle to prevent the induction of cardiac arrhythmias. Therefore, the patient's cardiac cycle is typically monitored using an electrocardiogram (ECG). Referring to Figure 20, a typical ECG trace 600 includes a repeating cycle of P waves 602 representing atrial depolarization, QRS complex 604 representing ventricular depolarization and atrial repolarization, and T waves 606 representing ventricular repolarization. Synchronization between energy delivery and the patient's cardiac cycle is employed to safely deliver energy into the airways in close proximity to the heart, thereby reducing the risk of cardiac arrhythmias. High-voltage energy can induce premature action potentials within the myocardium, as the delivered energy increases myocardial cell membrane permeability, enabling ion transport, which can induce cardiac arrhythmias, particularly ventricular fibrillation. To avoid cardiac arrhythmias, electrical energy is delivered to the airways in a manner that lies outside the myocardium's "vulnerable period." Within one cardiac cycle (heartbeat), the ventricular myocardium's vulnerable period is indicated on the ECG by the entire T wave 606. Typically, for ventricular myocardium, the vulnerable period coincides with the mid- and terminal phases of T wave 606. However, when high-energy pulses are delivered close to the ventricle, the vulnerable period may occur a few milliseconds earlier than the heartbeat. Therefore, the entire T wave can be considered to fall within the ventricular vulnerable period.

[0282]

[0339] The remainder of the cardiac cycle consists of the P wave 602 and QRS complex 604, both of which include periods in which the atrial or ventricular muscle is refractory to high-voltage energy stimulation. If the high-voltage energy pulse is delivered during the muscle's refractory period, the likelihood of arrhythmia can be minimized. The ST segment 608 (the interval between ventricular depolarization and repolarization) and the TQ interval 610 (the interval encompassing the end of the first cardiac cycle and the midpoint of the second cardiac cycle) of the first cardiac cycle are periods in which high-voltage energy is generated. This can be delivered without inducing cardiac arrhythmias due to the myocardial depolarization state (refractory period). Figure 20 includes shaded boxes showing exemplary portions of the cardiac cycle in which energy can be safely applied.

[0283]

[0340] Figure 21 is a flowchart illustrating one embodiment of a method for synchronizing energy delivery with the cardiac cycle, according to several embodiments. In this embodiment, the electrocardiogram (ECG) is acquired by an external cardiac monitor 170 (such as a cardiac monitor available from AccuSync Medical Research Corporation) operably connected to a communication port 167 on the energy generation generator 104. Any suitable monitor can be used. Here, the cardiac monitor 170 is used to continuously acquire the ECG, analyze one or more cardiac cycles, and identify the beginning of a period in which it is safe to apply energy. In some embodiments, when the cardiac monitor 170 detects this event / start (e.g., the R wave in the ECG trace), it sends a low-voltage transistor-to-transistor logic (TTL) pulse (e.g., ≤5V) to the communication port 167. In the start step 650, the processor 154 of the energy generation generator 104 monitors the communication port 167 (in step 652) to determine whether a cardiac synchronization pulse has been detected. If the TTL pulse is not detected by the generator 104 (step 654), the user is notified using the user interface 150 (step 656). For example, the user interface 150 displays a bright red heart and / or any other appropriate visual indicator. When a cardiac synchronization pulse is detected by the generator 104 (step 658), the user is notified using the user interface 150 (step 660). For example, the bright red heart changes to a blinking yellow heart and lights up when the cardiac synchronization pulse is detected.

[0284]

[0341] Since the external cardiac monitor 170 may transmit erroneous TTL pulses, and the generator should not continue treatment if the patient's heart rate is not within the normal expected range, is unstable, and / or has an extended QRS complex that deviates significantly from or differs from the patient's basic heart rhythm, the next step involves checking the heart rate to establish the reliability of the TTL pulses (i.e., cardiac synchronization pulses) (step 662). In one embodiment, the processor 154 of the generator 104 is used to monitor the TTL pulses and calculate the time between each beat, called Δt1, Δt2, Δt3, Δt4, and Δt5. These values ​​can be stored in the data storage module 156 of the generator 104 as a rolling buffer with the last five Δt calculations. Next, the average of these five values ​​can be calculated, called Δt-ave. The next Δt (e.g., Δt6, Δt7, etc.) can be calculated using one or more subsequent TTL pulses detected, and this can also be stored in the data storage module 156. For example, two TTL pulses can be used.

[0285]

[0342] Next, the algorithm module 152 of the generator 104 is used to compare these values ​​to a set of criteria, and if these criteria are met, it provides assurance that the patient's cardiac rhythm is normal / consistent and that the TTL pulse is reliable. For example, the heart rate can be calculated and verified to be 40-150 beats per minute (bpm). In this example, Δt6 and Δt7 can also be compared to Δt-ave to verify that the heart rate is not unstable. In one embodiment, to continue, Δt6 and / or Δt7 are within ±15% of Δt-ave. In this example, both criteria must be met to confirm reliability (in step 664). However, in other embodiments, both criteria may not be required. Once reliability is confirmed, the user can be notified that it is safe to proceed using the user interface 150 (step 666). For example, a flashing yellow heart on the user interface 150 changes to a flashing green heart. The user is then instructed using the user interface 150 to charge the high-energy storage unit (e.g., one or more capacitors) of the generator 104. In one example, the user interface 150 displays a soft key labeled "Charge," which the user can press to charge the high-energy storage unit. If the charge button is not pressed (step 668), the processor 154 continues to check the reliability of the heart rate and TTL signals.

[0286]

[0343] When the processor 154 recognizes that the charging button has been pressed (step 670), the processor 154 continues to check the reliability of the heart rate and TTL signals (step 672). During this time, if a predefined / predetermined amount of time has elapsed (e.g., approximately 30, 40, 50, 60, or up to 120 seconds, including all values ​​and partial ranges within that time), and the reliability of the heart rate and TTL has been verified and established (step 674), the system exits the charging mode and returns to a system state where the heart rate is being checked and the reliability of the cardiac synchronization pulse has been established (step 662). If the timeout has not been reached (step 676), the user interface 150 notifies the user (step 680) until reliability is established (step 678). The user interface 150 can be changed so that a soft key is labeled "Ready". The system 100 waits for the foot switch 168 to be pressed.

[0287]

[0344] While the system 100 waits for the foot switch 168 to be pressed (step 348), it continues to monitor the heart rate and check confidence (672). If the user does not press the foot switch 168 within that time (e.g., up to 120 seconds, including approximately 30, 40, 50, 60, or all values ​​and subranges in between), another timeout can be predefined. When the timeout is reached as shown in the figure (step 674), the system stops being ready to supply energy and returns to a system state where it is checking the heart rate and establishing confidence in the TTL pulse (step 662). When the user presses the foot switch (step 684), energy supply can begin (step 686). However, the generator 104 can be configured to wait until the next cardiac pulse is detected so that energy delivery is more reliable after the R wave is detected. In one embodiment, energy is not delivered until 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. The first energy packet can then be delivered (step 686). Next, processor 104 checks to determine whether all packets have been delivered (step 688). If not, processor 154 continues to monitor the heart rate (step 690) and check the reliability of the TTL pulse, and can continue supplying energy once the reliability of the cardiac synchronization pulse is re-established (step 662).

[0288]

[0345] For example, a TTL pulse immediately following energy delivery is a false trigger caused by the supplied high-voltage energy and should be ignored. For instance, processor 154 may ignore TTL pulses for approximately 400 ms after energy delivery, or for approximately 450 ms after the leading edge of the last TTL pulse. In other situations, TTL pulses can be ignored for approximately 50 ms to 1 second, including all values ​​and sub-ranges in between. When the processor detects the next TTL pulse, it can calculate the next Δt and compare it to a previously defined criterion (step 690) (i.e., based on a rolling average). If the next Δt falls outside the criterion due to the possibility of a transient delay in the heartbeat after energy delivery, it is simply ignored. The next Δt can then be calculated and compared to a previously defined criterion. If the criterion is met (step 700), the next packet is delivered (step 686). If not all packets have been delivered, the system continues to monitor the heart rate and check the reliability of the cardiac synchronization pulse as described above (step 690). If reliability is established (step 700), the cycle continues. If reliability is not established (step 702), the user is notified, for example, by the heart turning yellow and flashing or by it lighting up red (step 704).

[0289]

[0346] If system 100 cannot determine acceptable reliability or no longer detects a TTL pulse within a certain time (e.g., approximately 10, 20, 30, 40, 50, or 60 seconds), a timeout is reached (step 706). The user can be notified using the user interface 150 (step 708). At this point, the cycle ends and no remaining packets are delivered. The process then returns to the start (step 650). If the system can determine acceptable reliability within the set time limit (step 700), there is no timeout (step 688), and the system continues to monitor the heart rate and check reliability as described above (step 690). If reliability is obtained (step 700), the next energy packet is delivered (step 686). Once all packets have been delivered, the treatment is considered complete (step 710), and the user is notified of the completion of the treatment (step 708). If the current associated with the delivery of any of the high-energy packets exceeds a set value (e.g., approximately 45 amperes) (step 686), the cycle may also be terminated (step 708).

[0290]

[0347] In some embodiments, the components for acquiring the electrocardiogram 170 are formed integrally with the generator 104. If the cardiac monitor is limited to acquiring up to 5-lead electrocardiograms, it may be beneficial to incorporate additional leads into the system. As a result, the need to use the communication port 167 to receive cardiac synchronization pulses is eliminated. Rather, the processor 154 can be configured to directly detect R waves and assess the completeness of the entire QRS complex.

[0291]

[0348] In some embodiments, the processor 154 may be configured to use five or more, or five or fewer, Δt' values ​​to calculate Δt-ave. In some embodiments, the processor 154 may be configured to calculate Δt-ave using three to ten Δt' values. Furthermore, the processor 154 may be configured to use Δt values ​​other than Δt6 and Δt7 to verify reliability. For example, the processor 154 may be configured to use subsequent Δt values. The processor 154 may also be configured to enable heart rates greater than 40-150 bpm as described above. For example, the processor 154 may be configured to enable heart rates in the range of 30-160 bpm, including all values ​​and partial ranges between them. The processor 154 may also be configured to allow Δt6 or Δt7 to be greater than or less than ±10%. For example, the processor 154 may be configured to allow Δt6 or other data points, including the rolling average, to be within ±3% to ±50%. The examples of user interfaces 150 provided herein are merely examples and do not limit the invention.

