Methods, apparatuses and systems for treatment of diseases states and disorders

Abstract

To provide methods, apparatuses and systems for treatment of diseases states and disorders.SOLUTION: Apparatuses, systems and methods are provided for treating pulmonary tissues via delivery of energy, generally characterized by high voltage pulses, to target tissue using a pulmonary tissue modification system (e.g., an energy delivery catheter system). Example pulmonary tissues include, without limitation, the epithelium (goblet cells, pseudostratified ciliated columnar epithelial cells, and basal cells), lamina propria, submucosa, submucosal glands, basement membrane, smooth muscle, cartilage, nerves, pathogens resident near or within the tissue, or a combination of any of these.SELECTED DRAWING: Figure 11

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 610,430, filed December 26, 2017, and entitled "Methods, Devices, and Systems for the Treatment of Pulmonary Disorders," which is incorporated by reference in its entirety for all purposes. [Background technology]

[0002] I. Anatomy Figure 1 provides a diagram of the pulmonary anatomy. Air travels down the trachea (T) into the lungs (L), where it branches into multiple airways that extend throughout the lungs (L). The trachea (T) initially branches at the carina (CA) into left and right main bronchi (MB). These main bronchi (MB) further divide into lobar bronchi (LB), segmental bronchi (SB), and accessory bronchi (SSB), terminating at the alveoli (A). The diameter of the airways decreases as they branch. The trachea (T) can have a luminal diameter ranging from approximately 15 mm to 22 mm, the main bronchi (MB) can have a luminal diameter ranging from approximately 12 mm to 16 mm, and the lobar bronchi (LB) can have a luminal diameter ranging from approximately 9 mm to 12 mm, with the diameter of the subsequent bronchi continuing to decrease. The length of the airways also varies from segment to segment. In some patients, the trachea T ​​is approximately 12 cm long, the main bronchus MB is approximately 4.8 cm long, and the lobar bronchus LB is approximately 1.9 cm long, with the length of the subsequent bronchi continuing to decrease. Additionally, the airway walls become thinner, and there is less supportive lung tissue as one moves distally.

[0003] The airways of the lung (L) are composed of various layers, each containing one or several cell types. Figure 2 shows a cross-sectional view of the airway wall (W) with its various layers and structures. The innermost cell layer of the airway wall (W) is the epithelium or epithelial layer (E), which contains pseudostratified columnar epithelial cells (PCEC), goblet cells (GC), and basal cells (BC). Goblet cells (GC) are responsible for secreting mucus (M), which fills the inner wall of the airway and forms a mucus layer. The pseudostratified columnar epithelial cells (PCEC) contain cilia (C), which extend across the mucus layer. The cilia (C), attached to the epithelium (E), beat toward the nose and mouth, pushing mucus (M) up the airways and away from the lungs.

[0004] Basal cells (BC) are attached to the basement membrane (BM), and beneath the BM lies the submucosa, or lamina propria (LP). The lamina propria (LP) contains various cell and tissue types, including smooth muscle (SM). Smooth muscle is involved in bronchoconstriction and bronchodilation. The lamina propria (LP) also contains submucosal glands (SG), which are involved in many inflammatory responses to pathogens and foreign bodies. Similarly, the vagus nerve (N) is present. Branches of the vagus nerve are located outside the airway wall or travel within it, innervating various cell types, including fibroblasts, lymphocytes, and mast cells, in addition to mucous glands, airway smooth muscle, connective tissue, and many others. Finally, beneath the lamina propria (LP) lies the cartilage layer (CL).

[0005] Figure 3 provides a cross-sectional view of the epithelium (E) of the airway wall (W) illustrating the types of cellular connections within the airway. Pseudostratified columnar epithelial cells (PCEC) and goblet cells (GC) are connected to each other by tight junctions (TJ) and adherens junctions (AJ). Pseudostratified columnar epithelial cells (PCEC) and goblet cells (GC) are connected to basal cells (BC) by desmosomes (D). Basal cells (BC) are then connected to the basement membrane (BM) by hemidesmosomes (H).

[0006] II. Pulmonary disorders Figures 4A and 4B show bronchial airway B in healthy and disease states, respectively. Figure 4A shows bronchial airway B in a healthy state with a normal amount of mucus M and no inflammation. Figure 4B shows bronchial airway B in a disease state, such as chronic obstructive pulmonary disease, particularly chronic bronchitis. Chronic bronchitis is characterized by airflow obstruction, chronic cough, and sputum production that persists for at least three months per year for two consecutive years. Figure 4B shows both excess mucus M and inflammation I, which cause airway obstruction. Airway inflammation I is consistent with thickening of the epithelial layer E.

[0007] A variety of lung disorders and diseases can cause airway obstruction, some of which are briefly described herein.

[0008] A. Chronic obstructive pulmonary disease (COPD) Chronic obstructive pulmonary disease (COPD) is a common condition characterized by chronic, irreversible airflow obstruction and persistent inflammation as a result of harmful environmental stimuli, such as cigarette smoke and other pollutants. COPD encompasses a variety of disorders, primarily affecting the airways, including chronic bronchitis and asthma. Emphysema, on the other hand, affects the alveoli, the air sacs responsible for gas exchange. Some individuals have features of both conditions.

[0009] In chronic bronchitis, airway structure and function are altered. In chronic bronchitis, harmful stimuli, such as cigarette smoke and pollutants, are inhaled and recognized as foreign by the airways, initiating the inflammatory cascade. Neutrophils, lymphocytes, macrophages, cytokines, and other inflammatory markers are found in the airways with prolonged exposure, leading to chronic inflammation and airway remodeling. Goblet cells can undergo hyperplasia, which increases their number, or hypertrophy, which increases their size. Overall, goblet cells produce more mucus in response to inflammatory stimuli to remove inhaled toxins. Excess mucus further narrows the airway lumen, leading to increased obstruction and the potential for mucus blockage in distal airways. Cilia are damaged by harmful stimuli, allowing excess mucus to remain in the airway lumen, impeding airflow from proximal to distal during inspiration and from distal to proximal during expiration. Smooth muscle hypertrophy and thickening result in bronchoconstriction. Submucosal glands may also become hyperplastic and hypertrophied, increasing their mucus output and the overall thickness of the airway wall, further narrowing the luminal diameter. All of these mechanisms contribute to chronic coughing and the expectoration of copious amounts of mucus. In severe cases of mucus blockage, the blockage impedes airflow into the alveoli, contributing to chronic hypoxia and respiratory acidosis.

[0010] In addition to a decrease in luminal diameter or complete obstruction of the airway, mucus hypersecretion can also cause exacerbations or a general deterioration in health. As a result of excess mucus and damaged cilia, pathogens such as bacteria (e.g., Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, opportunistic gram-negative viruses, Mycoplasma pneumoniae, and Chlamydia pneumoniae), viruses (rhinovirus, influenza / parainfluenza virus, respiratory syncytial virus, coronavirus, herpes simplex virus, adenovirus), and other organisms (e.g., fungi) can thrive, causing exacerbations and resulting in a range of symptoms. These include worsening cough, congestion, increased sputum volume, changes in sputum quality, and / or shortness of breath. Treatment for acute exacerbations may include oral or intravenous steroids, antibiotics, oxygen, endotracheal intubation, and the need for mechanical ventilation via a ventilator.

[0011] B. Asthma Asthma is a disease of the airways characterized by airway hyperresponsiveness.In asthma, epithelium may thicken, mucus hypersecretion may occur as a result of excessive production from goblet cells and submucosal glands, and smooth muscle may thicken.As discussed herein, mucus hypersecretion or excess mucus may allow pathogens to multiply and cause infection.In addition, mucus blockage in distal bronchi and bronchioles can be a direct cause of asthma exacerbation, increasing the severity by completely blocking airflow to distal bronchiole and alveoli.

[0012] C. Interstitial pulmonary fibrosis Interstitial pulmonary fibrosis is thought to begin with acute injury to lung tissue that leads to chronic, abnormal inflammation. Fibroblasts become activated in response to inflammation, causing pulmonary fibrosis, scarring, and deterioration of lung function. Only 20 to 30 percent of patients survive five years after diagnosis.

[0013] D. Cystic fibrosis (CF) Cystic fibrosis (CF) is a systemic disease with pulmonary manifestations defined by a genetic defect: mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in thick, unexpelled secretions. Chronic inflammation, via goblet cells and submucosal glands, causes airway remodeling and hypersecretion, leading to airway narrowing and infections that are difficult to completely resolve.

[0014] E. Bronchiectasis Bronchiectasis is a condition in which the airways dilate, thicken, and scar. It is usually caused by infection or damage to the airway walls, preventing the airways from clearing mucus, or both. In this condition, the airways lose their ability to clear mucus and are susceptible to repeated infections. Each infection causes additional damage, eventually leading to moderate airflow obstruction. Bronchiectasis can be caused by inherited disorders, such as primary ciliary dyskinesia, or can have idiopathic causes.

[0015] III. Lung Treatment In some cases, the most effective treatment for lung disorders is lifestyle changes, particularly smoking cessation. This is particularly true for COPD. However, many patients are unable or unwilling to quit smoking. A variety of treatments are currently available to alleviate the symptoms of lung disease.

[0016] A. Medication COPD can be managed with one or more medications, such as short-acting beta-agonists (SABAs), long-acting beta-agonists (LABAs), long-acting muscarinic antagonists (LAMAs), steroids, chronic antibiotic therapy, or PDE4 inhibitors such as roflumilast. SABAs and LABAs act on beta-receptors in airway smooth muscle, causing bronchodilation. LAMAs act via anticholinergic pathways, inhibiting the release of acetylcholine, causing bronchodilation. LABAs and LAMAs have been shown to reduce shortness of breath, decrease exacerbation frequency, and improve quality of life, but have not been shown to reduce mortality. The LAMA tiotropium can slow the rate of decline in lung function and prolong the time to exacerbation. Inhaled corticosteroids directly target inflammation. Inhaled corticosteroids have been shown to reduce exacerbations but have little effect on lung function and mortality. Combinations of LABAs, LAMAs, and inhaled corticosteroids are prescribed. Inhaled oxygen is known to reduce shortness of breath and improve mortality, but these results are only relevant in advanced disease represented by stringent criteria, requiring chronic administration via nasal cannula or alternative devices.

[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 enzyme PDE4. While it has very potent anti-inflammatory effects, it has side effects, particularly diarrhea, weight loss, nausea, decreased appetite, and abdominal pain, and is poorly tolerated. To treat acute inflammation during an exacerbation, patients may be prescribed oral steroids, such as prednisone. Patients have been known to continue oral steroids long-term if withdrawal leads to other exacerbations. Oral steroids have many side effects, including weight gain, insomnia, thyroid dysfunction, and osteoporosis, among others. Long-term administration of azithromycin or antibiotics has been shown to reduce the frequency of COPD exacerbations. Antibiotics can achieve this through their antibacterial effects, by killing the pathogens causing the exacerbation, or through other mechanisms, such as the reduction in mucus secretion shown with macrolide antibiotics. Side effects of long-term antibiotic administration include hearing loss and antibiotic resistance.

[0018] Patients often do not comply with prescribed respiratory medications. Inhaled therapy requires deep inspiration and synchronization with inspiration, which many patients, especially the elderly, cannot perform. Patients may skip doses secondary to cost, experience side effects, or both. All of these factors combine to contribute to inappropriate and inconsistent medication dosing.

[0019] Asthma ranges in severity from mild disease to persistent adult asthma. While mild disease can be adequately managed with trigger avoidance and short-acting beta-agonists (SABAs), the mainstay of treatment for persistent asthma is inhaled glucocorticoids. Clinical trials have shown that regular use of inhaled glucocorticoids reduces the need for rescue inhalers, improves lung function, relieves symptoms, and prevents exacerbations. Some patients benefit from the addition of a leukotriene modifier or LABA. Tiotropium may be an alternative option for improving lung function over inhaled glucocorticoids alone. In very severe cases, temporary or long-term treatment with oral corticosteroids may be necessary.

[0020] There is no known cure for interstitial pulmonary fibrosis (IPF). The mainstay of treatment is supplemental oxygen when needed and preventative measures such as vaccinations. Pirfenidone is an antifibrotic drug approved for IPF that attempts to slow the fibroblast lesions, collagen deposition, and inflammatory cell infiltration of the disease. In clinical trials, pirfenidone has been shown to attenuate declines in vital capacity (a measure of lung function) and has been associated with reduced all-cause mortality. Nintedanib is another drug approved for IPF that acts via a receptor blocker of multiple tyrosine kinases that mediate the production of fibrogenic growth factors (e.g., platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor). It appears to slow the rate of disease progression in IPF. There are no approved device therapies for IPF.

[0021] Treatment for cystic fibrosis (CF) is rapidly evolving from chest physical therapy and supplemental oxygen to therapies targeting the underlying defect in the CFTR gene. Ivacaftor, a CFTR potentiator, is FDA-approved for some CFTR gene mutations and improves chloride transport through the ion channel. Clinical trials have shown it improves FEV1 and reduces exacerbation frequency. It also improves mucociliary and cough clearance. However, when used alone in patients with the most common delta F508 deletion, it does not improve outcomes. Other targeted therapies are undergoing clinical trials. Chronic antibiotics, including azithromycin, which appears to have anti-inflammatory effects, and inhaled tobramycin to treat Pseudomonas aeruginosa, are commonly prescribed for CF. As with other obstructive diseases, CF patients benefit from bronchodilators, including LABAs and LAMAs. Medications that promote airway secretion clearance include inhaled DNase, which reduces mucus viscosity; inhaled hypertonic saline, which draws water from mucus-filled airways; and inhaled N-acetylcysteine, which cleaves disulfide bonds within mucus glycoproteins. Guidelines do not recommend chronic use of inhaled corticosteroids, but oral steroids can be used in the event of an exacerbation.

[0022] Bronchiectasis is an anatomical manifestation of a host injury response resulting in excessive dilation of the airway lumen; therefore, treatment is often directed at the primary disease cause. These may be nontuberculous mycobacterial infections, primary immunodeficiencies, allergic bronchopneumonia, and aspergillosis, among others. Treatment of acute exacerbations focuses on treating the offending bacterial pathogen with antibiotics. Macrolide and nonmacrolide antibiotics have been shown to reduce the frequency of exacerbations. The use of inhaled antibiotics in the absence of CF, as with the use of mucolytic agents, is unclear. Bronchodilators can be used in patients with signs of airway obstruction on spirometry.

[0023] Interventions for primary ciliary dyskinesia (PCD) aim to improve secretion clearance and reduce respiratory infections through daily chest physiotherapy and prompt treatment of respiratory infections. The role of nebulized DNase and other mucolytic agents is less clear.

[0024] Respiratory tract infections caused by respiratory pathogens can occur in any of these diseases and are typically treated with antibiotics. Unfortunately, drug development in this area has declined, and current treatments have significant limitations. One problem is that there is no single drug that can treat the range of pathogens found in these patients. While sputum testing can be performed to determine resident or pathogenic pathogens, this sometimes requires special techniques for collecting specimens during bronchoscopy, avoiding sample contamination that typically affects other methods and collection methods. Another problem is that currently available medications are not always effective, as pathogens are developing resistance to these treatments.

[0025] B. Intervention More recently, several groups have developed interventional procedures for COPD. Although morbidity and mortality are high in this frail population, surgical lung volume reduction (LVR) has proven to be an effective treatment. Bronchoscopic lung volume reduction (BLVR) can be achieved by placement of one-way valves, coils, or vapor steam ablation, or by delivering biological or polymer-based tissue adhesives to the target lobe. The physiological target of LVR / BLVR is emphysema, specifically addressing the hyperinflation experienced by these patients. In several studies, BLVR has been shown to improve lung function and quality of life. Volume reduction therapy is ineffective in patients with chronic bronchitis, a disease of the airways rather than the alveoli.

[0026] Another emerging treatment is pulmonary denervation, in which parasympathetic nerves innervating the airways are removed, theoretically causing chronic bronchodilation by disabling reactive airway smooth muscle. The effect is similar to bronchodilators such as LABAs and LAMAs, but produces a long-lasting effect without the typical peaks and valleys seen with drug administration. Because this modality only treats proximal airways, the effect may be limited to the upper airways, but high-resistance airways are lowered in the airways.

[0027] Various thermal ablation approaches have also been described as therapeutic approaches for treating diseased airways, but all have limitations and challenges associated with controlling ablation and / or targeting specific cell types. Spray cryotherapy is applied by spraying liquid nitrogen directly onto the bronchial wall with the goal of ablating superficial airway cells and initiating a regenerative effect on the bronchial wall. Because the operator (e.g., a physician) is essentially "spray painting" the wall, without appropriate controls, the extent, dose, and / or depth of treatment can vary significantly between operators. This can lead to incomplete treatment in skipped areas where nitrogen was not directly sprayed. The lack of precise depth control can also lead to unintended damage to tissue beyond the treatment target, such as the lamina propria or cartilage, especially since the thickness of the airway wall can vary. Radiofrequency and microwave ablation techniques have also been described, in which energy is delivered to the airway wall at various locations to ablate diseased tissue. Due to uncontrolled heat conduction, the inability to measure actual tissue temperature to control energy delivery, the risk of treatment overlap, and the variable wall thickness of the bronchi, these treatments can also cause unintended damage to tissue beyond the treatment target. Furthermore, they all require catheter repositioning for multiple energy applications, potentially resulting in incomplete treatment. All of these thermal ablation techniques nonselectively ablate various layers of the airway wall, often unnecessarily ablating non-target tissue beyond the epithelium or submucosa. Damage to tissue beyond the epithelial treatment target can trigger an inflammatory cascade, leading to inflammation, exacerbation, and remodeling, potentially further reducing the airway lumen. Therefore, continued improvement of interventional procedures is needed that are more controlled and target specific depths and structures consistent with physiological disease while limiting the amount of inflammatory response and remodeling.

[0028] Asthmatx has previously developed a radiofrequency ablation system for bronchial thermoplasty. The surgeon places a catheter in the airway and activates electrodes, generating heat in the airway tissue and thermally ablating smooth muscle. Due to the acute inflammation associated with the heat generated during the procedure, many patients experience acute exacerbations. In the AIR2 clinical trial, patients did not experience clinically significant improvements in asthma quality of life questionnaires at 12 months compared with the sham group. However, the treatment group experienced fewer exacerbations and fewer emergency room visits. While the FDA has approved this procedure, it is not widely used due to side effects and insurance companies' designation as an interventional procedure.

[0029] Thus, there is an unmet need for more controlled interventional procedures that can target specific structures and / or pathogens consistent with pathophysiological abnormalities, treat relatively large surface areas at appropriate depths, and limit the amount of inflammatory response and remodeling. Embodiments of the present disclosure meet at least some of these objectives. Summary of the Invention

[0030] Described herein are embodiments of devices, systems, and methods for treating or manipulating tissue and / or treating diseases or disorders, particularly those related to pulmonary diseases and disorders such as COPD (e.g., chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, primary ciliary dyskinesia (PCD), acute bronchitis, and / or other pulmonary diseases and disorders; one or more features from any of these embodiments can be combined with one or more features from one or more other embodiments to form new embodiments within the scope of the present disclosure. Examples of pulmonary tissue include, but are not limited to, epithelium (goblet cells, ciliated pseudostratified columnar epithelial cells, and basal cells), lamina propria, submucosa, submucosal glands, basement membrane, smooth muscle, cartilage, nerves, pathogens present near or within the tissue, or combinations of any or all of the foregoing. Other treatable body passageways include blood vessels, lymphatic vessels, bile ducts, kidney tubules, esophagus, stomach, small intestine, large intestine, appendix, rectum, bladder, ureters, pharynx, mouth, vagina, urethra, or glandular ducts, to name a few.

[0031] The methods, devices, and systems disclosed herein can treat tissue through the delivery of energy, typically characterized by high-voltage pulses, to target tissue using a tissue modification system (e.g., an energy delivery catheter system). In some embodiments, the nature of the energy delivery allows for removal of the target tissue without a clinically significant inflammatory healing response, while in other embodiments, some inflammatory healing response may be acceptable. This further allows for the regeneration of healthy new target tissue within a few days of treatment.

[0032] This disclosure also relates to the following numbered clauses:

[0033] 1. A system for treating a body cavity having at least one side branch, comprising: a catheter comprising a shaft having a proximal end, a distal end, and at least one energy delivery body disposed near the distal end, the distal end configured to be advanced into a body lumen near the at least one side branch; a generator in electrical communication with the at least one energy delivery body, the generator providing an electrical signal of non-thermal energy transmittable by the at least one energy delivery body to a wall of the body cavity, the generator including at least one energy delivery algorithm configured to treat specific cells up to a depth of 2.5 cm within the wall.

[0034] 2. The system of claim 1, wherein the distal end of the shaft comprises a Y-shape having a first arm configured to be advanced into the body cavity and a second arm configured to be advanced into one of the at least one side branches, and wherein the at least one energy delivery comprises a first energy delivery body disposed on the first arm of the Y-shape and a second energy delivery disposed on the second arm of the Y-shape.

[0035] 3. The system of claim 2, wherein the first energy delivery body and the second energy delivery body function as a bipolar pair.

[0036] 4. The system of any of claims 1 to 3, wherein the shaft has a pre-bend configured to direct the distal end into at least one side branch.

[0037] 5. A system according to any preceding claim, further comprising a delivery device having at least one lumen for passage of at least a catheter therethrough.

[0038] 6. The system of claim 5, further comprising a second catheter configured to pass through at least one lumen of the delivery device, the second catheter having at least one energy delivery body disposed near its distal end, the system configured to enable placement of the at least one energy delivery body of the catheter within the body cavity while enabling placement of the at least one energy body of the second catheter in one of the at least one side branches.

[0039] 7. A system according to any preceding claim, wherein at least one energy delivery body includes at least one piercing element configured to extend into and deliver energy to the wall.

[0040] 8. The system of any preceding claim, wherein at least one energy delivery body comprises an expandable member configured to expand within a body cavity over and at least partially into at least one side branch.

[0041] 9. The system of claim 8, wherein the expandable member comprises at least one finger configured to extend into the at least one side branch.

[0042] 10. The system of claim 8, wherein the catheter further includes a lumen within the shaft, and the expandable member has the shape of an elongated balloon attached to the distal end of the catheter such that the expandable member is positionable within the lumen of the shaft.

[0043] 11. The system of claim 10, wherein the expandable member has an inner surface, and the expandable member is positionable within the lumen such that the inner surface of the expandable member faces the surface of the lumen.

[0044] 12. The system of claim 8, wherein the expandable member comprises at least one electrode trace.

[0045] 13. The system of claim 12, wherein at least one electrode trace includes at least two activation points that function in a bipolar or multipolar fashion in combination with a dispersive external electrode.

[0046] 14. The system of claim 1, wherein at least one energy delivery body comprises an expandable member configured to expand within a body lumen covering at least one side branch, and wherein the at least one energy delivery body includes a first set of electrodes having a first central spine extending longitudinally along the expandable member and a first series of ribs, each of the first series of ribs extending at least partially around the expandable member.

[0047] 15. The system of claim 14, wherein at least one energy delivery body includes a second set of electrodes having a second central spine extending longitudinally along the expandable member and a second series of ribs, each of the second series of ribs extending at least partially around the expandable member.

[0048] 16. The system of claim 15, wherein each of the first series of ribs interlaces with each of the second series of ribs.

[0049] 17. The system of claim 16, wherein the first and second series of ribs have opposite polarities.

[0050] 18. The system of claim 15, wherein the first set of electrodes and the second set of electrodes create overlapping treatment zones along the body cavity.

[0051] 19. A system according to any preceding claim, further comprising a liquid electrode positionable within the body lumen to extend into at least one side branch.

[0052] 20. The system of claim 19, wherein the liquid electrode comprises a conductive solution.

[0053] 21. A system for treating a body passageway of a patient, comprising: a catheter including at least one electrode disposed near a distal end thereof, the distal end of the catheter configured to be positioned within a body passageway such that the at least one electrode can transmit energy to a wall of the pulmonary passageway; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm configured to provide an electrical signal of energy transmittable to the wall that selectively treats at least specific cells on a surface of the wall, the electrical signal including a biphasic pulse.

[0054] 22. The system of claim 21, wherein the electrical signal comprises a frequency and a voltage, and the effect of the frequency counterbalances the effect of the voltage to target specific cells.

[0055] 23. A system according to any of claims 21 to 22, wherein the biphasic pulses have the same duration and voltage.

[0056] 24. A system according to any of claims 21 to 22, wherein at least two of the biphasic pulses have different voltages.

[0057] 25. A system according to any of claims 21 to 22, wherein at least two of the biphasic pulses have different durations.

[0058] 26. A system according to any of claims 21 to 25, wherein at least some of the biphasic pulses are separated by dead time to reduce biphasic cancellation.

[0059] 27. A system according to any one of claims 21 to 26, wherein the specific cells include operable contractile cells.

[0060] 28. The system of claim 27, wherein the operable contractile cells comprise smooth muscle cells.

[0061] 29. A system according to any of claims 21 to 28, wherein each of the biphasic pulses has a voltage between about 100V and 10kV.

[0062] 30. The system of claim 29, wherein each of the biphasic pulses has a voltage of between about 500 and 4000V.

[0063] 31. A system according to any one of claims 21 to 30, wherein the electrical signal has a frequency in the range of approximately 100 to 1000 kHz.

[0064] 32. A system for delivering therapy to a body passageway of a patient, comprising: at least one energy delivery body positionable within the body passageway and configured to deliver energy to a wall of the body passageway; at least one sensor positionable on or within the patient, the at least one sensor configured to receive sensed information from the patient; 1. A system comprising: a generator having at least one energy delivery algorithm configured to provide energy electrical signals to at least one energy delivery body, the electrical signals including a test signal configured to generate sensing information and a therapeutic electrical signal configured to provide therapy to a body passageway.

[0065] 33. The system of claim 32, wherein the at least one energy delivery algorithm includes an energy delivery algorithm that generates a therapeutic electrical signal based on the sensed information.

[0066] 34. The system of claim 32, wherein the sensed information indicates that at least one energy delivery body is preferably positioned within the body passageway.

[0067] 35. The system of claim 32, wherein the sensed information indicates that the therapeutic electrical signal configured to provide therapy to the body passageway corresponds to a desired therapeutic electrical signal.

[0068] 36. The system of claim 35, wherein the at least one energy delivery algorithm is configured to withhold the therapeutic electrical signal unless the sensing information indicates that the therapeutic electrical signal corresponds to a desired therapeutic electrical signal.

[0069] 37. A system according to any of claims 32 to 36, wherein at least one sensor is disposed on or is part of at least one energy delivery body.

[0070] 38. A system according to any of claims 32 to 36, wherein at least one sensor is disposed on or is part of a dispersive electrode.

[0071] 39. The system of any of claims 32 to 38, wherein the test signal has a lower voltage than the therapeutic electrical signal.

[0072] 40. The system of any of claims 32-39, wherein at least one energy delivery algorithm is configured to deliver a test signal before the therapeutic electrical signal is delivered.

[0073] 41. The system of claim 40, wherein the at least one energy delivery algorithm is configured to deliver a test signal at least one heartbeat before the therapeutic electrical signal is delivered.

[0074] 42. The system of claim 40, wherein at least one energy delivery algorithm is configured to deliver a test signal 500 ms before the therapeutic electrical signal is delivered.

[0075] 43. A system according to any of claims 32 to 42, wherein the test signal comprises a short pulse having a duration of 1 us, 100 us, 1 ms or 100 ms.

[0076] 44. A system according to any of claims 32 to 43, wherein the test signal comprises a continuous low voltage waveform having a voltage of 0.5V, 1V, 5V, 10V, 50V or 500V.

[0077] 45. A system according to any of claims 32 to 44, wherein the sensed information comprises impedance.

[0078] 46. ​​The system of claim 45, wherein at least one energy delivery algorithm is configured to withhold the therapeutic electrical signal if the sensing information indicates an impedance measurement of >200 Ω.

[0079] 47. A system according to any of claims 32 to 46, wherein the sensed information includes temperature.

[0080] 48. A system for treating a body lumen, comprising: at least one energy delivery body positionable within the lumen and configured to deliver energy to a wall of the lumen; a generator having at least one energy delivery algorithm configured to provide an electrical signal of energy to at least one energy delivery body, the electrical signal selectively targeting specific cells of the lumen while avoiding collateral cells.

[0081] 49. The system of claim 48, wherein the electrical signal selectively targets specific cells based at least on its frequency.

[0082] 50. The system of claim 49, wherein the frequency is in the range of 400 to 800 kHz.

[0083] 51. The system of claim 48, wherein specific cells are targeted based on their size.

[0084] 52. The system of claim 51, wherein the specific cells have a diameter of 15 μm or more.

[0085] 53. The system of claim 48, wherein the lumen comprises an airway and the specific cells comprise cells involved in mucus hypersecretion.

[0086] 54. The system of claim 52, wherein the specific cells include goblet cells, dysfunctional pseudostratified columnar epithelial cells and / or submucosal glands.

[0087] 55. The system of claim 52, wherein the collateral cells comprise basal cells and / or chondrocytes.

[0088] 56. The system of claim 48, wherein specific cells are targeted based on their location within the wall of the lumen.

