JP7725067B2 - Delivery catheter and method for treating disease - Google Patents

Description

(Related Applications)
This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/866,266, filed June 25, 2019, U.S. Patent Application No. 16/563,235, filed September 6, 2019, and U.S. Patent Application No. 16/690,992, filed November 21, 2019, the disclosures of which are incorporated herein by reference in their entireties.

Hypertension, or high blood pressure, is a major global health problem. An estimated 30 to 40 percent of the world's adult population suffers from this problem. Moreover, its prevalence is expected to increase, especially in developing countries. Diagnosis and treatment of hypertension remain poor, and many patients struggle to adequately control their blood pressure.

Benign prostatic hyperplasia (BPH) is a noncancerous enlargement of the prostate gland that affects more than 50% of men over the age of 60. In young men, the prostate is approximately the size of a walnut and weighs approximately 20 grams. It is normal for the prostate to enlarge over time. With age, the prostate gradually increases to at least twice its original size. The growth of the prostate puts pressure on the adjacent urethra, causing urethral narrowing and eventual urethral obstruction, making urination difficult.

Chronic obstructive pulmonary disease (COPD) involves two major respiratory obstructive disorders: chronic bronchitis and emphysema. Chronic bronchitis is caused by inflammation of the bronchial airways, which connect the trachea to the lungs. Emphysema is caused by overinflation of the alveoli, or air sacs, in the lungs. This problem leads to shortness of breath. Approximately 16 million Americans suffer from COPD, the majority of whom (80-90%) are lifelong smokers. COPD is the leading cause of death in the United States.

Asthma is a chronic respiratory disease characterized by excessive narrowing of the airways and caused by airway inflammation, excessive mucus production, and airway hyperresponsiveness. Airway narrowing can significantly impact a patient's life, making it difficult to breathe and limiting participation in several activities. In severe cases, asthma attacks can be life-threatening. There is currently no known cure for asthma.

Chronic sinusitis (CS) results from inflammation of the mucous membrane lining one or more paranasal sinuses and is usually associated with significant tissue damage. Approximately 37 million cases of CS are reported to the U.S. Centers for Disease Control and Prevention (CDC) annually.

Diabetes is a metabolic disease or combination of diseases that causes patients to experience high blood glucose levels. The disease is caused by insufficient insulin production in the body or the inability of cells to respond properly to insulin. Glycated hemoglobin (HbAlc) is an indicator of plasma glucose concentration and is used clinically to diagnose diabetes. In humans, normal HbAlc levels are generally <6.0%, pre-diabetic HbAlc levels vary between 6.0 and 6.4%, and diabetic HbAlc levels exceed 6.5%.

Diabetes is a leading cause of death and disability in the United States and other developed countries. Diabetes is associated with long-term complications that affect nearly every part of the body. For example, diabetes is associated with blindness, heart and vascular disease, stroke, kidney failure, amputation, and nerve damage.

In the United States, diabetes affects approximately 8% of the population and costs nearly $250 billion.

Diabetes is usually classified as type 1 (also called insulin-dependent diabetes or juvenile-onset diabetes), in which patients do not produce enough insulin; type 2 (non-insulin-dependent diabetes, also called adult-onset diabetes or obesity-related diabetes), in which patients do not respond properly to insulin; or gestational diabetes, a disease that develops later in pregnant women.

Type 2 diabetes is the most common type of diabetes, accounting for 90% to 95% of all cases. Type 2 diabetes is generally associated with older age, obesity, family history, previous gestational diabetes, and physical inactivity. It is more prevalent in certain ethnic groups. Type 2 diabetes is also called insulin-resistant diabetes because the pancreas normally produces sufficient amounts of insulin, but the body does not respond properly to insulin. Symptoms associated with type 2 diabetes include fatigue, frequent urination, increased thirst and hunger, weight loss, blurred vision, and slow healing of wounds or abrasions.

The liver is critical for maintaining normal glucose homeostasis, producing glucose during fasting and storing it after meals. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes, and this imbalance leads to hyperglycemia during fasting and postprandial states. Net hepatic glucose production is the sum of glucose flux from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis, and other pathways. Glucose levels are sensed by neurons and glial cells that express glucose transporters (GLUTs) in the central nervous system (CNS) and in peripheral tissues such as the taste buds, intestine, and carotid body. In the liver, glucose levels are also sensed in the portal vein. Sympathetic nervous system efferent activity amplifies glucose production and suppresses glucogenogenesis.

To measure fasting blood glucose levels, a blood sample may be taken after an overnight fast. A fasting blood glucose level below 100 mg/dL (5.6 mmol/L) is normal. A fasting blood glucose level of 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is considered prediabetic. A fasting blood glucose level of 126 mg/dL (7 mmol/L) or higher on two separate tests is considered indicative of diabetes. Fasting blood glucose levels in diabetics range from 126 mg/dL to 400 mg/dL or higher, or from 126 mg/dL to 300 mg/dL, or from 126 mg/dL to 250 mg/dL. The liver serves as the body's glucose (or fuel) store, helping to maintain stable and consistent levels of circulating blood glucose and other body fuels. The liver stores and produces glucose according to the body's needs. The need to store or release glucose is primarily dictated by insulin and glucagon. During a meal, the liver stores sugar, or glucose, as glycogen for later use when the body needs it. High insulin levels and suppressed glucagon levels promote the storage of glucose as glycogen. During fasting, especially at night or between meals, the body needs to produce its own sugar. The liver supplies sugar, or glucose, by converting glycogen into glucose in a process called glycogenolysis. The liver can also produce the necessary sugar, or glucose, by harvesting amino acids, waste products, and fat by-products. This process is called gluconeogenesis. When the body's glycogen stores are low, the body begins to conserve its sugar supply for organs that constantly need sugar. Such organs include the brain, red blood cells, and parts of the kidneys. To supplement limited sugar stores, the liver produces an alternative fuel from fat called ketones. This process is called ketogenesis. The hormonal signal that initiates ketogenesis is low levels of insulin. Ketones are consumed as fuel by muscles and other organs of the body, and sugar is stored for organs that need it.

Glucagon, epinephrine, norepinephrine, cortisol, and growth hormone help maintain blood sugar levels and increase blood glucose. Concentrations of glucagon, epinephrine, norepinephrine, cortisol, and growth hormone are elevated in people with diabetes. Glucagon, produced by the cells of the islets of Langerhans (alpha cells) in the pancreas, controls the production of glucose and other fuels, ketones, in the liver. Glucagon is released overnight and between meals and is important in maintaining the body's glucose and fuel balance. Glucagon signals the liver to break down its starch or glycogen stores, helping to generate new glucose and ketone units from other substances. Glucagon also promotes the breakdown of fat in fat cells. Epinephrine and norepinephrine are very similar. Both epinephrine and norepinephrine are neurotransmitters, and both increase blood pressure and blood glucose levels. Epinephrine (adrenaline) is released from nerve endings and the adrenal glands and acts directly on the liver to promote glucose production (through glycogenolysis). Epinephrine promotes the breakdown and release of fat nutrients, which are transported to the liver and converted to glucose and ketones. Cortisol is a steroid hormone secreted by the adrenal glands. Cortisol increases the resistance of fat and muscle cells to the action of insulin, thereby increasing glucose production by the liver. Under normal conditions, cortisol counterbalances the action of insulin. Under stress or when synthetic cortisol is administered as a medication (e.g., through prednisone therapy or cortisol injections), cortisol levels are increased, resulting in insulin resistance. Patients with type 2 diabetes may need to take more medication or insulin to control blood sugar levels. Growth hormone is released from the pituitary gland, part of the brain. Like cortisol, growth hormone counterbalances the effects of insulin in muscle and fat cells. High growth hormone levels result in resistance to insulin.

Obesity is another significant health problem, particularly in developed countries. Obesity is a complex, multifactorial, chronic disease characterized by excess body fat resulting from an imbalance between energy expenditure and caloric intake. The causes of this imbalance are not fully understood, but genetic and/or acquired physiological events and environmental factors are thought to contribute. The adverse health consequences associated with obesity, and particularly severe obesity, have been established in recent years. These consequences include, but are not limited to, cardiovascular disease, diabetes, hypertension, rheumatoid arthritis, and sleep apnea. Generally, as a patient's body mass index (BMI) increases, so does the likelihood of suffering from obesity-related adverse effects.

Metabolic syndrome is a serious health condition that affects up to one-third of American adults and increases the risk of cardiovascular disease, type 2 diabetes, stroke, and diseases related to the accumulation of fat in artery walls. Metabolic syndrome is a group of health conditions that occur together. These conditions include increased blood pressure, high blood sugar levels, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. National Institutes of Health guidelines define metabolic syndrome as having three or more of the following characteristics, including those requiring medication to control them: a large waist (a waistline of at least 35 inches (89 centimeters) in women and at least 40 inches (102 centimeters) in men); high triglyceride levels (above 150 milligrams per deciliter (mg/dL) or above 1.7 millimoles per liter (mmol/L) of this type of fat found in the blood); decreased "good" or HDL cholesterol (below 40 mg/dL (1.04 mmol/L) in men and below 50 mg/dL (1.3 mmol/L) in women); increased blood pressure (above 130/85 millimeters of mercury (mmHg)); and elevated fasting blood sugar (above 100 mg/dL (5.6 mmol/L)).

Nonalcoholic fatty liver disease (NAFLD) is another health problem that occurs when the liver has difficulty breaking down fat, resulting in the accumulation of fat in liver tissue in people who drink little or no alcohol. It's normal for the liver to contain a small amount of fat. However, when more than 5% to 10% of the liver's weight is fat, the liver is called fatty liver (steatosis). Nonalcoholic fatty liver disease (NAFLD) is common and causes no signs, symptoms, or complications in many people. In some people with NAFLD, the accumulated fat can lead to inflammation and scarring in the liver. This more serious form of NAFLD is sometimes called nonalcoholic steatohepatitis (NASH). NASH causes the liver to swell and become damaged. In its most severe forms, NAFLD can progress to liver failure. NASH is associated with dyslipidemia, low HDL cholesterol (<40 mg/dL in men or <50 mg/dL in women), hypertriglyceridemia (>150 mg/dL), hypercholesterolemia (>200 mg/dL), and triglycerides (TG)/HDL greater than 5.0. Resolution of NASH is associated with a decrease in TG and the TG/HDL ratio.

The spleen is the primary filter for bloodborne pathogens and a key organ in iron metabolism and red blood cell homeostasis. It plays a key role in the immune response to inflammatory conditions, including rheumatoid arthritis (RA), cancer, myocardial infarction, and atherosclerosis. The autonomic nervous system regulates immunity by upregulating sympathetic nerve trafficking to the spleen, or in response to inflammatory stimuli, the spleen can recruit monocytes to areas of tissue damage and release cytokines that modulate the inflammatory response.