[0292]

[0349] Therefore, the generator can be configured to continuously monitor the patient's heart rate, and if a cardiac arrhythmia is induced, the treatment will automatically stop and an alarm will sound.

[0293] V. IMAGING

[0350] Imaging can be used in the following ways: (a) to detect affected target tissue, (b) to identify areas to be treated, (c) to evaluate treatment areas to determine the effectiveness of energy delivery, (d) to assess whether areas have been missed or whether treatment is insufficient, (e) to measure the target treatment depth by imaging before and after treatment, and to use that depth to select a specific energy delivery algorithm and achieve tissue effect up to that depth, (f) to perform intra-procedure imaging to identify target cell types or cell interfaces, and to use their location or depth to select a specific energy delivery algorithm and obtain tissue effect on target cell types or cell interfaces, and / or (g) to identify the presence of pathogens by post-procedure imaging, regardless of the presence or absence of inflammatory tissue.

[0294]

[0351] In some embodiments, confocal laser endoscopy (CLE), optical coherence tomography (OCT), ultrasound, static or dynamic CT, X-ray, magnetic resonance imaging (MRI), and / or other imaging devices can be used. By incorporating the energy delivery catheter 102 or another device, it can be incorporated (functionally and / or structurally) into a separate device / system or the lung tissue modification system 100. One or more imaging devices can be used to locate and / or access various tissue sections, including areas of thickened epithelium, goblet cell hyperplasia, submucosal gland, smooth muscle, and / or other abnormal sites, relative to where the system is deployed in the chest. In some embodiments, it can be used to measure the target treatment depth and select a treatment algorithm 152 sufficient to treat up to the target treatment depth. At least one energy delivery device can then be positioned at a site of abnormal airway wall tissue and energy can be delivered to affect the target tissue. Imaging devices (one or more) can be used before, during, between, and / or after treatment to determine where or not treatment was performed, or whether the energy adequately affected the airway wall. If it is determined that a certain area was missed or not sufficiently affected, energy delivery can be repeated, followed by repeated imaging (one or more), until adequate treatment is achieved. Furthermore, imaging information can be used to determine whether a specific cell type and / or desired treatment depth was applied. This allows for the customization of energy delivery algorithms to treat the diverse anatomical structures of patients.

[0295]

[0352] In some embodiments, imaging combined with the use of a fluorescent agent (e.g., fluorescein) is performed to enhance the recognition of pathogens that may be present in the airways. The fluorescent agent can be selected to directly tag specific pathogens (e.g., bacteria) or indirectly tag cells (e.g., neutrophils) associated with various infection states. In some embodiments, such imaging methods / approaches include gaining access to the airways, delivering the fluorescent agent into the airways, exciting the fluorescent agent by delivering an excitation signal to the airways, and evaluating the presence or absence of fluorescence in response to the excitation signal.

[0296] A. IM for access

[0353] Generally, the methods, apparatus, and systems disclosed herein can access lung tissue or target areas (e.g., trachea, main bronchi, lobar bronchi, segmental bronchi, accessory bronchi, parenchymal tissue) through natural opening pathways (e.g., mouth or nose), artificially created openings (e.g., tracheostomy, surgically generated stoma, and / or appropriate intraoperative and / or postoperative openings), and / or artificially created openings in the lungs and / or other areas of tissue through the airway. The types of techniques available depend on factors such as the patient's age, comorbidities, the need for other concomitant procedures, and / or past surgical history.

[0297]

[0354] Methods for accessing the airway and / or other lung tissue (e.g., parenchyma) include using a working channel of a bronchoscope delivered to the trachea and / or more distal bronchi via the nose or mouth. Referring to Figures 8A–8B, the bronchoscope 112 is inserted into the patient P's mouth or oral cavity OC, or other natural openings such as the nose or nasal cavity NC. Similarly, other lung tissue LT, such as parenchyma, can be accessed via the nose or mouth as shown in Figure 22. As shown, the distal end of the catheter 102 is advanced to the trachea T, main bronchus MB, and lobar bronchus LB, which crosses from the airway to the surrounding lung tissue LT. This is achieved using an instrument or catheter having a guidance system that allows guidance to the outside of the lung passages.

[0298]

[0355] In one example, direct visualization may not be necessary and / or desirable, and the therapeutic catheter can be delivered directly to the airway via the nose or mouth.

[0299]

[0356] In other embodiments, access to the airway and / or lung tissue (e.g., parenchymal tissue) is achieved via other instruments inserted into the chest. Similarly, in some embodiments, one or more different imaging modes (e.g., CLE, OCT) are used with or instead of direct visualization. As an example, the bronchoscope 112 may be delivered via the mouth to allow direct visualization and delivery of the catheter 102, while alternative imaging modes are delivered via another working channel of the bronchoscope 112, via the nose, or via the mouth, adjacent to the bronchi. In some embodiments, the imaging device (e.g., direct visualization, CLE, and / or OCT) is incorporated into the catheter 102 with appropriate mechanisms for connecting the imaging device to either the system generator 104 or a commercially available console. Figures 23A and 23B show exemplary images obtainable using CLE and OCT, respectively. These images can be used to guide delivery to predetermined locations previously identified on a CT scan using airway wall thickness (AWT) measurements, to target treatments based on visualization of cellular structures, and / or to evaluate the effectiveness of treatments.

[0300] B. Imaging for treatment planning

[0357] The imaging method includes using pre-imaging processing to plan the procedure. Imaging is used to detect the affected target tissue, identify the area to be treated, and / or determine an appropriate energy delivery algorithm to achieve the desired treatment depth. For example, a CT scan can be obtained pre-procedure or intraoperatively from which AWT or Pi10 (theoretical airway wall thickness of an airway with an inner circumference of 10 mm) measurements can be obtained. The target area can be identified using these metrics. The target treatment depth can be measured using CLE or OCT as shown in Figures 23A-23B. The desired treatment depth can be based on the thickness t of the epithelium E measured from the airway lumen LMN to the basement membrane BM, the distance d to the target cell type such as goblet cells GC or smooth muscle (not shown), and / or any other structure that the physician deems medically appropriate. Figure 23B provides an exemplary OCT image of an affected airway. The airway thickness t' can be determined by measuring the distance from the airway lumen LMN to the outer edge EDG of the airway. Next, these measurements can be used to select a specific energy delivery algorithm 152 to achieve tissue effects up to that depth. For example, the generator 104 may have a user interface 150 (e.g., a touchscreen) that allows selection of a desired treatment depth. Once the operator selects the desired depth, the system 100 can be configured to automatically select an appropriate energy delivery algorithm 152 to achieve that depth. Other anatomical assessments can also be performed to assist in selecting the target treatment site. For example, CLE can be used to assess the size and / or density of goblet cells GC, along with the distance d from the airway lumen LMN to the goblet cells GC, to target both the treatment location and the target depth. These methods allow for the customization of treatment to each patient.

[0301]

[0358] In some embodiments, the use of a bronchoscope 112 allows for a pre-treatment plan in which sputum samples are taken for analysis. If one or more pathogens are found, this information is used to determine an appropriate energy delivery algorithm 152 to achieve the desired treatment depth as a result of the initial data. In some cases, it is desirable to limit the treatment depth to only the mucous layer M where the pathogens proliferate, such as a combination of pathogen identification combined with improved tissue imaging. In other cases, it is desirable to affect deeper airway structures. To plan the treatment, sputum samples can be taken and evaluated to determine whether or not an infection of the tracheobronchial tree is present. If an infection is suspected to be present, the generator can be programmed to affect the mucous layer of the airway without substantially affecting other layers, including the pathogen causing the infection or other lung tissue. The method of performing the sputum examination is also used to evaluate the effectiveness of the treatment. To evaluate the effectiveness of the treatment, additional sputum samples, as well as biopsy material, can be taken after or after the energy delivery procedure. The effectiveness of the procedure can be determined by comparing these samples and biopsies with the planned samples and with each other. These data, combined with the patient's clinical test results, can be used to further optimize treatment.

[0302]

[0359] Methods involving the performance of one or more tissue biopsies can be used for treatment planning and / or evaluation of treatment effectiveness. To plan treatment, biopsies are performed and microscopically determined the patient's suitability (e.g., excessive mucus production, goblet cell density, goblet cell hypertrophy, epithelial thickness, inflammation, basement membrane thickening, submucosal inflammation, submucosal eosinophilia, submucosal gland thickening, etc., smooth muscle hypertrophy, or other parameters) and / or the degree of airway obstruction (e.g., thickness of epithelial and / or other layers). By measuring one or more of these parameters, the generator can be programmed to affect tissue at a specific depth, allowing for customization of the energy delivery algorithm for each patient. For example, the voltage can be increased for patients with thicker epithelial layers. To evaluate the effectiveness of treatment, additional biopsies can be performed immediately or after the energy delivery procedure. By comparing these biopsies with the planning biopsy and each other, the effectiveness of the procedure can be determined. For example, if a post-treatment biopsy shows no change from the planning biopsy, the site was either not treated or insufficient energy was applied to affect the tissue. However, if post-treatment biopsies show a reduction in epithelial thickness and / or structure (i.e., regeneration of healthy epithelium), the effectiveness of energy delivery can be verified. Performing multiple biopsies along the airway can further assess whether a sufficient proportion of the total surface area has been treated. These data, combined with the patient's clinical examinations, can be used to further optimize treatment.