[0089] 57. The system of claim 56, wherein the electrical signal selectively targets specific cells based on the number of packets delivered.

[0090] 58. The system of claim 57, wherein the specific cells are on or near the surface of the lumen and the number of packets delivered is a maximum of 5 packets.

[0091] 59. The system of claim 48, wherein the lumen comprises an airway, the specific cells comprise goblet cells and / or submucosal glands, the collateral cells comprise chondrocytes, and the electrical signal has a frequency of 600 kHz, a packet duration of 100 μsec, a voltage of 2500 to 3000 V, and 1 to 5 packets.

[0092] 60. The system of claim 48, wherein the lumen comprises a vascular lumen, the specific cells comprise cardiac muscle cells, and the collateral cells comprise cells within the sinoatrial node or atrioventricular node that generate normal cardiac rhythm.

[0093] 61. The system of claim 48, wherein the specific cells include precancerous or cancerous cells and the collateral cells include noncancerous cells.

[0094] 62. A method for treating one or more target cells in a cellular lining of a body passage, comprising: modulating one or more target cells; and delivering energy to a surface of an intracellular lining to treat one or more target cells for a period of time below a thermal ablation threshold of the one or more target cells and to treat one or more target cells to a depth of no more than 2.5 cm from the surface of the intracellular lining.

[0095] 63. The method of claim 62, wherein adjusting comprises delivering an adjusting solution.

[0096] 64. The method of claim 63, wherein the conditioning solution comprises a drug, genetic material, a bioactive compound, or an antimicrobial agent.

[0097] 65. The method of any of claims 63 to 64, wherein the conditioning solution comprises cells.

[0098] 66. The method of claim 65, wherein the cells comprise stem cells, autologous cells, or allogeneic cells.

[0099] 67. The method of claim 65, wherein the cells are of a type suitable for repopulating the cell lining with desired cells.

[0100] 68. The method of claim 67, further comprising cleaning or mechanically stimulating the cellular lining of the body passageway prior to the conditioning step.

[0101] 69. The method of any of claims 63-68, further comprising warming the conditioning solution prior to delivery.

[0102] 70. The method of any of claims 63-68, further comprising cooling the conditioning solution prior to delivery.

[0103] 71. The method of any of claims 62-70, wherein modulating comprises delivering a modulating therapy that increases the likelihood that one or more target cells will expire after receiving energy.

[0104] 72. The method of claim 71, wherein the conditioning therapy comprises a conditioning solution containing a chemotherapeutic agent, calcium, an antibiotic, or a toxin.

[0105] 73. The method of any of claims 62-72, wherein modulating comprises delivering a modulating therapy that alters the response to energy from non-target cells.

[0106] 74. The method of claim 73, wherein the conditioning therapy comprises a conditioning solution comprising a cytokine, an immunostimulant, an interleukin, a gene, VEGF, or a cell differentiation factor.

[0107] 75. The method of any of claims 62-74, wherein modulating comprises delivering a modulating therapy that selectively alters an electrical property of one or more target cells.

[0108] 76. The method of claim 62, wherein adjusting comprises delivering a conditioning therapy, the conditioning therapy comprising radiation therapy, radiotherapy, or proton beam therapy.

[0109] 77. The method of any of claims 62-76, wherein the modulating step elicits a targeted immune response.

[0110] 78. The method of any of claims 62-77, further comprising advancing an energy delivery catheter into the body passageway, the energy delivery catheter comprising at least one energy delivery body configured to provide the transmitting step.

[0111] 79. The method of claim 78, wherein the energy delivery catheter includes at least one port, and the conditioning step comprises delivering a conditioning solution through the at least one port, the conditioning solution providing the conditioning step.

[0112] 80. The method of claim 79, wherein delivering the conditioning solution comprises delivering a predetermined amount of the conditioning solution.

[0113] 81. A system for reducing mucus hypersecretion in the pulmonary passages of a patient, comprising: a catheter including at least one electrode disposed near a distal end thereof, the distal end of the catheter configured to be positioned within the pulmonary passageway such that the at least one electrode can transmit non-thermal energy to an airway wall of the pulmonary passageway; a generator in electrical communication with the at least one electrode, the generator including at least one energy delivery algorithm configured to provide an electrical signal of non-thermal energy transmittable to the airway wall that selectively treats specific cells associated with mucus hypersecretion in the airway wall that cause mucus hypersecretion by the airway wall.

[0114] 82. The system of claim 81, wherein selectively treating comprises altering organelle and cell transmembrane potentials.

[0115] 83. The system of claim 81, wherein selectively treating comprises increasing organelle and cell membrane permeability.

[0116] 84. The system of claim 81, wherein selectively treating comprises ablating specific cells.

[0117] 85. The system of claim 84, wherein the removing comprises immune cell phagocytosis.

[0118] 86. The system of claim 84, wherein selectively treating comprises eliminating by cell death caused by apoptosis.

[0119] 87. The system of claim 84, wherein selectively treating comprises removing by cell death caused by necrosis.

[0120] 88. The system of claim 84, wherein selectively treating comprises eliminating by cell death caused by immune cell interactions.

[0121] 89. The system of claim 81, wherein the specific cells include operable contractile cells.

[0122] 90. The system of claim 89, wherein the operable contractile cells comprise smooth muscle cells.

[0123] 91. The system of claim 81, wherein selectively treating comprises selectively reducing cellular contractile ability.

[0124] 92. The system of claim 81, wherein the reduction in hypersecretion causes clearance of mucus blockages.

[0125] 93. The system of claim 81, wherein the specific cells comprise actionable contractile cells, and selectively treating comprises selectively reducing the cellular contractile ability that contributes to the clearance of mucus plugging.

[0126] 94. The system of claim 81, wherein the non-thermal energy has a frequency selected to counterbalance a voltage selection that causes targeting of specific cell populations.

[0127] 95. The system of claim 81, wherein the non-thermal energy comprises opposite polarity pulses having the same duration and voltage.

[0128] 96. The system of claim 81, wherein the non-thermal energy comprises pulses of opposite polarity having different voltages.

[0129] 97. The system of claim 81, wherein the non-thermal energy has pulses of opposite polarity having different durations.

[0130] 98. The system of claim 81, wherein the non-thermal energy has opposite polarity pulses separated by dead time to reduce bipolar cancellation.

[0131] 99. The system of claim 81, wherein the non-thermal energy comprises pulses, each pulse being between about 100V and 10kV.

[0132] 100. The system of claim 99, wherein each pulse is between about 500 and 4000V.

[0133] 101. The system of claim 81, wherein the non-thermal energy comprises at least one energy packet having a frequency in the range of approximately 100 to 1000 kHz.

[0134] 102. The system of claim 101, wherein the frequency is selected to counterbalance the voltage to specifically target different cell populations.

[0135] 103. The system of claim 81, wherein the non-thermal energy consists of pulses, each pulse being of the same polarity.

[0136] 104. The system of claim 81, wherein the catheter is attached to an access device and / or a visualization device.

[0137] 105. The system of claim 104, comprising a mechanism that allows the catheter to undergo small positioning changes, including advancement and retraction, relative to the access device and / or visualization device while attached to the access device and / or visualization device.

[0138] 106. The system of claim 81, wherein the catheter comprises at least two protrusions expandable to contact the airway walls of the pulmonary passageway, the at least two protrusions configured to deploy and contact the airway walls with the aid of an internal dielectric inflatable device.

[0139] 107. The system of claim 106, wherein the dielectric inflatable device uses a liquid or gas fluid for inflation.

[0140] 108. The system of claim 81, wherein the catheter comprises at least two prongs expandable to contact the airway wall of the pulmonary passageway, the at least two prongs configured to deploy and contact the airway wall with the aid of an internal electrically conductive continuously inflatable device.

[0141] 109. The system of claim 108, wherein the electrically conductive continuously inflatable device uses a liquid or gas fluid for inflation.

[0142] 110. The system of claim 81, wherein the generator includes a processor that decreases voltage, pulse duration, or dead time, or increases packet delivery delay, when impedance decays below an impedance threshold.

[0143] 111. The system of claim 110, wherein the impedance is obtained from a low-voltage impedance determination, from an AC complex impedance, from an AC frequency sweep and the resulting complex impedance, or from impedance obtained directly from therapeutic pulse delivery energy.

[0144] 112. A system for treating a body passageway, comprising: a catheter including at least one energy delivery body disposed near a distal end thereof, the catheter configured to be disposed within the body passage at the distal end such that the at least one energy delivery body can transfer non-thermal energy to a wall of the body passage; a generator in electrical communication with the at least one energy delivery body, the generator including at least one energy delivery algorithm configured to provide an electrical signal of non-thermal energy transmittable to the body passageway that selectively treats a target cell population within the body passageway.

[0145] 113. The system of claim 112, wherein the body passageway comprises a blood vessel, lymphatic vessel, bile duct, renal tubule, esophagus, stomach, small intestine, large intestine, appendix, rectum, bladder, ureter, pharynx, mouth, vagina, urethra, or glandular duct.

[0146] 114. The system of claim 112, wherein selectively treating comprises altering organelle and cell transmembrane potentials.

[0147] 115. The system of claim 112, wherein selectively treating comprises increasing organelle and cell membrane permeability.

[0148] 116. The system of claim 112, wherein selectively treating comprises selectively removing specific cells from the airway wall.

[0149] 117. The system of claim 116, wherein the removing comprises cell separation.

[0150] 118. The system of claim 117, wherein cell separation is achieved by dielectrophoresis.

[0151] 119. The system of claim 116, wherein the removing comprises cell death.

[0152] 120. The system of claim 119, wherein the removing comprises immune cell phagocytosis.

[0153] 121. The system of claim 119, wherein cell death is caused by apoptosis.

[0154] 122. The system of claim 119, wherein cell death is caused by necrosis.

[0155] 123. The system of claim 119, wherein cell death is triggered by immune cell interactions.

[0156] 124. The system of claim 112, wherein the cell population comprises epithelial cells but not basal cells.

[0157] 125. The system of claim 124, wherein the epithelial cells comprise abnormal or hyperplastic goblet cells.

[0158] 126. The system of claim 124, wherein the epithelial cells comprise abnormally ciliated pseudostratified columnar epithelial cells.

[0159] 127. The system of claim 112, wherein the cell population comprises cells of a basement membrane, and selectively treating comprises modifying the cells of the basement membrane to alter the permeability of the basement membrane.

[0160] 128. The system of claim 112, wherein the cell population comprises submucosal glands, and selectively treating comprises causing cell death of the submucosal glands.

[0161] 129. The system of claim 112, wherein the cell population comprises a pathogen, and selectively treating comprises causing cell death of the pathogen.

[0162] 130. The system of claim 112, wherein selectively treating comprises selectively modifying a cell population to alter mucus production.

[0163] 131. The system of claim 112, wherein the cell population comprises operable contractile cells.

[0164] 132. The system of claim 131, wherein the operable contractile cells comprise smooth muscle cells.

[0165] 133. The system of claim 112, wherein selectively treating comprises reducing cellular contractile capacity.

[0166] 134. The system of claim 112, wherein selectively treating allows for regeneration of the wall with normal healthy tissue.

[0167] 135. A method for treating a body passageway of a patient, comprising: positioning at least one electrode within the body passage such that the at least one electrode is positioned near or against a portion of a wall of the body passage; A method comprising: energizing at least one electrode to deliver non-thermal energy to a portion of the wall, the non-thermal energy selectively treating specific cells within the portion of the wall.

[0168] 136. The method of claim 135, further comprising administering a solution that alters physical properties into the body passageway prior to applying the current.

[0169] 137. The system of claim 136, wherein the solution that changes the physical property comprises hypertonic saline, isotonic saline, hypotonic saline, or a glucose buffer.

[0170] 138. The system of claim 135, further comprising administering, before or after application of the current, a cell-activating bioactive solution containing hypertonic calcium, a solution containing a drug, a solution containing a gene, or a solution having other effect-inducing properties on cells.

[0171] 139. The system of claim 135, further comprising administering, before or after application of the current, a tissue-level bioactive solution containing hypertonic calcium, a solution containing a drug, a solution containing a gene, or a solution with other effect-inducing properties.

[0172] 140. The system of claim 135, further comprising systemically administering a physiologically active solution containing hypertonic calcium, a solution containing a drug, a solution containing a gene, or a solution with other effect-inducing properties before or after administering the current.

[0173] 141. The system of claim 135, further comprising systemic administration of a tissue-level bioactive solution containing hypertonic calcium, a drug-containing solution, a gene-containing solution, a cytokine-containing solution, or a solution with other property-inducing effects, before or after application of electricity.

[0174] 142. The system of claim 135, further comprising introducing at least one cell population comprising stem cells, healthy normal cells, or genetically modified cells before or after applying the current.

[0175] 143. The system of claim 135, further comprising administering a physical property-modifying solution comprising hypertonic saline, isotonic saline, hypotonic saline, or dextrose buffer before or after administering the current.

[0176] These and other embodiments are described in further detail in the following description taken in conjunction with the accompanying drawings.

[0177] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety, as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0178] The novel features of the embodiments of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention, made possible by several embodiments, will be obtained by reference to the following detailed description that describes exemplary embodiments and the accompanying drawings. [Brief explanation of the drawings]

[0179] [Figure 1] Figure 1 provides an illustration of the anatomy of the lung.

[0180] [Figure 2] FIG. 2 shows a cross-sectional view of the airway wall, depicting various layers and structures.

[0181] [Figure 3] Figure 3 provides a cross-section of the epithelium of the airway wall showing the types of cellular connections within the airway.

[0182] [Figure 4A] FIG. 4A shows a healthy bronchial airway. [Figure 4B] FIG. 4B shows the bronchial airways in a diseased state.

[0183] [Figure 5] FIG. 5 illustrates an embodiment of a lung tissue modification system for use in treating a patient.

[0184] [Figure 6] FIG. 6 provides a detailed view of the embodiment of the therapeutic energy delivery catheter shown in FIG.

[0185] [Figure 7] FIG. 7 is a schematic diagram of an embodiment of a lung tissue modification system.

[0186] [Figure 8A] FIG. 8A shows a bronchoscope being inserted into the patient's mouth / oral cavity. [Figure 8B] FIG. 8B shows a bronchoscope being inserted into the patient's nose / nasal cavity.

[0187] [Figure 9] FIG. 9 shows the placement of the distal end of the catheter into the main bronchus for treatment of the airway. [Figure 10] FIG. 10 shows the placement of the distal end of the catheter into the main bronchus for treatment of the airway. [Figure 11] FIG. 11 shows the placement of the distal end of the catheter into the main bronchus for treatment of the airway.

[0188] [Figure 12] FIG. 12 is a flow chart illustrating the methods described herein in a stepwise approach to treating a patient. [Figure 12A] FIG. 12A is a flow chart illustrating the methods described herein in a stepwise approach to treating a patient. [Figure 12B]FIG. 12B is a flow chart illustrating the methods described herein in a stepwise approach to treating a patient.

[0189] [Figure 13] FIG. 13 shows an embodiment of a waveform of a signal provided by the energy delivery algorithm.

[0190] [Figure 13A] FIG. 13A shows various examples of biphasic pulses (including a positive peak and a negative peak) with a switching time between them.

[0191] [Figure 13B] FIG. 13B shows the relationship between the effective field threshold and the switching time.

[0192] [Figure 14] FIG. 14 shows an exemplary waveform for another energy delivery algorithm.

[0193] [Figure 14A] FIG. 14A shows a further example of a waveform having unequal voltages. [Figure 14B] FIG. 14B shows a further example of a waveform having unequal voltages.

[0194] [Figure 15] FIG. 15 shows an example waveform for another energy delivery algorithm.

[0195] [Figure 15A] FIG. 15A shows a further example of a waveform having a monophasic pulse.

[0196] [Figure 15B] FIG. 15B shows an example of a waveform with a phase imbalance achieved by delivering two or more pulses of one polarity before reversing to an unequal number of pulses of the opposite polarity.

[0197] [Figure 16] FIG. 16 shows an example waveform for another energy delivery algorithm.

[0198] [Figure 17] FIG. 17 illustrates an embodiment in which the delivered energy removes cells by detaching them from the airway wall.

[0199] [Figure 18] FIG. 18 illustrates an embodiment in which the delivered energy kills and ultimately removes cells from the airway wall.

[0200] [Figure 19] FIG. 19 shows a schematic representation of epithelial cell removal by dielectrophoretic effects.

[0201] [Figure 20A] FIG. 20A shows a cross section of the wall of an affected lung airway with an energy delivery body disposed thereon.

[0202] [Figure 20B] FIG. 20B shows a schematic representation of cells of different sizes. [Figure 20C] FIG. 20C shows a schematic representation of cells of different sizes.

[0203] [Figure 20D] FIG. 20D shows an example of cell / organelle membrane potential versus time.

[0204] [Figure 20E] FIG. 20E shows a waveform having a lower frequency, such as 250 kHz.

[0205] [Figure 20F] FIG. 20F shows a waveform with a higher frequency, such as 1000 kHz.

[0206] [Figure 21] FIG. 21 is a graph showing a portion of a sample electrocardiogram (ECG) tracing of a highlighted period of a human heart where it is desired to deliver an energy pulse to a pulmonary passageway via an energy delivery body.

[0207] [Figure 21A] FIG. 21A is a flowchart depicting an embodiment of a method for synchronizing the delivery of energy with the cardiac cycle.

[0208] [Figure 22] FIG. 22 illustrates accessing lung tissue, such as the parenchyma, through the nose or mouth.

[0209] [Figure 23A] FIG. 23A shows an exemplary image of a pulmonary passageway that can be obtained using confocal laser endoscopy (CLE). [Figure 23B] FIG. 23B shows an exemplary image of a pulmonary passageway that can be obtained using optical coherence tomography (OCT).

[0210] [Figure 24] FIG. 24 shows an embodiment of an energy delivery catheter having a single energy delivery body consisting of electrodes formed by multiple ribbons or wires forming a helical basket.

[0211] [Figure 25] FIG. 25 depicts an embodiment in which the energy delivery catheter includes two energy delivery bodies.

[0212] [Figure 26] FIG. 26 depicts an embodiment of an energy delivery catheter having a single energy delivery body configured with the energy delivery body attached to a shaft extending through the energy delivery body.

[0213] [Figure 27]FIG. 27 shows an embodiment in which both energy delivery bodies are mounted on a single shaft.

[0214] [Figure 28A] FIG. 28A shows an embodiment in which one energy delivery body is unconstrained at one end to form a half-basket shape when expanded.

[0215] [Figure 28B] FIG. 28B shows an embodiment in which both energy delivery bodies are constructed from braided metal wires configured to form half-baskets when expanded.

[0216] [Figure 29] FIG. 29 shows a braided wire basket energy delivery body constructed from energizable wires, some of which have been insulated by removing portions of the insulation to define active areas.

[0217] [Figure 30] FIG. 30 shows another embodiment in which the tube is laser cut to form a collapsed basket with both ends restrained through the tube itself.

[0218] [Figure 31] FIG. 31 shows an embodiment of an energy delivery body constructed from insulated wire with one or more separate additional electrodes (shown as coils) connected to the insulated basket wire to form the active region.

[0219] [Figure 32] FIG. 32 shows an embodiment of an energy delivery body with multiple tines.

[0220] [Figure 33] FIG. 33 shows an embodiment of an energy delivery body that includes one or more protrusions.

[0221] [Figure 34] FIG. 34 shows an embodiment of an energy delivery body that includes one or more protrusions, each protrusion formed from a non-conductive material and carrying, supporting, and / or otherwise coupled to a separate electrode.

[0222] [Figure 35] FIG. 35 shows an embodiment of a catheter having two energy delivery bodies, each having the shape of an expandable coil.

[0223] [Figure 36] FIG. 36 shows an embodiment of an energy delivery body comprising a coil having a width and a length, where the length of the coil is pre-shaped into a substantially circular pattern.

[0224] [Figure 37] FIG. 37 shows an embodiment of an energy delivery body comprising a rod with electrodes, the length of the rod being pre-shaped into a substantially circular pattern.

[0225] [Figure 38] FIG. 38 shows an embodiment of a catheter having the sheath retracted proximally, thus exposing one or more prongs.

[0226] [Figure 38A] FIG. 38A is a cross-sectional view taken along line AA in FIG.

[0227] [Figure 39] FIG. 39 shows an embodiment of a prong having two electrodes attached to an insulating substrate between them as a means of maintaining distance between the electrodes.

[0228] [Figure 40] FIG. 40 shows an embodiment of the prongs having a narrower insulating substrate than that shown in FIG.

[0229] [Figure 41] FIG. 41 shows an embodiment of a prong having an even narrower insulating substrate and more than two electrodes.

[0230] [Figure 42] FIG. 42 shows multiple electrodes mounted on an insulating substrate.

[0231] [Figure 43] FIG. 43 shows an insulating substrate having electrodes such as those shown in FIGS. 36-37 configured as a spiral.

[0232] [Figure 44] FIG. 44 shows an insulating substrate with electrodes such as those shown in FIG. 38 configured as a spiral.

[0233] [Figure 45A] FIG. 45A shows expanding the expandable member until the desired interface between the prongs and the bronchial wall is achieved. [Figure 45B] FIG. 45B shows expanding the expandable member until the desired interface between the prongs and the bronchial wall is achieved.

[0234] [Figure 45C] FIG. 45C shows an embodiment of a catheter having an energy delivery body with wires forming an expandable basket, where the energy delivery body transitions from a collapsed configuration to an expanded configuration upon expansion of an internal expandable member.

[0235] [Figure 45D] FIG. 45D shows an expandable member having a conductive surface.

[0236] [Figure 45E] FIG. 45E shows various energy delivery catheters having expandable members with printed electrodes. [Figure 45F]FIG. 45F shows various energy delivery catheters having expandable members with printed electrodes. [Figure 45G] FIG. 45G shows various energy delivery catheters having expandable members with printed electrodes.

[0237] [Figure 45H] FIG. 45H shows an embodiment of an energy delivery catheter having an energy delivery body with two prongs that is expandable by an expandable member.

[0238] [Figure 46] FIG. 46 shows an embodiment of an energy delivery catheter having four energy delivery bodies that can be activated in a bipolar / multiplexed fashion.

[0239] [Figure 47] FIG. 47 illustrates monopolar energy delivery by supplying energy between the energy delivery body and a dispersive (return) electrode applied externally to the patient's skin.

[0240] [Figure 48] FIG. 48 shows an exemplary catheter removably connected to a bronchoscope.

[0241] [Figure 49A] FIG. 49A shows the introduction of a catheter with two energy delivery bodies through a bronchoscope. [Figure 49B] FIG. 49B shows the introduction of a catheter with two energy delivery bodies through a bronchoscope. [Figure 49C] FIG. 49C shows the introduction of a catheter with two energy delivery bodies through a bronchoscope.

[0242] [Figure 50] FIG. 50 is a schematic diagram of a single target segment within the mainstem bronchus of the lung.

[0243] [Figure 51] FIG. 51 is a schematic diagram of two target segments positioned adjacent to each other so that their overall target or treatment zones are approximately adjacent.

[0244] [Figure 51A] FIG. 51A illustrates a method for creating two intentionally overlapping target segments where some overlapping areas of tissue are to be treated more than once to ensure complete and continuous treatment effect. [Figure 51B] FIG. 51B illustrates a method for creating two intentionally overlapping target segments where some overlapping areas of tissue are to be treated more than once to ensure complete and continuous treatment effect. [Figure 51C] FIG. 51C illustrates a method for creating two intentionally overlapping target segments where some overlapping areas of tissue are to be treated more than once to ensure complete and continuous treatment effect. [Figure 51D] FIG. 51D illustrates a method for creating two intentionally overlapping target segments where some overlapping areas of tissue are to be treated more than once to ensure complete and continuous treatment effect.

[0245] [Figure 51E] Figure 51E shows the combined effect strength of overlapping treatment segments. [Figure 51F] Figure 51F shows the combined effect strength of overlapping treatment segments.

[0246] [Figure 52] FIG. 52 is a schematic diagram of two target zones within a patient.

[0247] [Figure 52A] FIG. 52A shows various target segments along various branching lung passageways, including within the ostium and along various smaller branches.

[0248] [Figure 52B]FIG. 52B illustrates the treatment of different lung passageways, such as branches from the same main bronchus.

[0249] [Figure 52C] FIG. 52C shows a catheter with a Y-shaped distal end that splits into a first end having a first energy delivery body and a second distal end having a second energy delivery body.

[0250] [Figure 52D] FIG. 52D shows an energy delivery body comprising an expandable member that is closed at one end and attached at the other end to the distal end of a catheter. [Figure 52E] FIG. 52E shows an energy delivery body comprising an expandable member that is closed at one end and attached at the other end to the distal end of a catheter.

[0251] [Figure 52F] FIG. 52F shows an embodiment of an expandable member having multiple electrodes, where the electrodes have a bipolar design. [Figure 52G] FIG. 52G shows an embodiment of an expandable member having multiple electrodes, where the electrodes have a bipolar design. [Figure 52H] FIG. 52H shows an embodiment of an expandable member having multiple electrodes, where the electrodes have a bipolar design.

[0252] [Figure 52I] FIG. 52I shows an additional embodiment of an energy delivery body design configured to treat multiple branches. [Figure 52J] FIG. 52J shows an additional embodiment of an energy delivery body design configured to treat multiple branches. [Figure 52K] FIG. 52K shows an additional embodiment of an energy delivery body design configured to treat multiple branches.

[0253] [Figure 53A]FIG. 53A is a schematic side view of a portion of an energy delivery body constructed from a braided basket.

[0254] [Figure 53B] FIG. 53B is a schematic cross-sectional view of the energy delivery body of FIG. 50 positioned within a lung passageway having an airway wall.

[0255] [Figure 54] FIG. 54 is a schematic illustration of the effect of continuous circumferential treatment of the airway along the length of the energy delivery body.

[0256] [Figure 55] FIG. 55 is a schematic illustration of discontinuous tissue effects in the lung passageways.

[0257] [Figure 56A] FIG. 56A shows an embodiment of an energy delivery catheter configured to deliver a conditioning solution. [Figure 56B] FIG. 56B illustrates an embodiment of an energy delivery catheter configured to deliver a conditioning solution. [Figure 56C] FIG. 56C illustrates an embodiment of an energy delivery catheter configured to deliver a conditioning solution. [Figure 56D] FIG. 56D illustrates an embodiment of an energy delivery catheter configured to deliver a conditioning solution.

[0258] [Figure 57A] Figure 57A shows an example of histology (Laboratory 6, Animal 1-10085), where Figure 57A shows a cross section from an untreated airway. [Figure 57B] Figure 57B shows an example of histology (Laboratory 6, Animal 1-10085), where Figure 57B shows a cross section from a treated airway.

[0259] [Figure 58A]Figure 58A shows another histology example (Laboratory 6, Animal 1-10085), where Figure 58A shows a cross section of an untreated airway. [Figure 58B] Figure 58B shows another histology example (Laboratory 6, Animal 1-10085), where Figure 58B shows a cross section of a treated airway. DETAILED DESCRIPTION OF THE INVENTION

[0260] Particular embodiments of the disclosed devices, delivery systems, and methods will now be described with reference to the drawings. Nothing in this detailed description is intended to imply that any particular component, feature, or step is essential to the implementation of any embodiment.

[0261] I. Overview Mucus secretion in the bronchial airways is an essential part of lung defense, protecting the lining and helping to fight infection. The amount of mucus secretion varies with a range of stimuli, including bacteria, particles, and chemical irritants. Normal secretion levels increase or decrease depending on transient environmental conditions. Mucus on the epithelial lining of the bronchial airways traps particles, and ciliated cells transport it from the lower respiratory tract, ultimately allowing it to be cleared by coughing or swallowing. Mucus also contains antibacterial agents that aid in its defensive function. Thus, pathogens and harmless inhaled proteins are removed from the airways, limiting their encounter with other immune components. In the bronchial airways, mucus is produced by goblet cells. Goblet cells produce mucin, which is complexed with water in secretory granules and released into the airway lumen. In the larger airways, mucus is also produced by mucous glands. After infection or toxic exposure, the airway epithelium upregulates its mucus secretory capacity, triggering coughing and sputum production. The airway epithelium then recovers to normal, goblet cells disappear, and coughing subsides.

[0262] However, in some cases, such as the development of many lung disorders and diseases, the body does not recover and chronically produces excess mucus, which accumulates in the lungs and blocks the distal airways. This results in symptoms such as chronic cough, dyspnea, fatigue, and chest pain and discomfort. Such mucus hypersecretion occurs in many pathologies and is a major clinical and pathological feature of conditions such as cystic fibrosis (CF)-associated bronchiectasis, non-CF bronchiectasis, chronic obstructive pulmonary disease, and asthma.

[0263] All of these disorders are associated with impaired innate lung defenses and significant activation of the host inflammatory response. Abnormal levels of antimicrobial peptides, surfactant, salivary lysozyme, salivary leukocyte protease inhibitors, and macrophages trigger mucin transcription and NF-KB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathways, in addition to Toll-like receptor (TLR) signaling. Increased mucus production and decreased clearance lead to decreased ventilation and increased exacerbations and airway epithelial damage. Ciliary activity is disrupted, and mucin production is upregulated. There is an expansion of the goblet cell population. Epithelial cell proliferation, accompanied by differentiation into goblet cells, increases. Similarly, exacerbations trigger inflammation, activating proteases that disrupt elastic fibers, allowing air and CO2 to enter and exit the alveoli. In response to injury, the airway epithelium produces more mucus and clears inflammatory cells from the airways, contributing to the progression of the disorder. Pathogens invade the mucus, which cannot be removed. This prepares the airways for another exacerbation cycle. As the cycle continues, excess mucus production leads to a pathological condition that increases the risk of infection, hospitalization, and morbidity.