Embodiments of the present invention relate to a delivery catheter for delivering chemical agents and/or energy and a method for treating at least one disease by treating at least two different target tissues in a single procedure. The at least one disease may include hypertension, pulmonary hypertension, diabetes, obesity, metabolic syndrome, heart failure, myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), end-stage renal disease, digestive disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), urological disease, cancer, tumor, pain, rheumatoid arthritis (RA), asthma, chronic obstructive pulmonary disease (COPD), or a combination thereof. The delivery catheter can deliver effective amounts of energy and/or chemical agents to target tissues in the body to alleviate disease symptoms, such as reducing blood pressure in hypertension, reducing blood glucose and AIC in diabetes, reducing weight in obesity, reducing restenosis in coronary and peripheral disease, reducing liver fat in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and reducing pain in rheumatoid arthritis and cancer. The energy can be radio frequency, cryoablation, microwave, laser, ultrasound, high intensity focused ultrasound energy, or a combination thereof. The target tissue may include a renal artery (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of left main renal artery, distal end of right main renal artery bifurcation, or distal end of right main renal artery bifurcation), renal vein, gastric artery, gastric vein, hepatic artery, hepatic vein, pulmonary artery, pulmonary vein, celiac artery, celiac vein, gastroduodenal artery, gastroduodenal vein, splenic artery, splenic vein, suprarenal artery, adrenal vein, phrenic artery, phrenic vein, mesenteric artery, mesenteric vein, airway, esophagus, stomach, duodenum, jejunum, urological lumen. The delivery catheter may include a radiofrequency catheter, a cryoablation catheter, a microwave catheter, a laser catheter, an ultrasound catheter, a high intensity focused ultrasound catheter, or a combination thereof. The delivery catheter may include a combination balloon and infusion catheter, along with other delivery devices. The formulation delivered by the delivery catheter may include one or more materials in the form of a gas, vapor, liquid, solution, emulsion, suspension, or combinations thereof. Delivery of the formulation from the delivery catheter to the target tissue within the body via chemical infusion can improve the safety and efficacy of the treatment.

Various embodiments of the present invention provide methods for treating at least one disease, the method including treating at least two different target tissues in at least two different body lumens. The method includes performing a therapeutic procedure in a body lumen, the body lumen being a first body lumen. The therapeutic procedure includes inserting a delivery catheter into the body lumen. The delivery catheter has a catheter shaft, a balloon at the distal end of the shaft, and an inflation lumen in fluid communication with the interior of the balloon. The therapeutic procedure includes inflating the balloon to center the distal end of the shaft in the body lumen. The therapeutic procedure includes denervating or ablating the target tissue in the body lumen with the delivery catheter, and delivering an amount of energy or compound to the target tissue effective to injure or damage the target tissue to alleviate symptoms of the disease. The therapeutic procedure includes deflating the balloon. The therapeutic procedure also includes removing the delivery catheter from the body lumen. The method includes performing a therapeutic procedure in a second body lumen, different from the first body lumen.

A method for treating at least one disease that includes treating at least two different target tissues in at least two different body lumens using a delivery catheter may be a method for treating metabolic syndrome. The method may include treating first, second, third, and fourth target tissues that are all different from one another and are located in first, second, third, and fourth body lumens, respectively. The first body lumen may include a renal artery (e.g., a left main renal artery, a right main renal artery, a renal artery bifurcation, a left renal artery bifurcation, a right renal artery bifurcation, a distal end of the left main renal artery, a distal end of the right main renal artery, a distal end of a branch of the left main renal artery, or a distal end of a branch of the right main renal artery), a renal vein, a pulmonary artery, a vascular lumen, a celiac artery, a common hepatic artery, a proper hepatic artery, a gastroduodenal artery, a right hepatic artery, a left hepatic artery, a splenic artery, a right gastric artery, a left gastric artery, a right adrenal artery, a left adrenal artery, a right inferior phrenic artery, a left inferior phrenic artery, a non-vascular lumen, an esophagus, a lumen of the digestive system, a stomach, a duodenum, a jejunum, or a combination thereof. The second body lumen may include the right main renal artery, the left main renal artery, a bifurcation of the right renal artery, a bifurcation of the left renal artery, the common hepatic artery, the proper hepatic artery, the gastroduodenal artery, the right hepatic artery, the left hepatic artery, the splenic artery, the right gastric artery, the left gastric artery, the right adrenal artery, the left adrenal artery, the right inferior phrenic artery, the left inferior phrenic artery, or a combination thereof. The third body lumen may include the splenic artery, the gastric artery, the left gastric artery, or a combination thereof. The fourth body lumen may include the gastroduodenal artery, the gastric artery, the left gastric artery, the right adrenal artery, the left adrenal artery, the right inferior phrenic artery, the left inferior phrenic artery, or a combination thereof. The chemical agent and/or energy delivered to the target tissue may reduce body weight, reduce high blood pressure, reduce AIC, reduce blood glucose levels, reduce adipose tissue around the waist, or a combination thereof.

A method for treating at least one disease, including treating at least two different target tissues in at least two different body lumens using a delivery catheter, may be a method for treating hypertension. The method may include treating first, second, third, and fourth target tissues, all distinct from one another and disposed in first, second, third, and fourth body lumens, respectively. The first body lumen may include a renal artery, e.g., the left main renal artery, the right main renal artery, a bifurcation of the renal artery, a bifurcation of the left renal artery, a bifurcation of the right renal artery, the distal end of the left main renal artery, the distal end of the bifurcation of the right main renal artery, or a combination thereof. The second body lumen may include the common hepatic artery, the proper hepatic artery, the gastroduodenal artery, the right hepatic artery, the left hepatic artery, the splenic artery, the right gastric artery, the left gastric artery, or a combination thereof. The third body lumen may include the splenic artery, the right gastric artery, the left gastric artery, or a combination thereof. The fourth body lumen may include the gastroduodenal artery, the right gastric artery, the left gastric artery, the right adrenal artery, the left adrenal artery, the right inferior phrenic artery, the left inferior phrenic artery, or a combination thereof. The chemical agent and/or energy delivered to the target tissue may reduce hypertension.

A method for treating at least one disease, including treating at least two different target tissues in at least two different body lumens using a delivery catheter, may be a method for treating diabetes. The method may include treating first, second, third, and fourth target tissues, all distinct from one another and disposed in first, second, third, and fourth body lumens, respectively. The first body lumen may include the common hepatic artery, proper hepatic artery, right hepatic artery, left hepatic artery, or a combination thereof. The second body lumen may include a renal artery (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of left main renal artery, distal end of right main renal artery, distal end of left main renal artery bifurcation, or distal end of right main renal artery bifurcation), splenic artery, right gastric artery, left gastric artery, or a combination thereof. The third body lumen may include the splenic artery, the right gastric artery, the left gastric artery, or a combination thereof. The fourth body lumen may include the gastroduodenal artery, the right gastric artery, the left gastric artery, the right adrenal artery, the left adrenal artery, the right inferior phrenic artery, the left inferior phrenic artery, or a combination thereof. The chemical agent and/or energy delivered to the target tissue may decrease blood glucose levels, decrease AIC, or a combination thereof.

A method for treating at least one disease, including treating at least two different target tissues in at least two different body lumens using a delivery catheter, may be a method for treating obesity. The method may include treating first, second, third, and fourth target tissues, all distinct from one another and disposed in first, second, third, and fourth body lumens, respectively. The first body lumen may include the common hepatic artery, proper hepatic artery, right hepatic artery, left hepatic artery, or a combination thereof. The second body lumen may include a renal artery (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of left main renal artery, distal end of right main renal artery, distal end of left main renal artery bifurcation, or distal end of right main renal artery bifurcation), splenic artery, right gastric artery, left gastric artery, or a combination thereof. The third body lumen may include the splenic artery, the right gastric artery, the left gastric artery, or a combination thereof. The fourth body lumen may include the gastroduodenal artery, the right gastric artery, the left gastric artery, the right adrenal artery, the left adrenal artery, the right inferior phrenic artery, the left inferior phrenic artery, or a combination thereof. The chemical agent and/or energy delivered to the target tissue may reduce body weight, reduce body mass index, or a combination thereof.

A method for treating at least one disease, including treating at least two different target tissues in at least two different body lumens using a delivery catheter, may be a method for treating nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or a combination thereof. The method may include treating first, second, third, and fourth target tissues, all distinct from one another and disposed in first, second, third, and fourth body lumens, respectively. The first body lumen may include the common hepatic artery, proper hepatic artery, right hepatic artery, left hepatic artery, or a combination thereof. The second body lumen may include a renal artery (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of left main renal artery, distal end of right main renal artery, distal end of left main renal artery bifurcation, or distal end of right main renal artery bifurcation), splenic artery, right gastric artery, left gastric artery, or combinations thereof. The third body lumen may include a splenic artery, right gastric artery, left gastric artery, or combinations thereof. The fourth body lumen may include a gastroduodenal artery, right gastric artery, left gastric artery, right adrenal artery, left adrenal artery, right inferior phrenic artery, left inferior phrenic artery, or combinations thereof. The chemical agent and/or energy delivered to the target tissue may reduce fat in the liver.

In various embodiments, the present invention provides a method for treating a disease. The method includes inserting a delivery catheter into a body lumen, the delivery catheter including a catheter shaft, at least one spray hole, and at least one marker band. The method includes spraying a formulation through the at least one spray hole, wherein an amount of the formulation delivered is effective to injure or damage the target tissue so as to alleviate symptoms of the disease. The method optionally includes removing the formulation from the tissue. The method includes retracting the delivery catheter from the body lumen.

In various embodiments, the present invention provides a method for treating a disease. The method includes inserting a centering balloon delivery catheter into a body lumen, the balloon delivery catheter including at least one centering balloon and catheter shaft, at least one injection needle, and at least one marker band. The method includes inflating the centering balloon to center the delivery catheter shaft in the body lumen. The method includes placing at least one injection needle within, outside, or inside a wall of the body lumen. The method includes infusing a formulation through the at least one injection needle, the amount of formulation delivered being effective to injure or damage the target tissue to alleviate symptoms of the disease. The method optionally includes removing the formulation from the tissue. The method includes retracting the needle within the delivery catheter and deflating the centering balloon. The method includes retracting the delivery catheter from the body lumen.

In various embodiments, the present invention provides a centrally positioned balloon catheter for delivering a substance to a target location in a lumen of a patient's body. The centrally positioned balloon catheter includes a proximal end; a distal end; a wire lumen; a balloon inflation lumen; a formulation infusion lumen and/or a vacuum lumen; an inflatable balloon portion; at least one injection needle; at least one marker band adjacent to the centrally positioned balloon; and at least one needle-exit opening adjacent to the marker band for placement of the injection needle.