[0303] C. Imaging during treatment

[0360] The use of the bronchoscope 112 allows for direct visualization of the target tissue, as well as the positioning and visual confirmation of the positioning of the catheter 102. In some embodiments, direct visualization may not be necessary, and the catheter 102 is delivered directly to the airway. Alternatively, various imaging techniques (e.g., CLE, OCT) can be used with or instead of direct visualization. As an example, the bronchoscope 112 is introduced through the mouth to allow for direct visualization and delivery of the catheter 102. Alternatively, an imaging device may be introduced through a separate working channel of the bronchoscope 112, via the nose, or through the mouth while remaining adjacent to the bronchoscope. In some embodiments, the imaging technique (e.g., direct visualization, CLE, and / or OCT) is incorporated into the catheter along with a suitable mechanism for connecting the imaging technique to either a system generator or a commercially available console.

[0304] D. Imaging after treatment

[0361] In some embodiments, the imaging method may include using imaging to evaluate the effectiveness of intraoperative and / or postoperative procedures (e.g., using an imaging device 169). In some embodiments, during a procedure, the operator can use imaging to evaluate the target treatment area and determine whether the area was missed or inadequately treated. For example, if the area is inadequately treated, the operator can observe that the target depth was not achieved. The operator can then remeasure the depth, select an appropriate treatment algorithm 152, and treat again at the same location. In some embodiments, if the generator 104 does not have a variety of preset algorithms based on the desired depth, the same energy delivery algorithm can be used. Imaging is also used postoperatively to monitor the healing process and correlate tissue changes with clinical outcomes. The healing process can make it easier to visualize tissue changes and evaluate the effectiveness of the procedure. This data may further lead the physician to decide to perform additional procedures to affect additional tissue.

[0305] VII. Catheter Embodiments

[0362] Various embodiments of the energy delivery catheter 102 are conceivable. The features and characteristics described herein can be used in any combination to achieve the desired tissue effect. Typically, such a catheter 102 is sized and configured to treat a pulmonary passage having a lumen diameter of about 3 to 20 mm. Typically, the energy delivery body 108 expands within the pulmonary passage lumen to be near the lumen wall W, against the wall W, in contact with the wall W, or to exert pressure or force against the wall W. In some embodiments, the energy delivery body 108 expands to a diameter of up to 22 mm, particularly 3 to 20 mm or 3 to 22 mm.

[0306]

[0363] Figure 24 shows an embodiment of an energy delivery catheter 102 having a single energy delivery body 108 consisting of at least two projections, each projection extending radially outward to contact the luminal wall of the lung passage. A single projection may be present, but typically two projections are present to support the catheter between them by applying substantially opposite forces to the wall of the lung passage. In this embodiment, at least two projections include a plurality of ribbons or wires 120 constrained by a proximal end constrainer 122 and a distal end constrainer 124 that form a helical cage. In this embodiment, the proximal end constrainer 122 is attached to a shaft 106, and the shaft 106 does not penetrate the energy delivery body 108. This makes it possible to fold the energy delivery body 108 without adding the dimensions of the shaft 106. The energy delivery body 108 is delivered to the target area in a folded configuration. This folded configuration can be achieved, for example, by positioning a sheath 126 over the energy delivery body 108. In Figure 24, the catheter shaft 106 terminates at the proximal restraint 122 and moves freely relative to the shaft 106 of the catheter 102 with minimal restraint at the distal restraint 124. When the sheath 126 is advanced, covering the energy delivery body 108, the distal restraint 124 moves forward, thereby stretching / folding and subsequently restraining the energy delivery body 108. As the sheath 126 retracts, the energy delivery body 108 expands by self-expansion or the like. In other embodiments, the wire or ribbon 120 is linear rather than helical (i.e., configured to form a linear cage). In yet another embodiment, the energy delivery body 108 is formed by laser cutting a tube.

[0307]

[0364] In some embodiments, the energy delivery body 108 includes a plurality of electrodes 107, and each wire 120 acts as a separate electrode 107 and can be emitted separately using an adjacent wire as a counter electrode or using a dispersed electrode attached to the patient as a counter electrode. In one example, each wire 120 of the energy delivery body 108 can be electrically isolated from each other, and separate conductor wires can transfer energy from the generator 104 to the wires 120 of the energy delivery body 108. In another example, two or more wires 120 can be electrically connected to each other to form one or more wire sets. The algorithm 152 of the generator 104 can perform appropriate switching from one wire (or a set of wires) to another, as well as switching the function of the wires between an active state and a return (ground) state.

[0308]

[0365] Figure 25 shows an embodiment in which the energy delivery catheter 102 includes two energy delivery bodies, namely a first energy delivery body 108 and a second energy delivery body 108', and each body 108, 108' functions similarly to the embodiment in Figure 24. In this embodiment, the first energy delivery body 108 is positioned along the distal end of the first shaft 106, and the second energy delivery body 108' is positioned along the distal end of the second shaft 106'. As shown, the shafts 106, 106' are aligned parallel to each other so that they can pass through the sheath 126 together. In some embodiments, the shafts 106, 106' are fixed to each other so that they move as a whole. In this embodiment, the shafts 106, 106' are arranged so that the energy delivery bodies 108, 108' are staggered, such as the second energy delivery body 108' being positioned distal to the first energy delivery body 108, as illustrated in Figure 25. In such a configuration, the energy deliverers 108, 108' can be separated at any appropriate distance. Similarly, since the energy deliverers 108, 108' are aligned with respect to the shafts 106, 106', the expansion of the energy deliverers 108, 108' is never affected. For example, in this embodiment, the energy deliverers 108, 108' are aligned such that the second shaft 106' does not obstruct the expansion of the first energy deliverer 108. Rather, the second shaft 106' passes through the cage-shaped energy deliverer 108 between the wires 120. In some embodiments, the shafts 106, 106' are not fixed to each other but can move relative to each other, and in particular, the shafts 106, 106' can slide longitudinally parallel to each other. In this embodiment, the shafts 106, 106' may be moved relative to each other to increase or decrease the distance between the energy deliverers 108, 108'. Once the desired distance is achieved, the shafts 106, 106' are fixed in place to maintain the desired distance between the energy deliverers 108, 108'.

[0309]

[0366] In the embodiment shown in Figure 25, each energy delivery body 108, 108' consists of a helical cage made of electrodes 107 in the form of wires 120. The energy delivery bodies 108, 108' can be operated in a bipolar and / or unipolar manner. In other embodiments, the wire or ribbon 120 is linear rather than helical (i.e., configured to form a linear cage). In some embodiments, the energy delivery bodies 108, 108' are formed by laser cutting a tube. In this embodiment, the first shaft 106 terminates at the first proximal end restraint 122 of the first electrode body 108, leaving the first distal end restraint 124 essentially unrestrained. The second shaft 106' terminates at the second proximal end restraint 122' of the second electrode body 108', leaving the second distal end restraint 124' essentially unrestrained. Advancing the sheath 126 over the energy deliverers 108, 108' allows the distal end restraints 124, 124' to move forward, thereby folding, stretching, and restraining the energy deliverers 108, 108'. Retracting the sheath 126 exposes the energy deliverers 108, 108' for energy expansion and delivery.

[0310]

[0367] Figure 26 shows an embodiment of an energy delivery catheter 102 having a single energy delivery body 108 consisting of a unipolar electrode 107 formed by multiple ribbons or wires 120, the energy delivery body 108 being attached to a shaft 106 that extends through the energy delivery body 108. The energy delivery body 108 is also cage-shaped, constrained by a proximal end restraint 122 and a distal end restraint 124. In this configuration, either the proximal end restraint 122 or the distal end restraint 124 slides freely on the shaft 106 so that the energy delivery body 108 can be folded, while the other end is fixedly attached to the shaft 106. Once the energy delivery body 108 is delivered to the target therapeutic area, the sheath 126 is withdrawn by an operator, for example, via a lever, slider, or plunger on the catheter handle 110 which is operably connected to the sheath 126. The withdrawal of the sheath 126 removes the constraints that keep the energy delivery body 108 compressed, thereby allowing the wire 120 of the energy delivery body 108 to make contact with the bronchial wall.

[0311]

[0368] In some embodiments, the folding configuration of the energy delivery body 108 can be achieved by a mechanism that restricts its expansion without using a sheath 126. For example, in some embodiments, a pull wire is attached to a proximal end restraint 122 of the energy delivery body 108 and extends along the lumen along a shaft 126 which is operably connected to a lever, slider, or plunger on the catheter handle 110. In this embodiment, a distal end restraint 124 is fixedly attached to the shaft 106, and the proximal end restraint 122 is configured to slide freely on the shaft 106. While the pull wire is subjected to a tensile force, the proximal end restraint 122 is positioned so that the energy delivery body 108 folds. The pull wire can be maintained in this position by being restrained within the handle 110. Release of the tensile force, such as by reducing or removing the restraint within the handle 110, allows the pull wire to move. Therefore, as the energy delivery body 108 expands due to its self-expanding properties, the proximal end restraint portion 122 becomes free and moves closer to the distal end restraint portion 124.

[0312]

[0369] In another embodiment, the proximal restraint 122 is fixed to the shaft 106, and the distal restraint 124 is free to slide along the shaft 106. Furthermore, a push rod (or a tube for achieving higher column strength) is attached to the distal restraint 124, extends along the inner axis 106 and along the lumen, and is operably connected to a mechanism such as a lever, slider, or plunger on the catheter handle 110. When the push rod is pushed and subsequently restrained within the handle 110 of the catheter 102, the distal restraint 124 moves away from the proximal restraint 122, thereby crushing the energy delivery body 108. When the energy delivery body 108 self-expands, the release of the push rod allows the energy delivery body 108 to expand. Alternatively, the push rod can be retracted, pulling the distal restraint 124 toward the proximal restraint 122, thereby expanding the energy delivery body 108.