[0264] To interrupt or prevent the cycle of disease progression, airways are treated with lung tissue modification systems that affect one or more cellular structures in the airway wall, restoring the airway wall structure from a diseased / remodeled state to a relatively normal state of architecture, function, and activity. Lung tissue modification systems treat lung tissue via the delivery of energy, typically characterized by high-voltage pulses. In some embodiments, energy delivery allows for the modification or removal of targeted tissue without a clinically significant inflammatory response, while in other embodiments, some inflammatory response is tolerated. This allows for the regeneration of healthy new tissue within a few days of treatment.

[0265] In one method, energy output from the lung tissue modification system induces separation in the epithelial layer E, causing abnormal, dysfunctional ciliated pseudostratified columnar epithelial cells (PCEC) and hyperplastic and abnormal goblet cells (GC) to separate from the basal cells (BC) and retract into the airway lumen, where they are expelled from the bronchial lumen. In the other method, energy output induces epithelial cell death, causing abnormal, dysfunctional ciliated epithelial cells and hyperplastic or abnormal goblet cells to expire. The expired cells are either reabsorbed into the airway tissue by infiltrating immune cells and phagocytosis, or expelled into the airway lumen and subsequently removed by normal airway debris clearance processes.

[0266] As a result, basal cells (BC) remain on the basement membrane (BM) and regenerate normal goblet cells (GC) and normal ciliated pseudostratified columnar epithelial cells (PCEC), thereby inducing reverse remodeling of the disease to reduce mucus hypersecretion. The newly regenerated goblet cells (GC) significantly reduce mucus production, and the newly regenerated ciliated columnar epithelial cells (PCEC) regrow normally functioning cilia, allowing mucus to be expelled more easily. The reduction in mucus volume is directly felt by patients, who experience reduced coughing and airway obstruction. Alveoli are better ventilated, thus improving hypoxia and respiratory acidosis. If patients are hyperinflated at baseline, the reduction in mucus blockage may reduce the volume of trapped air and result in a lower inhalation-to-exhalation ratio. Other subjects may suffer from low baseline lung volumes that may increase as mucus blockage is relieved. Over the following weeks, this translates to reduced exacerbations and improved quality of life.

[0267] In some embodiments, energy induces epithelial separation between basal cells (BC) and the more superficial goblet cells (GC) and ciliated pseudostratified columnar cells (PCEC) due to the relative strength of their intercellular connections. Basal cells (BC) are connected to the basement membrane (BM) by hemidesmosomes (H) (shown in Figure 3), while basal cells (BC) connect to goblet cells (GC) and ciliated pseudostratified columnar cells (PCEC) via desmosomes (D) (shown in Figure 3). The energy parameters and electrode configuration of the lung tissue modification system can be designed to separate desmosome connections (D) but leave hemidesmosomes (H) intact, thereby removing superficial cells and leaving basal cells (BC) substantially intact and ready to regenerate the epithelium. The regeneration process occurs more rapidly than typically occurs with trauma or thermal ablation modalities, where the basement membrane (BM) is disrupted and necrosis occurs. Basement membrane destruction and necrosis, such as in thermal ablation procedures, can lead to the activation of inflammatory pathways, including T cells, macrophages, IL-13, IL-4, monocytes, proteases, cytokines, and chemokines, among others. In the methods disclosed herein, there is no substantial destruction of the basement membrane BM, and there is little or no acute inflammation. This allows for the regeneration of healthy new target tissue within a few days of treatment. In other embodiments, it can be understood that the energy output from the lung tissue modification system induces other or additional changes in the airway wall W, leading to the regeneration of healthy target tissue.

[0268] FIG. 5 illustrates an embodiment of a lung tissue modification system 100 for use in treating a patient P. In this embodiment, the system 100 includes a therapeutic energy delivery catheter 102 connectable to a generator 104. The catheter 102 includes an elongate shaft 106 having at least one energy delivery body 108 near its distal end and a handle 110 at its proximal end. Connection of the catheter 102 to the generator 104 provides, among other things, electrical energy to the energy delivery body 108. The catheter 102 can be inserted into the bronchial passages of the patient P by various methods, such as through a lumen of a bronchoscope 112, as shown in FIG. 5.

[0269] FIG. 6 provides a more detailed view of the embodiment of the therapeutic energy delivery catheter 102 shown in FIG. 5 . In this embodiment, the energy delivery body 108 includes a single monopolar delivery electrode, although it can be understood that other types, numbers, and configurations may be used, further examples of which are provided herein. In this embodiment, the energy delivery body 108 is comprised of multiple wires or ribbons 120 constrained by a proximal end constraint 122 and a distal end constraint 124 that form a helical-shaped basket that functions as an electrode. In alternative embodiments, the wires or ribbons are straight rather than formed into a helical shape (i.e., configured to form a straight-shaped basket). In yet other embodiments, the energy delivery body 108 is laser cut from a tube. In some embodiments, the energy delivery body 108 is self-expandable and is delivered to the target area in a collapsed configuration. This collapsed configuration can be achieved, for example, by placing a sheath 126 over the energy delivery body 108. 6 , the catheter shaft 106 (within the sheath 126) terminates in the proximal end constraint 122, and the distal end constraint 124 is essentially unconstrained and free to move relative to the shaft 106 of the catheter 102. Advancing the sheath 126 over the energy delivery body 108 allows the distal end constraint 124 to move forward, thereby extending / retracting and constraining the energy delivery body 108.

[0270] The catheter 102 includes a handle 110 at its proximal end. In some embodiments, the handle 110 is removable, for example, by pressing a handle removal button 130. In this embodiment, the handle 110 includes an energy delivery body manipulation knob 132, movement of which causes the expansion or contraction / collapse of the basket-shaped electrodes. In this example, the handle 110 also includes a bronchoscope working port snap 134 for connection to the bronchoscope 112 and a cable plug-in port 136 for connection to the generator 104.

[0271] Referring again to FIG. 5 , in this embodiment, the therapeutic energy delivery catheter 102 is connectable to the generator 104 with a dispersive (return) electrode 140 applied externally to the patient P's skin. Thus, in this embodiment, monopolar energy delivery is achieved by supplying energy between the energy delivery body 108 located near the distal end of the catheter 102 and the return electrode 140. It can be understood that bipolar energy delivery and other configurations can alternatively be used, as described in further detail 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 / acquisition unit 156 (e.g., memory and / or database), and an energy storage subsystem 158 that generates and stores the energy to be delivered. In some embodiments, one or more capacitors are used for energy storage / delivery, although any suitable elements can be used as new technologies are developed. Additionally, one or more communication ports are included.

[0272] In some embodiments, the generator 104 can be understood to be composed of three subsystems: 1) a high-energy storage system; 2) a high-voltage, mid-frequency switching amplifier; and 3) a system control, firmware, and user interface. The system controller includes a cardiac synchronization trigger monitor that allows the pulse energy output to be synchronized to the patient's cardiac rhythm. The generator draws AC (alternating current) mains power to power multiple DC (direct current) power supplies. The generator controller directs the DC power supplies to charge a high-energy capacitor storage bank before energy delivery begins. At the start of therapeutic energy delivery, the generator controller, high-energy storage bank, and biphasic pulse amplifier operate simultaneously to generate a high-voltage, mid-frequency output.

[0273] Processor 154 may be, for example, a general-purpose processor, a field programmable gate array (FPGA), an application specific integrated circuit (ASIC), a digital signal processor (DSP), etc. Processor 154 may be configured to execute and / or perform application processes and / or other modules, processes and / or functions associated with system 100 and / or networks associated with system 100.

[0274] As used herein, the term "module" refers to any assembly and / or operatively coupled electrical components including, for example, memory, processor, electrical traces, optical connectors, software (executed in hardware), etc. For example, a module executed on a processor can be any combination of hardware-based modules (e.g., FPGA, ASIC, DSP) and / or software-based modules (e.g., modules of computer code stored in memory and / or executed on a processor) that can perform one or more specific functions associated with that module.

[0275] 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), flash memory, etc. The data storage / retrieval unit 156 may store instructions that cause the processor 154 to execute modules, processes and / or functions associated with the system 100.

[0276] In some embodiments, the data storage / retrieval unit 156 comprises a computer storage product having a non-transitory computer-readable medium (which may also be referred to as a non-transitory processor-readable medium) bearing instructions or computer code for performing various computer-implemented operations. The computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not itself comprise a transitory propagating signal (e.g., a propagating electromagnetic wave carrying information over a transmission medium such as space or a cable). The medium and computer code (which may also be referred to as code) may be one designed and constructed for a specific purpose. Examples of non-transitory computer-readable media include, but are not limited to: magnetic storage media such as hard disks, floppy disks, and magnetic tape; optical storage media such as compact disks / digital video disks (CDs / DVDs), compact disk-read-only memory (CD-ROMs), and holographic devices; magneto-optical storage media such as optical disks; carrier wave signal processing modules; and hardware devices specially configured to store and execute program code, such as ASICs, programmable logic devices (PLDs), read-only memory (ROM), and random access memory (RAM) devices. Other embodiments described herein relate to computer program products that may include, for example, instructions and / or computer code described herein.

[0277] Examples of computer code include, but are not limited to, microcode or microinstructions, machine instructions such as those generated by a compiler, code used to generate web services, and files containing high-level instructions executed by a computer using an interpreter. For example, embodiments may be implemented using imperative programming languages ​​(e.g., C, Fortran, etc.), functional programming languages ​​(Haskell, Erlang, etc.), logic programming languages ​​(e.g., Prolog), object-oriented programming languages ​​(e.g., Java, C++, etc.), or other suitable programming languages ​​and / or development tools. Additional examples of computer code include, but are not limited to, control signals, encryption code, and compression code.

[0278] In some embodiments, system 100 may be communicatively coupled to a network, which may be any type of network, such as, for example, a local area network (LAN), a wide area network (WAN), a virtual network, a telecommunications network, a data network, and / or the Internet, implemented as a wired and / or wireless network. In some embodiments, any or all communications may be protected using any suitable type and / or method of secure communications (e.g., Secure Sockets Layer (SSL)) and / or encryption. In other embodiments, any or all communications may not be secure.

[0279] The user interface 150 may include a touch screen and / or more traditional buttons that allow the operator to input patient data, select a treatment algorithm (i.e., the energy delivery algorithm 152), initiate energy delivery, view records stored in the storage / acquisition unit 156, or communicate with the generator 104.

[0280] Any of the systems disclosed herein can include a user interface 150 configured to allow operator-defined input. Operator-defined input can include energy delivery duration or other timing aspects of the energy delivery pulse, power, target temperature, operating mode, or a combination thereof. For example, various operating modes can include system initiation and self-test, operator input, algorithm selection, pre-treatment system status and feedback, energy delivery, post-energy delivery display or feedback, treatment data review and / or download, software update, or a combination thereof.

[0281] In some embodiments, the system 100 also includes a mechanism for acquiring an electrocardiogram (ECG), such as an external cardiac monitor 170. An example cardiac monitor is available from AccuSync Medical Research Corporation. In some embodiments, the external cardiac monitor 170 is operably connected to the generator 104. Here, the cardiac monitor 170 is used to continuously acquire an ECG. External electrodes 172 can be applied to the patient P to acquire the ECG. The generator 104 analyzes one or more cardiac cycles and identifies the beginning of a period when it is safe to apply energy to the patient P, thus providing the ability to synchronize energy delivery with the cardiac cycle. In some embodiments, this period is within milliseconds of the R wave to avoid induction of arrhythmias, which can occur if the energy pulse is delivered at the T wave. It can be understood that such cardiac synchronization is typically utilized when using unipolar energy delivery, but may be utilized in other instances.

[0282] In some embodiments, the processor 154, among other things, changes and / or switches energy delivery algorithms, monitors energy delivery and any sensor data, and responds to the monitored data via a feedback loop. It can be understood that in some embodiments, the processor 154 is configured to execute one or more algorithms for implementing the feedback control loop based on one or more measured system parameters (e.g., current), one or more measured tissue parameters (e.g., impedance), and / or combinations thereof. In these embodiments, signal sensing for collecting data can be provided by using the energy delivery body or a dedicated, energetically isolated sensor located on or near the energy delivery body.

[0283] The data storage / acquisition unit 156 stores data related to the delivered treatment, which can be downloaded as needed by connecting a device (e.g., a laptop or thumb drive) to the communications port. In some embodiments, the device has local software used to direct the download of information, such as instructions executable by the processor 154, stored in the data storage / acquisition unit 156. In some embodiments, the user interface 150 allows the operator to select download of data to devices and / or systems, such as, but not limited to, computer devices, tablets, mobile devices, servers, workstations, cloud computing devices / systems, etc. The communications port, which can allow for wired and / or wireless connections, not only allows for downloading data as just described, but also allows for uploading data, such as uploading custom algorithms or providing software updates.

[0284] As described herein, various energy delivery algorithms 152 can be programmable or pre-programmed into the generator 104, such as stored in memory or the data storage / acquisition unit 156. Alternatively, the energy delivery algorithms can be added to the data storage / acquisition unit so as to be executed by the processor 154. Each of these algorithms 152 can be executed by the processor 154. Example algorithms are described in detail below. In some embodiments, the catheter 102 includes one or more sensors 160 that can be used to determine temperature, impedance, resistance, capacitance, conductivity, permittivity, and / or conductance, to name a few. Sensor data can be used to plan treatment, monitor treatment, and / or provide feedback directly via the processor 154, which can modify the energy delivery algorithm 152. For example, impedance measurements can be used to determine not only the initial dose to be applied, but also whether further treatment is necessary.

[0285] It can be appreciated that any of the systems disclosed herein can include automatic treatment delivery algorithms that can dynamically respond and adjust and / or terminate treatment depending on inputs such as temperature, impedance, treatment duration or other timing aspects of the energy delivery pulse, treatment power and / or system state.

[0286] In some embodiments, imaging is accomplished using a commercially available system, such as a bronchoscope 112 connected to a separate imaging screen 180, as shown in Figure 5. It can be appreciated that the imaging modality can be incorporated into the catheter 102 or used with or in combination with the catheter 102. The imaging modality can be mechanically, operatively, and / or communicatively coupled to the catheter 102 using any suitable mechanism.

[0287] FIG. 7 is a schematic diagram of an embodiment of a lung tissue modification system 100. In this embodiment, the catheter 102 is configured for monopolar energy delivery. As shown, a distributed (neutral) or return electrode 140 is operably connected to the generator 104 while attached to the patient's skin to provide a return path for energy delivered through the catheter 102. The energy delivery catheter 102 includes one or more energy delivery bodies 108 (comprised of electrodes), one or more sensors 160, one or more imaging modalities 162, one or more buttons 164, and / or a positioning mechanism 166 (e.g., but not limited to, a lever and / or dial on a handle with a pull wire, telescoping tubing, sheath, etc.) that brings the one or more energy delivery bodies 108 into contact with tissue. In some embodiments, a footswitch 168 is operably connected to the generator 104 and is used to initiate energy delivery.

[0288] As previously mentioned, the user interface 150 may include a touch screen or conventional buttons to allow the operator to input patient data, select a treatment algorithm 152, initiate energy delivery, view records stored in the storage / acquisition unit 156, or communicate with the generator 104. The processor 154 manages and executes the energy delivery algorithm, monitors energy delivery and any sensor data, and responds to the monitored data via a feedback loop. The data storage / acquisition unit 156 stores data regarding the delivered treatment, which can be downloaded by connecting a device (e.g., a laptop or thumb drive) to the communication port 167.

[0289] The catheter 102 is operatively connected to the generator 104 and / or a separate imaging screen 180. The imaging modality 162 may be incorporated into the catheter 102 or may be used with or in combination with the catheter 102. Alternatively or additionally, a separate imaging modality or device 169, such as a commercially available system (e.g., a bronchoscope), may be used. The separate imaging device 169 may be mechanically, operatively, and / or communicatively coupled to the catheter 102 using any suitable mechanism.

[0290] Referring to FIG. 8A, a bronchoscope 112 is inserted into the mouth or oral cavity OC of a patient P. It can be understood that methods for accessing the airway can include the use of other natural openings, such as the nose or nasal cavity NC (shown in FIG. 8B). Alternatively, a suitable artificial opening may be used (e.g., a stoma, tracheotomy, not shown). The use of the bronchoscope 112 allows for direct visualization of the target tissue, and the working channel of the bronchoscope 112 can be used to deliver the catheter 102 in accordance with the devices and systems disclosed herein, allowing for visual confirmation of catheter placement and deployment. While FIGS. 8A-8B show the advancement of the distal end of the catheter 102 into the trachea T ​​and main bronchus MB, it can be understood that the catheter 102 can be advanced into the lobar bronchus LB, the more distal segmental bronchus SB, and the accessory segmental bronchus SSB, as needed.

[0291] 9-11 illustrate the placement of the distal end of the catheter 102 within the mainstem bronchus MB for treatment of the airway. In some embodiments, the catheter 102 has an atraumatic tip 125 that allows it to be advanced through the airway or airway wall W without damage. FIG. 9 illustrates the catheter 102 advanced into the mainstem bronchus MB while a sheath 126 covers the energy delivery body 108. Placement of the catheter 102 can be aided by various imaging techniques. For example, a bronchoscope 112 can be used to provide real-time direct visual guidance to the target site and can be used to observe the precise placement of the catheter 102 before, during, and after delivery of treatment. FIG. 10 illustrates the withdrawal of the sheath 126, exposing the energy delivery body 108. It can be appreciated that in some embodiments, the energy delivery body 108 is self-expanding such that the sheath 126 holds the energy delivery body 108 in a collapsed configuration. In such embodiments, retraction of the sheath 126 releases the energy delivery body 108 and allows it to self-expand. In other embodiments, the energy delivery body 108 expands by other mechanisms, such as movement of the knob 132, which may occur after the sheath 126 is withdrawn. Figure 11 shows the basket-shaped energy delivery body 108 in an expanded configuration, where the energy delivery body 108 contacts the airway wall W. Additional imaging can be used to confirm placement and / or take additional measurements (e.g., depth).

[0292] Once the energy delivery body 108 is desirably positioned, therapeutic energy is provided by the energy delivery body 108 to the airway wall W. The therapeutic energy is applied according to at least one energy delivery algorithm.

[0293] In some embodiments, the user interface 150 of the generator 104 is used to select 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 on the catheter 102, which is described in more detail in a later section. Various energy delivery algorithms can be used. In some embodiments, the algorithm 152 generates a signal having a waveform including a series of energy packets with rest periods between each packet, and each energy packet includes a series of high-voltage pulses. In some embodiments, each high-voltage pulse is between about 500 V and 10 kV, or between about 500 V and about 5000 V, including all values ​​and subranges therebetween. In some embodiments, the delivered energy is within a frequency range of about 10 kHz to about 10 MHz, or about 100 kHz to about 1 MHz, including all values ​​and subranges therebetween.

[0294] The algorithm 152 delivers energy to the airway walls to provide the desired treatment with minimal or no tissue heating. In some embodiments, a temperature sensor is used to measure electrode and / or tissue temperature during treatment to ensure that the energy deposited in the tissue does not cause clinically significant tissue heating. For example, the temperature sensor can monitor the temperature of the tissue and / or electrodes, and if a predefined threshold temperature (e.g., 65°C) is exceeded, the generator can modify the algorithm to automatically stop energy delivery or to reduce the temperature below the predefined threshold. For example, if the temperature exceeds 65°C, the generator can decrease the pulse width or increase the time between pulses or packets to further reduce the cumulative temperature rise. This can occur in a predefined stepwise approach, as a percentage of a parameter, or in other ways.

[0295] Conventional radiofrequency ablation (RFA) kills cells by applying high-frequency alternating current (AC) in the 350 to 550 kHz range, generating heat in tissue and causing thermal necrosis of cells. Many RFA devices have been developed to treat arrhythmias, solid tumors, renal nerves, and other conditions. Microwave ablation is another thermal ablation modality that uses AC currents between 300 MHz and 300 GHz, which also causes thermal necrosis. This energy source is used to target solid tumors due to its large ablation zone and uniform heating. Generally, heat-related thermal ablation denatures proteins within tissue, triggering significant inflammatory responses that are difficult to control and often lead to non-target tissue damage. While inflammation is tolerated in certain types of treatments (e.g., tumor treatment), when concentrated within the pulmonary airways, substantial inflammation can cause serious complications (e.g., exacerbations). While protein denaturation alone may or may not result in clinical morbidity, more intact and less denatured proteins offer the immune system the opportunity to enhance its host response to various challenges, whether they affect pathogenicity or tumorigenesis. These limitations make heat-related thermal ablation, particularly in the airways, less than desirable.

[0296] In contrast, algorithm 152 prescribes energy delivery to the airway wall W that is non-thermal (e.g., below the threshold for thermal ablation; below the threshold for inducing coagulative thermal damage), thereby reducing or avoiding inflammation. In some embodiments, algorithm 152 is tailored to affect tissue to a predetermined depth and / or to target specific cell types within the airway wall. Typically, particularly when treating the lining of an airway or lung passageway, a depth of up to 0.01 mm, up to 0.02 mm, 0.01-0.02 mm, up to 0.03 mm, 0.03-0.05 mm, up to 0.05 mm, up to 0.08 mm, up to 0.09 mm, up to 0.1 mm, up to 0.2 mm, up to 0.5 mm, up to 0.7 mm, up to 1.0 mm, up to 1.5 mm, up to 2.0 mm, or up to 2.3 mm, or less than 2.3 mm, may be targeted. In some examples, the predetermined depth of targeting is 0.5 mm, such as when targeting the airway epithelium and submucosal glands, with a significant safety margin to prevent morbidity-related cartilage effects at a depth of 2.3 mm. In other examples, the targeted depth of effect is more aggressive to treat all airway epithelial cells and submucosal glands up to a depth of 1.36 mm, while preventing safety-related effects on cartilage at a depth of 2.3 mm. In other embodiments, such as when applying such treatment to other clinical applications, such as cardiac applications, algorithm 152 is adjusted to affect tissue to a greater predetermined depth, such as up to 0.1 cm, up to 0.2 cm, up to 0.3 cm, up to 0.5 cm, up to 0.8 cm, up to 0.9 cm, up to 1 cm, or between 0.5 cm and 1 cm. In yet other embodiments, such as when applying such treatment to clinical applications involving deeper targets, algorithm 152 is adjusted to affect tissue to an even greater predetermined depth, such as up to 2 cm or up to 2.5 cm.

[0297] In some embodiments, the generator has several fixed algorithm settings, whereby each setting reflects the cell depth being targeted. For example, when treating a lung passageway, one setting / algorithm may primarily affect pathogens present in the mucus layer, another setting / algorithm may target the epithelium, another setting / algorithm may primarily target the epithelium, basement membrane, submucosa, and / or smooth muscle, and yet another setting / algorithm may primarily target the epithelium, basement membrane, submucosa, smooth muscle, submucosal glands, and / or nerves. In some embodiments, treatment occurs at the same location, while in other embodiments, the operator can choose to affect specific cell types at different locations. The settings the operator utilizes may depend on the physiology of the patient's condition.

[0298] The biological mechanisms and cellular processes by which energy removes cells are described in detail in later sections. Energy treats the airway wall W at the target location in a manner that allows for the regeneration of healthy tissue. For example, normal goblet cells (GC) and normal ciliated pseudostratified columnar epithelial cells (PCEC) can regenerate, inducing reverse remodeling of the disease and reducing mucus hypersecretion. The newly regenerated goblet cells (GC) produce significantly less mucus, and the newly regenerated ciliated pseudostratified columnar epithelial cells (PCEC) regrow normally functioning cilia (C) and more easily expel mucus (M). Thus, healthy new target tissue can be regenerated within days of treatment. This dramatically reduces the patient's symptoms of cough, mucus hypersecretion, and mucus plugging, resulting in fewer and fewer severe exacerbations and an improved quality of life.

[0299] FIG. 12 is a flowchart illustrating the method described herein in a stepwise approach for treating a patient, performed by a practitioner, a therapeutic energy delivery catheter, or a generator, as appropriate. In some embodiments, one or more of the steps disclosed herein may be optional. An initial series of steps may be used to assess the patient's anatomy and / or suitability for treatment to determine whether to treat. In some embodiments, this assessment may be optional but may include one or more of the following steps: First, obtain access to the airway (300, if necessary). Second, perform any appropriate pre-treatment imaging, sputum collection, and / or biopsy (301) that may be necessary and / or desirable. Pre-treatment imaging may include non-invasive CT scan, bronchoscopy, confocal laser endoscopic examination (CLE), optical coherence tomography (OCT), or any other appropriate technique, along with any measurements (e.g., depth) that may be taken. Sputum collection may include nasal mucosa brushing, nasal wash, bronchial brushing, bronchial lavage, and / or bronchoalveolar lavage. Next, a decision is made whether to treat the patient. If the decision is "no" 302, proceed to end 322. If the decision is "yes" 303, obtain access if necessary 304. In some embodiments, treatment can occur one or more days after the pre-treatment assessment. In this embodiment, obtaining access 304 is necessary.

[0300] In some embodiments, treatment can be performed immediately after the pre-treatment assessment. In this embodiment, re-access may not be necessary. In this embodiment, the next step 305 of the treatment is delivering the catheter. As described above, the catheter can be delivered in a variety of ways, but for purposes of example, the catheter is delivered through the working channel of a bronchoscope. In the next step 306, the catheter is positioned at the target site. Again, by way of example, a bronchoscope can be used to provide real-time direct visual guidance to the target site and observe the precise placement of the catheter. This may include placement of one or more energy delivery bodies in contact with the airway wall. Additional imaging 307 can then be used to confirm positioning and / or take additional measurements (e.g., depth). In the next step 308, the operator can optionally select a desired energy delivery algorithm 152. As described in detail above, this may include selecting an algorithm based on, for example, the target depth of the treatment. Alternatively, the generator is configured to apply a predefined algorithm that is suitable for most patients. In this embodiment, the next step 309 is executing or applying an energy delivery algorithm. This can be accomplished via a foot pedal or other mechanism described herein.

[0301] In some embodiments, as shown in FIG. 12A, a test pulse is delivered 307a after the step of positioning at the target site 306. After sensing and reading, the setup is confirmed 307b. If the determination is "yes," an energy algorithm is selected 308. If the determination is "no," the step of positioning at the target site 306 is repeated with subsequent steps. After the "yes" confirmation and application of energy 309, sensing energy may be delivered as needed 309a. Sensing is used with energy sources other than therapeutic pulses (low voltage sense pulses, AC spectroscopy, etc.).

[0302] 12-12A, after energy is applied, the surgeon may evaluate the energy application 310. This may include performing additional imaging with or without measurements and / or responding to messages communicated by the generator (e.g., errors in energy delivery that may result in incomplete treatment). If the treatment is unacceptable 311, then the surgeon returns to the Positioning at Target Site step 306. If the treatment is acceptable 312, the surgeon continues. The next step in the procedure is to determine whether to treat additional treatment sites. If "No" 313, the surgeon proceeds with the remaining steps to Final Imaging 315 and End 322. If "Yes" 314, the surgeon repositions to the next target site 316 and repeats the steps to apply treatment. Once all treatments are complete, the surgeon proceeds to the optional Final Imaging 315, and the surgeon may perform additional confirmation imaging to ensure all target areas have been satisfactorily treated. If "No" 317, the surgeon returns to "Repositioning at Next Target Site" 316 and administers additional treatments. If the answer is "yes" 318, the surgeon may then decide to perform one or more acute biopsies and / or sputum samples 319 to compare with any pre-treatment biopsies and / or sputum samples 301 that may have been taken. Follow-up images and / or biopsies and / or sputum samples may be taken 320 at a later date and compared with other images, biopsies, and / or sputum samples to assist in evaluating and / or documenting the results of treatment. The surgeon may then decide on the delivery of materials, active agents, etc. 321 to aid in the normal healing process, thereby further reducing the likelihood of perioperative problems or complications. Furthermore, this may further reduce the severity or frequency of exacerbations, especially in the short term. Some examples of these agents include isotonic saline gel, medicated films, antibacterial agents, antiviral agents, antifungal agents, anti-inflammatory agents, genetic material, stem cells, autologous cells, or allogeneic cells, to name a few. As a result of exposing the tissue to the high-energy field, the treated tissue may be conditioned to improve drug uptake. The treatment is then terminated at 322. In some embodiments, the agent is delivered prior to the pulsed electric field delivery.The patient can then continue to be followed by a physician and may undergo this entire treatment again if the disease or disorder recurs and / or persists.

[0303] Thus, in certain embodiments where the desired clinical effect is not achieved, or is achieved but the condition subsequently recurs, it may be desirable to repeat the treatment. In these embodiments, it may be desirable to target a different portion of the pulmonary anatomy rather than just re-treating a specific area. Thus, system 100 may be used to specifically re-treat the same portion of tissue as the initial treatment or a portion of tissue that is distinctly different from the initial intervention.