In various embodiments, the present invention provides a needle-based balloon catheter for delivery of a substance to a target tissue in a lumen of a patient's body. The delivery catheter includes a catheter shaft having proximal and distal ends. The delivery catheter includes at least one marker band disposed near the distal end of the shaft. The delivery catheter includes at least one needle disposed in a needle lumen, the needle lumen opening to the exterior of the catheter shaft through at least one needle exit hole. The delivery catheter includes a flushing port at the proximal end of the shaft in fluid communication with a flushing lumen, the flushing lumen in fluid communication with the distal end of the needle lumen, and the flushing port in fluid communication with the needle exit hole through the flushing lumen. The delivery catheter includes a guidewire lumen extending through at least the distal end of the shaft. The delivery catheter includes at least one balloon adjacent the distal end of the catheter. The delivery catheter includes an inflation lumen. The delivery catheter includes an inflation port in fluid communication with the inflation lumen and in fluid communication with the interior of the balloon. The balloon is inflatable through the inflation port via the inflation lumen and generally centers the distal end of the catheter shaft within the body lumen. The delivery catheter includes an ablation or denervation port at the proximal end of the shaft. The ablation or denervation port is in fluid communication with the at least one needle for delivering ablation energy or a formulation to the at least one needle. The delivery catheter also includes a needle movement controller in electrical or mechanical communication with the at least one needle. The needle movement controller positions the at least one needle within the body lumen, within the wall of the body lumen, or outside the body lumen.

In various embodiments, the present invention provides a delivery catheter. The delivery catheter includes a shaft having proximal and distal ends. The delivery catheter includes one or more needles for infusion therapy located near the distal end of the shaft. The delivery catheter includes an inflatable balloon located near the distal end of the shaft such that when the delivery catheter is positioned in a lumen and the balloon is inflated, the distal end of the catheter shaft is centered in the lumen. The delivery catheter includes a marker band at the distal end of the shaft.

In various embodiments, the present invention provides a delivery catheter. The delivery catheter includes a shaft having a proximal and distal end. The delivery catheter includes one or more needles for infusion therapy located near the distal end of the shaft. The delivery catheter includes a steering mechanism associated with the shaft such that the distal end of the shaft can be steered away from the longitudinal axis of the shaft.

In various embodiments, the present invention includes a delivery catheter. The delivery catheter includes a shaft having a proximal and distal end. The delivery catheter includes one or more needles for infusion therapy located near the distal end of the shaft. The delivery catheter includes an inflatable balloon located near the distal end of the shaft so that when the delivery catheter is positioned in the lumen and the balloon is inflated, the distal end of the catheter shaft is centered in the lumen, the distal end of the shaft includes a marker band; or includes a steering mechanism associated with the shaft so that the distal end of the shaft can be steered away from the longitudinal axis of the shaft; or any combination thereof.

Embodiments of the present invention are directed to the treatment of hypertension, diabetes, obesity, metabolic syndrome, heart failure, myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), end-stage renal disease, digestive disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), urological disorders, cancer, tumors, pain, rheumatoid arthritis (RA), asthma, and chronic obstructive pulmonary disease (COPD) by delivering an effective amount of a formulation to a target tissue. Such formulations include gases, vapors, liquids, solutions, emulsions, suspensions, or combinations thereof, of one or more materials. Methods include controlled delivery of the formulation to luminal surfaces and tissues within the human body to effect alterations to these areas. Such methods may result in denervation of nerves and nerve endings within and adjacent to body lumens. Methods may include beneficial severing of nerves and nerve endings to interrupt nerve transmission. Temperature may enhance the safety and efficacy of therapeutic formulations. The temperature of the formulation may be -40 to 140°C, -30 to 100°C, -30 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or greater than 140°C. In some embodiments, the formulation comprises one of two, three, or four components, and may comprise more than four components. Delivery methods are less invasive, including percutaneous and non-invasive techniques. Embodiments of the present invention provide formulations and delivery catheters that improve absorption and penetration of the formulation into body tissues, luminal nerves, and nerve endings.

In some embodiments, the formulation comprises water, saline, hypertonic saline, phenols, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, urea, lipiodol, surfactants, derivatives thereof, or combinations thereof.

In some embodiments, at least one ingredient of the formulation is a gas, including one of oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, vapors of organic and inorganic compounds, water, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, derivatives thereof, or combinations thereof.

In some embodiments, at least one ingredient of the formulation is a surfactant. The surfactant may be PEG laurate, Tween 20, Tween 40, Tween 60, or Tween 80, PEG oleate, PEG stearate, glyceryl laurate, glyceryl oleate, glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, sorbitan PEG stearate, PEG oleate Examples of suitable glycerols include hydroxypropyl ether, PEG lauryl ether, organic acids, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerol, galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol), penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, Pluronic®, Pluronic 85, derivatives thereof, or combinations thereof.

In some embodiments, the formulation includes at least one of an oil, a fatty acid, and a lipid. In some embodiments, the at least one of the oil, fatty acid, and lipid in the formulation is butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, acid), eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di-, or triacylglycerol, cardiolipin, phosphatidylglycerol, phosphatidyl The lipids are selected from the group consisting of phosphate, phosphatidylcholine, alpha-tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobees, niosomes, and derivatives thereof.

In other embodiments, the formulation includes a therapeutic agent or drug for denervation. The therapeutic agent includes at least one of sodium channel blockers, tetrodotoxin, saxitoxin, decarbamoylsaxitoxin, vanilloids, neosaxitoxin, lidocaine, conotoxin, cardiac glycosides, digoxin, glutamate, staurosporine, amlodipine, verapamil, cymarin, digitoxin, proscillaridins, quabains, veratridine, domoic acid, ethanol, oleandrin, carbamazepine, aflatoxin, guanathidine, and guanathidine sulfate. In other embodiments, the formulation includes a contrast agent for imaging denervation. Such contrast agents include iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodoxanol, ioxaglate, derivatives thereof, or any combination thereof.

In certain embodiments, the formulation comprises an azeotrope. An azeotrope is a mixture of two or more materials that cannot be altered by simple distillation. This occurs because the vapor produced by boiling has a composition proportional to the composition of the original mixture. Candidates for azeotropes for the formulation include ethanol/water, ethanol/water/contrast agent, ethanol/water/surfactant, ethanol/water/contrast agent/surfactant, propanol/water, isopropanol/water, butanol/water, acetic acid/water, or combinations thereof.

In some embodiments, the formulation is in a gas or vapor state and includes one or more materials. The vapor or gas formulation may include oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, water, phenol, methanol, ethanol, dehydrated alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl sulfate, isopropyl acetate, ethyl lactate, or combinations thereof. In some embodiments, the formulation may be binary, ternary, or quaternary, and may include more than four components. The vapor formulation may include an azeotrope or a contrast agent such as lipiodol or iodine, and may include a surfactant and/or a therapeutic agent. The temperature of the vapor formulation may be from 0 to 140°C, preferably from 15 to 100°C, more preferably from 20 to 85°C, or below 0°C, or below, equal to, or above 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140°C.

In some embodiments, the formulation is in a liquid state and includes one or more ingredients. The liquid formulation may include one of water, saline, hypertonic saline, phenols, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, lipiodol, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, urea, surfactants, and others. The liquid formulation may include an azeotrope or a contrast agent, and may include a therapeutic agent. In some embodiments, the formulation may be binary, ternary, or quaternary, and may include more than four components. In some embodiments, the liquid formulation may have a temperature of -40 to 140°C, -30 to 100°C, -30 to 80°C, or less than -40°C, or less than, equal to, or greater than -30, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or greater than 140°C. The liquid formulation may include a solution, a suspension, an emulsion, or a combination thereof.

In certain embodiments, a method of treating at least one disease includes percutaneously and/or orally inserting a delivery catheter into a target tissue within a human body; using the catheter to infuse a therapeutic compound into the body tissue; an amount of the compound delivered is effective to beneficially injure or damage the tissue, selectively removing the compound; and withdrawing the delivery catheter from the body. The injury or damage to the tissue can alleviate symptoms of the disease, such as by reducing blood pressure, reducing glucose levels, reducing weight, reducing shortness of breath, reducing heart disease, reducing vascular disease, reducing joint pain, reducing stiffness, reducing swelling, or a combination thereof. The at least one disease to be treated includes one or more of hypertension, pulmonary hypertension, diabetes, obesity, metabolic syndrome, heart failure, myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), end-stage renal disease, inflammatory diseases, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), urological diseases, cancer, tumors, pain, rheumatoid arthritis (RA), asthma, and chronic obstructive pulmonary disease (COPD). For example, in patients with a combination of two or more of hypertension, obesity, and type 2 diabetes, it may be more effective to treat multiple related diseases with a single treatment. Treatable tissues may include the renal artery (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of the left main renal artery, or distal end of the right main renal artery, distal end of the left main renal artery bifurcation, or distal end of the right main renal artery bifurcation), renal vein, gastric artery, gastric vein, hepatic artery, hepatic vein, pulmonary artery, pulmonary vein, celiac artery, celiac vein, gastroduodenal artery, gastroduodenal vein, splenic artery, splenic vein, adrenal artery, adrenal vein, phrenic artery, phrenic vein, mesenteric artery, mesenteric vein, airway, esophagus, stomach, duodenum, jejunum, and urological lumens. Digestive system lumens may include the esophagus, stomach, duodenum, jejunum, small intestine, large intestine, and colon. The formulation may comprise a gas, vapor, liquid, solution, emulsion, suspension, or combination thereof of one or more materials. If the formulation comprises a vapor of one or more materials, heat is generated by condensation of the vapor into a liquid within the tissue. If the formulation comprises a liquid or solution, cooling or heating can be achieved by lowering or raising the temperature of the formulation below body temperature. The temperature of a liquid formulation may be from -40 to 140°C, from -30 to 100°C, from -30 to 80°C, or below -40°C, or below, equal to, or greater than -30°C, -20°C, -10°C, -5°C, 0°C, 5°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, or above 140°C. In some embodiments, the temperature of the formulation may be equal to room temperature. In some embodiments, the temperature of the formulation may be from -40 to -20°C. In other embodiments, the temperature of the formulation may be from 15 to 80°C. In some embodiments, the temperature of the formulation may be equal to body temperature. In other embodiments, the temperature of the formulation may be from 50 to 80°C. In other embodiments, the temperature of the tissue being treated may be lower than the temperature of the formulation but higher than body temperature. The temperature of the tissue being treated may be from -40 to 100°C, from -30 to 90°C, from -20 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or above 100°C. In some embodiments, the temperature of the tissue being treated may be from -40 to -20°C. In other embodiments, the temperature of the tissue being treated may be from 15 to 80°C. In some embodiments, the temperature of the tissue being treated may be equal to body temperature. In other embodiments, the temperature of the treated tissue may be between 50 and 80°C. Delivery catheters applicable for such treatments include needle or needle-type catheters under imaging guidance. The imaging guidance may include one of ultrasound, X-ray, CT scan, MRI, OCT, or endoscopes. The delivery catheter may be a balloon-type catheter. Such a balloon-type catheter may have a balloon and a needle in one catheter. The delivery catheter may be a spray-type catheter. A spray-type catheter can generate a very fine mist to large droplets. In some embodiments, the procedure may use a combination of a balloon and spray catheter (e.g., needle-free), a combination of a needle catheter and a spray catheter, or a combination of a needle catheter, a spray catheter, and a balloon catheter (e.g., including both spray-type and needle-type formulation administration). In some embodiments, the method includes flushing the distal tip of the catheter to protect and dilute migrated chemicals and prevent runaway chemicals from entering portions distal to the untreated area, flushing the delivery catheter, flushing the endoscope, removing and withdrawing the formulation from the body tissues and lumens following treatment, and flushing the target area with saline after treatment. If a needle is present, the method may further include deploying the needle, administering the formulation from the needle, and retracting the needle.