[0313]

[0370] In the embodiment shown in Figure 26, the energy delivery body 108 is formed by a braided metal tube configured to form a cage, constrained at both the proximal end constrainer 122 and the distal end constrainer 124. The energy delivery body 108 can be controlled (i.e., folded and unfolded) as described above. When the energy delivery body 108 includes a braided metal tube, each wire within the braided tube is supported by multiple adjacent wires, as well as by the weaving properties of the braid itself. This support and weaving configuration can ensure minimal variation in the space between wires, otherwise known as the hole or opening size of the braid. Furthermore, this support and weaving configuration allows the braided tube to be constructed from very small wires and can also have remarkable radial stability of the cage. This makes it possible to use a large number of wires (e.g., 12, 16, 18, 20, 22, 24, etc.) while maintaining the relatively small external shape of the energy delivery body 108 in a folded / constrained state and optimizing the size of the opening of the braided tube when the electrodes are unfolded / expanded. In this embodiment, the space between the wires is quite narrow, resulting in essentially continuous treatment across 360 degrees of the lumen of the lung passage.

[0314]

[0371] Figure 27 shows an embodiment in which both energy deliverers 108, 108' are supported on a single shaft 106. To crush the energy deliverers 108, 108', the first proximal end restraint 122 of the first energy deliverer 108 is firmly attached to the catheter shaft 106. The other end restraints 122', 124, 124' can slide freely on the catheter shaft 106. The catheter is delivered with a sheath 126 that restrains the energy deliverers 108, 108'. Once the energy deliverers 108, 108' are delivered to the target region, the sheath 126 can be withdrawn by the operator via a mechanism such as a lever or slider or a plunger on the catheter handle 110. Withdrawing the sheath 126 removes the restraint that keeps the energy deliverers 108, 108' crushed, thereby allowing the surfaces of the energy deliverers 108, 108' to contact the bronchial wall. Furthermore, in some embodiments, the first distal end restraint 124 and the second proximal end restraint 122'' are connected to each other via a coupler 800. The coupler 800 is constructed using an electrically insulating material (e.g., polyether block amide (Pebax®) tube, polyimide tube, etc.) and provides an insulating gap 802 between the energy delivery bodies 108, 108' to achieve electrical discontinuity between them. In some embodiments, this gap 802 is between 1 and 20 mm. This prevents arc discharge within the catheter shaft 106.

[0315]

[0372] In some embodiments, the folded configuration of the energy delivery bodies 108, 108' can be achieved by restricting their expansion without using a sheath 126. For example, in one embodiment, the distal end of a pull wire (not shown) is attached to a second distal end restraint 124', and the proximal end of the pull wire is attached to a mechanism (e.g., lever, plunger, slider) of the handle 110. The first proximal end restraint 122 is fixedly attached to the catheter shaft 106, while the other end restraints 124, 122', 124' slide freely on the catheter shaft 106. Such a configuration assumes that the energy delivery bodies 108, 108' are in a folded configuration before positioning begins via the bronchoscope, and that the operator is required to unfold / expand them. This deployment / expansion is achieved by the operator activating a mechanism (e.g., a lever, plunger, or slider) of the handle 110 that pulls the second distal end restraint 124' toward the first proximal end restraint 122, thereby efficiently deploying / expanding the energy deliverers 108, 108'. In an alternative configuration, expansion can be achieved by using two pull wires, each separately attached to each energy deliverer 108, 108'. In this embodiment, the operator can independently control the expansion levels of the energy deliverers 108, 108'.

[0316]

[0373] In some embodiments, one or more energy delivery bodies 108, 108' are not constrained at both ends, or rather, one end is not constrained, thus creating a semi-cage shape. Figure 28A shows an embodiment in which one energy delivery body energy 108' forms a semi-cage shape when expanded, without being constrained at one end. In this embodiment, both energy delivery bodies 108, 108' consist of braided metal wire. The most distal energy delivery body 108' is constrained at both a second proximal end constrainer 122' and a second distal end constrainer 124', and is configured to form a closed braided cage shape. The most distal energy delivery body 108' is typically expandable so that at least its widest expanded diameter contacts the wall W of the lung passage. The most proximal or first energy delivery body 108 is constrained at the first proximal end constrainer 122, and is configured to form a substantially semi-open cage or semi-cage when expanded, as shown. The proximal energy delivery body 108 is typically expandable so that at least its widest expanded diameter contacts the wall W of the lung passage. The shaft 106 is securely attached to the first and second proximal end restraints 122, 122'. The semi-cage shape of the proximal energy delivery body 108 allows its widest expanded diameter to be closer to that of the farthest energy delivery body 108' than if the proximal energy delivery body 108 were in its whole shape. Reducing this distance between the energy delivery bodies 108, 108' allows for therapeutic effects between the energy delivery bodies 108, 108', in addition to those in the energy delivery bodies 108, 108'. Given the effects between the bodies 108, 108', this ultimately produces a greater surface treatment effect. Furthermore, the semi-cage shape helps to avoid arc discharge.

[0317]

[0374] The configuration shown in Figure 28A is delivered using a sheath (not shown) as described in detail above, and both energy deliverers 108, 108' are self-expandable. In other embodiments, the second energy deliverer 108' is placed in a folded state before being delivered into the bronchoscope, and once positioned in the desired target area, is deployed / expanded via a tension wire (not shown) connected to its second distal end restraint 124') and mechanism in the handle 110. This combination of full basket (energy deliverer 108') and half basket (energy deliverer 108) can be used for bipolar or unipolar energy delivery. When the electrodes are made of braided metal wire, each wire is supported by multiple adjacent wires, as well as by the weaving nature of the braid itself. This support and weaving configuration can ensure minimal variation in the spacing between wires, which is otherwise known as the hole or opening size of the braid. Furthermore, this support and weaving configuration allows the braid to be constructed from very small wires, and still has remarkable radial stability of the basket. This makes it possible to use many wires (e.g., 12, 16, 18, 20, 22, 24, etc.) while maintaining the small contours of the energy delivery bodies 108, 108' in a folded or constrained state, while optimizing the opening size of the braid when the energy delivery bodies 108, 108' are deployed or expanded. In this embodiment, the spacing between the wires is quite narrow, resulting in 360-degree treatment within the lung passage.

[0318]

[0375] Figure 28B shows an embodiment in which both energy carriers 108 and 108' consist of braided metal wire with proximal end restraints 122 and 122' fixed to the shaft 106. In this embodiment, both energy carriers 108 and 108' are configured to form a half-basket. A sheath (not shown) of this configuration can be used for delivery as described above, and the energy carriers 108 and 108' are self-expanding. This configuration of the half-basket energy carriers 108 and 108' can be used for bipolar and / or unipolar energy delivery.

[0319]

[0376] In some embodiments, the entire surface of one or more energy delivery bodies 108 is energized by an energy signal for delivery to a target tissue. However, in other embodiments, an active surface area of ​​the energy delivery body 108 is provided, and the rest is not active. In some embodiments, this is achieved by partially insulating one or more portions of the energy delivery body 108, leaving one or more active regions. For example, Figure 29 shows a braided wire cage energy delivery body 108 consisting of energizing wires 120 (acting as one or more electrodes), with a portion of the wire 120 insulated, with a portion of the insulator removed to define an active region 820. In some embodiments, the insulator is removed from the outer (tissue contact) surface of the wire 120. This technique is useful, for example, when the measurement impedance through the electrode wire 120 is affected by the amount of exposed metal, and when it is desirable that the measurement impedance represents the interface between the electrode and the tissue. In other embodiments, the insulating material can be removed from both the outer and inner surfaces of the electrode wire 120. One method for manufacturing an energy delivery body 108 having this configuration involves creating a braid using insulated wires and then removing the insulation using appropriate means (e.g., laser, machine) to create one or more active regions 820. Although this example shows a single active region 820, multiple active regions are also conceivable to generate any treatment pattern. Similar techniques can be used for the unbraided energy delivery body 108 described herein. In these embodiments, insulation can be applied or removed as part of the manufacturing process to define any configuration of active regions (one or more) 820 that is desirable for achieving various treatment patterns.

[0320]

[0377] Figure 30 shows another embodiment in which a metal (e.g., nitinol) tube 830 is laser-cut to form a folding cage 832 with both ends constrained via the tube 830 itself. The cage 832 can then be expanded and shaped so that it can self-expand during use to function as an energy delivery body 108. Alternatively, a push / pull mechanism can be used to expand / fold the cage 832 for delivery and treatment. In some embodiments, as shown in Figure 31, one end 834 of the cage 832 is removed to form a free end 836. An insulating material (e.g., polymer tube) can then be advanced beyond the free end 836 and applied to a portion of the cage 832. In some embodiments, the insulating material is applied to the proximal and distal portions of the cage, leaving one or more conductive / active regions 820 between them. In other embodiments, as shown in Figure 31, the wires 120 of the cage 832 are insulated, and one or more separate additional electrodes 840 (shown as coils) are connected to the insulated cage wires to form the active regions 820. Next, this assembly can be fixed to the catheter 102, allowing the energy delivery body 108 to operate as a unipolar electrode having a plurality of predetermined active regions 832.

[0321]

[0378] Figure 32 shows another embodiment of the energy delivery body 108. In this embodiment, the body 108 comprises a plurality of teeth 840, similar to the free end 836 in Figure 31. The tines 840 can expand outward to contact the lung passage wall. In some embodiments, one or more teeth 840 are insulated with insulating material 842. Electrodes 107 positioned along each tine 840, such as near the distal end of each tine 840, can be created by removing the insulating material 842 to expose the underlying activatable element or wire. Alternatively, separate electrodes 107 can be mounted on the insulating material 842, as shown in Figure 32. In some embodiments, the tines 840 are formed of polymer-coated wire, which can act as a structural support for self-expanding the tines 840, be biasable to deliver therapeutic energy, and / or have an impedance that can be used to sense temperature. In some embodiments, the teeth 840 are foldable via a sheath 126 for delivery, and can expand to contact tissue when the sheath 126 retracts. All electrodes can emit simultaneously in a unipolar manner, emit independently in a unipolar manner, and / or emit between each other in any pattern necessary to produce the desired therapeutic effect. Electrode lengths range from approximately 3mm to 5cm, such as 3mm, 5mm, 1cm, 2cm, 3cm, 4cm, or 5cm. Although all are depicted as the same size in Figure 32, the dimensions (e.g., length, width) vary.