[0304] While various embodiments have been described above, it should be understood that they have been presented by way of example only, and not limitation. Where the methods described above show certain events occurring in a particular order, the order of the certain events can be changed. Furthermore, certain events can be performed simultaneously in parallel processes, where possible, or sequentially as described above.

[0305] II. Energy Delivery Algorithm As previously described, one or more energy delivery algorithms 152 can be programmable or pre-programmed into the generator 104 for delivery to the patient P. The one or more energy delivery algorithms 152 specify electrical signals that provide energy delivered to the airway wall W that is non-thermal (e.g., below the threshold for thermal ablation; below the threshold for inducing coagulative thermal damage), reduces or avoids inflammation, and prevents denaturation of interstitial proteins. Generally, the algorithms 152 are tailored to affect tissue to a predetermined depth and / or target specific types of cellular responses to the delivered energy. It can be understood that depth and / or targeting can be influenced by parameters of the energy signal defined by the one or more energy delivery algorithms 152, the design of the catheter 102 (particularly the one or more energy delivery bodies 108), and / or the selection of monopolar or bipolar energy delivery. In some cases, bipolar energy delivery allows for the use of lower voltages to achieve a therapeutic effect compared to monopolar energy delivery. In a bipolar configuration, the positive and negative poles are close enough to provide therapeutic effects at both the electrode poles. This allows for the therapeutic effect to be focused on a specific tissue region, allowing for therapeutic effects to be achieved at lower voltages compared to monopolar configurations. Similarly, this focal ability to use lower voltages can be used to reduce the depth of penetration, such as affecting epithelial cells rather than submucosal cells. In other instances, this reduced effective penetration depth can be used to focus energy, such as targeting the epithelium and submucosa while sparing cartilage tissue. Furthermore, if the delivered voltage is low enough to avoid stimulation of cardiomyocytes, the lower voltage requirement may obviate the use of cardiac synchronization.

[0306] It can be appreciated that a variety of energy delivery algorithms 152 can be used. In some embodiments, the algorithm 152 defines a signal having a waveform including a series of energy packets, each containing a series of high-voltage pulses. In such embodiments, the algorithm 152 specifies parameters of the signal, such as the energy amplitude (e.g., voltage) and duration of applied energy, consisting of the number of packets, the number of pulses within a packet, and the fundamental frequency of the pulse sequence, to name a few. Additional parameters can include the switching time between polarities of the biphasic pulses, the dead time between biphasic cycles, and the rest time between packets, which are described in more detail in later sections. There can be a fixed rest period between packets, or the packets can be gated to the cardiac cycle and therefore variable depending on the patient's heart rate. There can be an intentionally varying rest period algorithm, or no rest period can be applied between packets. Feedback loops based on sensor information, automatic shut-off specifications, and the like can be included.

[0307] FIG. 13 illustrates an embodiment of a waveform 400 of a signal prescribed by the energy delivery algorithm 152. Two packets are shown: a first packet 402 and a second packet 404, separated by a rest period 406. In this embodiment, each packet 402, 404 is composed of a first biphasic cycle (including a first positive pulse peak 408 and a first negative pulse peak 410) and a second biphasic cycle (including a second positive pulse peak 408' and a second negative pulse peak 410'). The first and second biphasic pulses are separated by a dead time 412 (i.e., a rest) between each pulse. In this embodiment, the biphasic pulses are symmetric, such that the set voltage 416 is the same for the positive and negative peaks. Here, the biphasic symmetric wave is also a square wave, such that the magnitude and duration of the positive voltage wave are approximately equal to the magnitude and duration of the negative voltage wave. When using a bipolar configuration, the portions of the airway wall W cells facing the negative voltage wave experience cell depolarization, where normally negatively charged cell membrane regions temporarily become positive. Conversely, the portions of the airway wall W cells facing the positive voltage wave experience hyperpolarization, where the potential of the cell membrane region becomes extremely negative. It can be appreciated that during each positive or negative phase of the biphasic pulse, the portions of the airway wall W cells experience opposite effects. For example, the portions of the cell membrane facing the negative voltage experience depolarization, while the portions 180° to this portion experience hyperpolarization. In some embodiments, the hyperpolarized portions face the dispersion or return electrode 140.

[0308] A. Voltage The voltages used and considered can be the crest of a square wave, the peak of a sine wave or sawtooth wave, or the RMS voltage of a sine wave or sawtooth wave. In some embodiments, the energy is delivered in a unipolar manner and each high voltage pulse or set voltage 416 is about 500V to 10,000V, particularly about 500V to 5000V, about 500V to 4000V, about 1000V to 4000V, about 2500V to 4000V, about 2000V to 3500V, about 2000V to 2500V, or about 2500V to 3500V, including all values ​​and subranges including about 500V, 1000V, 1500V, 2000V, 2500V, 3000V, 3500V, and 4000V. In some embodiments, each high-voltage pulse is in the range of about 1000V to 2500V and can penetrate the airway wall W with a specific combination of parameters to treat or affect specific cells more superficially, such as epithelial cells. In some embodiments, each high-voltage pulse is in the range of about 2500V to 4000V and can penetrate the airway W with a specific combination of parameters to treat or affect specific cells located more deeply, such as submucosal cells or smooth muscle cells.

[0309] It can be appreciated that the set voltage 416 can vary depending on whether the energy is delivered monopolarly or bipolarly. With bipolar delivery, lower voltages can be used due to the smaller, more directed electric field. In some embodiments, the energy is delivered in a bipolar manner, with each pulse ranging from about 100V to 1900V, particularly 100V to 999V, and more particularly about 500V to 800V, such as 500V, 550V, 600V, 650V, 700V, 750V, and 800V. In other embodiments, the energy is delivered in a bipolar manner, with each pulse ranging from about 50 to 5000V, including 250 to 1500V.

[0310] While the bipolar voltage selected for treatment depends on the electrode separation distance, a monopolar electrode configuration using a separate dispersive pad electrode can be delivered without significant consideration for the precise placement of the catheter electrode and dispersive electrode within the body. In monopolar electrode configurations, due to the dispersive behavior of the energy delivered through the body, larger voltages are generally used, reaching the dispersive electrode at effective separation distances of approximately 10 cm to 100 cm. Conversely, in bipolar electrode configurations, the relatively close active area of ​​the electrodes is on the order of 0.5 mm to 10 cm, including 1 mm to 1 cm, and the separation distance significantly impacts the electrical energy concentration and effective dose delivered to the tissue. For example, if the target voltage-to-distance ratio is 3000 V / cm and induces the desired clinical effect at the appropriate tissue depth (1.3 mm), changing the separation distance from 1 mm to 1.2 mm results in a required increase in treatment voltage from 300 to approximately 360 V, a change of 20%.

[0311] B.Frequency The frequency is the number of biphasic cycles per second of time. In some embodiments, biphasic pulses are utilized to reduce undesired muscle stimulation, particularly myocardial stimulation. In other embodiments, the pulse waveform is monophasic and does not have a distinct inherent frequency; instead, a fundamental phase frequency can be considered by doubling the monophasic pulse length to derive the frequency. In some embodiments, the signal has a frequency ranging from 100 kHz to 1 MHz, more specifically, from 100 kHz to 1000 kHz. In some embodiments, the signal has a frequency ranging from approximately 100 to 600 kHz, which typically penetrates the airway W to treat or affect certain cells located somewhat deeper, such as submucosal or smooth muscle cells. In some embodiments, the signal has a frequency ranging from approximately 600 kHz to 1000 kHz or 600 kHz to 1 MHz, which typically penetrates the airway wall W to treat or affect certain cells somewhat shallower, such as epithelial cells. It can be appreciated that at some voltages, frequencies below 300 kHz may cause undesired muscle stimulation. Thus, in some embodiments, the signal has a frequency in the range of 400 to 800 kHz or 500 to 800 kHz, e.g., 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, 800 kHz, etc. In particular, in some embodiments, the signal has a frequency of 600 kHz. Furthermore, cardiac synchronization is typically utilized to reduce or avoid unwanted myocardial stimulation during sensitive rhythm periods. It can be appreciated that even higher frequencies can be used with components that minimize signal artifacts.

[0312] C. Voltage-Frequency Balance The frequency of the delivered waveform can be varied in synchrony with the treatment voltage to maintain the appropriate therapeutic effect. Such synergistic variations include lowering the frequency to produce a stronger effect and lowering the voltage to produce a weaker effect. For example, in some cases, treatment can be delivered using 3000V in a monopolar manner with an 800kHz waveform frequency, while in other cases, treatment can be delivered using 2000V with a 400kHz waveform frequency.

[0313] Using the opposite direction can result in overly effective treatment parameters, potentially increasing the likelihood of muscle contraction or posing a risk to unwanted tissues, such as cartilage for airway treatment. For example, increasing the frequency and decreasing the voltage, such as using 2000 V at 800 kHz, can result in a treatment that does not achieve sufficient clinical efficacy. Conversely, if the voltage is increased to 3000 V and the frequency is decreased to 400 kHz, there may be an undesired degree of therapeutic effect on cartilage or other collateral tissues. In some cases, overtreatment of these unwanted tissues can result in patient morbidity or safety issues.

[0314] D. Packet As previously described, the algorithm 152 defines a signal having a waveform including a series of energy packets, each containing a series of high-voltage pulses. The cycle count 420 is half the number of pulses in each biphasic packet. Referring to FIG. 13, the first packet 402 has a cycle count 420 of two (i.e., four biphasic pulses). In some embodiments, the cycle count 420 is set between 1 and 100 per packet, including all values ​​and subranges therebetween. In some embodiments, the cycle count 420 is a maximum of 5 pulses, a maximum of 10 pulses, a maximum of 25 pulses, a maximum of 40 pulses, a maximum of 60 pulses, a maximum of 80 pulses, a maximum of 100 pulses, a maximum of 1000 pulses, or a maximum of 2000 pulses, including all values ​​and subranges therebetween.

[0315] The duration of the packet is determined by the number of cycles. The more cycles, the longer the packet duration and the greater the amount of energy delivered. In some embodiments, the packet duration is in the range of about 50 to 100 μsec, such as 50 μsec, 60 μsec, 70 μsec, 80 μsec, 90 μsec, or 100 μsec. In other embodiments, the packet duration is in the range of about 100 to 1000 μsec, such as 150 μsec, 200 μsec, 250 μsec, 500 μsec, or 1000 μsec.

[0316] The number of packets, or packet count, delivered during treatment can include 1 packet, 2 packets, 3 packets, 4 packets, 5 packets, 10 packets, 15 packets, 20 packets, 50 packets, 100 packets, 1000 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 subranges therebetween. In some embodiments, 5 packets are delivered, each having a 100 μsec packet duration and a set voltage of 2500 V. In some embodiments, 5 to 10 packets are delivered, each having a 100 μsec packet duration and a set voltage of 2500 V, resulting in a more intense and uniform treatment effect. In some embodiments, fewer than 20 packets, each having a 100 μsec packet duration and a set voltage of 2500 V, are delivered to avoid impacting the cartilage layer CL. In some embodiments, a total energy delivery duration between 0.5 and 100 milliseconds at a set voltage of 2500V may be optimal for therapeutic effect.

[0317] E. Break Period In some embodiments, the time between packets, referred to as the pause period 406, is set between about 0.1 seconds and about 5 seconds, including all values ​​and subranges therebetween. In other embodiments, the pause period 406 ranges from about 0.001 seconds to about 10 seconds, including all values ​​and subranges therebetween. In some embodiments, the pause period 406 is about 1 second. Notably, in some embodiments, the signal is synchronized with the cardiac rhythm, such that each packet is delivered synchronously within a specified period relative to the heartbeat, and therefore the remaining period coincides with the heartbeat. In other embodiments in which cardiac synchronization is utilized, the pause period 406 can vary, as the pause period between packets can be affected by cardiac synchronization, as described in a later section.

[0318] F. Switching Times and Dead Times The switching time is the delay or period of no energy delivered between the positive and negative peaks of a biphasic pulse, as shown in Figures 13A-13B. Figure 13A shows various examples of biphasic pulses (including positive peak 408 and negative peak 410) with a switching time 403 therebetween (however, if switching time 403 is zero, it does not appear). In some embodiments, the switching time ranges from about 0 to about 1 microsecond, including all values ​​and subranges therebetween. In other embodiments, the switching time ranges from 1 to 20 microseconds, including all values ​​and subranges therebetween. Figure 13B shows the relationship between effective electric field threshold and switching time.

[0319] A delay called a "dead time" can also be inserted between each cycle of the biphasic pulse. The dead time occurs within a packet, but between biphasic pulses. This is in contrast to the rest period that occurs between packets. In some embodiments, the dead time 412 is set between about 0 and about 500 nanoseconds, including 0 to 20 microseconds, and all values ​​and subranges therebetween. In other embodiments, the dead time 412 ranges from about 0 to 10 microseconds, or from about 0 to about 100 microseconds, or from about 0 to about 100 milliseconds, including all values ​​and subranges therebetween. In some embodiments, the dead time 412 ranges from 0.2 to 0.3 microseconds. The dead time can also be used to define the period between separate monophasic pulses within a packet.

[0320] Delays, such as switching and dead times, are introduced into the packets to reduce the effects of biphasic cancellation within the waveform. Biphasic cancellation or bipolar cancellation is a term used to refer to the reduced induction of cellular modulation in response to biphasic versus monophasic waveforms, especially when switching and dead times are small, such as less than 10 μs. While one explanation for this phenomenon is presented here, it is understood that there are likely other biological, physical, or electrical properties or changes that result in reduced modulation from biphasic waveforms. When cells are exposed to electromotive forces induced by the presence of an electric field, electrokinetic movement of ions and solutes occurs within the intracellular and extracellular fluids. These charges accumulate at dielectric boundaries, such as cell and organelle membranes, altering the resting transmembrane potential (TMP). When the electric field is removed, the driving force that generated the engineered TMP is also eliminated, and normal biological transport and ion dynamics operating on concentration gradients begin to restore the normal distribution of solutes. This causes a logarithmic decay of the engineered TMP across the membrane. However, rather than removing the electric field, the polarity of the electric field is maintained but reversed. The new electromotive force actively removes the existing induced TMP, followed by the accumulation of TMP with the opposite polarity. This active depletion of the initially manipulated TMP significantly limits the downstream cascade that can occur in cells, weakening the therapeutic effect of the initial electric field exposure. Furthermore, subsequent electric fields with reversed polarity must "cancel" the original TMP manipulation, and then begin to accumulate their own TMP with the opposite polarity. The final TMP reached in the second phase of the electric field is not as strong as the original TMP, assuming the duration of each phase of the cycle is the same. This reduces the therapeutic effect generated from each phase of the waveform, making it lower than the therapeutic effect achieved by any one pulse in the cycle alone. This phenomenon is called biphasic cancellation. For packets with many cycles, this pattern repeats throughout the set of cycles and phase changes within the packet. This dramatically limits the therapeutic effect.It can be appreciated that if cellular behavior is modulated as a result of pulsed electric fields by mechanisms other than pure transmembrane potential manipulation, the effect of biphasic cancellation will be less pronounced and therefore the impact of switching and dead times on therapeutic outcome will be reduced.

[0321] Thus, in some embodiments, the effect of biphasic cancellation is reduced by introducing a switching time delay and dead time. In some cases, both the switching time and dead time are increased simultaneously to enhance the effect. In other instances, only the switching time or only the dead time is increased to induce this effect.

[0322] Typically, it can be seen that the appropriate timing is for the relaxation of the TMP to be complete after 5 times the charging time constant τ. For most cells, the time constant is estimated to be 1 μs. Therefore, in some embodiments, the switching time and dead time are both set to at least 5 μs to eliminate biphasic cancellation. In other embodiments, reducing biphasic cancellation may not require complete cell relaxation before reversing polarity, and therefore the switching time and dead time are both set to 0.5 μs to 2 μs. In other embodiments, the switching time and dead time are set to the same length as the individual pulse length, since further increases in these delays only provide diminishing returns in terms of increased therapeutic effect and concomitant increases in muscle contraction. Thus, the combination of longer-scale pulse durations (>500 ns) and stacked pulse cycles with substantial switching and dead time delays allows the use of biphasic waveforms without significantly reducing the therapeutic effect generated by biphasic cancellation. In some cases, adjustments to these parameters can be made to induce stronger therapeutic effects without a relatively proportionate increase in muscle contraction. For example, using a 600 kHz waveform with a switching time = dead time = 1.66 μs (twice the duration as a pulse) can maintain a stronger therapeutic effect while maintaining a reduction in muscle contraction compared to a monophasic pulse waveform.

[0323] In some embodiments, the switching time period is adjusted so that the degree of therapeutic effect relative to the distant cellular effect is optimized for the therapeutic target. In some embodiments, the switching time duration is minimized to reduce the local therapeutic effect and reduce distant muscle cell contraction. In other embodiments, the switching time duration is extended to increase the local therapeutic effect, potentially with additional distant muscle cell contraction. In some embodiments, the switching time or dead time period is extended to increase the local therapeutic effect, and the use of a neuromuscular paralytic agent is employed to control the resulting increase in muscle contraction. In some embodiments, the switching duration is 10 nsec to 2 μsec, and in other embodiments, the switching duration is 2 μsec to 20 μsec. In some instances, when cellular modulation is targeted in a manner where transmembrane potential manipulation is not the primary mechanism required to induce the targeted therapeutic effect, the switching time and dead time delay are minimized to less than 0.1 μsec or 0 μsec. Eliminating this delay minimizes peripheral, non-targeted therapeutic effects, such as skeletal muscle contraction or cardiac action potential and contraction, but does not alter the strength of the therapeutic effect at the target site.

[0324] Another advantage of using switching and dead-time delays to enhance the therapeutic effect of biphasic waveforms is that they reduce generator demands, allowing for the introduction of pauses to achieve a more powerful therapeutic effect without the need for asymmetric / unbalanced pulse waveforms. In this context, an unbalanced waveform is described as a monophasic waveform or a waveform with an unbalanced duration, voltage, or combination of one polarity with the other. In some cases, imbalance means that the integral of the positive portion of the waveform is not equal to the integral of the negative portion of the waveform. Generators capable of delivering unbalanced waveforms have separate design considerations that must be taken into account, which can increase the complexity of the generator.

[0325] G. Waveform FIG. 13 shows an embodiment of a waveform 400 having symmetric pulses such that the voltage and duration of the pulse in one direction (i.e., positive or negative) are equal to the voltage and duration of the pulse in the other direction. FIG. 14 shows an example waveform 400 defined by another energy delivery algorithm 152, in which the waveform 400 has a voltage imbalance. Here, two packets are shown: a first packet 402 and a second packet 404, separated by a rest period 406. In this embodiment, each packet 402, 404 is comprised of a first biphasic cycle (including a first positive pulse peak 408 having a first voltage V1 and a first negative pulse peak 410 having a second voltage V2) and a second biphasic cycle (including a second positive pulse peak 408' having a first voltage V1 and a second negative pulse peak 410' having a second voltage V2). Here, the first voltage V1 is greater than the second voltage V2. The first and second biphasic cycles are separated by a dead time 412 between each pulse. Therefore, because the voltage in one direction (i.e., positive or negative) is greater than the voltage in the other direction, the area under the positive portion of the curve is not equal to the area under the negative portion of the curve. This unbalanced waveform can produce a more pronounced therapeutic effect because the dominant positive or negative amplitude increases the duration of the same charge cell membrane charge potential. In this embodiment, the first positive peak 408 has a set voltage 416 (V1) that is greater than the set voltage 416' (V2) of the first negative peak 410. Figure 14A shows another example of a waveform with unequal voltages. Here, four different types of packets are summarized in one diagram. The first packet 402 has pulses of unequal voltage but equal pulse width, with no switching time or dead time. Thus, the first packet 402 is comprised of four biphasic pulses, each including a positive peak 408 having a first voltage V1 and a negative peak 410 having a second voltage V2, where the first voltage V1 is greater than the second voltage V2. The second packet 404 is comprised of pulses having unequal voltages but symmetric pulse widths (as in the first pulses 402), with a switching time equal to the dead time.The third packet 405 consists of pulses with unequal voltages but symmetric pulse widths (as in the first pulse 402), with a switching time shorter than the dead time. The fourth packet 407 consists of pulses with unequal voltages but symmetric pulse widths (as in the first pulse 402), with a switching time longer than the dead time. In some embodiments, the positive and negative phases of the biphasic waveform are not identical but are balanced, with the voltage in one direction (i.e., positive or negative) greater than the voltage in the other direction, but the pulse lengths are calculated so that the area under the curve for the positive phase is equal to the area under the curve for the negative phase.

[0326] In some embodiments, the imbalance includes pulses having pulse widths that are unequal in duration. In some embodiments, a biphasic waveform is imbalanced such that the voltage in one direction is equal to the voltage in the other direction, but the duration of one direction (i.e., positive or negative) is longer than the duration of the other direction, so that the area under the curve of the positive portion of the waveform is not equal to the area under the negative portion of the waveform.

[0327] FIG. 14B shows further examples of waveforms with unequal pulse widths. Here, four different types of packets are summarized in one diagram. The first packet 402 consists of pulses with equal voltages but different pulse widths, with no switching time or dead time. Thus, the first packet 402 consists of four biphasic pulses, each including a positive peak 408 with a first pulse width PW1 and a negative peak 410 with a second pulse width PW2. Here, the first pulse width PW1 is greater than the second pulse width PW2. The second packet 404 consists of pulses with equal voltages but unequal pulse widths (as in the first pulses 402), with a switching time equal to the dead time. The third packet 405 consists of pulses with equal voltages but unequal pulse widths (as in the first pulses 402), with a switching time shorter than the dead time. The fourth packet 407 consists of pulses with equal voltages but unequal pulse widths (as in the first pulses 402), with switching times longer than the dead time.

[0328] FIG. 15 illustrates an exemplary waveform 400 defined by another energy delivery algorithm 152 in which the waveform is monophasic, a special case of imbalance where there is only a positive or negative portion of the waveform. Two packets, a first packet 402 and a second packet 404, are shown, separated by a rest period 406. In this embodiment, each packet 402, 404 is composed of a first monophasic pulse 430 and a second monophasic pulse 432. The first and second monophasic pulses 430, 432 are separated by a dead time 412 between each pulse. This monophasic waveform may produce 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 by the monophasic waveform compared to a biphasic waveform.

[0329] FIG. 15A shows another example of a waveform with monophasic pulses. Here, four different types of packets are summarized in one diagram. The first packet 402 consists of pulses with the same voltage and pulse width, with no switching time (because the pulses are monophasic), and a dead time equal to the active time. In some cases, the dead time period may be shorter than the active time of a particular pulse. Thus, the first packet 402 consists of three monophasic pulses 430, each containing a positive peak. If the dead time is equal to the active time, the waveform represents a cycle period twice the active time and can be considered unbalanced at the fundamental frequency with no dead time. The second packet 404 consists of monophasic pulses 430 with the same voltage and pulse width (as in the first packet 402) but with a larger dead time. The third packet 405 consists of monophasic pulses 430 with the same voltage and pulse width (as in the first packet 402) and an even larger dead time. The fourth packet 407 consists of monophasic pulses 430 with equal voltage and pulse width (as in the first packet 402), but with a larger dead time.

[0330] In some embodiments, an imbalanced waveform is achieved by delivering two or more pulses of one polarity before reversing to an unequal number of pulses of the opposite polarity. Figure 15B shows further examples of waveforms with such phase imbalance. Here, four different types of packets are summarized in one diagram. The first packet 402 consists of four cycles with equal voltage and pulse width, but pulses of opposite polarity are mixed with monophasic pulses. Thus, the first cycle includes a positive peak 408 and a negative peak 410. The second cycle is monophasic and includes a single positive pulse without a subsequent negative pulse 430. This repeats. The second packet 404 consists of mixed biphasic and monophasic cycles (as in the first packet 402), but the pulses have unequal voltages. The third packet 405 consists of mixed biphasic and monophasic cycles (as in the first packet 402), but the pulses have unequal pulse widths. The fourth packet 407 is composed of mixed biphasic and monophasic pulses (as in the first packet 402), but the pulses have unequal voltages and unequal pulse widths. Thus, multiple combinations and permutations are possible.

[0331] It should be noted that during each positive or negative phase of the biphasic cycle, the portion of the airway wall W cell facing the opposite side of the energy source experiences the opposite effect. In some embodiments, the hyperpolarized portion faces the dispersive or return electrode 140. It can also be understood that cells have a naturally negative resting electrical transmembrane potential (TMP). Therefore, alterations to the native TMP on the cell side that promote a negative TMP result in an exaggerated absolute TMP. Conversely, on the cell side that induces a positive TMP, the absolute TMP is reduced. In either case, interfering with the native cellular TMP and altering cellular behavior can evoke a desired therapeutic outcome, regardless of the final absolute TMP. Furthermore, this difference may be different when considering TMP induced in intracellular organelles.

[0332] Regarding the usefulness of asymmetric waveforms, the achieved unbalanced TMP maneuver reduces the effects of biphasic cancellation. There is a correlation between the degree of imbalance and the intensity of TMP maneuver as one approaches a fully unbalanced monopolar waveform. This results in a proportional relationship between the degree of therapeutic effect and the degree of muscle contraction. Therefore, approaching a more unbalanced waveform results in a stronger therapeutic effect at the same voltage and frequency (if applicable) as a biphasic waveform than that produced by a purely balanced biphasic waveform. For example, a therapeutic effect induced by a pulse length sequence such as 830 ns-415 ns-830 ns within a packet would result in pulses comprising the second half of the cycle being half the duration of the original phase. This limits the induction of TMP maneuver by the second phase of the cycle, but also generates less reverse TMP, resulting in a stronger effect from the original polarity of subsequent cycles at the original length. In other examples, the "positive" portion of the waveform can be 2500 V and the "negative" portion 1500 V (e.g., 2500-1250-2500 V), which induces the same degree of effect on TMP polarization as described for pulse duration imbalances. In both of these cases, manipulating the intensity of the opposite polarity results in a cumulative stronger TMP manipulation relative to the positive pulse within the cycle. This therefore reduces the effects of biphasic cancellation and produces a stronger therapeutic effect than 830-830-830 ns or 2500-2500-2500 V protocols, despite delivering less total energy to the tissue. In this way, if TMP manipulation is essential to the mechanism of action of the therapy, less total energy can be delivered to the tissue, yet still evoke the desired therapeutic effect.

[0333] By extension, a fully unbalanced waveform may contain no opposite polarity components, but may contain short portions of pulses delivered only on the positive phase. An example of this would be 830 ns of positive polarity, 830 ns of pause with no energy delivered, followed by another 830 ns of positive polarity, etc. The absence of a negative pulse is equivalent to setting either of these parameters to zero during the "negative" portion, so the same approach applies whether considering pulse length imbalance or voltage imbalance.

[0334] However, providing adequate therapy requires balancing the benefits provided by biphasic waveforms—i.e., the reduction in muscle contraction resulting from biphasic cancellation—with the appropriate therapeutic effect. Therefore, the appropriate level of therapeutic effect must be balanced with the acceptable level of muscle contraction. For example, ideal voltage imbalances might be 2500-1000-2500-V, or 2500-2000-2500-V; or 830-100-830-n seconds, or 830-500-830-n seconds.

[0335] H.Wave shape FIG. 16 shows an example waveform 400 defined by another energy delivery algorithm 152 in which the pulses are sinusoidal rather than square. Similarly, two packets are shown: a first packet 402 and a second packet 404, separated by a rest period 406. In this embodiment, each packet 402, 404 is composed of three biphasic pulses 440, 442, 444. And, rather than square waves, these pulses 440, 442, 444 are sinusoidal in shape. One advantage of a sinusoidal waveform is that it is balanced, or symmetrical, so the shape of each phase is equal. Balancing helps reduce unwanted muscle stimulation.

[0336] Energy delivery can be activated by various mechanisms, such as using a button 164 on the catheter 102 or a footswitch 168 operably connected to the generator 104. Such activation typically provides a single energy dose. The energy dose is defined by the number of packets delivered and the voltage of the packets. Each energy dose delivered to the airway wall W maintains the temperature at or within the wall W below the threshold for heat removal, particularly of the basement membrane BM, including denatured interstitial proteins of the basement membrane or the deeper submucosal extracellular protein matrix. Furthermore, the dose can be titrated or relaxed over time to further reduce or eliminate heat accumulation during the treatment procedure. Instead of inducing thermal damage, defined as protein coagulation, the energy dose provides energy at a level that triggers biological mechanisms and cellular effects that ultimately lead to the regeneration of healthy tissue.

[0337] III. Biological Mechanisms and Cellular Effects As previously described, the algorithm provides energy to the airway wall W at a level that induces biological mechanisms and cellular effects while reducing or avoiding inflammation. Examples of biological mechanisms and cellular processes are described herein, but are not limited thereto.

[0338] The energy delivered to the airway wall W can induce various cellular effects that ultimately lead to the regeneration of healthy lung airway tissue. Examples of cellular effects include the removal of specific cell types, such as by detachment of cells from the airway wall W (which can be carried away naturally or induced) or cell death (e.g., lysis or apoptosis). Other cellular effects include modifying specific cell types without elimination, such as by reprogramming cells, or improving drug uptake by improving drug uptake into cells.