In some embodiments, the delivery catheter includes at least one needle used to deliver the formulation to the interior of the vessel wall, the exterior of the vessel, or a combination thereof. In some needle catheter embodiments, at least one balloon is used to approximately center the distal end of the catheter within the vessel lumen, or to approximately center the portion of the catheter where the needle emerges within the vessel lumen. Centering the distal end of the catheter within the treatment lumen provides the user with greater control over the needle and injection depth. In some needle catheter embodiments, there are two centrally located balloons, with at least one needle located between the two balloons. In some needle catheter embodiments, there is only one balloon, with at least one needle located proximally or distally to the balloons, in either case adjacent to the balloon to utilize a catheter shaft centered within the treatment lumen. In some needle catheter embodiments, there is no centrally located balloon.

In some embodiments, the delivery catheter includes a spray catheter. In this embodiment, the formulation is delivered through spray holes at or near the distal end of the catheter, thereby delivering the formulation to the wall of the treatment lumen as a mist. This embodiment may include a sleeve positioned over the spray holes to provide a more uniform distribution of the formulation to the wall of the treatment lumen. This embodiment may also include a vacuum port to remove excess formulation from the treatment lumen.

The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present invention.

1 is a perspective view of an exemplary embodiment of a dual balloon delivery catheter according to the present invention. 1 is an embodiment showing formulation infusion into the airways using a spray catheter. 3 is an embodiment showing pharmaceutical infusion into the renal artery using a balloon delivery catheter. 1 is a partial cross-sectional view of an embodiment of a two-balloon delivery catheter in a body lumen. 1 is an embodiment of a partial cross-sectional view of a three-needle, two-balloon delivery catheter inside a body lumen with needles deployed. 1 is a perspective view of an exemplary embodiment of an over-the-wire (OTW) three-balloon delivery catheter according to the present invention. 1 is a perspective view of an exemplary embodiment of an OTW three-balloon delivery catheter with balloons and needles in place, according to the present invention. 1 is another exemplary embodiment of a perspective view of a rapid-exchange three-balloon delivery catheter before needle placement in accordance with the present invention. FIG. 10 is a perspective view of another exemplary embodiment of a rapid-exchange triple balloon delivery catheter with a flushing lumen after the needle has been placed in accordance with the present invention. 7C-7C is a cross-sectional view of the catheter shown in FIG. 7B, according to various embodiments. 7D is a cross-sectional view of the catheter shown in FIG. 7B at section 7D-7D, in accordance with various embodiments. 7E-7E are cross-sectional views of the catheter shown in FIG. 7B, in accordance with various embodiments. 7F-7F is another cross-sectional view of the catheter shown in FIG. 7B, according to various embodiments. 7G-7G is a cross-sectional view of the catheter shown in FIG. 7B, in accordance with various embodiments. 1 is an exemplary embodiment of a perspective view of a steerable catheter prior to needle placement. 1 is an exemplary embodiment of a perspective view of a steerable catheter after needle placement. 1 is an exemplary embodiment of a perspective view of a steerable catheter prior to needle placement. 1 is an exemplary embodiment of a perspective view of a steerable catheter with needle placement. 1 is a partial cross-sectional view of an embodiment of a unidirectionally steerable catheter in deployment in a body lumen with a deployed needle. 1 is a bar graph showing the reduction in norepinephrine (NE) after renal denervation from ethanol-treated versus control groups, according to various embodiments. 10A-10C are histopathological images showing necrosis of a severed renal nerve (indicated by black arrow) after ethanol treatment, in accordance with various embodiments. 1 is a bar graph showing the reduction in norepinephrine (NE) after hepatic denervation from ethanol-treated versus control groups, according to various embodiments. 1 is a perspective view of an exemplary embodiment of a spray delivery catheter according to the present invention. 1 is a perspective view of an exemplary embodiment of a spray delivery catheter having dual suction features according to the present invention. 3 is an embodiment of pharmaceutical infusion into the left gastric artery using a balloon delivery catheter. 3 is an embodiment of pharmaceutical infusion into the hepatic artery using a balloon delivery catheter.

Reference will now be made in more detail to particular embodiments of the disclosed subject matter. While the disclosed subject matter is set forth in conjunction with numbered claims, it will be understood that there is no intention to limit the claims to the disclosed subject matter as exemplified.

Throughout this document, values stated as ranges should be interpreted flexibly and include not only the numerical values explicitly stated as range limits, but also all of the individual numerical values or subranges subsumed within that range, as if each numerical value and subrange were expressly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted as including the individual numerical values (e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the stated range, rather than including only about 0.1% to about 5%. The phrase "about X to Y" has the same meaning as "about X to about Y" unless otherwise specified. Similarly, the phrase "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise specified.

In this document, the terms "a" or "an" are used to include one or more than one, unless the context clearly dictates otherwise. The term "or" is used to indicate an inclusive "or" unless otherwise stated. The statements "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B." Additionally, statements or terms used herein, unless otherwise defined, are for descriptive purposes only, not limitation. The use of section headings is intended to enhance the readability of the document and should not be construed as limiting. Information associated with a section heading may be found within or outside of that particular section.

In the methods described herein, actions may be performed in any order without departing from the principles of the invention, unless an explicit temporal or operational order is recited. Furthermore, certain actions may be performed simultaneously unless the claim recitation explicitly recites that they be performed separately. For example, a claimed action of doing X and a claimed action of doing Y may be performed simultaneously in a single operation, and the resulting process is within the actual scope of the claimed process.

As used herein, the term "approximately" means that a value or range may allow for variation to the extent of, for example, within 10%, within 5%, or within 1% of the stated limits of the stated value or range, and includes the exact value or range stated.

As used herein, the term "substantially" means a majority, or approximately, at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least approximately 99.999% or more or 100%. As used herein, the term "substantially free" means free of or having a trace amount of a material, such that the amount of material present does not affect the material properties of the composition including the material, and the material is present in an amount of about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or less than about 5 wt%, or less than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or less than about 0.001 wt%, or about 0 wt%.

As used herein, the term "polymer" means a molecule having at least one repeating unit and may include copolymers.

In various embodiments, the present invention provides a method for treating at least one disease (e.g., one disease, two diseases, at least two diseases, three diseases, at least three diseases, four diseases, or at least four diseases). The method includes using a delivery catheter in a body lumen to treat at least two different target tissues in at least two different body lumens. The method includes performing a therapeutic procedure in the body lumen, the body lumen being a first body lumen. The therapeutic procedure may include inserting the delivery catheter into the body lumen. The delivery catheter may include a catheter shaft, a balloon at a distal end of the shaft, and an inflation lumen in fluid communication with the interior of the balloon. The therapeutic procedure may include inflating the balloon to center the distal end of the shaft in the body lumen. The therapeutic procedure may include denervating or ablating the target tissue in the body lumen with the delivery catheter, and delivering an amount of energy or compound to the target tissue effective to injure or damage the target tissue to alleviate symptoms of the disease. The therapeutic procedure may include deflating the balloon. The therapeutic procedure may also include removing the delivery catheter from the body lumen. The method may also include performing the therapeutic procedure in a second body lumen different from the first body lumen.

Performing a therapeutic procedure on the lumen of the second body may include using the same delivery catheter or a different delivery catheter. Performing a therapeutic procedure on the lumen of the second body may include reusing the same delivery catheter used to treat the lumen of the first body for the therapeutic procedure on the lumen of the second body. Performing a therapeutic procedure on the lumen of the second body may include using a different delivery catheter to treat the lumen of the second body than was used to treat the lumen of the first body, the different delivery catheter including a catheter shaft, a balloon at the distal end of the shaft, and an inflation lumen in fluid communication with the interior of the balloon.

Treating at least two different target tissues in at least two different body lumens means treating at least two classes of body lumens selected from the renal artery, renal vein, gastric artery, gastric vein, hepatic artery, hepatic vein, pulmonary artery, pulmonary vein, celiac artery, celiac vein, gastroduodenal artery, gastroduodenal vein, splenic artery, splenic vein, adrenal artery, adrenal vein, phrenic artery, phrenic vein, mesenteric artery, mesenteric vein, airway, esophagus, stomach, duodenum, jejunum, and urological lumens. The renal artery may include the left main renal artery, the right main renal artery, a bifurcation of the renal artery, a bifurcation of the left renal artery, a bifurcation of the right renal artery, a distal end of the left main renal artery, a distal end of the right main renal artery, a distal end of a bifurcation of the left main renal artery, and a distal end of a bifurcation of the right main renal artery. The gastric arteries may include the left gastric artery, the right gastric artery, a branch of the left gastric artery, and a branch of the right gastric artery. The hepatic arteries may include the hepatic artery, the common hepatic artery, the proper hepatic artery, the left hepatic artery, the middle hepatic artery, and branches of the hepatic artery. The splenic arteries may include the main splenic artery and branches of the splenic artery. The adrenal arteries may include the right adrenal artery and the left adrenal artery. The celiac arteries may include the right inferior celiac artery and the left inferior celiac artery. The mesenteric arteries may include the superior mesenteric artery, the inferior mesenteric artery, and branches of the mesenteric artery. The urological lumen may include the urethra and ureter. For example, treatment of the left gastric artery and branches of the left gastric artery is considered treatment of one class of body lumen. Treatment of the left gastric artery and the main splenic artery is considered treatment of two different classes of body lumens. Treatment of at least three target tissues in at least three different body lumens, or treatment of at least four target tissues in at least four different body lumens, is defined as treatment of three or four different classes of body lumens, respectively.