[0322]

[0379] Figure 33 shows another embodiment of the energy delivery body 108. In this embodiment, the energy delivery body 108 includes one or more projections 850 instead of a cage weave. Each projection 850 acts as an electrode and is formed by a wire or ribbon 120 that curves radially outward from the longitudinal axis or shaft 106 of the catheter 102. In this embodiment, each projection 850 is electrically insulated from each other. The projections 850 may be made of a variety of suitable materials to act as electrodes, such as stainless steel, spring steel, or other alloys, and may be, for example, round wire or ribbon. Each projection 850 is insulated by an insulating segment 852, such as a polymer (e.g., PET, polyether block amide, polyimide), over at least a portion of the proximal and distal ends of the energy delivery body 108. The exposed portion 854 of the wire or ribbon can then act as an electrode on each projection 850. In one embodiment, the exposed portion 854 of the projection 850 does not contain the insulator 852 at all. In other embodiments, the insulator 852 is removed only from the outer surface of the projection 850, leaving the sides of the projection 850 that do not come into contact with the tissue that is completely insulated (e.g., the inner surface facing the shaft 106 of the catheter 102). In one embodiment, each projection 850 is independently biased, with two projections 850 acting as a neutral electrode (pair) and two projections 850 acting as an active electrode. The neutral and active electrodes can be positioned adjacent to each other. Neutral electrodes (counter electrodes) positioned 180 degrees apart can be electrically connected to each other and thus can also be an active electrode. In this embodiment, only two wires (power lines) are required to connect the two pairs of projections 850 to the generator 104. Furthermore, the pair of projections 850 used in the bipolar configuration can be further multiplexed to allow any combination or rotation of the active electrode vs. neutral electrode. The generator 104 can be configured to have enough channels (i.e., 1 to 4 channels) to support any of these methods. This embodiment of the energy delivery body 108 can be delivered in a folded configuration as needed and extended to tissue contact via a pull-back wire and mechanism within the handle.

[0323]

[0380] Figure 34 shows another embodiment of the energy delivery body 108 including one or more projections 850, each projection 850 curving radially outward from the longitudinal axis of the catheter 102 or shaft 106. However, in this embodiment, each projection 850 is formed of a non-conductive material and carries, supports, and / or is otherwise coupled to a separate electrode 107. Each electrode 107 has a conductor 860 that connects the electrode 107 to the generator 104. The projections 850 position the electrode 107 relative to the tissue during expansion, for example, via a pull wire and mechanism in the handle. In this embodiment, each electrode 107 is positioned on or adjacent to each projection 850. If the projections 850 are made of metal, an insulator is provided to electrically insulate the electrode 107 from the projections 850 themselves. If the projections 850 are made of polymer or other non-conductive material, additional insulation is not required. In some embodiments, the projections 850 consist of a circular wire or ribbon and are configured to form a straight cage as shown. In other embodiments (not shown), the projections 850 are configured in a helical shape. Separate electrodes 107, as shown in Figure 34, are similarly applicable to other embodiments, such as when the cage is made of braided material. As with the embodiment in Figure 33, each electrode 107 may be energized in various combinations. Furthermore, each projection 850 carries electrodes 107 that are electrically connected to each other or electrically insulated from each other. To increase the surface area of ​​the electrodes 107, each can be constructed, for example, from a metal coil or in the form of a slotted (e.g., laser-cut) tube. These configurations allow for a larger spatial range and maintain the flexibility of the electrodes 107 to allow the projections 850 of the cage to bend and straighten freely. As in Figure 33, the surface of the projections 850 can be completely exposed or insulated over areas that do not come into contact with the tissue.

[0324]

[0381] Figure 35 shows another embodiment of the catheter 102 having at least one energy delivery body. In this embodiment, each energy delivery body comprises an expandable coil which can either act as an electrode itself or act as a carrier for separate electrodes mounted thereon. In this embodiment, the catheter 102 comprises two energy delivery bodies, namely a first energy delivery body 108 positioned adjacent to a second energy delivery body 108'. Each energy delivery body 108, 108' has the shape of an expandable coil. The distal end 870 of the second energy delivery body 108' is connected to or formed on an inner member 872, and the proximal end 874 of the first energy delivery body 108 is connected to an outer member 876. The outer member 876 is rotatable relative to the inner member 872, causing the energy delivery bodies 108, 108' to fold and / or expand. The coupler 878 mounts the energy deliverers 108 and 108' together and, if desired, insulates them from each other. The energy deliverers 108 and 108' can be operated unipolar and / or bipolar. The sizes of the energy deliverers 108 and 108' may be the same or different as described herein. The length of each expansion coil ranges from approximately 5 mm to approximately 20 mm.

[0325]

[0382] Figure 36 depicts an energy delivery body 108 configured for more limited application of therapeutic energy, such as along a narrow region along the lung passage wall or along a partial inner circumference of the lung passage. In this embodiment, the energy delivery body 108 includes a coil that limits the length of the active area. Such embodiments can be used when a very localized tissue effect is desired, or when the tissue effect extends beyond the active area in contact with the tissue. In this embodiment, the energy delivery body 108 includes a coil 880 having width and length, the length of which the coil 880 can be pre-formed into a semicircular or circular pattern, as shown. The therapeutic length L1 is provided by the width of the coil 880 when it contacts the lung passage wall W. This configuration can be operated in a unipolar configuration, as shown. However, it is further conceivable to use two or more coils 880 to enable bipolar and / or multiplexed energy delivery. Similarly, Figure 37 shows an embodiment of the energy delivery body 108 including a rod 882 (such as a shaft 106) having width and length, the length of which the rod 882 is pre-formed into a semicircular or circular pattern. The rod 882 includes one or more electrodes 107 arranged along its length. The one or more electrodes 107 may be embedded within the rod 882 or otherwise fixed. The therapeutic length L1 is provided by the width of the one or more electrodes 107 in contact with the lung passage wall W. This embodiment allows for unipolar activation between all electrodes and a dispersive (neutral) electrode, bipolar activation between individual electrodes, and / or multiple activation between any combination of electrodes. It is further assumed that two or more of these devices can be used to enable energy delivery between them. When the energy delivery body 108 is pre-formed into a semicircular or circular shape, the energy delivery body 108 can be folded and constrained for self-expansion using a sheath 126, and / or the energy delivery body 108 can be expanded using a pull / push wire. These methods for expanding and / or folding the energy delivery body 108 are described in detail in other examples provided.

[0326]

[0383] The energy delivery body 108 is optimized for situations where a higher degree of control over the force exerted on the bronchial wall is desired. In this embodiment, the energy delivery body 108 is delivered to the bronchial lumen via a three-step process. First, as shown in Figure 38, the sheath 126 is retracted proximally, thereby exposing one or more prongs 900 that act as projections. This embodiment includes four prongs 900 arranged symmetrically around the central lumen 902, as shown in the cross-sectional view of Figure 38A. Any number of prongs 900 may be present, including one, two, three, four, five, six or more. Each projection 900 includes at least one electrode 107. Figure 39 shows an embodiment of a prong 900 having two electrodes 107 having an elongated shape (like a wire) attached to an insulating substrate 904 such as a polymer substrate (e.g., ribbon, strip) as a means for maintaining the distance between the electrodes 107. The electrodes 107 may have a circular or square / rectangular cross-section and are typically fixed to the insulating substrate 904 so that they are substantially parallel to each other. Methods for attaching the electrodes 107 to the insulating substrate 904 include, but are not limited to, co-extrusion, deposition, adhesive-based bonding, and thermal bonding. The width of the insulating substrate 904 can be varied.

[0327]

[0384] Figure 40 shows one embodiment of the prong 900 having a narrower insulating substrate 904 than that shown in Figure 39. Similarly, Figure 41 shows an embodiment of the prong 900 having an even narrower insulating substrate 904 and more than two electrodes 107. In particular, Figure 41 shows five electrodes 107, but any number of electrodes 107 may exist, such as one, two, three, four, five, six, seven, eight, or more. Figure 42 shows a plurality of electrodes 107 mounted on a polymer substrate (e.g., ribbon, strip), where the electrodes 107 have an elongated shape (such as wires) and are positioned substantially parallel to each other with gaps between each wire.

[0328]

[0385] In some embodiments, the insulating substrate 904 having electrodes 107 is configured as a strip (Figures 39-42). Thus, the electrodes 107 are deployed as a linear strip positioned along the length of the airway. In other embodiments, the insulating substrate 904 having electrodes 107 is configured as a helical, and the electrodes are deployed in a helical manner. Figure 43 shows an insulating substrate 904 having electrodes 107 configured as a helical, as illustrated in Figures 39-40. Figure 44 shows an insulating substrate 904 having electrodes 107 configured as a helical, as shown in Figure 41.

[0329]

[0386] In some embodiments, the strip or ribbon can be unfolded using a push-pull mechanism as described in relation to other embodiments. In the case of a helical strip, a rotation mechanism can also be used. Depending on the energy application algorithm controlled by the generator, the electrodes 107 can be electrically connected to each other, isolated from each other, or have different interconnection patterns between them.

[0330]

[0387] Once one or more prongs 900 are exposed, the second step of the three-step process includes introducing an expandable member 910, such as a balloon, by advancing the expandable member 910 from the lumen 902 while it is in an unexpanded state. The third step includes expanding the expandable member 901, such as inflating a balloon, as shown in Figures 45A to 45B. It is inserted until a desired interface between the prong 900 (and thus the electrode 107) and the bronchial wall W is achieved. In other embodiments, the prongs 900 are positioned while the expandable member 910 is already positioned beneath the prongs 900, so their relative longitudinal positions do not change. In this configuration, withdrawal of the sheath 126 exposes both the expandable member 910 and the prongs 900 simultaneously, thus eliminating the step of advancing the expandable member 910 from the lumen 902. As described above, the expandable member 910 is then expanded (e.g., inflated) until the desired interface between the prong 900 and the bronchial wall S is achieved. The size (e.g., length, width) of the prong 900 may be the same or different. The number of prongs 900 varies between 1 (unipolar configuration) and 100 (unipolar and / or bipolar) configurations. The energy application to the electrode 107 varies widely depending on the algorithm of the energy delivery device (e.g., generator).