[0339] In some embodiments, specific cells are removed by detachment of the cells from the airway wall W. FIG. 17 illustrates an embodiment in which energy (indicated by arrows 200) is provided to the airway wall W by one or more energy delivery bodies. In this embodiment, the energy 200 has a target cell depth set to impact the epithelial layer E without extending beyond the basement membrane BM. The energy 200 is configured to detach specific epithelial cells, in this example, pseudostratified columnar epithelial cells PCEC and goblet cells GC, which are configured to induce cilia, from the remaining epithelial layer (e.g., basal cells BC) and / or basement membrane BM. The detached cells are then freed within the lung passageway and can be removed by natural excretion processes or by interventional methods such as suction.

[0340] In other embodiments, specific cells are removed by cell death, with affected cells dying by lysis or apoptosis, ultimately removing them from the airway wall W. FIG. 18 illustrates an embodiment in which energy 202 is delivered to the airway wall W by one or more energy delivery bodies, again with a target cell depth set so that the energy 202 impacts the epithelial layer E without extending beyond the basement membrane BM. However, in this embodiment, the energy 202 is configured to kill specific epithelial cells—in this case, ciliated pseudostratified columnar epithelial cells PCEC and goblet cells GC—while other cells (e.g., basal cells BC) remain (as indicated by the dashed lines). Cell death can be achieved by various mechanisms. For example, in some embodiments, cell death occurs through disruption of the cell membrane. In such embodiments, the delivered energy can disrupt the lipid bilayer of the cell membrane, such that the cell membrane cannot maintain its barrier function. Without a plasma membrane, cells cannot maintain appropriate intracellular concentrations of sodium, potassium, calcium, and adenosine triphosphate (ATP). As a result, cells lose homeostasis and die. In some embodiments, cell death occurs through the destruction of intracellular organelles. In such embodiments, the delivered energy can permanently prevent intracellular organelles from functioning. These organelles include the endoplasmic reticulum, Golgi apparatus, mitochondria, nuclei, nucleoli, etc. Without the normal function of these intracellular organelles, cells die. It can be understood that in some instances, both the cell membrane and intracellular organelles are targeted by the delivered energy. Thus, if the delivered energy only partially affects the cell membrane or intracellular organelles, the cumulative effect on both targets ultimately leads to cell death.

[0341] After cell death, an inflammatory cascade ensues. Cell fragments and intracellular contents signal leukocytes and macrophages to enter the affected area of ​​the airway wall. Over hours to days, the dead cells are removed from the area by phagocytosis. Unlike thermal ablation, which damages the extracellular matrix, phagocytosis is limited to cellular debris, not collagen or matrix components of the extracellular matrix.

[0342] In some embodiments, specific cells are not eliminated, but rather, targeted cells are altered or affected, such as by reprogramming. For example, in some embodiments, the ability of goblet cell GCs to secrete accumulated mucus or produce mucus is altered. Alternatively, the degeneration restores function to the cilia C of ciliated pseudostratified columnar epithelial cells PCECs, allowing them to more easily expel mucus into the airways. In other embodiments, ciliated pseudostratified columnar epithelial cells PCECs and goblet cell GCs are not altered, but deeper structures are primarily affected, such as reduced smooth muscle hypertrophy or neutralization of chronic inflammatory cells and eosinophils.

[0343] Even if cells are removed or degenerated, the airway wall W regenerates and regains normal function. In some cases, epithelial cells regenerate to a pre-treated state, but it can be understood that deeper cells such as smooth muscle SM, eosinophils, submucosal gland SG, and chronic inflammatory cells may be permanently reduced.

[0344] As previously described, algorithms can be tailored to affect tissue to a predetermined depth and / or target specific cell types within the airway wall. For example, various algorithms can 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 various combinations thereof. In one embodiment, an algorithm is configured to generate energy that penetrates the epithelial layer E of the airway wall W down to the basement membrane BM. Within this embodiment, various different cell types can be targeted. For example, energy can be configured to target ciliated pseudostratified columnar epithelial cells PCEC and goblet cells GC, causing their removal while leaving basal cells BC intact. In such an embodiment, the airway wall W can have abnormal, non-functioning ciliated pseudostratified columnar epithelial cells PCEC and hyperplastic, dysplastic goblet cells GC, causing mucus hypersecretion. The delivered energy causes the abnormal ciliated pseudostratified columnar epithelial cells PCEC and goblet cells GC to be removed, such as by cell death or detachment, while leaving the basal cells BC intact along the basement membrane BM. Recall that the ciliated polystratified columnar epithelial cells PCEC and goblet cell GC are connected to each other by tight junctions TJ and adherens junctions AJ. Furthermore, the ciliated polystratified columnar epithelial cells PCEC and goblet cell GC are connected to the basal cell BC by desmosomes D. In some embodiments, the energy is configured to dissolve the tight junctions TJ and adherens junctions AJ, further enabling the desmosomes D to remove the ciliated polystratified columnar epithelial cells PCEC and goblet cell GC. Similarly, the energy may be configured to enable the preservation of hemidesmosomes H, which connect the basal cell BC to the basement membrane 126. Thus, the basal cell BC remains intact.

[0345] Removal of ciliated pseudostratified columnar epithelial cells (PCECs) and goblet cells (GCs) can reduce mucus production and secretion through various mechanisms. For example, such removal can attenuate signaling mechanisms that lead to the expression of proteins found in mucins, thereby reducing mucus production. In particular, Muc5ac is a protein contained in the mucins of airway goblet cell GCs, encoded by the MUC5AC gene. Several ligands and transcription factors are involved in Muc5ac expression. Interleukin-13 binds to a receptor containing the interleukin-4Rα subunit, which activates Janus kinase 1 (Jak1), leading to the phosphorylation of Stat6. Although there are no consensus Stat6 binding sites in the MUC5AC and Muc5ac promoters, activation of Stat6 leads to increased expression of SPDEF (a SAM-directed domain-containing Ets transcription factor), which upregulates multiple genes involved in mucosal metaplasia and inhibits the expression of Foxa2, which negatively regulates Muc5ac. Several ligands bind to ErbB receptors, including epidermal growth factor, transforming growth factor α, amphiregulin, and neuregulin, which activate mitogen-activated protein kinases (MAPKs). Hypoxia-inducible factor 1 (HIF-1) can also be activated downstream of ErbB receptors, and there are conserved HIF-1 binding sites in the proximal MUC5AC and Muc5ac promoters. Complement C3 and β2-adrenergic receptor signaling also amplify Muc5ac production, but transcription factors such as Sox2, Notch, E2f4, and Math primarily regulate expression.

[0346] In the case of removal of ciliated pseudostratified columnar epithelial cells (PCECs) and goblet cells (GCs), cell death or detachment silences the signaling mechanism that leads to Muc5ac expression. Therefore, mucus is not produced, resulting in reduced mucus in the airways. This benefits patients with COPD (chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, acute bronchitis, and other lung diseases or disorders.

[0347] Removal of such epithelial cells can also reduce mucus secretion through various mechanisms. In particular, removal of mucus-producing goblet cells (GCs) leaves no cells secreting mucus into the airways. Mucus secretion is triggered by the molecular mechanism of mucin exocytosis. Mucin-containing secretory granules are docked to the plasma membrane through the interaction of granule-bound Rab proteins with effector proteins that act as tethers to Munc18, which binds the closed conformation of syntaxin anchored to the plasma membrane. Secretion is triggered by ATP binding to Gq-coupled P2Y2 purinergic receptors (P2Y2R), which activate phospholipase C (PLC) to generate the second messengers diacylglycerol (DAG) and inositol triphosphate (IP3). DAG activates Munc1314 to open Syntaxin, thereby mobilizing it along with granules and the plasma membrane, allowing it to form a four-helix SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex with SNAP-23 (synaptosomal-associated protein 23) and VAMP (vesicle-associated membrane protein). IP3 induces calcium release from IP3 receptors (IP3R) in the endoplasmic reticulum (ER), activating synaptotagmin to induce the final coiling of the SNARE complex, resulting in membrane fusion and mucin release.

[0348] When these epithelial cells are removed, the signaling mechanisms that lead to mucin exocytosis are weakened. Therefore, less mucus is secreted, resulting in reduced mucus in the airways. This benefits patients with COPD (chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, acute bronchitis, and other lung diseases or disorders.

[0349] In some embodiments, the basal membrane (BM)-remaining basal cells (BC) can regenerate normal goblet cells (GC) and normal ciliated pseudostratified columnar epithelial cells (PCEC), thereby inducing reverse remodeling to reduce mucus hypersecretion. In some embodiments, the ciliated pseudostratified columnar epithelial cells (PCEC) further regrow by migrating from surrounding areas of the airway wall (W) to support the regeneration of healthy tissue in the target area. Goblet cells (GC) typically regenerate at a lower level compared to the mild, moderate, or severe goblet cell hyperplasia present prior to energy application. The newly regenerated goblet cells (GC) significantly reduce mucus production, and the newly regenerated ciliated pseudostratified columnar epithelial cells (PCEC) regrow normally functioning cilia (C) and more readily expel mucus (M). Thus, healthy new target tissue can be regenerated within a few days of treatment. This dramatically reduces the patient's cough and mucus hypersecretion symptoms, reducing the severity of exacerbations and improving quality of life.

[0350] In other embodiments, it can be understood that energy can be configured to target abnormal goblet cells CG, removing them by cell death or desquamation, etc., leaving behind ciliated multistratified columnar epithelial cells PCEC and basal cells BC. Removal of abnormal goblet cells CG can reduce mucus production and / or secretion by many of the mechanisms described above. Similarly, energy can be configured to target abnormal ciliated multistratified columnar epithelial cells PCEC, removing them by cell death or desquamation, etc., leaving behind goblet cells CG and basal cells BC. Similarly, energy can be configured to target abnormal basal cells BC, removing them by cell death or desquamation, etc., leaving behind ciliated multistratified columnar epithelial cells PCEC and goblet cells GC. It can be understood that in any of these combinations of cell removal, the remaining cells can be further modified or affected by the delivered energy or by subsequently delivered energy. For example, the remaining abnormal goblet cells CG can be modified to reduce mucus production and / or secretion while remaining intact. It can also be understood that a cell population may be partially ablated, with some cells of a particular cell type being ablated by the delivered energy and some remaining and optionally denatured.

[0351] In other embodiments, the algorithm is configured to generate energy that penetrates the epithelial layer E of the airway wall W, including down to the basement membrane BM. In such embodiments, changes to the epithelial layer E can occur as described above. Furthermore, the basement membrane BM can be affected by the delivered energy to aid in rebuilding the airway wall W to a healthy state. In some embodiments, the basement membrane BM is altered to stabilize or reduce its thickness. Thickening of the basement membrane BM is a hallmark of many lung diseases, including chronic bronchitis and asthma. Thus, the delivered energy can target the basement membrane BM to halt or reverse such thickening. In some embodiments, such changes to the basement membrane BM affect the ability of cells, such as neutrophils, and inflammatory molecules, such as cytokines, to pass through the basement membrane BM, thus aiding in the regeneration of a healthy airway wall W.

[0352] In some embodiments, the algorithm is configured to generate energy that penetrates the epithelial layer E of the airway wall W and beyond the basement membrane BM. The location of various layers of the airway wall W beyond the basement membrane BM can vary due to variations in anatomy along the pulmonary passageway. For example, the location of the smooth muscle layer SM can vary along the length of the pulmonary passageway, ranging from adjacent to the basement membrane BM to below the lamina propria LP. Thus, energy delivery can be titrated to target selected layers of the airway wall W for specific pulmonary passageway segments. For example, the algorithm may be selected or adjusted to affect the smooth muscle layer SM at its specific location. Smooth muscle hypertrophy is a hallmark of many pulmonary diseases, including chronic bronchitis, asthma, and several other airway diseases that cause airway hyperresponsiveness. In some embodiments, the delivered energy induces smooth muscle cell death, which can reduce airway hyperresponsiveness and cause desirable bronchodilation.

[0353] In some embodiments, the algorithm is selected or adjusted to affect submucosal gland SGs. Submucosal glands overproduce and hypersecrete mucus in affected airways. In some embodiments, the delivered energy induces cell death of submucosal gland SGs. A reduction in submucosal gland SGs can lead to a reduction in airway mucus and improved patient outcomes.

[0354] In some embodiments, the algorithm is selected or adjusted to affect the delivered energy in the lamina propria LP. The lamina propria LP is composed of loose connective tissue. The connective tissue and matrix structure of the lamina propria LP are highly compressible and elastic, allowing for the expansion of lung passageways. Furthermore, the loose structure allows for the presence of many cell types. The cell population in the lamina propria LP is variable and can include, for example, fibroblasts, lymphocytes, plasma cells, macrophages, eosinophils, and mast cells. Patients with airway diseases often experience chronic inflammation, particularly increased numbers 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 LP, such as by cell death, while maintaining the extracellular matrix. Maintaining the matrix structure allows stem cells and / or other cells to repopulate the matrix to form healthy tissue. This is in contrast to fibrosis or other scarring mechanisms in which the layers of the airway wall W, including the extracellular matrix, are permanently altered, such as by melting or disintegrating the layers together. Furthermore, the cartilage layer CL remains intact to maintain the structural integrity of the airway and prevent collapse.

[0355] It is understood, therefore, that energy can be delivered using one or more algorithms to affect one or more layers of the airway wall W. The energy can penetrate to a specific depth of the airway wall W and affect multiple layers extending from the surface of the wall W to a specific depth. Alternatively, the energy can be configured to affect cells at a specific depth without affecting surrounding layers. The effect can include cell removal, such as by cell death or detachment, or cell modification, such as by altering a specific function of the cell. In some cases, only a portion of cells of the same type or layer can be affected by the delivered energy. If desired, additional energy utilizing either the same or a different algorithm can be delivered to affect a larger portion or all of the cells of the same type or layer. Alternatively, additional energy utilizing the same or a different algorithm can be delivered to increase the effect. For example, the additional energy can result in cell removal of previously modified cells. Furthermore, additional energy utilizing the same or a different algorithm can be delivered to affect different portions or depths of the airway wall.

[0356] The actual mechanism for removing or modifying the cells can vary depending on the algorithm 152, the energy delivery body 108, and the patient's anatomy, to name a few. In some embodiments, the cells are removed (e.g., separated) by dielectrophoresis.

[0357] Dielectrophoresis describes the movement of particles under the influence of a non-uniform applied electric field. Dielectrophoretic motion is determined by the magnitude and polarity of the charge induced on 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. This induced charge is not uniformly distributed across the particle's surface, resulting in the formation of a macroscopic dipole. Because the applied electric field is non-uniform, the local electric field and the resulting forces on both sides of the particle are different. Therefore, depending on the particle's relative polarizability to the surrounding medium, it will be induced to move toward an internal electrode and a region of high electric field (positive dielectrophoresis) or toward an external electrode where the electric field is weak (negative dielectrophoresis). The dielectrophoretic force is a function of the cell's volume and polarization, the conductivity and permittivity of the surrounding medium, and the frequency and spatial gradient of the magnitude of the generated electric field.

[0358] In some embodiments, removal of abnormal epithelial cells, such as ciliated polystratified columnar epithelial cells PCEC and goblet cells GC, is the result of dielectrophoresis induced by one or more energy pulses delivered by the energy delivery body 108. In particular, in some embodiments, the epithelial layer E is separated by the action of dielectrophoresis, and the abnormal ciliated polystratified columnar epithelial cells PCEC and goblet cells GC are pulled away from the anchored basal cells BC and removed from the airway wall W. Recall that the basal cells BC are connected to the basement membrane BM by hemidesmosomes H, while the basal cells BC connect to the goblet cells GC and ciliated epithelial cells EC via desmosomes D. Energy parameters and electrode configurations can be designed to separate the desmosome connections D but leave the hemidesmosomes H intact, thereby removing the surface cells and leaving the basal cells BC substantially intact, regenerating the epithelium.

[0359] FIG. 19 schematically illustrates the removal of epithelial cells by the dielectrophoretic effect. Here, the distal portion of an embodiment of a catheter 102 having an energy delivery body 108 is shown positioned within a pulmonary passageway. Energy 204 is delivered from the energy delivery body 108, as indicated by the dashed electric field lines. The electric field is non-uniform due to the shape of the energy delivery body 108 and the placement of the return electrode 140 applied externally to the skin of the patient P. In this embodiment, the energy delivery body 108 is positively charged, which is the strongest / most concentrated pole of the electric field. The return electrode 140 is negatively charged, which is the weakest pole of the electric field. The resulting non-uniform electric field causes detachment and displacement of epithelial cells (e.g., ciliated pseudostratified columnar epithelial cells PCEC and goblet cells GC) from the airway wall W (indicated by downward arrows). The epithelial cells are then removed by natural or induced mechanisms.

[0360] Alternatively or additionally to affecting tissue cells within the airway wall W, the delivered energy can affect pathogens present within or near the airway wall W. Examples of types of pathogens include, but are not limited to, bacteria (e.g., Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, opportunistic gram-negative viruses, Mycoplasma pneumoniae, and Chlamydia pneumoniae), viruses (rhinoviruses, influenza / parainfluenza viruses, respiratory syncytial viruses, coronaviruses, herpes simplex viruses, adenoviruses), and other organisms (e.g., fungi).

[0361] In some embodiments, lung tissue modification system 100 may additionally or alternatively be useful for affecting pathogens found within the lumen of a patient's airways (e.g., within the mucus layer M) or within the tissue layer of the patient's airway wall W so that infection is controlled, reduced, and / or eliminated. In some embodiments, energy output from system 100 affects the mucus layer M and any pathogens that may be present in or near the airways. The mucus layer M becomes less viscous and therefore easier for the patient to cough up. Pathogens are killed or programmed to die (e.g., apoptosis), thereby reducing or eliminating infection.

[0362] In some embodiments, system 100 can assist a patient in the development of antibodies or other commensal and supportive immune responses against a target pathogen, improving future immunity and resistance to that pathogen. Because system 100 affects pathogens in a substantially non-thermal manner, resulting in cell death, the cell fragments still contain proteins. As these more intact proteins are released into the local environment and circulation, the immune system can develop new ways of monitoring, recognizing, and responding to these threats, enhancing future host defenses against these challenges or pathogens.

[0363] As previously discussed, it can be appreciated that energy signal parameters can be manipulated to produce different effects, such as different penetration depths. In some cases, the system 100 can be configured so that only the mucus layer M and any resident pathogens are affected. In some cases, the system can be configured so that cell death of the epithelial layer occurs. In some cases, the system can be configured so that epithelial and submucosal cell death occurs via a single energy delivery algorithm. In some cases, the system can be configured so that epithelial and submucosal cell death occurs and pathogens are affected via a single energy delivery algorithm. In some cases, separation of the epithelial layer E occurs. In some cases, the system 100 can be configured so that separation of the epithelial layer E occurs, pathogens are affected, and / or deeper structures are affected via a single energy delivery algorithm. In some cases, the generator can have various energy delivery algorithms stored therein, and a user can apply two or more of these algorithms to tailor treatment to an individual patient. This can be done in a single treatment session or multiple treatment sessions to address the needs of an individual patient.

[0364] In some cases, it may be desirable to affect deeper cells, including smooth muscle cells (SM), submucosal gland SGs, and / or nerves (N). Because a patient's pathology can be more complex than mucus hypersecretion caused by the epithelium, the goal of treatment is to affect deeper structures. Airway smooth muscle cells (SM) are known to contribute to bronchial hyperresponsiveness, submucosal gland SGs may contribute to severe mucus hypersecretion, and nerves (N) innervate both submucosal gland SGs and airway smooth muscle (SM). Alternatively, patients with mixed pathologies, such as asthma and chronic obstructive pulmonary disease (COPD) (e.g., asthma-COPD overlap syndrome), may benefit from treatments that target several mechanisms (e.g., mucus hypersecretion, smooth muscle hypertrophy, ciliary dysfunction, etc.) and / or target tissues. The energy dose can be titrated (e.g., iteratively altered based on sensor or other feedback) to affect structures deeper than the epithelium. In some cases, as the energy dose increases, submucosal gland SGs undergo mild partial membrane lysis or significant loss of structural integrity. Unlike thermal energy, the lamina propria LP, the cell layer between the epithelium E and the submucosal gland SG, remains intact. Thermal energy sources induce significant changes in the structure of the extracellular matrix, leading to fibrosis.

[0365] In addition to the submucosal glands (SG), smooth muscle (SM) may be affected depending on the dose, ranging from focal changes to obstruction, causing removal of the epithelium (E) over days to weeks. The cartilaginous layer (CL), the deepest structure of the airway wall, is not affected by the energy, shows no signs of inflammation or necrosis, and functions as an insulating barrier.

[0366] IV. Cell Targeting In some embodiments, the energy delivery algorithm 152 is designed to target specific cells. Such targeting can be based on a variety of different aspects, including size, shape, location, type, function, and often a combination of these. In some embodiments, specific cell populations are targeted while other cell populations are avoided. Such avoidance may or may not be complete, but it can be understood that avoidance includes minimizing impact. Such avoided cell populations may be considered collateral cell populations, which may be adjacent to, nearby, or distant from the targeted cell population. In some cases, specific cell populations are targeted due to their involvement in a particular disease process. Collateral cell populations are typically avoided because they are not involved in the disease process or because they are beneficial to safety, recovery, and / or improved outcomes. Thus, in some instances, collateral cells are simply benign bystanders, while in other instances, collateral cells are cells of critical function, such that excessive damage to these cells impairs tissue function and harms the patient.

[0367] In the pulmonary airways, target cells include goblet cells, dysfunctional pseudostratified columnar epithelial cells, and submucosal glands, while collateral cells may include basal cells, chondrocytes, and other more distant tissue cells not involved in airway-centered disease processes, such as mucus hypersecretion. Chondrocytes secrete and embed themselves in the cartilage matrix. Thus, chondrocytes build and maintain the cartilage tissue that maintains the patency and structural integrity of the airways. Typically, chondrocytes are avoided in the treatment of mucus hypersecretion, maintaining airway structure through preserved cartilage morphology and ongoing maintenance manipulation.

[0368] In pulmonary veins, target cells can include cardiomyocytes, which are muscle cells (myocytes) that make up the heart muscle. In some embodiments, cardiomyocytes are targeted because of their association with ganglia that are involved in abnormal arrhythmias. In such situations, collateral cells can include distant cells that generate normal cardiac rhythms within the sinoatrial node or atrioventricular node. In the esophagus, target cells can include precancerous cells, such as those involved in Barrett's esophagus. Collateral cells can include structural cells that maintain the extracellular matrix. In the colon, target cells can include precancerous cells, such as those that form polyps. Collateral cells can include healthy mucosal and submucosal cells. Similarly, in the colon, target cells can include cells involved in the epithelium affected by ulcerative colitis. Thus, collateral cells can include smooth muscle cells involved in peristalsis. Collateral cells can also include cells that are part of the host environment, such as commensal bacteria that inhabit the intestine and airways and can be both beneficial and harmless bystanders.

[0369] In the example of a pulmonary airway, specific cell populations can be targeted based on various aspects. Figure 20A shows a cross-section of a diseased pulmonary airway wall W with an energy delivery body 108 positioned thereon. Here, the wall W is covered with a thick layer of mucus M. Beneath the mucus M layer are pseudostratified columnar epithelial cells PCEC and goblet cells GC, followed by the basement membrane BM. Beneath the basement membrane BM is the lamina propria LP, a layer of loose connective tissue in the areola that forms part of the mucosa. In this example, the airway wall W is diseased, and the lamina propria LP contains abundant mast cells MC, eosinophils ES, and macrophages MPH. Adjacent to the lamina propria LP is a layer of smooth muscle cells SM, and beyond the layer of smooth muscle cells SM is the submucosal gland SG. Below the smooth muscle cells CM is the cartilage layer CL, which contains chondrocytes CH.

[0370] In some embodiments, goblet cells GC and submucosal gland SG are targeted while chondrocytes CH are spared. As previously mentioned, these epithelial cells and submucosal glands are often involved in the overproduction and accumulation of excess mucus layer M. Therefore, modulating or eliminating these cells can reduce or alleviate such hypersecretion. Similarly, preserving cartilage layer CL is desirable due to its role in maintaining the matrix structure of the airway, thereby maintaining its structural integrity and preventing collapse. As shown in Figure 20A, these cells differ somewhat in size, location, and function, among other things. These different aspects can be exploited for cell targeting. In some embodiments, goblet cells GC and submucosal gland SG are selectively targeted due to their larger size, while chondrocytes CH are spared based on their smaller size.

[0371] As shown in FIG. 20A , the targeted goblet cells GC are large, cylindrical cells with their longest dimension or major axis oriented perpendicular to the airway lumen. Because these cells are located closest to the energy delivery body 108, the electric field emanating from them is primarily aligned along the major axis of the goblet cells GC. In some embodiments, the size of the goblet cells GC is approximately 20 μm along this major axis. The submucosal gland SG is roughly spherical with no clear orientation. A typical submucosal gland SG has a diameter of approximately 15 μm. Thus, the goblet cells GC and the submucosal gland SG are somewhat similar in size along these dimensions. In contrast, the chondrocytes CH are small, ellipsoidal cells with their minor axis oriented perpendicular to the airway lumen. Along this axis, the chondrocytes CH typically measure approximately 5 μm, which is significantly smaller than the goblet cells GC and the submucosal gland SG.

[0372] Figures 20B and 20C show schematic diagrams of cells of different sizes. Figure 20B shows a first cell C1 with a first radius R1, and Figure 20C shows a second cell C2 with a second radius R2. In this example, the second cell C2 is larger than the first cell C1, such that R2 > R1. Cell size influences how electromotive forces alter the accumulation of transmembrane potential. Changes in transmembrane potential can be used to exploit various electrochemical and biological transport properties within cells, causing cell modulation or cell death. Small cells are charged more quickly because the charge has a shorter distance to travel within the cell. However, because there is less intracellular fluid in small cells, fewer ions are driven by such electromotive forces. Therefore, the accumulation of cumulative charge in small cells is less than that in large cells. These principles are illustrated in Figure 20D, which shows the cell / organelle membrane potential as a function of time. The first curve 415 represents the membrane potential of the first cell C1, and the second curve 417 represents the membrane potential of the second cell C2. As shown, the membrane potential of the smaller first cell C1 rises rapidly, up to transition time λ, before the larger second cell C2. However, while the membrane potential of the smaller first cell C1 reaches a plateau, the membrane potential of the larger second cell C2 continues to increase. Thus, the membrane potential of the larger second cell reaches a higher level, but takes longer to achieve. It can be appreciated that the principles described herein are not only applicable to spherical cells. Such principles relate to the distance from the center of the cell or organelle to the boundary in the direction of the electric field. Thus, as previously mentioned, goblet cells GC and submucosal gland SG are considered larger than chondrocytes CH and follow the same principles outlined for spherical cells.

[0373] One or more energy delivery algorithms 152 specify the electrical signals that provide the energy delivered to the airway wall W in the treatment of various conditions and diseases. In some embodiments, the frequency of the electrical signal is modulated to ensure that goblet cells GC and submucosal gland SG are affected based on their larger size compared to chondrocytes CH. This can be thought of as a target, in that the frequency is adjusted to ensure destruction. It can be understood that lower frequencies (e.g., 100 kHz or in the 100-300 kHz range) result in cell death of all cell populations throughout the airway wall. This is because lower frequencies allow more time for charge to build up, allowing even larger cells to respond. The frequency is sufficiently low so that the pulse duration is longer than the transition time λ. Figure 20E shows a waveform with a lower frequency, such as 250 kHz. Higher frequencies (e.g., toward 1000 kHz) do not affect or kill any of these cells. This is because higher frequencies have shorter periods, thereby shortening the period for charge to build up. In this example, the frequency is so high that even the smallest cells do not have time to respond. The frequency is high enough that the pulse duration is shorter than the transition time λ. Figure 20F shows a waveform with a higher frequency, such as 1000 kHz.

[0374] Thus, in some embodiments, frequencies in the range of 400 to 800 kHz (e.g., 400 kHz, 450 kHz, 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, 800 kHz) are used that provide a general degree of therapeutic effect on the target cell population while remaining within an acceptable range for chondrocyte effects. It can be appreciated that in some embodiments, frequencies in the range of 300 to 400 kHz can be used, depending on other parameter values.

[0375] Examples of applicable setting ranges, and selected specific combinations, are shown in Table 1 below. [Table 1]

[0376] It can be understood that frequency values ​​in this desired range target the larger goblet cells GC and submucosal glands SG by ensuring no deleterious effects on these cells. Smaller chondrocytes CH are typically affected in this frequency range based on their size, but other factors prevent chondrocyte destruction. For example, the voltage of the electrical signal used at these frequencies is selected so that the electric field reaching the chondrocytes CH (far from the electrode body 108, as shown in FIG. 20A) is low enough to spare the chondrocytes CH. Therefore, parameter values ​​are selected to target goblet cells GC and submucosal glands SG based on both their size and location within the airway.