The target tissues of the lumen of the first body and the lumen of the second body may be different and may be independently selected from target tissues of the renal artery (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of left main renal artery, distal end of right main renal artery, distal end of left main renal artery bifurcation, or distal end of right main renal artery bifurcation), renal vein, gastric artery, gastric vein, hepatic artery, hepatic vein, pulmonary artery, pulmonary vein, celiac artery, celiac vein, gastroduodenal artery, gastroduodenal vein, splenic artery, splenic vein, adrenal artery, adrenal vein, phrenic artery, phrenic vein, mesenteric artery, mesenteric vein, airway, esophagus, stomach, duodenum, jejunum, and urological lumen. The disease to be treated may be selected from hypertension, pulmonary hypertension, diabetes, obesity, metabolic syndrome, heart failure, myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), end-stage renal disease, digestive disorders, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), urological disorders, cancer, tumors, pain, rheumatoid arthritis (RA), asthma, chronic obstructive pulmonary disease (COPD), and combinations thereof.

Alleviating disease symptoms includes alleviating symptoms of hypertension, diabetes, obesity, coronary artery disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cancer, rheumatoid arthritis, or a combination thereof. Alleviating disease symptoms may include reducing blood pressure, reducing blood glucose and AIC, reducing weight, reducing restenosis, reducing liver fat, and reducing pain, or a combination thereof.

The at least one disease treated by the method through treatment of different target tissues in the first and second body lumens may include at least two diseases, such as both renal hypertension and diabetes (e.g., by treating both the renal artery and the hepatic artery); or both renal hypertension and obesity (e.g., by treating both the hepatic artery and the splenic artery); or diabetes and obesity (e.g., by treating the splenic artery, the hepatic artery, and the left gastric artery); or a combination thereof. The first or second body lumen may include the splenic artery. The first or second body lumen may include a renal artery (e.g., the left main renal artery, the right main renal artery, a renal artery bifurcation, a left renal artery bifurcation, a right renal artery bifurcation, the distal end of the left main renal artery, the distal end of the right main renal artery, the distal end of the left main renal artery bifurcation, or the distal end of the right main renal artery bifurcation). The first or second body lumen may include the splenic artery. The lumen of the first or second body may include a branch of the main renal artery, a branch of the renal artery outside the kidney, or a combination thereof. The lumen of the first or second body may include the hepatic artery, a branch of the hepatic artery, the right hepatic artery, the left hepatic artery, the common hepatic artery, the proper hepatic artery, the celiac artery, or a combination thereof. The lumen of the first or second body may include a renal artery (e.g., the left main renal artery, the right main renal artery, a renal artery branch, a left renal artery branch, a right renal artery branch, the distal end of the left main renal artery, the distal end of the right main renal artery, the distal end of a branch of the left main renal artery, the distal end of a branch of a branch of the right main renal artery, or a combination thereof), and the method may result in a reduction of renal norepinephrine by at least 40%, or at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50%.

The delivery catheter may further include a guidewire lumen extending through at least the distal end of the shaft, and the method may further include advancing the delivery catheter over the guidewire. The delivery catheter may further include a marker band on or adjacent to the balloon, and the method may further include monitoring the position of the marker band under fluoroscopy.

The delivery catheter may be a chemical infusion delivery catheter. The delivery catheter may be an energy delivery catheter. The delivery catheter may be a combination of a chemical infusion delivery catheter and an energy delivery catheter. In an energy delivery catheter, denervating or ablating target tissue in a body lumen with the delivery catheter may include delivering a quantity of energy (e.g., thermal energy) from the delivery catheter to the target tissue using radiofrequency, cryoablation, microwave, laser, ultrasound, high-intensity focused ultrasound, condensation of vapor into a liquid in at least a portion of the formulation, or a combination thereof. The energy delivery catheter may therefore be one of a radiofrequency catheter, cryoablation catheter, microwave catheter, laser catheter, ultrasound catheter, high-intensity focused ultrasound catheter, infusion catheter, or a combination thereof.

The delivery catheter may be a radiofrequency energy delivery catheter or a combination of a radiofrequency energy delivery catheter and a chemical infusion catheter. In some embodiments, increasing the size of the ablation produced by energy delivery improves the safety and effectiveness of radiofrequency energy delivery while minimizing the risk of problems that may occur during energy delivery. Examples of these problems include thrombus formation in the target tissue, steam pops, bubbling, charring, restenosis, fibrosis in the media and adventitia, and other problems associated with catheter manipulation (e.g., perforation). Spot thermal ablation (RF ablation) is not uniform and does not reach nerves in the adventitia. Partial spot ablation produces a small effect (small blood pressure reduction). The radiofrequency energy delivery catheter may include one or more electrodes. In various embodiments, the delivery catheter includes one or more needles, and the tip of one or more needles may function as an electrode (e.g., the needle may be insulated so that only the portion used as an electrode, e.g., 1 mm to 5 mm of the needle is exposed without insulation; in other embodiments, the needle is not insulated). The needles used for radiofrequency ablation may be the same as or different from the needles used for chemical infusion described herein. For example, radiofrequency energy delivery needles may have any suitable diameter, may be solid or hollow, and may be used to deliver radiofrequency energy into a body lumen, to the wall of a body lumen, or to the exterior of the wall of a body lumen. For radiofrequency delivery, a return electrode may be placed on the catheter, or a device such as a mat may be used. The delivery catheter may include one or more electrodes on a wire (e.g., a wire with spring or shape memory properties to ensure good contact with the target tissue), one or more electrodes on a polymer shaft, one or more electrodes on the outer surface of a balloon, or a combination thereof. The delivery catheter may include multiple electrodes to achieve shorter treatment times. The method may include cooling the electrode by passive cooling through blood flow and/or active fluid cooling, such as internal active cooling (closed-loop) or external active fluid cooling (open-loop). The electrode may be reduced in size to enhance passive cooling through blood flow. Cooling the electrode may increase energy delivery to the neural tissue of the target tissue. Cooling the needle electrode may include flowing a coolant or liquid (e.g., a chemical formulation described herein or a different liquid composition) through the needle to enhance RF delivery before, during, or after radio frequency delivery. In some embodiments of external cooling of the electrode (open-loop), the active cooling fluid may be replaced with a chemical formulation described herein. The disclosed formulations may be used not only for electrode cooling but also for chemical ablation of the target tissue. In some embodiments, the formulation can uniformly diffuse and penetrate neural tissue, allowing for uniform adventitial nerve ablation in the body lumen. Thus, chemical ablation formulations may be delivered before, during, and/or after energy ablation.

In a delivery catheter that delivers microwave or ultrasound, the delivery catheter may include a centrally located mechanism (e.g., a centrally located balloon) and a cooling system for the energy source. The microwave or ultrasound energy source may be located inside the balloon, and cooling may be on the surface of the balloon or inside the balloon. The microwave or ultrasound energy source may be focused so that only a subset of the circumference of the body lumen is treated, or the energy source may deliver energy throughout the entire circumference of the body lumen. In a delivery catheter that delivers laser energy, the delivery catheter may be configured to emit laser energy from the shaft wall. In a delivery catheter that can perform cryoablation (i.e., negative energy delivery), a needle or spray hole may be used to deliver the cryoablation medium. During cryoablation, the cryoablation medium may be delivered to the target tissue, for example, through a needle. As the material exits the delivery catheter, a pressure drop, vaporization, or phase change of the cryoablation medium may provide the cryoablation treatment. If a liquid is used for cryoablation, the needle or spray holes may be sealed to prevent delivery until the delivery catheter is in place, and the delivery catheter may include a gas return channel to vent vapors from the cryoablation medium outside the body. In performing cryoablation through the spray holes, multiple balloons may be used to contain the cryoablation fluid during treatment and form a treatment window that prevents cryoablation of tissue in the body lumen outside the treatment.

In either type of energy delivery, the method of using the delivery catheter may include cooling the energy source through flushing the lumen to reduce the temperature of the energy source and clean the lumen (e.g., to clean an artery and prevent blood from clogging). In various embodiments, a needle may be used for cooling. Delivery catheters for energy delivery may include a guidewire lumen to facilitate insertion and placement of the delivery catheter.

In some embodiments, the delivery catheter does not have an electrode. The delivery catheter may not have any ablative energy source, such as a radio frequency, ultrasound, or microwave energy source.

Embodiments of the present invention are directed to the treatment of at least one disease by delivering an effective amount of a formulation and/or energy to a target tissue. The disease may include hypertension, pulmonary hypertension, diabetes, obesity, metabolic syndrome, heart failure, myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), end-stage renal disease, digestive disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), urological disorders, cancer, tumors, pain, rheumatoid arthritis (RA), asthma, chronic obstructive pulmonary disease (COPD), or a combination thereof. Cancer includes cancer of the adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, uterus, or a combination thereof. The formulation may include a gas, vapor, liquid, solution, emulsion, suspension, or combination thereof of one or more materials. The methods include delivering formulations and/or energy to luminal surfaces, tissues, and nerves within the human body to modify such surfaces, tissues, and nerves, including renal arteries (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of left main renal artery, distal end of right main renal artery, distal end of left main renal artery bifurcation, distal end of right main renal artery bifurcation, or combinations thereof), renal veins, gastric artery, gastric vein, hepatic artery, hepatic vein, pulmonary artery, pulmonary vein, celiac artery, celiac vein, gastroduodenal artery, gastroduodenal vein, splenic artery, splenic vein, adrenal artery, adrenal vein, phrenic artery, phrenic vein, mesenteric artery, mesenteric vein, airway, esophagus, stomach, duodenum, jejunum, urological lumens, or combinations thereof. The lumen of the digestive system includes the esophagus, stomach, duodenum, jejunum, small intestine, large intestine, colon, or a combination thereof. Temperature may improve the safety and efficacy of the therapeutic formulation. The temperature of the formulation may be from -40 to 140°C, from -30 to 100°C, from -30 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140°C. The temperature of the tissue being treated may be different from the temperature of the formulation. The temperature of the formulation at the tissue to be treated may be from -40 to 100°C, from -30 to 90°C, from -20 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or above 100°C. The amount of formulation and energy delivered may be effective to beneficially injure, damage, or eliminate (e.g., kill) the target tissue, thereby alleviating symptoms of disease, such as by reducing blood pressure, shrinking tumors, alleviating pain, alleviating symptoms of asthma or COPD, or a combination thereof. Energy or heat may enhance the effectiveness of the injury/damage/elimination by increasing the rate of reaction between the formulation and the tissue. Methods of delivery include delivering the formulation to ablate nerves surrounding a lumen of the human body. Methods may also include removing or withdrawing the formulation from the tissue. Without direct observation, nerve ablation may be identified based on corresponding physiological functions of the nerve, such as glucose and norepinephrine (NE) levels. Norepinephrine is the primary neurotransmitter used by the sympathetic nervous system and is connected to multiple organs, including the heart, lungs, liver, spleen, gallbladder, stomach, intestines, kidneys, bladder, and several other organs. For example, increasing the sympathetic effects of norepinephrine in the liver increases glucose production through glycogenolysis after a meal or through gluconeogenesis if food has not been recently consumed. Correspondingly, correcting overactive hepatic sympathetic nerves reduces the amount of NE, resulting in lower glucose levels. In the kidneys, renin release and sodium retention in the blood increase blood pressure. The amount of norepinephrine (NE) in tissues may be used as a biomarker to demonstrate or indicate the effectiveness of treatment. Compared to untreated (controller) subjects, various embodiments of the present invention involving treatment of overactive hepatic sympathetic nerves can result in a percentage reduction in the amount of NE of 20% to 99%, preferably 50% to 98%, and most preferably 75% to 97%.