[0331]

[0388] Figure 46 shows an embodiment of an energy delivery catheter 102 having more than two energy delivery bodies 108 (four energy delivery bodies 108 are shown) that can operate in a bipolar / multipolar manner. In this embodiment, the energy delivery bodies 108 consist of braided metal wires, and the wires function as electrodes. The energy delivery bodies 108 can be operated bipolarly by circulating power supplied by an external generator 104 between any pair of two energy delivery bodies 108, one of which is neutral. The combination between the active energy delivery body 108 and the neutral energy delivery body 108 also varies. For example, in one embodiment, energy can be applied to two or more energy delivery bodies 108 while one energy delivery body 108 functions as the neutral electrode. The combination of active energy deliverers 108 and neutral energy deliverers 108, the switching / circulation of energy between active energy deliverers 108 and neutral energy deliverers 108, and the selection between active energy deliverers 108 and inactive energy deliverers 108 are achieved by the energy delivery algorithm 152 of the generator 104. The algorithm 152 can apply and distribute energy among the energy deliverers 108 based on a predetermined method, image data, and other factors determining the desired region and treatment depth.

[0332]

[0389] Figure 47 illustrates another embodiment of the energy delivery catheter 102 having a multi-energy delivery body design. In this embodiment, the energy delivery bodies 108 operate in a unipolar and / or bipolar multiplexing manner. Unipolar energy delivery is achieved by supplying energy between one or more energy delivery bodies 108 positioned near the distal end 920 of the catheter 102 and dispersed(pair) electrodes 922 applied externally to the patient P's skin. Switching / circulating energy between the delivery bodies 108, the active energy delivery body 108 and the dispersed electrodes 922, and the selection between the active energy delivery body 108 and the inactive energy delivery body 108 are achieved via the energy delivery algorithm 152 of the generator 102. The algorithm 152 can apply and distribute energy among the energy delivery bodies 108 based on a predetermined technique, image data, and other factors determining the desired area and depth of treatment.

[0333]

[0390] The drawings herein depict energy delivery bodies 108 of substantially the same size (e.g., length, diameter) and shape for illustrative purposes, but the configuration is not limited thereto. In some embodiments, the energy delivery bodies can be sized to take into account the tapering of the airway lumen, to better localize the energy field, and / or to enhance tissue treatment. For example, if the desired catheter positioning requires the distal energy delivery body to be in the lobe bronchus (approximately 9-12 mm in diameter) and the proximal energy delivery body to be in the main bronchus (approximately 12-16 mm in diameter), the distal energy delivery body may be designed to expand to approximately 12 mm, and the proximal energy delivery body may be designed to expand to approximately 16 mm. Energy delivery bodies are also different sizes to better localize the energy field. For example, if unipolar energy delivery is desired, it is beneficial to incorporate a dispersed (neutral) electrode into the catheter or another device for positioning (rather than being positioned outside the patient as shown in Figure 47). It is closer to the therapeutic energy deliverer to better localize the energy. This can reduce the risk of causing muscle contraction or arrhythmias because a lower voltage can be applied to generate the same electric field. Energy deliverers are also different sizes to enhance their ability to separate tissues. In some embodiments, the active portion of an energy deliverer is its area in contact with the airway. Thus, for example, if two energy deliverers of the same size are positioned in airways of the same size and expanded in approximately the same way, the contact area of ​​the two different energy deliverers may be approximately the same. However, if two energy deliverers of the same size are positioned in airways of different sizes and / or are not expanded in the same way, the active portions of each energy deliverer will be significantly different. If one electrode is configured to have a larger contact area than the other, the non-uniform electric field will polarize the cells, resulting in the generation of a greater force in the effort to separate the tissue. Energy deliverers are also configured to bias the energy field perpendicular to the epithelium or to generate a shear force along the epithelium.

[0334]

[0391] Figure 48 shows an exemplary catheter 102 configured to be detachably connected to a bronchoscope 112. In this embodiment, the handle 110 of the catheter 102 includes a docking mechanism 950 that is detachably connected (e.g., by a snap fastener) to an external port 952 of the working channel of the bronchoscope 112. Such a docking mechanism 950 makes it easier for the operator to control both the bronchoscope 112 and the catheter 102 during a procedure. In other embodiments, the handle 110 is connectable to various bronchoscopy attachments and / or accessories (e.g., valves, not shown) that can be installed on the external port 952 of the working channel of the bronchoscope 112. In yet another embodiment, the handle 110 has no mechanism to connect to an external port or valve of the working channel of the bronchoscope 112. In such a case, the stability of the catheter 102 is achieved by friction between the shaft of the catheter 102 and an accessory (e.g., a valve) installed on the external port 952 of the working channel of the bronchoscope 112.

[0335]

[0392] In some embodiments, the length between the distal end 954 of the catheter handle 110 and the proximal end 956 of the most proximal energy delivery body 108 is adjusted to be substantially equal to the length of the working channel of the bronchoscope 112, based on the distance between the proximal and distal ends of the working channel. Once the catheter handle 110 is connected (e.g., by snapping) to the external port 952 of the working channel of the bronchoscope 112, the energy delivery body(s) 108 are introduced into the lung passage. The step of positioning one or more energy delivery bodies 108 within a target area of ​​the lung passage can be achieved by moving the bronchoscope 112, thereby moving the catheter 102 therein. Once one or more energy delivery units 108 are successfully positioned within the target area and this position is visually evaluated and confirmed by the operator (e.g., using visual bronchoscopy), the one or more energy delivery units are deployed / expanded or positioned to make contact with the tissue by a mechanism in the catheter handle 110 that is operably connected to the one or more energy delivery units 108 (e.g., levers, sliders, plungers, buttons that are operably connected to the one or more energy delivery units 108) (or by a pull wire or other mechanism), and are ready for energy delivery.

[0336]

[0393] In some embodiments, the length between the distal end 954 of the catheter handle 110 and the most distal end 958 of one or more energy deliverers 108 is adjusted to be substantially equal to the length of the working channel of the bronchoscope 112, based on the distance between the proximal end of the working channel 954 and the distal end of the working channel 960. Once the catheter handle 110 is connected (e.g., by snapping) to the external port 952 of the bronchoscope working channel, one or more energy deliverers 108 are not yet introduced into the bronchial lumen (Figure 49A) but are positioned within the channel of the bronchoscope 112. The process of introducing one or more energy deliverers 108 into the bronchial lumen (Figure 49B) can be achieved via the main mechanism of the handle 112 (e.g., lever, slider, plunger, button). Once one or more energy deliverers 108 are successfully positioned within the target area and this position is visually evaluated and confirmed by the operator (e.g., using visual bronchoscopy). The electrodes are prepared for energy delivery via a secondary mechanism (e.g., lever, slider, plunger, button) of the handle 112, to a position where they can be extended or deployed or in contact with tissue (Figure 49C). In one configuration, the secondary handle mechanism (e.g., lever, slider, plunger, button) is operably connected (e.g., glued or welded) to the proximal end of the catheter sheath. To deploy / expand one or more energy deliverers 108, the operator moves the secondary mechanism proximal, thereby moving the catheter sheath proximal, thereby releasing the constraints on one or more energy deliverers 108 and allowing them to expand. In another configuration, the secondary handle mechanism (e.g., lever, slider, plunger, button) is operably connected (e.g., glued or welded) to the proximal end of a pull or push wire / tube. To deploy or expand one or more energy deliverers 108, the operator moves the secondary mechanism proximal to pull the pull wire or tube, or distally to push the push wire / tube. In both embodiments, depending on the specific configuration of the catheter and its deployment mechanism, actions performed by the operator using the secondary handle mechanism result in the deployment or expansion of one or more energy delivery bodies 108.In yet another configuration, there is one or more secondary handle mechanisms connected to one or more pull wires or push wires or tubes. In this scenario, the extension of one or more energy deliverers 108 can be controlled independently by activating different secondary handle mechanisms at different time and magnitude levels.

[0337]

[0394] In some embodiments, the length between the distal end of the catheter handle and the proximal end of one or more energy deliverers 108 is adjusted to be substantially longer than the length of the working channel. When one or more energy deliverers 108 are introduced into the lung passage, the handle is not in contact with the external port of the working channel of the bronchoscope. The step of positioning one or more energy deliverers 108 within the target area is achieved by moving the bronchoscope or by moving the catheter itself. In this case, the catheter is long enough so that the catheter handle can be held by the operator or placed on or near the patient, allowing the operator to hold the bronchoscope. Once one or more energy deliverers 108 are successfully positioned within the target area and this position is visually evaluated and confirmed by the operator (e.g., using visual bronchoscopy), one or more energy deliverers 108 are prepared for energy delivery by mechanisms (e.g., levers, sliders, plungers, buttons) in the catheter handle that are operably connected to one or more energy deliverers 108, so that they can be deployed or in contact with tissue.

[0338]

[0395] According to embodiments described herein, which can be combined in part or in whole with other embodiments, the catheter handle includes a docking mechanism that can be detachably connected (e.g., by snap-fastening) to an external port of the bronchoscopy working channel. In other embodiments, the handle can be connected to various accessories and / or accessories (e.g., valves) attached to the external port of the bronchoscopy working channel. In yet another embodiment, the handle may not have any mechanism for snap-fitting to the external port of the bronchoscopy working channel, and the stability of the device is achieved by friction between the catheter shaft and the accessories (e.g., valves) attached to the external port of the bronchoscopy working channel.