[0377] In some embodiments, specific cells are targeted based on their ability to recover from injury. For example, in some embodiments, goblet cells (GC) and submucosal gland cells (SC) are targeted based on their superior ability to recover from injury compared to chondrocytes (CH). Typically, chondrocytes (CH) have a lower ability to recover from injury and are therefore more susceptible to damage accumulation. Because chondrocytes (CH) are essential functional cells, their survival is a guide to the upper limit of the tolerable dose and tissue damage that can occur from treatment. This is at least in part due to the environment of chondrocytes (CH). Chondrocytes (CH) are immersed in cartilage matrix material, an avascular tissue type. Therefore, chondrocytes (CH) have a lower ability to access energy sources and waste removal, relying on diffusion processes over large areas. This is evidenced by the increased lethality of chondrocytes located near the center of the cartilage layer compared to those at the center of the cartilage layer's border. In contrast, goblet cells (GC) and submucosal gland cells (SG) are more likely to recover from injury due to their well-vascularized environment.

[0378] These differences can be exploited by varying the number of packets delivered by the electrical signal. This is due to the different modes in which electrical signals alter cells and stimulate regeneration and resurfacing. In some cases, the cellular effect is achieved immediately due to the general strength of the electric field generated by the electrical signal. In these instances, delivery of additional packets does not affect the cellular response. In other instances, the cellular effect is achieved after the accumulation of several smaller effects, such as a cumulative loss of homeostasis due to cell or organelle leakage, which overwhelms the cell's ability to restore its native environment and leads to cell lysis or apoptosis. In these instances, cumulative cellular damage is the driving force behind cell death, and therefore subsequent packets further exacerbate the damage and effects of previous packets.

[0379] Thus, in some embodiments, goblet cells GC and submucosal gland SG are targeted while sparing chondrocytes CH by delivering a small number of packets. In some embodiments, one packet is delivered, and in other embodiments, up to five packets are delivered. Such variations are due to myriad factors based on the individual patient, other parameters, and the type and location of the energy delivery body 108, to name a few. Overall, however, delivering packets in the range of approximately 1 to 5 (e.g., frequency 600 kHz, packet duration 100 μsec, voltage 2500 to 3000 V) is a method for targeting goblet cells GC and submucosal gland SG while sparing chondrocytes CH in the pulmonary airways. This is in contrast to targeting chondrocytes CH, where, for example, 10 packets are delivered, and in other embodiments, up to 100 packets are delivered.

[0380] It can be appreciated that other signal parameters may be adjusted to support or modify the effects of a particular parameter selection. For example, at a given frequency, the voltage can be altered to further control cellular effects. Similarly, when a given number of packets is used, the voltage can also be altered to further control cellular outcomes. For example, it can be appreciated that in some cases, altering the number of packets will affect all cell types to some extent. To counteract this, in some embodiments, the voltage is increased (e.g., from 2500V to 3000V to move from 5 packets to 1 packet) to focus energy on targeting goblet cells (GC) and submucosal glands (SG). This ensures adequate stimulation of these cells before accumulation affects chondrocytes (CH).

[0381] In some embodiments, goblet cells GC and submucosal glands SG are targeted based on their location and distribution in the airway wall W. This can be considered "geographic targeting." As shown in FIG. 20A , goblet cells GC and submucosal glands SG are located closer to the airway lumen and energy delivery body 108 than chondrocytes CH, which are located deeper in the airway wall W. By titrating the overall intensity of the energy provided by the energy delivery algorithm 152, it is possible to affect cells at a desired depth, with a rapid decline in therapeutic effect before reaching non-targeted cell populations. This titration of therapeutic effect will vary depending on the condition being treated and, therefore, the cells being targeted.

[0382] In summary, goblet cells (GC), other mucus-producing cells, and submucosal gland (SG) cells can be targeted for the treatment of mucus hypersecretion while avoiding chondrocytes (CH) in the cartilage layer (CL) by various methods as described herein. It can also be appreciated that in some embodiments, such targeting can also alter cell signaling in the local environment, thus further reducing mucus production. In some embodiments, this is achieved by an energy delivery algorithm 152 providing an energy signal with a frequency of 600 kHz, a voltage of 3000 V, and 10 packets, each with a duration of 200 μsec. In other embodiments, this is achieved by an energy delivery algorithm 152 providing an energy signal with a frequency of 550 kHz, a voltage of 2500 V, and 5 packets, each with a duration of 100 μsec. It can be appreciated that other combinations of parameters may be used, including combinations including one or more of these parameter selections. The selection of such parameters can be based on various factors, including the need for treatment, such as preventing charring of tissue at the tissue-electrode interface and denaturation of interstitial proteins. In some embodiments, this is achieved by using more packets, such as 20 or 50, or a lower frequency, such as 300 V or 400 KHz, at a lower voltage, such as 2000 V or 1000 V, and / or a shorter packet duration, such as 50 μsec or 100 μsec. Other treatment needs may include preventing unacceptable levels of muscle contraction. In some embodiments, this is achieved by using more packets at higher frequencies, lower voltages, or shorter packet durations. Other treatment needs may include avoiding treating a particular area for too long. In some embodiments, this is achieved by using fewer packets at higher voltages, lower frequencies, or longer packet durations.

[0383] In some embodiments, mucus hypersecretion is treated by targeting cells within the pulmonary airway wall W at even shallower depths. In some embodiments, this is achieved by the energy delivery algorithm 152 providing an energy signal using a higher frequency than described above, such as 800 kHz, or a lower voltage than described above, such as 2000 V, or fewer packets than described above, such as two packets, or a shorter packet duration than described above, such as 50 μsec. In some embodiments, this is achieved using the energy delivery algorithm 152 providing an energy signal that combines all of these variations, thus having a frequency of 800 kHz, a voltage of 2000 V, and two packets, each with a 50 μsec duration. It can be understood that other combinations of parameters may be used, and combinations including one or more of these parameter selections may be used.

[0384] In some embodiments, greater penetration depth is desirable, such as to affect smooth muscle cells (SM) in the treatment of asthma or other indications. In some embodiments, this is achieved by an energy delivery algorithm 152 providing an energy signal using a lower frequency than described above, such as 400 kHz, or a higher voltage than described above, such as 3250 V, or more packets than described above, such as 20 packets, or a longer packet duration than described above, such as 500 μs. In some embodiments, this is achieved using an energy delivery algorithm 152 providing an energy signal that combines all of these variations, thus having a frequency of 400 kHz, a voltage of 3500 V, and 20 packets, each with a 500 μs duration. It can be appreciated that such an algorithm 152 takes into account the aforementioned parameters. For example, smooth muscle cells (SM) are more resilient to energy signals than chondrocytes (CH) and submucosal gland cells (SG). Therefore, additional energy is delivered to overcome the geographic location of these target smooth muscle cells (SM) along with their higher efficacy thresholds. It can be understood that other combinations of parameters may be used, and combinations including one or more of these parameter selections may be used.

[0385] It is understood that these principles can be carried over to other anatomical locations and other types of cells. Furthermore, other types of diseases may offer additional targeting capabilities. For example, in some embodiments, cells are targeted based on their metabolic activity or energy demands. Cancer cells are cells with higher metabolic activity and energy demands than normal tissue cells. Such cells generally require more energy to maintain function. Similarly, these cells are more susceptible to combined damage from multiple energy packets and cumulative loss of homeostasis than mature, differentiated, or undifferentiated cells present in the same environmental region. This capability can be utilized for various clinical indications, such as cancer treatment, where rapidly dividing, immature neoplastic cells are less resilient to damage.

[0386] In some embodiments, a larger number of packets preferentially increases the lethality of the applied electric field to cancer cells compared to healthy cells exposed to the same electric field parameters. For example, cancer cells, like chondrocytes, are generally less responsive to repeated accumulation of mild injury mechanisms. Therefore, preferential targeting of cancer cells can be exploited by exposing them to 50, 100, or 200 packets. This results in a disproportionate increase in cancer cell death compared to the increase in cell death occurring in healthy, mature, differentiated cells. In the case of colon cancer, cancer cells may be compared to healthy smooth muscle cells. Thus, in some embodiments, 10 packets are delivered, which treats some cancer cells but not smooth muscle cells. In other embodiments, up to 100 packets are delivered, treating more cancer cells and some smooth muscle cells. In yet other embodiments, up to 1000 packets are delivered, treating even greater numbers of cancer cells as well as additional smooth muscle cells. The number of packets used will vary depending on the type of tissue being treated, the time allowed for treatment, the generator's capacity, and muscle contraction constraints, to name a few. It can be appreciated that muscle contraction constraints may limit the allowable applied voltage and increase the required frequency, reducing the effectiveness of individual packets. It can be appreciated, therefore, that this reduced efficacy can be compensated for by increasing the number of packets, resulting in reduced muscle contraction but maintaining therapeutic efficacy. In this example, additional packets may result in a longer treatment time.

[0387] V. Sensor In some embodiments, one or more sensors 160 are included in 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 sensors 160 can include impedance, membrane potential or capacitance, and / or temperature, to name a few. Sensors 160 can be used to, among other things, (a) obtain baseline measurements, (b) measure parameters during delivery of energy, and / or (c) measure parameters following energy delivery.

[0388] The sensor 160 can be positioned adjacent to the energy delivery body 108, on the energy delivery body 108, on the dispersive or return electrode 140, adjacent to the dispersive or return electrode 140, or at any suitable location along the catheter 102 or on the patient. The dispersive electrode can also include its own sensor, which can be checked by the system prior to therapy delivery to ensure the dispersive electrode is sufficiently connected. The system can inhibit therapy delivery until these sensor requirements are met. These can include one or more sensors on the dispersive or active electrode to sense tissue properties to ensure proper connection to the tissue. Temperature sensors can monitor the temperature of the electrode and / or the electrode / tissue interface. Impedance sensors can monitor tissue impedance across any two electrodes. In some embodiments, changes in impedance can be detected using a bipolar catheter sensor configuration to assess changes in local tissue properties relative to impedance. In other embodiments, changes in impedance are detected using a bipolar catheter sensor configuration to assess local changes in anatomical components of the system, such as mucus or edema clearance into the airway. A conductance sensor can monitor the transmission of electrical energy between two electrodes. A force / pressure sensor can monitor the amount of force or pressure an electrode applies to tissue.

[0389] This sensor information can be used as feedback to the system to determine proper deployment of the energy delivery bodies 108, drive the treatment algorithm 152, and / or terminate energy delivery for safety reasons, including, by way of non-limiting example, establishing and verifying that the physical therapy system setup is satisfactory. The sensors 160 can also be used to detect when proper treatment has been achieved. The algorithm 152 within the generator 104 can also use the sensed data to automatically titrate the treatment algorithm 152 so that targeted tissue treatment is achieved. Stated differently, one or more parameters and / or aspects of the treatment algorithm can be iteratively modified based on the sensor data. For example, in some embodiments, power and / or energy duration can be increased or decreased based on the sensor data.

[0390] The system can execute the algorithm using sensor data obtained during therapy pulse delivery. In other embodiments, the system can execute the algorithm using sensor data obtained from a dedicated probing signal. In this embodiment, the dedicated probing signal can be a low-voltage pulse or packet delivered before or during the therapy pulse, or can be an AC signal over a dedicated frequency or range of frequencies. In these embodiments, the signal used to control the algorithm can be selected to target optimal delivery of energy.

[0391] It can be appreciated that there is a vast array of possible electrical signals that can be monitored and / or test pulsed to determine desired system and patient conditions before or during treatment. In some embodiments, signals are delivered before the start of treatment therapy as a final check of tissue conditions, which may also be used to guide any changes before initiating treatment delivery. For example, signals may be delivered before a heartbeat, or 1 millisecond before, or 500 milliseconds before (if performed within / just before treatment activation), or 10 to 1000 seconds before (if performed at the start of EM activation or before the entire patient treatment). Alternatively, in some embodiments, monitoring or test signals are delivered during the treatment algorithm, such as between packets of delivered energy. This provides an updated check throughout activation to ensure system conditions are consistent with those required for successful treatment outcomes. In some embodiments, these monitoring or test signals are in the form of short pulses (e.g., 1 μsec, 100 μsec, 1 ms, 100 ms) that can be delivered sequentially, either in conjunction with cardiac gating or independently of the patient's ECG rhythm, depending in part on the type and strength of the signal used. Additionally, continuous waveforms can be implemented, such as the delivery of constant low-voltage DC signals (e.g., 0.5 V, 1 V, 5 V, 10 V, 50 V; 500 V) or continuous low-voltage AC waveforms (e.g., 0.5 V, 1 V, 5 V, 10 V). Both of these voltages are kept low to prevent potential effects on the treatment outcome, reduce the risk of significant thermal damage or other conditions at the target dispersive tissue site, and mitigate potential effects on the heart. In any of these cases, the resulting impedance, or either its real or imaginary components, can be used to derive and understand the characteristics of the patient's electrical system.These conditions can be used to guide treatment parameter settings such as voltage (e.g., 1000V, 2500V, 5000V with deviations based on feedback for 10 seconds, 100 seconds, or as low as 1000 seconds) or frequency (e.g., 600kHz baseline with deviations for 10 seconds and 100 seconds, or 100kHz, 500kHz, 1000kHz) or to indicate whether the system is properly established and treatment is occurring safely and effectively. In some cases, various combinations of these test signals and signal frequencies can be collected and analyzed together to assess the desired tissue condition.

[0392] In some embodiments, the treatment pulse itself is used to monitor the quality of the treatment system, whereby deviations from a normal range or baseline value are monitored and used as a cutoff to indicate good or poor quality electrical contact and energy delivery. In another example, a test pulse is performed using a lower voltage or energy than the treatment delivery. This test delivery uses the same waveform as the treatment energy dose (e.g., square, approximately 500 kHz, approximately 2500 V baseline) to reduce deviations in tissue impedance response due to tissue permittivity properties and dispersive frequency effects.

[0393] A. Impedance sensor 1. Ensuring proper placement of the energy delivery body In some embodiments, one or more impedance sensors are used to determine whether the energy delivery bodies 108 are properly inserted and deployed in the lung airways. In some embodiments, a short-duration, low-voltage signal is delivered to the energy delivery bodies 108 during their placement and deployment / expansion within the target region of the airways. Based on measured current feedback received by the generator 104 from the 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 deemed acceptable for a properly inserted and deployed energy delivery body 108. If the calculated impedance is outside the range of acceptable impedance, the generator 104 displays a specific message and / or emits a specific sound to alert the operator. For example, if the energy delivery body 108 is still within 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 then display a message (e.g., confirm electrode position) until the operator repositions the energy delivery body 108 into an airway where the impedance is significantly lower and within an acceptable range, at which point the message may change (e.g., ready).

[0394] It can be appreciated that other types of sensors, such as temperature, force, or pressure sensors, can additionally or alternatively be used to confirm electrode-tissue contact before initiation of treatment. It can also be appreciated that sufficient contact between the electrode and the airway wall is a key factor for effective treatment. Firm and consistent contact is desirable to adequately couple energy from the electrode to the tissue and achieve the desired tissue effect.

[0395] 2. Ensuring proper catheter function In some embodiments, one or more impedance sensors are utilized to determine whether the catheter 102 is functional or potentially defective. In such embodiments, a short-duration, low-voltage signal (e.g., a signal having a duration of 1 to 5 packets and a voltage of approximately 50 V, 100 V, or 500 V) is delivered to the energy delivery body during placement and deployment / expansion within its target region. 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 alert the operator. For example, if the catheter is defective, the impedance may be very high. In this embodiment, the generator 104 displays a message (e.g., "Replace catheter"). Once replaced, the generator 104 may detect a much lower impedance within the acceptable range and display another message (e.g., "Position catheter"). Therefore, impedance measurements can be used to detect malfunctioning catheters, thereby avoiding safety concerns.

[0396] In some embodiments, such monitoring activity is accomplished by delivering electrical signals to independent active portions of a single energy delivery body 108, with one active portion acting as the affected electrode and the other active portion acting as the dispersive electrode. Typically, an abnormally high impedance between the active portions indicates poor contact of the energy delivery body 108. For example, in some embodiments, an impedance measurement outside of the 50 to 150 Ω range indicates poor contact. Similarly, in some embodiments, an impedance measurement of >200 Ω indicates no contact, such as the catheter 102 not receiving current or being disconnected. In contrast, a low impedance between the active portions, such as <50 Ω, indicates good electrical conduction between the active portions and that the energy delivery body 108 has good tissue contact with its primary contact area components. In some embodiments, these active portions can be understood to independently deliver energy to tissue. Such delivery can be electrically coincident or remain separate during treatment delivery.

[0397] In some embodiments, the electrical environmental conditions are measured between two or more electrodes, such as between an energy delivery body 108 and a dispersive pad electrode within the catheter 102, or between two separate energy delivery bodies 108 within a patient operating in a bipolar configuration. In some embodiments, an impedance measurement outside of the 50 to 150 Ω range indicates poor contact of at least one of the energy delivery bodies 108. Similarly, in some embodiments, an impedance measurement of >200 Ω indicates a lack of contact of at least one of the energy delivery bodies 108, such as when the catheter 102 is not receiving current or is disconnected. It can be understood that such impedance values ​​may vary depending on the anatomy. The above values ​​relate to the airway. Catheters placed in other anatomical lumens may refer to different impedance values ​​to indicate sufficient contact. For example, typical impedance values ​​for the colon (when measured in a monopolar configuration using dispersive pads on the abdomen or legs) may range from 30 to 75 Ω. Similarly, typical impedance values ​​for the heart may range from 40 to 100 Ω. And typical impedance values ​​for the esophagus may range from 50 to 150 Ω. Impedance values ​​outside these ranges can indicate a poor contact or other problem with the energy supply.

[0398] In some embodiments, an abnormally low impedance reading (e.g., near 0 Ω when measuring between two points on the same electrode body, or <50 Ω when measuring between the electrode body and the dispersive pad) indicates other problems with the energy delivery system. In some situations, an abnormally low impedance reading indicates that the two energy delivery bodies 108 of a bipolar pair are too close to each other. In other situations, a low impedance reading indicates a short circuit in the electrical system or generator. In still other situations, a low impedance reading indicates an electrical arc. These conditions may risk injury to the patient due to higher current flow and concentration, which may cause ineffective therapy delivery via redistribution of energy delivery, electroporation or thermal damage or other non-target therapy outcome effects, or damage to the generator or other electrical / conductive components in the system.

[0399] Typically, impedance measurements from the low-voltage test pulses described herein should correlate well with impedance values ​​measured during delivery of treatment energy, especially when using a monopolar configuration. This is because the broader whole-body system involved in the circuit dominates the impedance of bulk tissue, muting local changes and contributing relatively little to the overall system impedance. This is in contrast to other conventional treatments, where changes in impedance are a known outcome of treatment due to a decrease in the dielectric capacitance of cell membranes passing through the circuit.

[0400] 3. Changes to the energy algorithm In some embodiments, impedance measurements can be made before or after energy application to define which energy delivery algorithm 152 to apply and / or the need to apply additional energy to the target location. In some embodiments, pre-treatment impedance measurements can be used to determine the settings of various signal parameters. In other embodiments, sensors can be used to determine whether the energy delivery algorithm should be adjusted.

[0401] In some embodiments, impedance measurements are performed as follows: A short-duration, low-voltage signal is delivered to the energy delivery body 108 via a generator (e.g., generator 104) upon placement at a target area within the pulmonary passageway. Based on measured current feedback received by the generator 104, the generator 104 performs a calculation using a set voltage and actual current to calculate the impedance. The calculated impedance is compared to an impedance value deemed acceptable for the measured impedance. The energy delivery algorithm 152 is then modified or adjusted based on the measured impedance. Adjustable parameters include, but are not limited to, voltage, frequency, pause period, cycle count, dead time, packet count or number of packets, or a combination thereof. Thus, a feedback control loop can be configured to modify parameters of energy delivery based on one or more measured system or tissue parameters.

[0402] In some embodiments, one or more impedance sensors are used to monitor the electrical properties of tissue. Impedance values ​​can be considered an indicator of tissue condition. In some embodiments, impedance is measured at different frequencies to provide an impedance spectrum. This spectrum characterizes the frequency-dependent, or reactive, component of impedance. Tissue has both resistive and reactive components, which are components of complex impedance. Reactance is a frequency-dependent component of impedance that includes tissue capacitance and inductance. Changes in tissue condition can result in changes in the resistive or reactive components of complex impedance, as well as changes in the overall impedance. Complex impedance measurements involve the conduction of a low-voltage sense signal between two electrodes. The signal can include, but is not limited to, a sinusoidal wave. Changes in complex impedance, including changes in resistance and reactance, can reflect the condition of treated tissue and can therefore be used as an indicator that treatment is not affecting the tissue or that treatment can be completed. In these embodiments, changes to impedance can be derived from a treatment pulse or a dedicated sense signal to assess tissue properties when not simultaneously experiencing a treatment effect. Impedance values ​​also vary depending on the contact conditions between the sensor and the airway tissue. In this manner, the sensor can also be used to determine the contact condition between the electrode and the tissue.

[0403] In some examples, the generator 104 indicates to the user that no further energy delivery is required at the target location. Optionally, the generator 104 displays a particular message and / or emits a particular sound to alert the practitioner as to which energy delivery algorithm 154 has been selected or that treatment at the target location is complete. Thus, the generator 104 can be configured to automatically select an appropriate algorithm for a particular measured impedance or to shut off delivery of the energy signal when treatment is determined to be complete. Additionally, impedance or other sensors can be used to determine that treatment should be automatically stopped due to safety concerns.

[0404] When continuous monitoring of treatment status is used, it is possible to provide real-time feedback and immediate intervention in treatment delivery if an abnormal condition occurs. For example, a sudden change in impedance may indicate arcing to tissue or equipment, poor electrode contact quality, movement of one or more electrodes within the system, or a combination of these effects. For example, if a rise or fall in impedance of 50 Ω occurs, the generator immediately interrupts and stops energy delivery, alerting the user to check the system before continuing. Interrupting the sequence when an abnormal condition occurs reduces the risk of injury or damage to the patient, operator, or equipment; reduces the risk of providing inadequate treatment; improves outcomes; and reduces the time to perform the procedure. This can be accomplished with either continuous monitoring for immediate response functions or intermittent or intra-treatment energy delivery; however, the response rate of pulsed monitoring conditions is delayed due to the intermittent nature of energy delivery.

[0405] In addition to pausing treatment, monitoring and test pulse conditions can be used to determine tissue characteristics within the electrical system and provide adjustments to the energy delivery algorithm. For example, in some embodiments, if the impedance determined prior to energy delivery is 125 Ω, the voltage is set to 2500 V. However, in other embodiments, if the impedance is measured as 175 Ω, the voltage is set to 2700 V. Generator designs include system-based power-dependent components, such as transformers, that vary output depending on the load; this information can also be used to establish a target "set voltage" for delivery to the tissue. For example, in instances involving transformers, power in equals power out through the transformer, i1V1 = i2V2, so changes in output current due to differences in the patient's tissue system impedance also result in a compensatory change in the delivered voltage. When voltage is a key electrical parameter in energy delivery therapy, this change can significantly alter treatment outcomes as tissue conditions vary within and between patients. For example, in the example above, if the impedance were 175 Ω instead of the 125 Ω calibrated load, the set voltage could be adjusted to 2300 V as the increased impedance would reduce the current and boost the final output voltage from the generator, bringing the final delivery at the exemplary clinical dose back down to the targeted 2500 V.

[0406] B. Temperature sensor 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 deposited in the tissue does not cause clinically dangerous tissue heating. In some embodiments, the temperature measured at or near the electrode is also used to determine the contact condition 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 dangerous substantial thermal damage to the patient or that region of tissue. The steady-state value or variability of the temperature will differ depending on whether the electrode is pressed against the airway wall, moving, or suspended in the airway lumen.

[0407] In some embodiments, one or more temperature sensors are positioned along the surface of one or more energy delivery bodies 108, contacting the tissue and ensuring that the tissue does not heat above a predetermined safety threshold. Thus, one or more temperature sensors can be used to monitor the temperature of the tissue during treatment. In one embodiment, a temperature change that meets pre-specified criteria, such as a temperature increase above a threshold value (e.g., 40°C, 45°C, 50°C, 60°C, 65°C), can result in a change to the energy delivery parameters (e.g., a change in the algorithm) to lower the measured temperature or to lower the temperature below the pre-set threshold. Adjustments can include, but are not limited to, increasing the dwell period or dead time, decreasing the packet count, decreasing the voltage, or decreasing the number of cycles per packet. Such adjustments can be made in a pre-defined, stepwise approach, as a percentage of a parameter, or in other ways.

[0408] In other embodiments, one or more temperature sensors monitor the temperature of the tissue and / or electrodes, and if a predetermined threshold temperature (e.g., 65° C.) is exceeded, the generator 104 changes its algorithm to automatically stop energy delivery. For example, if the safety threshold is set at 65° C. and the generator 104 receives feedback from one or more temperature sensors that the temperature safety threshold has been exceeded, treatment may be automatically stopped.

[0409] C. Sensors that monitor electrode contact or characteristics around the electrodes In some embodiments, one or more sensors (e.g., temperature, impedance, force, pressure, etc.) are positioned at various locations, such as circumferentially, on the surface of one or more energy delivery bodies 108. In such a configuration, the sensors can be used to indicate whether contact between the surface of one or more energy delivery bodies 108 and the bronchial airway wall is sufficient, such as being appropriately circumferential and / or stable. If the sensors indicate insufficient contact, such as not being circumferential (e.g., non-uniform temperature, impedance, force, etc.) and / or not being stable (e.g., continuously changing temperature, impedance, force, etc.), the operator can adjust the level of expansion of one or more energy delivery bodies or select a catheter 102 with a differently sized energy delivery body 108 that better matches the inner diameter of the bronchus / bronchus being treated. In some embodiments, the generator 104 is configured to interpret the degree, quality, and / or stability of contact and provide operator feedback to aid in proper positioning of the energy delivery bodies. For example, while the operator is placing one or more energy delivery bodies that are not in circumferential contact, the user interface 150 on the generator 104 may display a message such as "poor contact." In other embodiments where non-circumferential treatment is desired, the system may be used to verify that only the desired areas of the electrodes are active and in contact with the targeted passageway area.

[0410] It can be appreciated that such monitoring can detect potential user errors or failures in the electrical system that could prevent dangerous or harmful treatment conditions. For example, if monitoring of the contact integrity of the electrodes used throughout the circuit or the dispersive pad electrodes themselves is not performed, there is a risk of treatment energy being deposited in the patient's tissue, but there is no sink to dissipate the energy. In such cases, the electrical energy may find an alternative path to complete the circuit, which risks damage to the patient, the user / operator, or equipment connected to the patient (including the ECG system, ventilator system, life support system, treatment table, or other electrical / conductive components and systems within the treatment suite).

[0411] In some embodiments, a force or pressure sensor can be used to detect and measure the contact force between the energy delivery body and the wall of the airway, thereby determining the contact condition between the energy delivery body and the tissue.

[0412] It can be appreciated that any of the embodiments of the system 100 disclosed herein can incorporate one or more sensors to monitor the application of the therapy.

[0413] VI. Cardiac Synchronization In some embodiments, the energy signal is 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 FIG. 21 , a typical ECG trace 600 includes a repeating cycle of a P wave 602 representing atrial depolarization, a QRS complex 604 representing ventricular depolarization and atrial repolarization, and a T wave 606 representing ventricular repolarization. To safely deliver energy within the airways adjacent to the heart, synchronization between energy delivery and the patient's cardiac cycle is employed to reduce the risk of cardiac arrhythmias. High-voltage energy can induce premature action potentials within the myocardium because the delivered energy increases the permeability of myocardial cell membranes, allowing ion transport that can induce cardiac arrhythmias, particularly ventricular fibrillation. To avoid cardiac arrhythmias, the electrical energy is delivered to the airways in a manner that is outside the "vulnerable period" of the myocardium. Within one cardiac cycle (heartbeat), the vulnerable period of the ventricular muscle is indicated on the ECG by a full T wave 606. Typically, for ventricular myocardium, the vulnerable period coincides with the middle and end of the T wave 606. However, if a high-energy pulse is delivered very close to the ventricle, the vulnerable period may occur several milliseconds before the heartbeat. Thus, the entire T wave can be considered to be within the ventricular vulnerable period.

[0414] The remainder of the cardiac cycle includes the P wave 602 and QRS complex 604, both of which comprise periods during which the atrial or ventricular muscle is refractory to high-voltage energy stimulation. Delivering high-voltage energy pulses during the muscle's refractory period minimizes the likelihood of arrhythmia. The ST segment 608 of the first cardiac cycle (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) are periods during which high-voltage energy can be delivered without inducing arrhythmia due to the depolarized state (refractory period) of the myocardium. Figure 20 includes shaded boxes showing exemplary portions of the cardiac cycle during which energy can be safely applied.