In some embodiments, the formulation may be a single chemical, or one of two, three, or four components, and may include more than four components. In some embodiments, the delivery system is used in conjunction with less invasive, percutaneous, or non-invasive approaches. Embodiments of the present invention provide formulations that include one or more materials that effect surface modification of a body lumen by absorption and penetration into the tissues, nerves, and nerve endings of the body lumen.

In certain embodiments, the formulation may comprise or consist of water, saline, hypertonic saline, phenols, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, urea, lipiodol, surfactants, derivatives thereof, or combinations thereof.

In some embodiments, the formulation material is at least one gas. The gas may be selected from oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, vapors of organic and inorganic compounds, water, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, or mixtures thereof.

In some embodiments, the formulation ingredient is at least one surfactant. In some embodiments, the surfactant is PEG laurate, Tween 20, Tween 40, Tween 60, Tween 80, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PE The surfactant may be selected from the group consisting of PEG oleyl ether, PEG lauryl ether, organic acids, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerol, galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, di(propylene glycol), tri(propylene glycol), tetra(propylene glycol), penta(propylene glycol), poly(propylene glycol) oligomers, block copolymers of polyethylene glycol and polypropylene glycol, Pluronic, Pluronic 85, derivatives thereof, and combinations thereof. In certain embodiments, the amount of surfactant in the formulation may be 0.1 to 80% by weight, preferably 0.5 to 50% by weight, and most preferably 1 to 15% by weight.

In some embodiments, the formulation includes at least one of an oil, a fatty acid, and a lipid. The oil, fatty acid, and lipid in the formulation may be butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, or octadecatrienoic acid. acid), eicosanoic acid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, natural or synthetic phospholipids, mono-, di-, or triacylglycerol, cardiolipin, phosphatidylglycerol, phosphatidic acid, phosphatides, The lipid may be selected from the group consisting of phospholipids, alpha tocopherol, phosphatidylcholine, alpha tocopherol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol, dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingolipids, prostaglandins, gangliosides, neobees, niosomes, derivatives thereof, and combinations thereof.

In some embodiments, the formulation includes a therapeutic agent or drug for denervation and resurfacing. The therapeutic agent is at least one of sodium channel blockers, tetrodotoxin, saxitoxin, decarbamoylsaxitoxin, vanilloids, neosaxitoxin, lidocaine, conotoxin, cardiac glycosides, digoxin, glutamate, staurosporine, amlodipine, verapamil, cymarin, digitoxin, proscillaridins, quabains, veratridine, domoic acid, ethanol, oleandrin, carbamazepine, aflatoxin, guanathidine, and guanathidine sulfate. In other embodiments, the formulation includes a contrast agent for imaging denervation. Such contrast agents include at least one of iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodoxanol, ioxaglate, derivatives thereof, and combinations thereof. The amount of contrast agent in the formulation may be 2 to 25% by weight, preferably 5 to 15%.

In certain embodiments, the formulation comprises an azeotrope. An azeotrope is a mixture of two or more materials that cannot be altered by simple distillation. This occurs because the vapor produced by boiling has a composition proportional to the composition of the original mixture. The azeotrope of the formulation may be selected from ethanol/water, ethanol/water/contrast agent, ethanol/water/surfactant, ethanol/water/contrast agent/surfactant, propanol/water, isopropanol/water, butanol/water, and acetic acid/water.

In some embodiments, the formulation is in a gas or vapor state and includes one or more materials. In some embodiments, the gas or vapor formulation includes oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, vapors of organic and inorganic compounds, or combinations thereof. The vapors of organic and inorganic compounds include water, phenol, methanol, ethanol, dehydrated alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl sulfate, isopropyl acetate, ethyl lactate, and mixtures thereof.

In some embodiments, the vapor formulation includes at least one of a contrast agent, such as lipiodol or iodine, and an azeotrope, and may include a surfactant and/or a therapeutic agent. In some embodiments, the vapor is binary, ternary, or quaternary, and may include more than four components. The temperature of the vapor formulation may be from 0 to 140°C, from 15 to 100°C, from 30 to 80°C, or below 0°C, or less than, equal to, or greater than 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140°C.

In some embodiments, the formulation is in a liquid state and includes one or more ingredients. The liquid formulation includes at least one of water, saline, hypertonic saline, phenols, methanol, ethanol, dehydrated alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, lipiodol, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, urea, surfactants, and the like, and combinations thereof. In some embodiments, the liquid formulation includes one of a contrast agent and an azeotrope, and may include a therapeutic agent. In some embodiments, the liquid formulation is one of a binary, ternary, or quaternary formulation, and may include more than four components. In some embodiments, the liquid formulation includes a solution, emulsion, or suspension. The temperature of the liquid formulation may be -40 to 140°C, -30 to 100°C, -30 to 80°C, or less than -40°C, or less than, equal to, or greater than -30, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or greater than 140°C. In some embodiments, the temperature of the formulation may be room temperature. In some embodiments, the temperature of the formulation may be -40 to -20°C. In other embodiments, the temperature of the formulation may be 15 to 80°C. In some embodiments, the temperature of the formulation may be equal to body temperature. In other embodiments, the temperature of the formulation may be 50 to 80°C.

In some embodiments, a method of treating at least one disease includes percutaneously or orally inserting a delivery catheter into the body, using the catheter to infuse a therapeutic compound or deliver energy into a target tissue or body lumen, selectively removing or withdrawing the compound from the target tissue or body lumen, and withdrawing the delivery catheter from the body. The at least one disease to be treated may include hypertension, pulmonary hypertension, diabetes, obesity, metabolic syndrome, heart failure, myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), end-stage renal disease, digestive disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), urological disease, cancer, tumor, pain, rheumatoid arthritis (RA), asthma, and chronic obstructive pulmonary disease (COPD), or a combination thereof. The cancer may include cancer of the adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, uterus, or a combination thereof. The body tissue may include a renal artery (e.g., a left main renal artery, a right main renal artery, a renal artery bifurcation, a left renal artery bifurcation, a right renal artery bifurcation, a distal end of the left main renal artery, or a distal end of the right main renal artery, a distal end of a branch of the left main renal artery, a distal end of a branch of the right main renal artery, or a combination thereof), a renal vein, a gastric artery, a gastric vein, a hepatic artery, a hepatic vein, a pulmonary artery, a pulmonary vein, a celiac artery, a celiac vein, a gastroduodenal artery, a gastroduodenal vein, a splenic artery, a splenic vein, an adrenal artery, an adrenal vein, a phrenic artery, a phrenic vein, a mesenteric artery, a mesenteric vein, an airway, an esophagus, a stomach, a duodenum, a jejunum, a urological lumen, or a combination thereof. The digestive system lumen may include an esophagus, a stomach, a duodenum, a jejunum, a small intestine, a large intestine, a colon, or a combination thereof. The formulation may comprise a gas, vapor, liquid, solution, emulsion, suspension, and combinations thereof of one or more materials. In embodiments where the formulation comprises a vapor of one or more materials, heat is generated by condensation of the vapor into a liquid within the tissue. In embodiments where the formulation comprises a liquid or solution, cooling or heating can be achieved by the temperature of the formulation being below or above body temperature. The temperature of a liquid formulation may be from -40 to 140°C, from -30 to 100°C, from -30 to 80°C, or below -40°C, or below, equal to, or above -30°C, -20°C, -10°C, -5°C, 0°C, 5°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, or above 140°C. In some embodiments, the temperature of the tissue being treated may be different from the temperature of the formulation and may be below or above body temperature. The temperature of the treated tissue may be from 15 to 100°C, more preferably from 20 to 90°C, and most preferably from 36 to 80°C. In other embodiments, the temperature of the treated tissue may be from -40 to -20°C. In some embodiments, the delivery catheter is a needle or needle-type catheter under imaged guidance. The imaging guidance may be ultrasound, X-ray, CT scan, MRI, OCT, or endoscopy, or a combination thereof. The delivery catheter may be a balloon-type needle catheter. A balloon-type needle catheter may have a single or two balloons. A balloon-type needle catheter may have a single, two, or three needles. Infusion may be from a needle catheter element, which may be defined as a needle infusion method. The infusion volume may be 0.1 mL to 5 mL, preferably 0.2 mL to 2.5 mL, and most preferably 0.3 mL to 1.5 mL. If the delivery catheter is a combined balloon and needle infusion device, the balloon pressure may be maintained in the range of 0.1 to 3 atm, preferably 0.1 to 2 atm, and most preferably 0.3 to 1 atm, during the infusion period. Optionally, this low-pressure balloon inflation may be controlled and maintained by an injection needle, and balloon size may be monitored in real time by fluoroscopy. The infusion temperature of the formulation may be -40 to 140°C, -30 to 100°C, -30 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20°C, -10°C, -5°C, 0°C, 5°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, or above 140°C. More detailed examples of catheters, such as single-balloon needle and dual-balloon needle delivery catheters, are provided in subsequent sections.

In some embodiments, the infusion lumen may comprise at least one needle (see Figures 3 and 5-9), either as a single needle or as multiple needles. The needle tip may be movable and may be positioned inside the lumen wall by piercing the lumen wall or outside the lumen wall for delivery of the formulation. The needle may be extremely small, having a diameter (outer diameter, OD) of approximately 200 pm to 500 pm, preferably approximately 300 pm to 400 pm. The small size of the needle can prevent or significantly reduce leakage or bleeding after piercing and withdrawal. The needle device can infuse the formulation directly and precisely into the adventitial layer of the luminal tissue to achieve deep treatment. The infusion time of the needle device is within 3 minutes, preferably between 5 and 150 seconds.

In some embodiments, the formulation is or includes ethanol. The formulation may be delivered to the tissue of the body lumen as a vapor or liquid. The temperature of the vapor or liquid formulation may be -40 to 150°C, preferably -30 to 100°C, and most preferably -20 to 80°C. The temperature of the tissue may be -40 to 90°C, preferably -30 to 80°C.