[0339] VIII. Treatment Patterns

[0396] Patient P has a single or multiple target areas for treatment. A target area is an adjacent area of ​​a lung passage that is targeted for treatment. A single lung passage contains multiple target areas. Similarly, target areas may be positioned along separate lung passages. Each target area contains one or more target segments. A target segment is a portion of a lung passage that can be treated by a single positioning (i.e., a single treatment) of the catheter 102. Thus, a target segment is defined by an lateral region boundary along the lung airway wall W, where the wall tissue is being treated by one or more electrodes 108 of the catheter 102. Different embodiments of the catheter 102 may cover areas of different sizes within the lung passage. Thus, the size of the target segment varies based on the design of the catheter 102 / system 100. In addition, the catheter 102 can be moved continuously along the lung passage to create multiple adjacent target segments, which cover the target area.

[0340]

[0397] Therefore, methods for treating a patient's airway include (a) performing a single treatment on a target segment, (b) performing two or more treatments on adjacent target segments such that the overall treatment area is generally continuous, and / or (c) performing two or more treatments spaced apart from each other. Figure 50 is a schematic diagram of a single target segment 1000 in the main bronchus MB of the lung. In this embodiment, the target segment 1000 is treated by positioning one or more energy delivery bodies 108 of the catheter 102 and delivering therapeutic energy thereto. Figure 51 is a schematic diagram of two target segments 1000a and 1000b positioned adjacent to each other such that the overall target or treatment area 1002 is generally adjacent. Typically, the two target segments 1000a and 1000b are treated by first positioning the catheter 102 to treat the first target segment 1000a, and then repositioning the catheter 102 to treat the second target segment 1000b. Naturally, various target segments can be treated with different catheters 102. It will also be understood that target segments 1000a and 1000b may be treated in any order. Similarly, in some embodiments, target segments overlap. Thus, both figures 50-52 show a single target region within the pulmonary passage. Figure 52 is a schematic diagram of two target regions 1004 and 1006 in a patient. In this embodiment, the first target region 1004 is located within the main bronchus MB, and the second target region 1006 is located within the lobular bronchus LB of the lung. Here, the first target region 1004 is covered by target segment 1008, and the second target region 1006 is covered by target segment 1010, where target segments 1008 and 1010 are spatially separated from each other. Furthermore, the two target segments 1008 and 1010 can be treated by first positioning the catheter 102 to treat the first target segment 1008, and then repositioning the catheter 102 to treat the second target segment 1010. Naturally, various target segments can be treated with different catheters 102. The target segments 1008 and 1010 can be treated in any order. It is understood that these figures provide exemplary treatment patterns that can be used individually or in combination with each other to obtain the desired results.

[0341]

[0398] Within a target segment, it will also be understood that the pulmonary passage tissue can undergo various treatment patterns in any given cross-section. For example, some embodiments involve treating the entire circumference of the airway over a given length of the target segment, while other embodiments involve treating one or more discrete portions of the airway circumference over a given length of the target segment.

[0342]

[0399] Figure 53 is a schematic side view of a portion of an energy delivery body 108 consisting of a braided basket. The braid consists of individual wires 120 that deliver energy. There are holes 1050 between the wires. The diameter of the holes varies depending on the degree of expansion (indicated by diameter 1052). Figure 54 is a schematic cross-sectional view of the energy delivery body 108 of Figure 53 positioned within a lung passage having an airway wall W. Thus, the energy delivery body 108 is shown as multiple cross-sections of wires. 120 are 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 is achieved. Similarly, in some embodiments, continuous circumferential treatment along the length 1056 of the energy delivery body 108 is also achieved. This effect is shown in Figure 55.

[0343]

[0400] In some embodiments, at least the applied electric field (V / cm) and electrode design are considered to achieve substantially continuous circumferential treatment over a given length. In one example, the electric field is applied in a unipolar manner, the electric field is applied substantially to the energy delivery body 108, and the dispersed (neutral) electrode is positioned outside or elsewhere inside the patient's body. The change in the magnitude and / or distribution of the field depends on the applied voltage and the geometric relationship of the wires 120. Referring to the example in Figures 53-55, the energy delivery body 108, which is in contact with the periphery and length of the tissue to be treated, is composed of a metal braid of wires 120. By bringing a number of wires 120 close together, the electric field between each wire 120 is sufficient to produce the desired tissue effect continuously around the entire circumferential region of the contact area 1054. In this example, the diameter 1052 is designed to expand from a diameter of about 2-3 mm when fully folded for delivery to a diameter of about 10 mm, 12 mm, 15 mm, 18 mm, 20 mm, or 22 mm when fully extended. All values ​​within this range are applicable. Depending on the degree of expansion, the size of the pore diameter 1050 varies, but is generally effective in producing a continuous tissue effect with a pore diameter of at least 10 mm². If the pore size becomes significantly larger, the same applied field may result in a discontinuous tissue effect (indicated by the shadow 1056), as shown in Figure 56. In this embodiment, the energy delivery body consists of four wires 120, each wire 120 providing a tissue effect that contributes to a discontinuous tissue effect overall. This can accelerate the healing rate while still affecting a sufficient amount of tissue to provide clinical benefit. Discontinuous lesions can also be achieved by reducing the applied electric field.

[0344]

[0401] Some embodiments have an energy delivery body that includes peripheral treatment portions in the range of about 25 to about 50%, about 50% to about 75%, or about 75% to about 100%, encompassing all values. All values ​​within this range can be applied. Some embodiments include treatment lengths in the range of about 5 mm to about 20 mm, encompassing all values ​​and partial ranges in between, allowing sufficient flexibility to treat a wide range of patient anatomical structures while minimizing the number of individual treatments performed.

[0345] IX. General Embodiments

[0402] In some embodiments described herein, which can be combined in part or in whole with other embodiments, a lung tissue modification system for performing a lung procedure includes an energy generation generator, an energy delivery catheter, accessories, and one or more imaging devices.

[0346]

[0403] In some embodiments, a bipolar catheter having two energy deliverers attached near its distal end is connected to an extracorporeal energy generation generator. The distal end of the catheter is guided through the mouth or nose into the bronchial tree using a bronchoscope or other direct visualization system. The energy deliverers are deployed, expanded, and / or otherwise positioned so that they contact the airway wall. The operator can then activate the generator via any suitable interface, such as a foot switch, a button on the generator, a button on the catheter, or a remote control, to deliver energy to the airway tissue adjacent to and / or between the electrodes. In some embodiments, the operator may choose to move the energy deliverers to a different portion of the affected airway to deliver a different treatment, or to treat an entire surface of a portion of the airway or multiple portions of the airway. In some embodiments, multiple treatments can be performed on the same portion of the airway depending on the desired penetration depth. In some embodiments, two or more different energy delivery algorithms can be employed to influence the penetration depth.

[0347]

[0404] In some embodiments, a unipolar catheter having a single energy delivery body attached near its distal end is connected to an energy generation generator outside the body. The distal end of the catheter is guided through the mouth or nose into the bronchial tree using a bronchoscope or other direct visualization system. The electrode is deployed, expanded, and / or otherwise positioned so that it contacts the airway wall. A dispersive (neutral) electrode or counter electrode plate is fixed to another surface of the patient (e.g., an external location such as the patient's skin) and also connected to the generator. The operator can then activate the generator, for example via a foot switch, a button on the generator, a button on the catheter, or remote control, to deliver energy to the airway tissue via the electrode. The operator can move the energy delivery body to another part of the affected airway to deliver treatment, or choose to treat an entire surface of a portion of the airway, or multiple portions of the airway. In some embodiments, two or more unipolar energy delivery bodies can be incorporated into one or more catheters to enable treatment of multiple locations without repositioning the catheter. Depending on the desired penetration depth, multiple treatments can be performed on the same portion of the airway. In some embodiments, two or more different energy delivery algorithms can be employed to influence the penetration depth. In some embodiments, the desired treatment algorithm can be selected using a user interface on the generator, and in other embodiments, the algorithm can be automatically selected by the generator based on information obtained from one or more sensors.

[0348]

[0405] In some embodiments, a catheter having multiple energy deliverers attached near its distal end is connected to an extracorporeal energy generation generator. The distal end of the catheter is guided through the mouth or nose into the bronchial tree using a bronchoscope or other direct visualization system. The energy deliverers are deployed, expanded, or otherwise positioned so that they contact the airway wall. The operator can then activate the generator via, for example, a foot switch, a button on the generator, a button on the catheter, or a remote control to deliver energy to the airway tissue via the energy deliverers. In some embodiments, energy delivery can be multiplexed across any one or more energy deliverers in any suitable pattern to affect the desired target tissue. In some embodiments, a dispersed (neutral) electrode can be attached to another surface of the patient, such as the patient's skin, and further connected to the generator to enable unipolar energy delivery to any energy deliverer. Depending on the desired penetration depth, multiple treatments can be performed on the same portion of the airway. In some embodiments, two or more different energy delivery algorithms can be employed to affect the penetration depth. A user interface on the generator is used to select the desired treatment algorithm, or the algorithm is automatically selected by the generator based on the information.

[0349]

[0406] In some embodiments, a target therapeutic area is identified and used to select a therapeutic algorithm sufficient to affect pathogenic cells and / or deeper tissue. The electrode system can then be deployed to the site of pathogenic cells and / or abnormal airway wall tissue, and energy can be delivered to affect the target tissue. One or more imaging devices can be used before, during, and / or after treatment to determine where treatment occurred or not, and / or whether the energy adequately affected the airway wall. If it is determined that the target therapeutic area was missed or not adequately affected, energy delivery can be repeated and subsequently imaged as described herein until adequate treatment is achieved. Furthermore, imaging information can be used to determine whether a specific cell type and / or desired treatment depth was applied. This allows for the customization of energy delivery algorithms to treat a wide variety of patient anatomical structures.

[0350]

[0407] In some embodiments, any apparatus and / or system described herein can be used in methods for treating affected airways and / or other lung tissue (e.g., parenchymal tissue), including access to the airways and, optionally, pre-treatment, intra-treatment, and / or post-treatment imaging for the purpose of planning, guiding, and / or verifying treatment. In some embodiments, the method further includes one or more of customizing the treatment based on treating a sufficient treatment area with each energy application, treating a sufficient overall treatment area, treating to a sufficient depth, treating a given cell type, imaging and / or sensor information, and combinations thereof.