[0415] 21A is a flowchart illustrating an embodiment of a method for synchronizing the delivery of energy with cardiac cycles, according to some embodiments. In this embodiment, an 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 of the energy generating generator 104, although it will be understood that any suitable monitor can be used. Here, the cardiac monitor 170 continuously acquires an ECG, analyzes one or more cardiac cycles, and is used to identify the beginning of a period during which it is safe to apply energy. In some embodiments, when the cardiac monitor 170 detects this event / onset (e.g., an R wave in an ECG tracing), it sends a low-voltage transistor to transistor logic (TTL) pulse (e.g., ≦5V) to the communication port 167. At start step 650, the processor 154 of the energy generating generator 104 monitors the communication port 167 to determine (at step 652) whether a cardiac synchronization pulse has been detected. If a TTL pulse is not detected by generator 104 (at step 654), user interface 150 is used to notify the user (at step 656). For example, user interface 150 may display a solid red heart and / or any other suitable visual indicator. If a cardiac synchronization pulse is detected by generator 104 (at step 658), user interface 150 is used to notify the user (at step 660). For example, a solid red heart changes to a flashing yellow heart that turns on when a cardiac synchronization pulse is detected.

[0416] Because the external cardiac monitor 170 may send erroneous TTL pulses, and because the generator will not allow therapy to continue if the patient's heart rate is inconsistent and outside of the expected normal range and / or if there are extended QRS complexes that are unrelated / different from the patient's baseline rhythm, the next step may include 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, referred to as Δt1, Δt2, Δt3, Δt4, and Δt5. These values ​​may be stored in the data storage module 156 of the generator 104 as a rolling buffer containing the last five Δt calculations. An average of these five values, referred to as Δt-ave, may then be calculated. The next one or more detected TTL pulses may be used to calculate the next Δt (e.g., Δt6, Δt7, etc.), which may also be stored in the data storage module 156. For example, two TTL pulses may be utilized.

[0417] The generator 104's algorithm module 152 is then used to compare these values ​​to a set of criteria that provide confidence that the patient's heart rhythm is normal / consistent and the TTL pulses are reliable. For example, the heart rate may be calculated and checked to ensure it is between 40 and 150 beats per minute (bpm). In this example, Δt and Δt may also be compared to Δt to ensure the heart rate is not unstable. In one embodiment, Δt and / or Δt may be within ±15% of Δt to continue. In this example, both criteria must be met to confirm confidence (step 664). However, in other embodiments, both criteria may not be required. Once confidence is confirmed, the user interface 150 may be used to notify the user that it is safe to proceed (step 666). For example, the flashing yellow heart on the user interface 150 may change to a flashing green heart. The user interface 150 may then be used to instruct the user to charge a high-energy storage unit (e.g., one or more capacitors) in the generator 104. In one example, user interface 150 displays a softkey labeled "Charge," which the user can press to charge the high-energy storage unit. If the charge button is not pressed (at step 668), processor 154 continues to check the reliability of the heart rate and TTL signals.

[0418] When processor 154 recognizes that the charge button has been pressed (at step 670), processor 154 continues to check the reliability of the heart rate and TTL signals (at step 672). Meanwhile, if a predefined / predetermined time period elapses (e.g., approximately 30, 40, 50, 60, or up to 120 seconds, including all values ​​and subranges in between) without confirming (at step 674) that the reliability of the heart rate and TTL signals has been established, the system discontinues charging mode and returns to the system state where it is checking the heart rate and establishing the reliability of the cardiac synchronization pulses (at step 662). If the timeout has not been reached (step 676), user interface 150 notifies the user (at step 678) until reliability is established (at step 680). User interface 150 may modify a softkey to be labeled "Ready." System 100 now waits for footswitch 168 to be pressed.

[0419] While waiting for the footswitch 168 to be pressed (at step 348), the system 100 continues to monitor the heart rate and check reliability (672). Other timeouts can be predefined (e.g., approximately 30, 40, 50, 60, or up to 120 seconds, including all values ​​and subranges in between), and if the user does not press the footswitch 168 within that time (e.g., if the timeout is reached in step 674, as shown), the system aborts without being ready to deliver energy and returns to the system state checking the heart rate and establishing the reliability of the TTL pulse (step 662). Once the user presses the footswitch (at step 684), energy delivery can begin (at step 686). However, the generator 104 can be configured to wait until the next cardiac pulse is detected to more reliably ensure that energy delivery occurs after an 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 can range from approximately 0 to 300 milliseconds. The first energy packet can then be delivered (at step 686). Processor 104 then checks to determine if all packets have been delivered (step 688). If not, processor 154 continues to monitor the heart rate, checks the reliability of the TTL pulse (at step 690), and can continue energy delivery once the reliability of the cardiac synchronization pulse is re-established (at step 662).

[0420] In some cases, it may be beneficial to ignore TTL pulses immediately after energy delivery because they may be false triggers caused by the high-voltage energy being delivered. For example, processor 154 may ignore TTL pulses for approximately 400 ms after energy is delivered or for approximately 450 ms after the leading edge of the last TTL pulse. In other situations, TTL pulses may be ignored for approximately 50 ms to approximately 1 second, including all values ​​and subranges therebetween. When the processor detects the next TTL pulse, the next Δt is calculated and compared to a previously defined (i.e., based on a rolling average) criterion (step 690). Due to the possibility of a temporary delay in the heartbeat following energy delivery, if the next Δt falls outside the criterion, it is simply ignored. The next Δt is then calculated and compared to the previously defined criterion. If the criterion is met (step 700), the next packet is delivered (step 686). If all packets have not been delivered, the system continues to monitor the heart rate and check the reliability of the cardiac synchronization pulses as described above (step 690). If trust is established (at step 700), the cycle continues. If trust is not established (at step 702), the user is notified (step 704), for example, by the heart turning yellow, flashing, or glowing red.

[0421] If the system 100 cannot determine acceptable reliability or no longer detects a TTL pulse within a specified time (e.g., approximately 10, 20, 30, 40, 50, or 60 seconds), a timeout is reached (step 706) and the user interface 150 can be used to notify the user (step 708). At this point, the cycle can end and the remaining packets are not delivered. The process then returns to the beginning (at step 650). If the system is able to determine acceptable reliability (at step 700) within the set time limit, the timeout is not reached (step 688) and the cycle continues to monitor heart rate and check reliability (step 690), as described above. If confidence is achieved (at step 700), the next energy packet is delivered (at step 686). Once all packets have been delivered, the process is considered complete (step 710) and the user is notified of the completion of the process (step 708). If the current associated with the delivery of any of the high-energy packets (in step 686) exceeds a set value (eg, about 45 amps), the cycle may also be terminated (in step 708).

[0422] It can be appreciated that in some embodiments, the components for acquiring the electrocardiogram 170 are integrally formed with the generator 104. If the cardiac monitor is limited to acquiring a maximum of five-lead ECGs, it may be beneficial to incorporate additional leads into the system. This further eliminates the need to use the communications port 167 to receive cardiac synchronization pulses. Rather, the processor 154 can be configured to directly detect the R waves and assess the completeness of the entire QRS complex.

[0423] In some embodiments, processor 154 can be configured to use fewer or more than five Δt to calculate Δt-ave. In some embodiments, processor 154 can be configured to calculate Δt-ave using between three and ten Δt. Additionally, processor 154 can be configured to use Δts other than Δt6 and Δt7 to verify reliability. For example, processor 154 can be configured to use any subsequent Δt. Processor 154 can also be configured to allow heart rates greater than the 40 to 150 bpm range described above. For example, processor 154 can be configured to allow heart rates in the range of 30 to 160 bpm, including all values ​​and subranges therebetween. Processor 154 can also be configured to allow Δt6 or Δt7 to be greater or less than ±10%. For example, processor 154 can be configured to allow Δt6 or other data points, including rolling averages, to be within ±3% to ±50%. The examples of user interface 150 provided herein are merely examples and should not be considered limiting.

[0424] It can therefore be appreciated that the generator can be configured to continuously monitor the patient's heart rate and if a cardiac arrhythmia is induced, therapy can be automatically stopped and an alarm can sound.

[0425] VII. Imaging Imaging-related methods that may be useful include (a) detecting diseased target tissue, (b) identifying areas to treat, (c) assessing the treatment area to determine the effectiveness of energy delivery, (d) assessing target areas to determine if the area is missing or insufficiently treated, (e) using pre- or intra-treatment imaging to measure a target treatment depth and using that depth to select a specific energy delivery algorithm to achieve a tissue effect at that depth, (f) using pre- or intra-treatment imaging to identify a target cell type or cell interface and using that location or depth to select a specific energy delivery algorithm to achieve a tissue effect at that target cell type or cell interface, and / or (g) using pre-, intra-, or post-treatment imaging to identify the presence or absence of pathogens, with or without the presence of inflamed tissue.

[0426] In some embodiments, confocal laser endomicroscopy (CLE), optical coherence tomography (OCT), ultrasound, static or dynamic CT imaging, X-ray, magnetic resonance imaging (MRI), and / or other imaging modalities can be used as separate devices / systems or can be incorporated / integrated (functionally and / or structurally) into the lung tissue modification system 100 by being incorporated into the energy delivery catheter 102 or a separate device. The imaging modality (or multiple modalities) can be used to identify and / or access various sections of tissue, as indicated by thick areas of epithelium, goblet cell hyperplasia, submucosal glands, smooth muscle, and / or other abnormalities associated with where the system will be deployed in the chest. In some embodiments, imaging can include a CT scan performed immediately before or well before treatment administration, with the CT data analyzed to determine the best location for administering the treatment. In this embodiment, CT can be used to determine the location of mucus blockage before treatment is administered. CT scans can also be used to predict responsiveness. Patients with severe lobar emphysema may not respond as well to relief of mucus blockage compared to patients with less emphysema. Patients with low baseline lung volumes, airway counts, or airway diameters can see significant improvements. In some embodiments, a pre-treatment CT scan analysis is performed on asthma patients. In some embodiments, the target treatment depth can be measured and used to select a treatment algorithm 152 sufficient to treat to the target depth. At least one energy delivery body can then be deployed at the site of abnormal airway wall tissue, and energy can be delivered to affect the target tissue. An imaging modality (or multiple modalities) can be used before, during, and / or after treatment to determine whether treatment has occurred or whether the energy properly affected the airway wall. If it is determined that an area was missed or not properly affected, energy delivery can be repeated, followed by an imaging modality (or multiple modalities) until proper treatment is achieved. Additionally, imaging information can be utilized to determine whether a particular cell type and / or desired treatment depth has been applied.This can allow for customization of energy delivery algorithms to treat various patient anatomies.

[0427] In some embodiments, imaging can be performed in combination with the use of fluorescent agents (e.g., fluorescein) to enhance the recognition of possible pathogens within the airways. Fluorescent agents can be selected to directly tag specific pathogens (e.g., bacteria), indirectly tag cells associated with various infectious conditions (e.g., neutrophils), or indirectly or directly tag cells associated with autologous diseases (e.g., cancer), which are then displayed. In some embodiments, such imaging methods / techniques may include gaining access to the airway, delivering a fluorescent agent into the airway, exciting the fluorescent agent by delivering an excitation signal to the airway, and assessing the presence or absence of fluorescence in response to the excitation signal.

[0428] A. Imaging for access Generally, the methods, devices, and systems disclosed herein can access lung tissue or target tissue (e.g., trachea, trunk bronchi, lobar bronchi, segmental bronchi, subsegmental bronchi, parenchyma) via natural orifice routes (e.g., through the mouth or nose), through artificially created orifices (e.g., via tracheotomy, surgically created stoma, and / or appropriate intraoperative and / or surgical openings), and / or through artificially created orifices through the airway to other regions of the lung and / or tissue (e.g., parenchyma). The type of approach utilized can depend on factors such as the patient's age, comorbidities, need for other concomitant procedures, and / or previous surgical history.

[0429] Methods for accessing the airways and / or other lung tissue (e.g., parenchyma) can include using the working channel of a bronchoscope delivered through the nose or mouth into the trachea and / or more distal bronchi. As previously shown in Figures 8A-8B, the bronchoscope 112 may be inserted into the patient P's mouth or oral cavity OC or other natural opening, such as the nose or nasal cavity NC. Similarly, other lung tissue LT, such as the parenchyma, can be accessed through the nose or mouth, as shown in Figure 22. As shown, the distal end of the catheter 102 is advanced into the trachea T, into the main bronchus MB, and into the lobar bronchus LB, which crosses from the airways to the surrounding lung tissue LT. This can be accomplished by a tool or catheter with a guidance system that allows guidance out of the lung passages.

[0430] It can be appreciated that in some instances, direct visualization may not be necessary and / or desired and the therapeutic catheter can be delivered directly to the airways via the nose or mouth.

[0431] In other embodiments, access to the airways and / or lung tissue (e.g., parenchyma) is achieved through other instruments inserted into the chest. Similarly, in some embodiments, one or more of a variety of imaging modalities (e.g., CLE, OCT) are used in conjunction with or in place of direct visualization. As an example, the bronchoscope 112 is delivered through the mouth, allowing direct visualization and delivery of the catheter 102, while an alternative imaging modality can be delivered adjacent to the bronchoscope through the other working channel of the bronchoscope 112, through the nose, or through the mouth. In some embodiments, the imaging modality (e.g., direct visualization, CLE, and / or OCT) is incorporated into the catheter 102 with appropriate mechanisms to connect the imaging modality to either the system generator 104 or a commercially available console. Figures 23A and 23B show exemplary images that can be acquired using CLE and OCT, respectively. These images can be used to guide delivery to predetermined locations previously identified on CT scans using airway wall thickness (AWT) measurements, target therapy based on visualization of cellular structures, and / or assess efficacy of therapy.

[0432] B. Imaging for Treatment Planning Imaging-related methods can include using pre-imaging processing to plan treatment. Imaging can be used to detect diseased target tissue, identify areas to be treated, and / or determine appropriate energy delivery algorithms to achieve a desired treatment depth. In some embodiments, imaging is used in the lungs to determine areas of hyperinflation in patients with emphysema. Such determination can be used to plan treatment to reduce or eliminate mucus blockage and restore exhalation breathing ability. In other embodiments, imaging is used to determine areas of respiratory dysfunction, such as in certain cases of chronic bronchitis. In some embodiments, imaging, such as CT scans, is used to predict responsiveness. Patients with severe lobar emphysema may not respond as well to relief of mucus blockage compared to patients with less emphysema. Patients who experience air trapping as a result of mucus forcing or impaction may experience significant improvement. In some embodiments, pre-treatment CT scan analysis is performed on asthma patients.

[0433] In some embodiments, when multiple treatment sessions are desired to cover the entire target region, pre-treatment imaging is used to prioritize target segments. For example, pre-treatment images can be used to determine which lung is most affected and therefore will benefit most from treatment. Treating the most affected lung first to achieve the best immediate benefit can also reduce any risk of transient induced damage to the treated lung. Such transient damage can cause the patient to rely more heavily on the untreated lung during the recovery period. The untreated lung is a healthier lung, potentially reducing its impact on subsequent morbidity and mortality.

[0434] In some embodiments, imaging scans, such as CT scans, can be obtained preoperatively or intraoperatively, from which AWT or Pi10 (theoretical airway wall thickness for an airway with a 10 mm internal circumference) measurements are obtained. The target zone can be identified using these metrics. Referring again to FIGS. 23A-23B, CLE or OCT can be used to measure the target treatment depth. 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 a target cell type such as a goblet cell GC, submucosal glands (not shown), or smooth muscle (not shown), and / or any other structure determined by the physician to be medically appropriate. FIG. 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 of the airway EDG. These measurements can then be used to select a specific energy delivery algorithm 152 to achieve a tissue effect to that depth. For example, the generator 104 can have a user interface 150 (such as a touchscreen) that allows for selection of the desired treatment depth. Once the operator selects the desired depth, the system 100 can be configured to automatically select the appropriate energy delivery algorithm 152 to achieve that depth. Other anatomical assessments can also be performed to assist in the selection of 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 treatment to be customized for each patient.

[0435] In some embodiments, the use of the bronchoscope 112 can enable pre-treatment planning, in which a sputum sample is obtained for analysis. If one or more pathogens are found, this information can be used to determine the appropriate energy delivery algorithm 152 to achieve the desired treatment depth as a result of the initial data. In some cases, such as a combination of pathogen identification combined with improved tissue imaging, it may be desirable to limit the treatment depth to only the mucus layer M where pathogens thrive. Meanwhile, in other cases, it may be desirable to affect deeper airway structures. To plan treatment, a sputum sample can be obtained and evaluated to determine whether an infection of the tracheobronchial tree is present. If an infection is deemed present, the generator can be programmed to affect the mucus layer of the airway without substantially affecting other layers or other lung tissues that contain the pathogens causing the infection. The method of conducting sputum testing can also be used to evaluate the effectiveness of treatment. To evaluate the effectiveness of treatment, additional sputum samples and biopsies can be taken after or at a later time following the energy delivery procedure. These samples and biopsies can be compared to the planning samples to determine the effectiveness of the treatment. These data, in combination with clinical testing of the patient, can be used to further optimize treatment.

[0436] The method of performing one or more tissue biopsies can be used to plan treatment and / or evaluate the effectiveness of treatment. To plan treatment, biopsies can be performed and evaluated microscopically to determine patient 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, smooth muscle hypertrophy, or other parameters) and / or the extent of airway obstruction (e.g., thickness of the epithelium and / or other layers). By measuring one or more of these parameters, the generator can be programmed to affect specific depths of tissue, allowing for customized energy delivery algorithms for each patient. For example, increased voltage can be used for patients with thicker epithelial layers. To evaluate the effectiveness of treatment, additional biopsies can be performed immediately after or at a later time after the energy delivery procedure. These biopsies can be compared to the planned biopsy to determine the effectiveness of treatment. For example, if a post-treatment biopsy shows no change from the planned biopsy, the location was not treated or insufficient energy was applied to affect the tissue. However, if a post-treatment biopsy shows a decrease in epithelial thickness and / or structure (i.e., regeneration of healthy epithelium), the effectiveness of energy delivery can be verified. This also applies to treatments into deeper tissue layers. By performing multiple biopsies along the airway, it is possible to further evaluate whether a sufficient percentage of the total surface area has been treated. These data, combined with the patient's clinical examination, can be used to further optimize treatment.

[0437] C. Imaging during treatment Use of the bronchoscope 112 allows for direct visualization of the target tissue and visual confirmation of the placement and deployment 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 modalities (e.g., electromagnetic navigation, CLE, OCT) can be used in conjunction with or in place of direct visualization. As an example, the bronchoscope 112 is delivered through the mouth, allowing for direct visualization and delivery of the catheter 102, while an alternative imaging modality can be delivered adjacent to the bronchoscope through the other working channel of the bronchoscope 112, through the nose, or through the mouth. In some embodiments, the imaging technology (e.g., direct visualization, CLE, and / or OCT) can be incorporated into the catheter with appropriate mechanisms to connect the imaging technology to either a system generator or a commercially available console.

[0438] Such imaging during treatment can be used to guide the initial placement of the catheter 102 and further placement of the catheter 102, such as to specifically avoid overlapping target segments or to specifically create overlapping target segments. In some embodiments, imaging studies provide both the length and diameter of the airway within the target treatment zone. Thus, because the contact length of the energy delivery body is known at any given diameter, the clinician can determine the catheter placement or number of treatments that will cover the target treatment zone. Such imaging can also be used to monitor the degree of overlap of various target segments. Additionally, such images can be used to monitor focal treatments, such as the degree of rotation of the catheter 102 during various portions of a treatment. It can be appreciated that in some embodiments, tissue characteristics can be derived from the intrinsic OCT images themselves to guide placement of the focal target. In some embodiments, fiducial markers can be used to guide delivery to the focal target.

[0439] Some focal targets, such as abnormal cell proliferation, require complex guidance and targeting via a series of side branches to reach the target area. These focal targets and their complex access may benefit from advanced guidance to facilitate precise catheter placement and treatment delivery. Examples of appropriate guidance techniques include internal and external guidance. Internal guidance techniques can include direct visualization via bronchoscopy. Other methods may use alternative imaging approaches, such as optical coherence tomography (OCT) or intraluminal ultrasound, to navigate or identify tissue characteristics. In some embodiments, these techniques use the tissue's own characteristics to determine whether it is an appropriate area for treatment or allow for skipping of non-clinically significant areas if they are not clinically significant. External imaging methods for navigating complex anatomical passageways to reach the desired anatomical target include external ultrasound, X-ray / angiography, CT, MRI, electromagnetic induction, or proximity radio frequency identification (RFID) determination. These external monitoring methods can be used with catheters specifically designed to enhance visibility to these modalities, such as by including hyperechoic or ultra-attenuating materials. In other systems, fiducial markers may also be used in conjunction with these imaging modalities to further guide the catheter electrodes to the target area in three-dimensional space.

[0440] D. Post-imaging procedures In some embodiments, imaging-related methods can include using imaging (e.g., using the imaging modality 169) to evaluate the effectiveness of treatments applied either intraoperatively and / or postoperatively. In some embodiments, during a procedure, a surgeon can use images to evaluate treatment areas and determine whether an area was missed or insufficiently treated. For example, if an area was missed, there may be no sudden or sudden change observed in the treatment area. In another example, if an area was insufficiently treated, the surgeon can determine that the target depth was not achieved. The surgeon can then re-measure the depth, select the appropriate treatment algorithm 152, and treat again at the same location. In some embodiments, if the generator 104 does not have different preset algorithms based on the desired depth, the same energy delivery algorithm can be used. Imaging can also be used postoperatively to monitor the healing process and correlate tissue changes to clinical outcomes. The healing process makes it easier to visualize tissue changes and evaluate the effectiveness of the treatment. These data can further lead the physician to decide to perform additional procedures that affect additional tissue.

[0441] E. Comparison of pre- and post-treatment imaging In some embodiments, imaging, such as CT scans, is used preoperatively or postoperatively to determine total airway count and volume. In other embodiments, pre- and post-treatment bronchoscopy is compared to assess improvement / decrease in airway tissue condition, luminal diameter, or other characteristics of interest. In other embodiments, one or more images, such as CT scans, are compared between pre- and intra- or post-operative scans for total airway count and volume to assess changes in mucus plugging. Similar techniques can also be used to avoid promoting the progression of hyperinflated tissue by directing treatment only to the upper airways and branches that support healthy lung parenchymal regions. This technique can also be used in conjunction with efforts to acutely or chronically restore ventilation to hyperinflated tissue in a manner that promotes exhalation but does not promote or discourage further inspiration to these regions. This further enhances the benefits achieved by maintaining viable, properly functioning lung parenchyma occupying the lung space and improving ventilation to healthy lung lobes and subsegments.

[0442] VIII.MUCUS Plugin In particular, various methods, systems, and devices are provided to control the type, depth, and range or area of ​​therapeutic effect. Therapeutic results include short-term and long-term improvement of patient symptoms. In some embodiments, this includes reducing mucus hypersecretion by eliminating or reducing mucus blockage in the airways, thereby promoting improved breathing during the inhalation and exhalation processes and easing respiratory capacity. In addition to being uncomfortable and limiting general activity, mucus hypersecretion (poor expectoration ability) physically narrows the airway lumen available for airflow. When this is combined with patient conditions such as bronchiectasis, airway inflammation, pneumonia, lung fluid, or asthma, transient acute inflammation, and bronchiolar smooth muscle contraction, the narrowing can be exaggerated, significantly restricting the available lumen for airflow or completely obstructing the airways from airflow. Complete airflow restriction associated with mucus hypersecretion leads to mucus plugging, which has numerous morbidity effects on the downstream airways and lung parenchyma, as well as overall patient mortality.

[0443] In some conditions, mucus blockage can lead to respiratory acidosis. In other instances, restricted airflow, particularly mucus blockage, can further exacerbate disease states in other critical anatomical functions and systems, such as reduced circulatory function and increased pressure on the heart. Furthermore, it is important to consider that mucus blockage not only prevents fresh air from entering downstream airways and the lungs, but also prevents the exhalation of existing air contained in downstream regions. COPD conditions, such as emphysema, are characterized by the inability to expel trapped lung volume and hyperinflation of distal lung regions, reducing the space available for viable ventilated regions of the lung. Therefore, eliminating mucus blockage in airways supplying trapped air to hyperventilated lung tissue improves ventilation to the hyperventilated regions, allowing the trapped air to be exhaled and restoring normal lung volume distribution, thereby improving ventilation to healthy portions of the lung tissue.

[0444] In some embodiments, mucus hypersecretion is reduced to the point that the hyperresponsiveness of bronchiolar smooth muscle cells during an asthma attack does not cause mucus blockage in the airways, dramatically reducing the risk of morbidity and mortality encountered during an asthma attack.The elimination of mucus blockage through the resurfacing and redistribution of mucosal and submucosal airway cell populations can restore adequate ventilation to more lungs.This result is clearly demonstrated by the increase in the number and diameter of available airways when comparing data before and after treatment.

[0445] Furthermore, eliminating or reducing mucus hypersecretion, especially the incidence of mucus clogging in healthy or diseased lung volumes, significantly enhances the therapeutic efficacy of complementary inhaled medications. By improving the access of inhaled medications to all target areas of lung tissue, it becomes possible to most effectively treat lesions in the entire lung or in specific diseased areas.

[0446] In some instances, mucus plugs may be present prior to treatment administration. In these instances, a range of techniques can be used to address the mucus plugs. In the first instance, the mucus plugs are left in place and utilized as electrical conduits to transfer energy from the energy delivery body 108 to the tissue. In some instances, this may dilute the energy concentration, thus necessitating an increase in the intensity of the treatment protocol to ensure proper delivery. In other approaches, the mucus and mucus plugs of the present invention can be agitated or removed by brushing, and the patient is inhaled with saline to promote mucus secretion and coughing. In other instances, the mucus and mucus plugs may be ignored, thereby simply skipping treatment in that area.

[0447] In another approach, mucus plugging is eliminated as part of achieving a standardized tissue environment before treatment by irrigating the airway with one of several solutions, including isotonic saline, hypertonic saline, calcium, and others. The fluid and mucus combination can then be removed as part of a more extensive irrigation process by aspirating the irrigation solution. This method reduces or eliminates the impact of mucus on energy dilution and provides a more stable and predictable initial environment for treatment. This can lead to more consistent results and improved refinement and optimization of the ideal clinical dose. This technique can be used in tissues with or without visible mucus plugging as a pretreatment best practice.

[0448] IX. Catheter Embodiments Various energy delivery catheter 102 embodiments are contemplated. The features and characteristics described herein can be used in any combination to achieve the desired tissue effect. Typically, such catheters 102 are sized and configured to treat lung passageways having a lumen diameter of approximately 3 to 20 mm. Typically, the energy delivery body 108 expands within the lung cavity lumen and resides near, against, in contact with, or exerting pressure or force against the lumen 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.

[0449] FIG. 24 illustrates an embodiment of an energy delivery catheter 102 having a single energy delivery body 108 comprised of at least two lobes, each extending radially outward to contact the luminal wall of the lung passageway. While there can be a single lobe, it can be understood that there are typically two lobes, exerting substantially opposing forces on the wall of the lung passageway to support the catheter therebetween. In this embodiment, the at least two lobes comprise multiple ribbons or wires 120 constrained by a proximal end constraint 122 and a distal end constraint 124 that form a helical-shaped basket. In this embodiment, the proximal end constraint 122 is attached to the shaft 106, which does not pass through the energy delivery body 108. This allows the energy delivery body 108 to fold upon itself without the additional internal 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 placing a sheath 126 over the energy delivery body 108. 24 , the shaft 106 terminates at the proximal end constraint 122, so the distal end constraint 124 is essentially unconstrained and free to move relative to the shaft 106 of the catheter 102. Advancing the sheath 126 over the energy delivery body 108 allows the distal end constraint 124 to move forward, thereby extending / contracting and constraining the energy delivery body 108. Retraction of the sheath 126 allows the energy delivery body 108 to expand, for example, through self-expansion. It can be appreciated that in alternative embodiments, the ribbon or wire 120 is straight (i.e., configured to form a straight-shaped basket) rather than formed into a helical shape. In yet other embodiments, the energy delivery body 108 is laser cut from a tube.

[0450] In some embodiments, the energy delivery body 108 comprises multiple electrodes 107, with each wire 120 functioning as a separate electrode 107 and capable of firing separately using its neighboring wire as a return electrode or using a dispersive electrode attached to the patient as the return electrode. In some cases, each wire 120 of the energy delivery body 108 can be electrically insulated from each other wire 120, and a separate conductor wire can transmit energy from the generator 104 to the wire 120 of the energy delivery body 108. In other examples, two or more wires 120 can be electrically connected to each other to form one or more sets of wires. The algorithm 152 of the generator 104 can perform the appropriate switching from one wire (or set of wires) to another, as well as changing the wire function between an active state and a return (ground) state.

[0451] FIG. 25 illustrates an embodiment in which the energy delivery catheter 102 includes two energy delivery bodies, a first energy delivery body 108 and a second energy delivery body 108′, each of which functions similarly to the embodiment of FIG. 24 . In this embodiment, the first energy delivery body 108 is disposed along the distal end of the first shaft 106, and the second energy delivery body 108′ is disposed along the distal end of the second shaft 106′. As shown, the shafts 106, 106′ are aligned parallel so that they can both pass through the sheath 126. In some embodiments, the shafts 106, 106′ are fixed together so that they move in unison. In such embodiments, the shafts 106, 106′ are typically staggered, as shown in FIG. 25 , such that the second energy delivery body 108′ is disposed more distally than the first energy delivery body 108. In such an arrangement, the energy delivery bodies 108, 108' can be separated by any suitable distance. Similarly, because the energy bodies 108, 108' are positioned relative to the shafts 106, 106', the expansion of the energy bodies 108, 108' is not impeded in any way. For example, in this embodiment, the energy delivery bodies 108, 108' are positioned such that the second shaft 106' does not impede the expansion of the first energy delivery body 108. Rather, the second shaft 106' passes through the basket-shaped energy delivery body 108 between the wires 120. In some embodiments, the shafts 106, 106' are not fixed to one another and can move relative to one another; in particular, the shafts 106, 106' can slide longitudinally parallel to one another. In such embodiments, the shafts 106, 106' may be moved relative to one another to increase or decrease the distance between the energy delivery bodies 108, 108'. Once the desired distance is achieved, the shafts 106, 106' can be locked in place to maintain the desired distance between the energy delivery bodies 108, 108'.