In some embodiments, the formulation is or includes a mixture of ethanol and water. The ethanol content may vary from 10 to 100% by weight. The formulation may be delivered to the tissue of a body lumen as a vapor or liquid. The temperature of the vapor or liquid formulation may be from -40 to 150°C, preferably from -30 to 100°C, and most preferably from -20 to 80°C. The tissue temperature may be from -40 to 90°C, preferably from -30 to 80°C. The ethanol/water formulation may be a positive azeotrope. The azeotrope may be 95.63% ethanol and 4.37% water by weight. Ethanol boils at 78.4°C, water boils at 100°C, and the azeotrope boils at 78.2°C, lower than either component. 78.2°C is the lowest temperature at which any ethanol/water solution can boil at atmospheric pressure.

In other embodiments, the formulation is a vapor mixture comprising water, ethanol, and oxygen. In other embodiments, the formulation is a vapor mixture comprising water, ethanol, and air. In other embodiments, the formulation is a vapor mixture comprising water, ethanol, oxygen, and nitrogen. Formulations with oxygen and air may be particularly useful for treating asthma and COPD.

In another embodiment, the formulation is a vapor mixture comprising water, ethanol, and iodine, with the iodine present in an effective amount to image the vapor mixture within the wall of a body lumen. In another embodiment, the formulation is a liquid mixture comprising water and ethanol, and also includes a surfactant. In another embodiment, the formulation is a liquid mixture comprising water and ethanol, and also includes a contrast agent, with the contrast agent present in an effective amount to enable visualization of the mixture within the wall of a body lumen by x-ray. Such contrast agents may include iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodoxanol, ioxaglate, derivatives thereof, and combinations thereof. The amount of contrast agent in the formulation may be from 2 to 20% by weight, preferably from 5 to 15% by weight.

In one embodiment, the formulation is a mixture of acetic acid and water. The amount of acetic acid in the formulation may vary from 1 to 100% by weight, preferably from 10 to 75% by weight, and most preferably from 20 to 50% by weight. The formulation may be delivered to the tissue of a body lumen as a vapor or liquid. The temperature of the vapor or liquid formulation may be from -40 to 100°C, from -30 to 90°C, from -20 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or above 100°C. The tissue temperature may be from -30 to 80°C, preferably from 60 to 80°C, and most preferably from -30 to -20°C. The tissue temperature may be from -40 to 0°C, preferably from -30 to -20°C. The amount of acetic acid in the formulation may be from 2 to 75% by weight, preferably from 10 to 60%.

In other embodiments, the formulation is a liquid mixture containing ethanol and lipiodol (e.g., LIPIODOL ULTRA-FLUIDE), containing an effective amount of lipiodol to image the vapor mixture inside the wall of a body lumen and to beneficially damage target nerve tissue. The amount of lipiodol in the formulation may vary from 10 to 80% by weight, preferably from 15 to 75% by weight, and most preferably from 20 to 50% by weight. The formulation may be or include a liquid mixture containing water and lipiodol, or a liquid mixture containing acetic acid and lipiodol. The amount of lipiodol in the formulation may vary from 10 to 80% by weight, preferably from 15 to 75% by weight, and most preferably from 20 to 50% by weight.

In some embodiments, a delivery catheter is used to infuse a formulation into tissue in the human body. The delivery catheter may be a needle or needle-type balloon catheter, and may be guided to the delivery location using X-ray or ultrasound image guidance. A needle-type balloon delivery catheter may have one or two balloons. With a needle device, formulation infusion may be within the wall of a body lumen or outside the body lumen (e.g., inside or outside the body lumen).

In some embodiments, the delivery catheter is a spray catheter. The formulation may be applied to the inner wall of a body lumen. In some embodiments, the spray direction of the device is designed to be approximately perpendicular to the wall of the lumen. The spray catheter may be needle-less or may include a needle for both spraying and needle-based administration of the formulation. The spray catheter may or may not have a centrally located balloon. The spray catheter may optionally include the ability to deliver energy to the target tissue, such as radiofrequency, cryoablation, microwave, laser, ultrasound, high-intensity focused ultrasound energy, or a combination thereof.

As shown in FIG. 1, the delivery catheter 10 has an elongate shaft 11 with at least one inner lumen, a distal end 13, and a proximal end 14. At the distal end 13 is a proximal lumen conforming balloon 20 and a distal lumen conforming balloon 21. In either configuration, the tubing of the catheter shaft 11 may be extruded from a plastic material, such as thermoplastic, polyimide, polyetherimide, polyethylene, polyurethane, polyester, polyamide, Pebax, nylon, fluoropolyurethane, polyetheretherketone, polysulfone, or similar materials, or combinations thereof. The catheter shaft 11 may be extruded or formed with various luminal cross sections, including circular or oval lumens. As further shown in FIG. 1 , the catheter 10 includes a flushing port 43, a distal balloon inflation port 40 for inflation of the distal balloon 21, and a proximal balloon inflation port 41 for inflation of the proximal balloon 20, with the proximal and distal balloons 20 being independently inflatable. A luminal conformal balloon is one that can be inflated with less pressure than is required to deform the walls of the lumen. The balloon material is selected to be flexible and usable at high temperatures so that the balloon can easily deform upon inflation. In some embodiments, the balloon material is polyamide, nylon, Pebax, polyester, polyethylene terephthalate, or one of these copolymers. The inflated diameter of the balloon may range from approximately 2 millimeters to approximately 40 millimeters, depending on the treatment area. In some embodiments, the diameter of each balloon is approximately 2 millimeters ("mm"). Alternatively, the inflated diameter of each balloon is less than, equal to, or greater than 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or greater than or equal to about 40 mm.

In one embodiment, at least one marker band 22b is positioned proximal to the proximal balloon 20, and at least one marker band 23a is positioned distal to the distal balloon 21. The balloon catheter may be a rapid-exchange catheter or an over-the-wire catheter made of any suitable biocompatible material. Marker bands may be positioned on the other ends of the balloons (22a and 23b). Segment 25 is located between balloons 20 and 21 and has at least one infusion hole, with the non-inflatable section 30 and shaft proximal to balloon section 24. Ports for balloon inflation 40 and 41 are for the distal and proximal balloons, respectively. An infusion port 42 is for infusion of chemical agents.

The material of balloons 20 and 21 includes polyester, polyamide, nylon 12, nylon 11, polyamide 12, a block copolymer of polyether and polyamide, Pebax, polyurethane, a block copolymer of polyether and polyester, or a combination thereof. The diameter of balloon 21 is equal to or smaller than the diameter of balloon 20.

FIG. 2 shows a schematic diagram of an embodiment of a spray catheter positioned in the left main bronchus for the treatment of asthma and COPD. The delivery catheter 198 of FIG. 2 can treat airways distal to the main bronchus 21 and 22. For example, the delivery catheter 198 may be positioned in a sixth or eighth generation airway to affect more distal portions of the bronchial tree 27. The delivery system 198 may be maneuvered through tortuous airways to perform a wide range of procedures, such as denervating a portion of a lobe, an entire lobe, multiple lobes, or one or both lungs. In one embodiment, a lobar bronchi is treated to denervate that lobe. For example, one or more treatment sites along the lobar bronchus may be targeted to denervate the entire lobe connected to the lobar bronchus. The left lobar bronchus may be treated to affect the left upper lobe and/or the left lower lobe. The right lobar bronchus may be treated to affect the right upper lobe, right middle lobe, and/or right lower lobe. The lobes may be treated simultaneously or sequentially. In some embodiments, the physician may treat a lobe. Based on the effectiveness of the treatment, the physician may treat additional lobes simultaneously or sequentially. In this manner, different isolated regions of the bronchial tree may be treated.

The delivery catheter 198 may be used in segmental or sub-segmental bronchi. Each segmental bronchus may be treated by delivering formulation and/or energy to a single treatment site along the segmental bronchus. For example, formulation and/or energy may be delivered to each segmental bronchus of the right lung. In some procedures, one or two applications of formulation may treat most or all of the right lung. Depending on the anatomy of the bronchial tree, a segmental bronchus may be denervated using one or two applications.

The delivery catheter 198 can affect neural tissue while preserving the function of other tissues or biological features, such as mucous glands, cilia, smooth muscle, and body lumens (e.g., blood vessels or other body lumens). Nervous tissue may include supporting tissue, such as nerve cells, nerve fibers, dendrites, and glial cells. Nerve cells transmit electrical impulses, and nerve fibers are extending axons that conduct the impulses. Electrical impulses are converted into chemical signals for transmission to effector cells or other neural cells. By way of example, the delivery catheter 198 can denervate a portion of the airway of the bronchial tree 27 to attenuate one or more neural signals transmitted by the neural tissue. Denervating may include severing (by a treatment of the present invention) neural tissue in a portion of a nerve trunk to prevent signals from traveling through a particular region to a more distal location along the bronchial tree. When multiple nerve trunks extend along the airway, each nerve trunk may be severed, thus disrupting the nerve supply along a portion of the bronchial tree. When the signal is discontinued, smooth muscle in the distal airways relaxes, resulting in airway dilation. This airway dilation reduces airflow resistance to increase gas exchange in the lungs, thereby reducing or eliminating one or more clinical manifestations, such as shortness of breath, wheezing, or chest tightness. Tissue surrounding or adjacent to the targeted neural tissue may be affected but need not be permanently severed. In some embodiments, for example, bronchial blood vessels along the treated airway may supply blood in amounts similar to bronchial wall tissue, and pulmonary blood vessels along the treated airway may supply blood in amounts similar to alveolar sacs in the distal region of the bronchial tree 27 before and after treatment. These blood vessels may continue to transport blood to maintain adequate gas exchange. In some embodiments, airway smooth muscle is damaged to a degree that does not adversely affect the tissue. For example, a relatively small portion of smooth muscle in the walls of the airways that does not appreciably affect respiratory function may be reversibly altered by methods such as applying the formulation at a regulated temperature to avoid irreversibly damaging non-targeted smooth muscle tissue, such as nerve tissue outside the airways.

The delivery system 198 of FIG. 2 includes a therapy controller 202 and an intraluminal extension assembly 200 connected to the controller 202. The extension assembly 200 may be inserted into the trachea 20 and manipulated into and through the bronchial tree 27 with or without a delivery assembly such as a guidewire. The extension assembly 200 includes a distal tip 203.

The controller 202 of FIG. 2 may include one or more processors, microprocessors, digital signal processors (DSPs), field programmable gate arrays (FPGAs), application specific integrated circuits (ASICs), memory devices, buses, power sources, pumps, formulation resources, vapor resources, liquid resources, contrast resources, vapor generators, desired temperature formulation generators, etc.