[0351] X. Example

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

[0352]

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

[0353]

[0410] A non-thermal energy delivery device with bipolar expandable energy delivery bodies was developed. The device included two energy delivery bodies, each containing a nitinol, braid, and expandable electrode, mounted concentrically on a catheter shaft with a mechanism for expanding and contracting both energy delivery bodies (see, for example, Figure 27). The diameter of the expanded energy delivery bodies ranged from approximately 5 mm to approximately 20 mm. The energy delivery bodies were substantially equal in length, each approximately 3 cm, and spaced approximately 2.5 cm apart from end to end along the longitudinal axis of the catheter shaft. To evaluate the effect of pulsed high-voltage energy on the epithelial and submucosal layers in the airway, the device was introduced into the left and / or right bronchi of live anesthetized pigs, and energy was delivered in a bipolar wave. The pulse frequency was approximately 300 kHz, the pulse amplitude was approximately 4000 V, and the total energy delivery duration was approximately 415 microseconds (83 microseconds per packet, 5 packets).

[0354]

[0411] After the procedure, the animals were retrieved and euthanized approximately 24 hours later. The airways were then incised and fixed in formalin for approximately 48 hours. The airways were then sectioned in approximately 5 mm increments and processed for histology using standard methods. Both treated and untreated sections were processed for comparison. Slides were prepared using hematoxylin-eosin (H&E) staining.

[0355]

[0412] Figure 57A shows a typical portion of a healthy, untreated airway, and Figure 57B shows a typical portion of a treated airway 24 hours after energy delivery. In the untreated airway (Figure 57A), ciliated epithelium E with intact submucosal structure including pseudolaminar columnar epithelial cells (PCEC) and goblet cells (GC), as well as submucosal glandular cells (SG), connective tissue (CT), smooth muscle (SM), and cartilage (CL). In the treated airway (Figure 57B), epithelium E with pseudolaminar columnar epithelial cells (PCEC) and goblet cells (GC) is substantially removed or destroyed, leaving only cellular residue and basement membrane. Furthermore, the submucosal tissue is affected. Most notably, submucosal glandular cells (SG) are almost absent, and the extracellular glandular structure is destroyed. Smooth muscle (SM) and connective tissue (CT) also show signs of cellular damage and destruction, while cartilage (CL) remains unaffected.

[0356]

[0413] Example 2: Circumferential treatment and tissue effects using a unipolar system

[0357]

[0414] A non-thermal energy delivery device with a unipolar, expandable energy delivery body was developed. The device included a single energy delivery body containing nitinol, braid, and an expansion electrode, concentrically mounted on a catheter shaft, with a mechanism for expanding and contracting the energy delivery body (see, for example, Figure 26). The expanded energy delivery diameter ranged from approximately 5 mm to approximately 20 mm. To evaluate the effect of pulsed high-voltage energy on the epithelial and submucosal layers in the airway, the device was introduced into the left and / or right bronchi of live anesthetized pigs, and energy was delivered in a bipolar wave. The pulse frequency was approximately 300 kHz, the pulse amplitude was approximately 4000 V, and the total energy delivery duration was approximately 415 microseconds (83 microseconds per packet, 5 packets).

[0358]

[0415] After the procedure, the animals were retrieved and euthanized approximately 24 hours later. The airways were then incised and fixed in formalin for approximately 48 hours. The airways were then sectioned in approximately 5 mm increments and processed for histology using standard methods. Both treated and untreated sections were processed for comparison. Slides were prepared using hematoxylin-eosin (H&E) staining.

[0359]

[0416] Figure 58A shows a typical portion of a healthy, untreated airway, and Figure 58B shows a typical portion of a treated airway 24 hours after energy delivery. In the untreated airway (Figure 58A), ciliated epithelium E with intact submucosal structures including pseudolaminar columnar epithelial cells (PCEC) and goblet cells (GC), as well as submucosal glandular structures including submucosal glandular structures (SG), connective tissue (CT), cartilage (CL), and smooth muscle (SM) can be observed. In the treated airway (Figure 58B), epithelium E and goblet cells (GC) were substantially removed or destroyed, leaving only cellular residues and the basement membrane (BM). Furthermore, the submucosal tissue was affected. Most notably, submucosal glandular cells (SG) were absent in some locations. In this example, extracellular glandular structures, including smooth muscle (SM) and connective tissue (CT), remained largely unaffected. Cartilage (CL) was unaffected. The therapeutic effect was similar whether using a bipolar or unipolar system, where tissue changes were observed where the electrode was in contact with the airway.

[0360]

[0417] As used herein, the terms “about” and / or “approximately” generally refer to a range close to the number and / or enumerated number and / or range when used with a number and / or range. For example, the terms “about” and “approximately” mean within ±10% of the enumerated value. For example, “about 100 [units]” could mean within ±10% of 100 (e.g., 90 to 110). The terms “about” and “approximately” can be used interchangeably.

[0361]

[0418] While preferred embodiments of the present invention have been described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Those skilled in the art will be able to conceive of numerous variations, modifications, and substitutions without departing from the present invention. Various substitutes for the embodiments of the present invention described herein can be used in carrying out the present invention. The claims appended below define the scope of the present invention, and all methods and structures relating to these claims, as well as their equivalents, are considered to be part of the present invention.

Claims

1. A system for treating excessive mucus secretion in diseased areas of the walls of a patient's lung passages, A catheter comprising at least one electrode, wherein the at least one electrode is positioned within the lumen of the lung passage, and is configured to transmit pulsed high-voltage energy to the diseased portion of the wall of the lung passage. A generator that communicates with the at least one electrode, the generator comprising at least one energy delivery algorithm configured to supply an electrical signal to the at least one electrode, thereby delivering pulsed high-voltage energy to the diseased portion of the wall to induce reverse remodeling of the diseased portion of the wall and reduce excessive mucus secretion, wherein the electrical signal has a waveform comprising at least one energy packet, each of which comprises a plurality of biphasic pulses having a voltage of 500V to 10kV, a frequency of 500kHz to 800kHz, and a maximum of 2000 cycles of biphasic pulses, A counter electrode plate connected to the generator and providing a return path for energy delivered via the catheter, A system that includes this.

2. The system according to claim 1, wherein inducing reverse remodeling includes inducing cell removal or cell death within the diseased portion of the wall while maintaining the collagen matrix within the diseased portion of the wall configured to allow cell infiltration for reverse remodeling.

3. The system according to claim 2, wherein the cells include endothelial cells or submucosal cells.

4. The system according to claim 2, wherein the cells include any cells that do not include the cartilage layer, but are cells in the diseased portion of the wall up to the cartilage layer.

5. The system according to claim 1, wherein inducing reverse remodeling includes inducing modification of cells in the diseased portion of the wall.

6. The system according to claim 5, wherein the modification of the cells alters the mucus production by the cells.

7. The system according to claim 5, wherein the modification of the cells reprograms the cells or modifies the cells for improved drug uptake.

8. The system according to claim 1, wherein the pulsed high-voltage energy is transmitted to the diseased portion of the wall to a target cell depth set to avoid the cartilage layer.

9. The system according to claim 8, wherein the target cell depth is set to affect the epithelial layer without extending beyond the basement membrane.

10. The system according to claim 1, wherein each energy packet has a maximum duration of 100 microseconds.

11. The system according to claim 1, wherein the at least one energy packet comprises five distinct energy packets, each of the five distinct energy packets having a number of cycles in the range of 1 to 100 cycles per packet.

12. The system according to claim 1, wherein at least one electrode functions as a single electrode in a unipolar manner, with respect to the counter electrode plate located outside the patient.

13. The system according to claim 12, wherein the electrical signal has a waveform comprising at least one energy packet, and each energy packet comprises a series of pulses having a voltage between approximately 2,000 and 4,000 volts.

14. The system according to claim 1, wherein the at least one electrode includes at least one pair of bipolar electrodes, and the generator supplies the at least one pair of bipolar electrodes with an electrical signal by communicating with the at least one pair of bipolar electrodes so that the pulsed high-voltage energy is transmitted in a bipolar manner to the diseased portion of the wall of the lung passage.

15. The system according to claim 14, wherein the electrical signal has a waveform comprising at least one energy packet, and each energy packet comprises a series of pulses having a voltage between approximately 100 and 4000 volts.

16. The system according to claim 1, wherein at least one of the at least one electrodes includes a plurality of wires that form an expandable cage configured to expand within the lung passage.

17. The system according to claim 1, wherein at least one of the at least one electrodes includes an energy delivery body having a plurality of separate activation regions, each insulated from the others.

18. The system according to claim 1, wherein at least one of the at least one electrodes includes an energy delivery body having an activated region, the activated region being insulated from the rest of the energy delivery body.

19. The system according to claim 1, wherein the generator includes a processor that communicates with at least one sensor, and the processor modifies at least one parameter of the electrical signal supplied by the generator based on data from the at least one sensor.

20. The system according to claim 1, wherein each pulse has a voltage of approximately 500 to 4000V.

21. The system according to claim 1, further comprising: a generator configured to acquire the patient's cardiac signal; and a processor configured to determine a safe period for transferring non-thermal energy to the wall of the lung passage based on the cardiac signal.

22. The system according to claim 21, wherein the safety period occurs in the ST portion of the cardiac signal.

23. The system according to claim 21, wherein the safety period occurs during the QT interval of the cardiac signal.

24. The system according to claim 1, wherein each of the energy packets of the pulse is separated by a rest period having a period that changes and synchronizes with the patient's heartbeat.

25. The system according to claim 16, wherein the plurality of wires can be energized simultaneously.

26. The system according to claim 16, wherein at least some of the plurality of wires can be energized individually.

27. The system according to claim 1, further comprising an impedance sensor positioned along the catheter and in contact with the wall of the lung passage to monitor the impedance within the wall, wherein the impedance sensor communicates with an indicator indicating the state of the wall based on the impedance.

28. The system according to claim 27, wherein the state of the wall includes the completion of treatment.

29. The system according to claim 27, wherein the condition of the wall includes a lack of therapeutic effect.

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