[0452] In the embodiment shown in FIG. 25 , each energy delivery body 108, 108′ is comprised of a spiral-shaped basket comprised of electrodes 107 in the form of wires 120. The energy delivery bodies 108, 108′ can be activated in a bipolar and / or monopolar manner. It can be appreciated that in alternative embodiments, the wire or ribbon 120 can be straight (i.e., configured to form a straight-shaped basket) instead of being formed into a spiral shape. In some embodiments, the energy delivery bodies 108, 108′ are laser cut from a tube. In this embodiment, the first shaft 106 terminates at a first proximal end constraint 122 of the first electrode body 108, and the first distal end constraint 124 remains essentially unconstrained. The second shaft 106′ terminates at a second proximal end constraint 122′ of the second electrode body 108′, and the second distal end constraint 124′ remains essentially unconstrained. Advancing the sheath 126 over the energy delivery bodies 108, 108' allows the distal end restraints 124, 124' to move forward, thereby collapsing, extending, and restraining the energy delivery bodies 108, 108'. Retraction of the sheath 126 exposes the energy delivery bodies 108, 108' for expansion and delivery of energy.

[0453] 26 depicts an embodiment of an energy delivery catheter 102 having a single energy delivery body 108 comprised of a monopolar electrode 107 formed by multiple ribbons or wires 120 attached to a shaft 106 extending through the energy delivery body 108. Again, the energy delivery body 108 has a basket shape constrained by a proximal end constraint 122 and a distal end constraint 124. In this configuration, either the proximal end constraint 122 or the distal end constraint 124 slides freely on the shaft 106 to collapse the energy delivery body 108, while the other end is fixedly attached to the shaft 106. Upon delivery of the energy delivery body 108 to the target treatment area, the sheath 126 is withdrawn by the operator, for example, via a lever, slider, or plunger on the catheter handle 110, which is operably connected to the sheath 126. Retraction of the sheath 126 releases the constraint holding the collapsed energy delivery body 108, thus allowing it to expand, bringing the wires 120 of the energy delivery body 108 into contact with the bronchial wall.

[0454] In some embodiments, the energy delivery body 108 in a collapsed configuration can be achieved by a mechanism that limits its expansion without the use of a sheath 126. For example, in some embodiments, a pull wire is attached to a proximal end constraint 122 of the energy delivery body 108 and extends down a lumen along a shaft 126 that is operably connected to a lever, slider, or plunger in the catheter handle 110. In this embodiment, the distal end constraint 124 is fixedly attached to the shaft 106, and the proximal end constraint 122 is configured to slide freely on the shaft 106. While the pull wire is pulled, the proximal end constraint 122 is positioned such that the energy delivery body 108 collapses. The pull wire can be maintained in this position by a constraint in the handle 110. Releasing the tension force, such as by reducing or removing the constraint within the handle 110, allows the tension wire to move, thereby releasing the proximal end constraint 122 and allowing it to approach its distal end constraint 124 as the self-expanding properties of the energy delivery body 108 cause it to expand.

[0455] In other embodiments, the proximal end constraint 122 is attached to the shaft 106, and the distal end constraint 124 slides freely on the shaft 106. Additionally, a push rod (or a tube to achieve greater column strength) is attached to the distal end constraint 124 and extends down a lumen along the inner shaft 106, where it is operably connected to a mechanism such as a lever, slider, or plunger in the catheter handle 110. When the push rod is pushed and subsequently restrained within the handle 110 of the catheter 102, the distal end constraint 124 moves away from the proximal end constraint 122, thereby collapsing the energy delivery body 108. If the energy delivery body 108 is self-expanding, releasing the push rod allows the energy delivery body 108 to expand. Alternatively, the energy delivery body 108 can be expanded by retracting the push rod and pulling the distal end constraint 124 toward the proximal end constraint 122.

[0456] In the embodiment shown in FIG. 26 , the energy delivery body 108 is formed from a braided metal tube configured to be constrained by both the proximal end constraint 122 and the distal end constraint 124 to form a basket. The energy delivery body 108 can be controlled (i.e., collapsed and deployed) as described above. When the energy delivery body 108 comprises a braided metal tube, each wire in the braided tube is supported by its neighbors and the interwoven nature of the braid itself. This support and interwoven configuration minimizes variations in the spacing between wires, otherwise known as the pore or opening size of the braid. Furthermore, this support and interwoven configuration allows the braided tube to be constructed from very thin wires, greatly improving the radial stability of the basket. This allows for the use of a large number of wires (e.g., 12, 16, 18, 20, 22, 24, etc.) while maintaining a relatively small profile of the energy delivery body 108 in the collapsed / constrained state and optimizing the opening size of the braided tube when the electrodes are deployed / expanded. In this embodiment, the spacing between the wires is fairly small, leading to essentially continuous treatment throughout 360 degrees of the lumen of the lung passageway.

[0457] 27 shows an embodiment in which both energy delivery bodies 108, 108′ are carried on a single shaft 106. To collapse the energy delivery bodies 108, 108′, a first proximal end restraint 122 of the first energy delivery body 108 is fixedly attached to the catheter shaft 106. The other end restraints 122′, 124, 124′ are free to slide on the catheter shaft 106. The catheter is delivered by a sheath 126 that restrains the energy delivery bodies 108, 108′. Upon delivery of the energy delivery bodies 108, 108′ to the target area, the sheath 126 can be withdrawn by the operator via a mechanism such as a lever, slider, or plunger on the catheter handle 110. Retracting the sheath 126 releases the constraint holding the collapsed energy delivery bodies 108, 108′, thus allowing them to expand, bringing the faces of the energy delivery bodies 108, 108′ into contact with the bronchial wall. Furthermore, in some embodiments, the first distal end constraint 124 and the second proximal end constraint 122″ are connected to one another via a coupler 800. The coupler 800 is constructed using an electrically insulating material (e.g., polyether block amide (Pebax®) tubing, polyimide tubing, etc.) to provide an insulating gap 802 between the energy delivery bodies 108, 108′ to achieve electrical discontinuity therebetween. In some embodiments, this gap 802 is between 1 and 20 mm. This prevents arcing within the catheter shaft 106.

[0458] In some embodiments, the collapsed configuration of the energy delivery bodies 108, 108' can be achieved by restricting their expansion without the use of a sheath 126. For example, in one embodiment, the distal end of a puller wire (not shown) is attached to the second distal end constraint 124', and the proximal end of the puller wire is attached to a mechanism (e.g., a plunger, slider, or lever) on the handle 110. The first proximal end constraint 122 is fixedly attached to the catheter shaft 106, and the other end constraints 124, 122', 124' slide freely on the catheter shaft 106. In such a configuration, the energy delivery bodies 108, 108' are in the collapsed configuration prior to initiating placement through the bronchoscope, requiring the surgeon to unfold / expand them. This deployment / expansion is achieved by the operator actuating a mechanism (e.g., a lever, plunger, or slider) on the handle 110 that pulls the second distal end constraint 124' toward the first proximal end constraint 122, thus effectively deploying / expanding both energy delivery bodies 108, 108'. In other configurations, expansion can be achieved using two pull wires, one separately attached to each energy delivery body 108, 108'. In such an embodiment, the operator can independently control the level of expansion of the energy delivery bodies 108, 108'.

[0459] In some embodiments, one or more energy delivery bodies 108, 108' are unconstrained at both ends, but rather at one end, forming a half-basket shape. FIG. 28A illustrates an embodiment in which one energy delivery body 108' is unconstrained at one end to form a half-basket shape when expanded. In this embodiment, both energy delivery bodies 108, 108' are constructed from braided metal wire. The distal-most energy delivery body 108' is constrained by both a second proximal end constraint 122' and a second distal end constraint 124' and configured to form a closed braided basket shape. The distal-most energy delivery body 108' is expandable, such that typically at least its widest expanded diameter contacts the wall W of the lung passageway. The proximal-most or first energy delivery body 108 is constrained by a first proximal end constraint 122, as shown, and is configured to form an approximately half-open basket or half-basket shape when expanded. Because the proximal energy delivery body 108 is expandable, at least its widest expanded diameter typically contacts the wall W of the lung passageway. The shaft 106 is fixedly attached to the first and second proximal end restraints 122, 122′. The half-basket shape of the proximal energy delivery body 108 allows its widest expanded diameter to approach the diameter of the distal-most energy delivery body 108′ more than if the proximal energy delivery body 108 were in its entirety. Reducing this distance between the energy delivery bodies 108, 108′ allows for a therapeutic effect between the energy delivery bodies 108, 108′ in addition to at the energy bodies 108, 108′. This ultimately creates a greater surface treatment effect given the effect between the bodies 108, 108′. Additionally, the half-basket shape helps avoid arcing.

[0460] The configuration shown in FIG. 28A is delivered using a sheath (not shown), as described in detail above, and both energy delivery bodies 108, 108′ are self-expandable. In other embodiments, the second energy delivery body 108′ is placed in a collapsed state prior to delivery to the bronchoscope and, once positioned at the desired target area, is deployed / expanded via its second distal end constraint 124′) and a pull wire (not shown) connected to a mechanism on the handle 110. This combination of a full basket (energy delivery body 108′) and a half basket (energy delivery body 108) can be used for bipolar or monopolar energy delivery. When the electrodes are made of braided metal wire, each wire is supported by its neighbors and the interwoven nature of the braid itself. This supportive and interwoven configuration minimizes variations in the spacing between the wires, otherwise known as the pore or opening size of the braid. Furthermore, this supportive and interwoven configuration allows the braid to be constructed from very thin wires, greatly improving the radial stability of the basket. This allows for the use of many wires (e.g., 12, 16, 18, 20, 22, 24, etc.) while maintaining a small profile of the energy delivery body 108, 108' in the collapsed or constrained state and optimizing the braid opening size when the energy delivery body 108, 108' is deployed or expanded. In this embodiment, the spacing between the wires is fairly small, leading to 360-degree treatment within the lung passageways.

[0461] 28B shows an embodiment in which the energy delivery bodies 108, 108' are both constructed from braided metal wire with a proximal end constraint 122, 122' attached to the shaft 106. In this embodiment, the energy delivery bodies 108, 108' are both configured to form half-baskets. This configuration can be delivered using a sheath (not shown) as described above, and the energy delivery bodies 108, 108' are self-expandable. This configuration of half-basket energy delivery bodies 108, 108' can be used for bipolar and / or monopolar energy delivery.

[0462] In some embodiments, the entire surface of one or more energy delivery bodies 108 is energized with an energy signal for delivery to the target tissue. However, in other embodiments, an active surface area of ​​the energy delivery body 108 is provided, and the remaining portion is inactive. In some embodiments, this is achieved by partially insulating one or more portions of the energy delivery body 108, leaving one or more active areas. For example, FIG. 29 shows a braided wire basket energy delivery body 108 constructed from an energizable wire 120 (which functions as one or more electrodes), with a portion of the wire 120 insulated with a section of insulation removed to define an active area 820. In some embodiments, insulation is removed from the outer (tissue-contacting) surface of the wire 120. This approach may be useful, for example, when the impedance measured through the electrode wire 120 is affected by the amount of exposed metal and when it is desired that the measured impedance represent the electrode-tissue interface. In other embodiments, insulation may be removed from both the outer and inner surfaces of the electrode wire 120. One method of manufacturing an energy delivery body 108 in this configuration involves using insulated wire to form a braid and then removing the insulation using a suitable means (e.g., laser, mechanical) to form one or more active regions 820. While this example shows a single active region 820, multiple active regions are also envisioned to produce any treatment pattern. Similar techniques can be used for the non-braided energy delivery bodies 108 described herein. In these embodiments, insulation can be applied or removed as part of the manufacturing process to define any active region (or regions) 820 configuration desired to achieve various treatment patterns.

[0463] FIG. 30 shows another embodiment in which a metal (e.g., nitinol) tube 830 is laser cut to form a folded basket 832 with both ends constrained via the tube 830 itself. The basket 832 can then be expanded and shaped so that it can self-expand during use to perform as an energy delivery body 108. Alternatively, a push / pull mechanism can be used to expand / contract the basket 832 for delivery / treatment. In some embodiments, one end 834 of the basket 832 is removed to form a free end 836, as shown in FIG. 31. An insulating material (e.g., a polymer tube) can then be advanced over the free end 836 and applied to the basket 832. In some embodiments, the insulation is applied to the proximal and distal portions of the basket, leaving one or more conductive / active regions 820 between them. In other embodiments, as shown in FIG. 31, the wires 120 of the basket 832 are insulated, and one or more separate additional electrodes 840 (shown as coils) are connected to the insulated basket wire to form the active region 820. This assembly can then be attached to the catheter 102 so that the energy delivery body 108 can be activated as a unipolar electrode having multiple predefined active areas 832 .

[0464] FIG. 32 illustrates another embodiment of the energy delivery body 108. In this embodiment, the body 108 includes multiple tines 840, similar to the free end 836 of FIG. 31. The tines 840 can expand outward to contact the walls of the lung passageways. In some embodiments, one or more of the tines 840 are insulated from an insulating material 842. Electrodes 107 disposed along each tine 840, such as near the distal end of each tine 840, can be formed by removing the insulating material 842 to expose the underlying energizable element or wire. Alternatively, as shown in FIG. 32, separate electrodes 107 can be attached to the insulating material 842. In some embodiments, the tines 840 are formed from a polymer-covered wire, which can act as structural support for the self-expanding tines 840, can be energized to deliver therapeutic energy, and / or can be used to sense temperature and / or impedance. In some embodiments, the tines 840 are collapsible through the sheath 126 for delivery and can expand to contact tissue upon retraction of the sheath 126. The electrodes can all be fired simultaneously in a monopolar manner, fired independently in a monopolar manner, and / or fired from each other in any pattern necessary to produce the desired therapeutic effect. The length of the electrodes can range from about 3 mm to about 5 cm, such as 3 mm, 5 mm, 1 cm, 2 cm, 3 cm, 4 cm, or 5 cm. Although shown as all the same size in FIG. 32, the sizes (e.g., length, width) can vary.

[0465] FIG. 33 shows another embodiment of the energy delivery body 108. In this embodiment, rather than a basket weave, the energy delivery body 108 includes one or more protrusions 850. Each protrusion 850 acts as an electrode and is formed by a wire or ribbon 120 that bends radially outward from the longitudinal axis or shaft 106 of the catheter 102. In this embodiment, each protrusion 850 is electrically insulated from each of the other protrusions. The protrusions 850 may be constructed from a variety of suitable materials to function as electrodes, such as stainless steel, spring steel, or other alloys, and may be, for example, round wires or ribbons. Each protrusion 850 is insulated by segments of insulating material 852, such as a polymer (e.g., PET, polyether block amide, polyimide), covering at least a portion of the proximal and distal ends of the energy delivery body 108. An exposed portion 854 of the wire or ribbon can then function as an electrode on each protrusion 850. In one embodiment, the exposed portion 854 of the protrusion 850 is completely free of insulating material 852. In other embodiments, the insulation 852 is removed only from the outer surfaces of the prongs 850, leaving the sides of the prongs 850 that do not contact tissue (e.g., the inner surfaces facing the shaft 106 of the catheter 102) completely insulated. In one embodiment, each prong 850 is independently energized, with two prongs 850 functioning as neutral (return) electrodes and two prongs 850 functioning as active electrodes. The neutral and active electrodes can be positioned adjacent to each other. The neutral (opposite) electrodes located 180 degrees from each other can be electrically connected to each other and can also be active electrodes. In this embodiment, only two electrical leads (power lines) are required to connect the two pairs of prongs 850 to the generator 104. Furthermore, pairs of prongs 850 utilized in a bipolar fashion can be further multiplexed to allow any combination or rotation of active versus neutral electrodes. The generator 104 can be configured with enough channels (i.e., 1 to 4 channels) to support any of these approaches. This embodiment of the energy delivery body 108 can be delivered in a collapsed configuration and expanded into tissue contact via a pullback wire and mechanism in the handle, if desired.

[0466] FIG. 34 shows another embodiment of the energy delivery body 108 including one or more protrusions 850, each bending radially outward from the longitudinal axis or shaft 106 of the catheter 102. However, in this embodiment, each protrusion 850 is formed from a non-conductive material and carries, supports, and / or is coupled to a separate electrode 107. Each electrode 107 has a lead 860 connecting the electrode 107 to the generator 104. The protrusions 850 position the electrode 107 against the tissue upon expansion, such as via a pull wire and a mechanism in the handle. In this embodiment, each electrode 107 is positioned on or adjacent to a respective protrusion 850. If the protrusions 850 are constructed from a metal, insulation is provided to electrically insulate the electrode 107 from the protrusion 850 itself. If the protrusions 850 are constructed from a polymer or other non-conductive material, no additional insulation is required. In some embodiments, the protrusions 850 are made of round wire or ribbon, as shown, and are configured to form a straight basket. In other embodiments (not shown), the protrusions 850 are configured in a helical shape. It can be understood that separate electrodes 107, as shown in FIG. 34, may similarly be applied to other embodiments, such as when the basket is constructed from a braided material. As with the embodiment of FIG. 33, the electrodes 107 may be energized in various combinations. Furthermore, each protrusion 850 can carry electrodes 107 that can be electrically connected to one another or electrically insulated from one another. 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 greater spatial coverage and also maintain the flexibility of the electrodes 107, allowing the basket protrusions 850 to bend and straighten freely. As in FIG. 33, the surfaces of the protrusions 850 can be completely exposed or insulated in areas that do not contact tissue.

[0467] FIG. 35 shows another embodiment of a catheter 102 having at least one energy delivery body. In this embodiment, each energy delivery body comprises an expandable coil that can function as an electrode itself or as a carrier for a separate electrode mounted thereon. In this embodiment, the catheter 102 includes two energy delivery bodies: a first energy delivery body 108 disposed proximal 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 coupled or formed to an inner member 872, and the proximal end 874 of the first energy delivery body 108 is coupled to an outer member 876. The outer member 876 is rotatable relative to the inner member 872 to collapse and / or expand the energy delivery bodies 108, 108′. A coupler 878 attaches the energy delivery bodies 108, 108′ together and provides insulation between them, if necessary. The energy delivery bodies 108, 108' can be activated in monopolar and / or bipolar fashion. As described herein, the sizes of the energy delivery bodies 108, 108' can be the same or different. The length of each extension coil can range from about 5 mm to about 20 mm.

[0468] FIG. 36 depicts an energy delivery body 108 configured for more limited application of therapeutic energy, such as in a narrow region along a lung passageway wall or along a partial inner circumference of a lung passageway. In this embodiment, the energy delivery body 108 includes a coil that limits the length of the active region. Such an embodiment can be used when a very localized tissue effect is desired or when the tissue effect extends beyond the active region in contact with the tissue. In this embodiment, the energy delivery body 108 includes a coil 880 having a width and a length, where the length of the coil 880 can be pre-shaped into a semicircular or circular pattern, as shown. The treatment length L1 is provided by the width of the coil 880 when contacting the lung passageway wall W. This configuration can be operated in a monopolar configuration as shown. However, it is further envisioned that two or more coils 880 can be used to enable bipolar and / or multiplexed energy delivery. Similarly, FIG. 37 illustrates an embodiment of the energy delivery body 108 including a rod 882 (such as the shaft 106) having a width and a length, where the length of the rod 882 can be pre-shaped into a semicircular or circular pattern, as shown. The rod 882 includes one or more electrodes 107 disposed along its length. The one or more electrodes 107 may be embedded in or otherwise attached to the rod 882. The treatment length L1 is provided by the width of the one or more electrodes 107 that contact the lung passageway wall W. This embodiment allows for monopolar activation between all electrodes and a dispersive (neutral) electrode, bipolar activation between individual electrodes, and / or multiplexed activation between any combination of electrodes. It is further envisioned that two or more of these devices may be used to enable energy delivery between them. When the energy delivery body 108 is pre-formed into a semicircular or circular configuration, a sheath 126 can be used to fold and constrain the energy delivery body 108 for self-expansion, and / or a pull / push wire can be used to expand the energy delivery body 108. These methods for expanding and / or collapsing the energy delivery body 108 are described in detail within other examples provided.

[0469] The energy delivery body 108 can be optimized for situations where greater control of 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 FIG. 38, the sheath 126 is retracted proximally, thus exposing one or more prongs 900 that function as projections. This embodiment includes four prongs 900 symmetrically arranged around a central lumen 902, as shown in the cross-sectional view of FIG. 38A. It can be understood that there can be any number of prongs 900, including one, two, three, four, five, six, or more. Each prong 900 includes at least one electrode 107. FIG. 39 shows an embodiment of a prong 900 having two electrodes 107 having an elongated shape (e.g., wires) attached to an insulating substrate 904, such as a polymer substrate (e.g., ribbon, strip), as a means of maintaining the distance between the electrodes 107. It can be understood that the electrodes 107 can have a circular or square / rectangular cross section and are typically attached to the insulating substrate 904 so that the electrodes 107 are substantially parallel to one another. Manufacturing methods for attaching the electrodes 107 to the insulating substrate 904 can include, but are not limited to, co-extrusion, flexible circuits, deposition (printed electrodes), adhesive-based bonding, and thermal bonding. The width of the insulating substrate 904 can vary.

[0470] Figure 40 shows an embodiment of a prong 900 having a narrower insulating substrate 904 than shown in Figure 39. Similarly, Figure 41 shows an embodiment of a prong 900 having an even narrower insulating substrate 904 and more than two electrodes 107. In particular, while Figure 41 shows five electrodes 107, it can be understood that there may be any number of electrodes 107, such as 1, 2, 3, 4, 5, 6, 7, 8, or more. Figure 42 shows multiple electrodes 107 mounted on a polymer substrate (e.g., ribbon, strip) where the electrodes 107 have elongated shapes (such as wires) and are arranged substantially parallel to one another, leaving gaps between each wire.

[0471] In some embodiments, the insulating substrate 904 with the electrodes 107 is configured as a strip (FIGS. 39-42). Thus, the electrodes 107 are deployed as linear strips disposed along the length of the airway. In other embodiments, the insulating substrate 904 with the electrodes 107 is configured as a spiral, with the electrodes deployed in a spiral pattern. FIG. 43 shows an insulating substrate 904 with electrodes 107 as shown in FIGS. 39-40 configured as a spiral. FIG. 44 shows an insulating substrate 904 with electrodes 107 as shown in FIG. 41 configured as a spiral.

[0472] In some embodiments, the strips or ribbons can be deployed using the push-pull mechanisms described above in connection with other embodiments. In the case of helices, rotational mechanisms can also be used. The electrodes 107 can be electrically connected to each other, isolated from each other, or have different patterns of electrical interconnection between the electrodes depending on the energy application algorithm controlled by the generator.

[0473] Once one or more prongs 900 are exposed, the second step of the three-step process involves introducing the expandable member 910, such as a balloon, by advancing the expandable member 910 from the lumen 902 while the expandable member 910 is in an unexpanded state. The third step involves expanding the expandable member 901, such as by inflating a balloon, until a desired interface between the prongs 900 (and thus the electrodes 107) and the bronchial wall W is achieved, as shown in FIGS. 45A-45B . In other embodiments, the prongs 900 are positioned while the expandable member 910 is already positioned below the prongs 900, so their relative longitudinal positions do not change. In this configuration, retracting 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 prongs 900 and the bronchial wall S is achieved. The sizes (e.g., length, width) of the prongs 900 can be the same or different. The number of prongs 900 can vary between 1 (monopolar configuration) and 100 (monopolar and / or bipolar) configurations. The application of energy to the electrodes 107 can vary widely depending on the algorithm of the energy delivery device (e.g., generator).

[0474] It can be understood that other embodiments of the energy delivery catheter 102 can also include a portion that is expandable by an expandable member 910. For example, FIG. 45C shows an embodiment of a catheter 102 having an energy delivery body 108 comprising wires forming an expandable basket, at least one of the wires functioning as an electrode 107. In this embodiment, the energy delivery body 108 transitions from a collapsed configuration to an expanded configuration by expansion of an internal expandable member 910, such as a balloon. In some embodiments, the expandable member 910 has an electrically conductive surface 911, as shown in FIG. 45D.

[0475] In some embodiments, the expandable member 910 includes one or more printed electrodes 913 disposed on a surface of the expandable member 910. FIGS. 45E through 45G show various energy delivery catheters 102 having an expandable member 910 with printed electrodes 913. It can be understood that the electrodes 913 may extend around the expandable member 910, as shown, or may be on a particular side of the expandable member 910. Electrodes 913 on a particular side can be used to provide focal treatment, or the catheter 102 can be rotated to provide circumferential treatment. The electrodes 913 can be used in monopolar or bipolar modes.

[0476] 45H shows an embodiment of an energy delivery catheter 102 having an energy delivery body 108 with two prongs that are expandable by an expandable member 910. In this embodiment, the two prongs comprise wires that function as electrodes 107. It can be appreciated that in other embodiments, the electrodes 107 are comprised of printed electrodes 913 in the form of strips printed on the surface of the expandable member 913.

[0477] FIG. 46 illustrates 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 be operated in a bipolar / multiplexed manner. In this embodiment, the energy delivery bodies 108 are constructed from braided metal wire, which functions as electrodes. The energy delivery bodies 108 can be operated in a bipolar manner by cycling power supplied by the external generator 104 between any pair of two energy delivery bodies 108, one of which is neutral. The combination between active and neutral energy delivery bodies 108 can be varied as well. For example, in one embodiment, one energy delivery body 108 can function as a neutral electrode while applying energy to two or more energy delivery bodies 108. The combination of active and neutral energy delivery bodies 108, the switching / cycling of energy between active and neutral energy delivery bodies 108, and the selection between activated and deactivated energy delivery bodies 108 are achieved through the energy delivery algorithm 152 of the generator 104. The algorithm 152 can apply and distribute energy between the energy delivery bodies 108 based on a given approach, imaging data, and other factors that determine the area and depth of the desired treatment.

[0478] FIG. 47 shows another embodiment of an energy delivery catheter 102 having a multi-energy delivery body design. In this embodiment, the energy delivery bodies 108 are activated in a monopolar and / or bipolar multiplexed manner. Monopolar energy delivery can be achieved by supplying energy between one or more energy delivery bodies 108 positioned near the distal end 920 of the catheter 102 and a dispersive (return) electrode 922 applied externally to the skin of the patient P. The combination of active energy delivery bodies 108, the switching / cycling of energy between the active energy delivery bodies 108 and the dispersive electrodes 922, and the selection between activated and deactivated energy delivery bodies 108 are achieved through the energy delivery algorithm 152 of the generator 102. The algorithm 152 can apply and distribute energy between the energy delivery bodies 108 based on a given approach, imaging data, and other factors that determine the desired region and depth of treatment.

[0479] It can be understood that many of the figures herein show energy delivery bodies 108 of essentially the same size (e.g., length, diameter) and shape for illustrative purposes and should not be considered limiting. In some embodiments, the energy delivery bodies can be different sizes to account for the tapering of the airway lumen, better localize the energy field, and / or enhance tissue treatment. For example, if a desired catheter placement requires the distal energy delivery body to be in a lobar bronchus (approximately 9 mm to 12 mm in diameter) and the proximal energy delivery body to be in a mainstem bronchus (approximately 12 mm to 16 mm in diameter), the distal energy delivery body can be designed to extend to approximately 12 mm, and the proximal energy delivery body can be designed to extend to approximately 16 mm. The energy delivery bodies can also be of different sizes to better localize the energy field. For example, if monopolar energy delivery is required, it may be beneficial to incorporate a dispersive (neutral) electrode into the catheter or other device (instead of placing it outside the patient, as shown in FIG. 47) to position it closer to the therapeutic energy delivery body to better localize the energy. This allows for a lower voltage to be applied to generate the same electric field, reducing the risk of muscle contraction or arrhythmia. Energy delivery bodies can also be of different sizes to enhance their ability to separate tissue. In some embodiments, the active portion of an energy delivery body can be the area in contact with the airway. Thus, for example, if two similarly sized energy delivery bodies are placed in similarly sized airways and expanded in approximately the same way, the contact areas of the two different energy delivery bodies can be approximately the same. However, if two similarly sized energy delivery bodies are placed in differently sized airways and / or expanded in different ways, the active portions of each energy delivery body can be significantly different. If one electrode is configured to have a larger contact area than the other, a non-uniform electric field can polarize cells and generate greater forces in an attempt to separate the tissue.The energy delivery body can also be configured to bias the energy field perpendicular to the epithelium or to generate shear along the epithelium.

[0480] FIG. 48 illustrates an exemplary catheter 102 configured for removably connecting to a bronchoscope 112...

Claims

[Claim 1] The invention as set forth in the drawings.

Images