The distal tip 203 of FIG. 2 may target various locations in the lung 10, including, without limitation, neural tissue, fibrous tissue, diseased or abnormal tissue, muscle tissue, blood, blood vessels, various biofeatures (e.g., membranes, glands, cilia, etc.), and combinations thereof.

In one embodiment, a schematic diagram of a single balloon needle delivery catheter (three needle balloon lumens shown) placed in a renal artery is shown in FIG. 3 with the needle 110 extended. The delivery catheter 108 of FIG. 3 can treat hypertension. A compound may be infused through the needle into the inner or outer wall of the renal artery adjacent to the kidney for denervation. Nerve endings and small nerve fibers are typically located in the arterial wall, while larger nerve fibers and bundles are typically located outside or adjacent to the arterial wall. Different levels of denervation may be achieved by controlling the needle insertion depth during the procedure. Some elements of the renal vasculature are omitted in FIG. 3. In FIG. 3, 102 is the kidney, 105 is a guide catheter, 106 is the main renal artery, 108 is a three-needle balloon catheter, 109 is a guidewire, 301 is the trunk aorta, and 502 is the outer renal artery. In Figures 3-5, 6A-6B, 7A-7G, 8A-8B, and 9A-9C, needle delivery catheters are shown and described herein with respect to delivery of chemical agents through a needle. However, needle delivery catheter embodiments may additionally or alternatively be used for energy delivery to target tissue, for example, through the needle (e.g., radio frequency, cryoablation) and/or through other sources (e.g., microwave, laser, ultrasound), in the form of radio frequency, cryoablation, microwave, laser, and/or ultrasound.

In other embodiments, the delivery catheter 108 of FIG. 3 includes a balloon that is inflated to approximately center the catheter shaft, so that the needles are evenly spaced from the vessel wall and may pass through the arterial wall at a depth similar to that shown. In one embodiment, a renal artery is treated to treat high blood pressure. Because the needles penetrate through or beyond the vessel wall, the device can infuse a formulation into the vessel wall or outside the outer vessel wall. FIG. 3 shows that a formulation is infused through the needle 110 into the lateral wall of the main renal artery directly to the renal nerve (not shown) for denervation.

In other embodiments, three balloon catheters may be placed within the lateral renal arteries 502 and formulations may be infused within or outside the walls of these vessels. While three needles are shown, any suitable number of needles, such as one, two, three, four, five, or more, may be used.

In another embodiment, one denervation procedure can treat both the main and lateral renal arteries. A three-needle balloon catheter is placed inside the main renal artery 106 and the lateral renal artery 502 shown in FIG. 3 to infuse the formulation into the walls of multiple renal arteries, either intramurally or extramurally. Optionally, the arteries may be treated at multiple locations along the length of the artery.

In certain embodiments, a method for treating hypertension includes percutaneously inserting a delivery catheter into the renal artery and/or lateral renal artery adjacent to nerves and nerve endings, using the catheter to infuse the above-described compound and/or energy into tissue in the body lumen adjacent to the nerves, and withdrawing the delivery catheter from the body lumen once the amount of compound and/or energy delivered is effective to beneficially damage the nerves and nerve endings. Treatment also results in lower blood pressure in treated patients.

In some embodiments, needle delivery catheters may be used, for example, for the treatment of hypertension through renal ablation, for the treatment of diabetes through hepatic denervation, and/or for the treatment of obesity through gastric denervation, as shown in FIGS. 3 and 5-9. In some embodiments, the catheter 10 (shown in FIG. 1) disclosed herein regulates the flow and therapeutic dose of a formulation through a therapeutic window 30, as shown in FIG. 4. A balloon may be inflated through its inflation lumen. The placement, diameter, number, and frequency of the needle exit holes 31 result in the formulation being delivered to the therapeutic window 30 through needles (not shown, in the retracted position). FIG. 4 illustrates a catheter positioned within a body lumen 5 having two needle exit holes 31 positioned within the therapeutic window 30 for delivery of a therapeutic agent through the needles. In use, the needles extend outward from the needle holes, as shown at 3. As shown in FIG. 4, the needle exit holes 31 contain retracted needles that create fluid communication with the inner lumen 25. The needle residing within the needle exit hole 31 may create fluid communication with either the outer lumen 24 or the inner lumen 25 (not shown), thereby providing the formulation to the treatment window 30 (e.g., within the lumen, at the wall of the lumen, or outside the wall of the lumen).

A formulation treatment port may be located between the balloons on the shaft. A formulation infusion hole may be located in the non-inflatable shaft portion between the inflatable balloon portions. During treatment, the formulation may be ejected between the balloons through the infusion hole into a treatment window space formed by the balloons. This may include an infusion embodiment in which the treatment mechanism applies a drug to the inside of the vessel wall and allows the drug to diffuse out through the lumen wall to achieve a therapeutic effect.

In some embodiments, optional chemical agent/formulation residue may be recovered after treatment by suction techniques at one or more infusion holes. In this case, at least two treatment lumens, one for infusion and one for suction, are desirable. The formulation infusion and suction holes may be located on the non-inflatable shaft portion between the inflatable balloon portions.

In addition to withdrawing excess therapeutic agent, remaining therapeutic agent may be diluted with saline or water to an ineffective concentration. Flushing with saline or water may be performed using the catheter wire lumen, one of the infusion lumens, or by other means. The method of use depends on the location of protection or treatment. If a distal portion of the vessel requires protection from formulation treatment, flushing may be performed through the wire lumen.

In some embodiments, when deep treatment is required in the adventitia and/or periadventitial space, a needle-type catheter can achieve this goal by infusing a formulation through at least one needle into the interior of the lumen wall or into the outer wall of the lumen. To uniformly treat the lumen around its circumference, a three-needle (or four-or-more) balloon catheter infuses the formulation into the target area through the needles. Figure 5 shows a two-balloon, three-needle catheter positioned in a body lumen 5 and having three needles 50 positioned between two balloons. When advanced, the three needles may have a diameter larger than the balloon diameter. The needles establish fluid communication with the formulation source, delivering the formulation directly onto the vessel wall or into the interior of the outer wall of the body lumen. During the procedure, the balloon-needle catheter is advanced to the target lesion or location using standard procedures. Both balloons are inflated to center the central non-inflatable shaft, from which the needle is deployed, and the formulation is delivered through the needle to the wall of the lumen or vessel, or to the outer wall, or to the outside of the wall, depending on the needle insertion depth; for example, the needle tip may be inside or beyond the wall. After treatment, the needle is retracted into the shaft, the balloons are deflated, and the catheter is ready for withdrawal.

An example of a single-balloon needle catheter is shown in Figures 6A and 6B. Figure 6A shows a three-needle balloon catheter 600 in a ready-to-use state. The needles are housed within the distal head 601 (not shown in this figure), the distal portion of the catheter. The voids (not shown) that house the needles and corresponding needle exit openings 612 are located distal to the balloon, allowing the needles to protrude from the voids during needle placement. The distal head may function as a marker band or alternatively include a marker band 602, which may be formed from any medical-grade material, such as stainless steel, and may be atraumatic (tip 608) and radiopaque (e.g., when used as a marker band). The distal head and/or marker band are visible under x-ray (fluoroscopy), allowing the clinician to accurately place the needle. The needle has an off-center wire lumen design 603, allowing for a smaller catheter profile, e.g., better compatibility with guide catheters. The catheter shaft 610 may be a reinforced shaft reinforced with wire braid to improve compression resistance and tensile strength, so needle movement operated at the proximal end of the catheter may be smooth and precise. Needle movement is controlled by a handle 604 located at the proximal end, which connects to a formulation source. The catheter, which may be advanced over a guidewire for delivery, is shown with an over-the-wire configuration for the guidewire lumen 603. The balloon 606 may be inflated through the inflation lumen 605. Figure 6B shows the catheter 600 with the needle 611 in an advanced state and with the balloon 606 inflated. The balloon, located immediately after the needle, allows the distal end of the shaft 610 to be centered, allowing all three needles 611 to penetrate the vessel wall to a similar depth to ensure uniform delivery of the formulation around the circumference of the vessel. It may be desirable to position the balloon as close to the needle as possible, so that the needle is more likely to be an equal distance from the vessel wall. The distance between the needle exit opening on the distal head and the balloon cone/waist transition region may be approximately 2 mm to 12 mm, preferably approximately 5 mm to 9 mm. A smaller needle diameter results in a less noticeable needle puncture wound, which results in faster puncture wound healing. The outer diameter of the needle may be approximately 0.20 mm to 0.50 mm, preferably approximately 0.28 mm to 0.38 mm. The needle curvature may be designed to allow the needle 611 to be positioned perpendicular to the vessel wall when delivered.

The needle may be formed from any suitable material, such as stainless steel, platinum, titanium, tantalum, platinum-iridium alloy, platinum-chromium alloy, nickel-titanium alloy (nitinol), platinum (Pt), gold (Au), iridium (Ir), osmium (Os), rhenium (Re), tungsten (W), palladium (Pd), tantalum (Ta), and combinations thereof, and/or cobalt-based alloys containing chromium (Cr), molybdenum (Mo), and/or nickel (Ni). The needle may be formed from a nitinol material and may have shape memory for a designed curve upon exiting the receiving cavity/chamber. Because nitinol needles are small and thin, they may not be sufficiently radiopaque under x-rays during the procedure. However, it is important for the clinician to know where the needle is during the procedure. To achieve this, the needle may be modified with a number of suitable radiopaque metallic materials, for example, by sputtering a thin film of radiopaque material onto its surface, or by connecting a radiopaque material to the needle (e.g., as a marker band that may be included on the shaft), or by cladding a metal needle/tube, such as combining one or two layers of radiopaque material with a Nitinol needle/tube. Coating or cladding or additional connecting materials may include, but are not limited to, tungsten (W), gold (Au), tantalum (Ta), platinum (Pt), and iridium (Ir), or combinations or alloys thereof, to make the Nitinol needle radiopaque. The radius of curvature of the needle 611 may be approximately 2 mm to 6 mm, for example, approximately 3 mm to 4 mm. When fully deployed, the needle tip-to-tip span diameter (the diameter of an imaginary circle touching all needle tips) may be 5 mm to 40 mm, or approximately 5 mm to 30 mm, for example, approximately 5 mm to 15 mm, and the diameter may be determined by the treatment vessel diameter and desired needle insertion depth. For example, for a 6 mm vessel and a 2 mm needle insertion depth, the needle tip-to-tip span distance may be approximately 10 mm.

After treatment, the needles are first retracted into the distal head or chamber, the balloon is deflated, and the catheter is withdrawn. Optionally, the distal head, needles, and vascular region to be treated may be flushed with saline or heparinized saline through the wire lumen (in over-the-wire catheters) or a dedicated lumen, if present, to dilute any residual formulation in the lumen. In some procedures, the formulation lumen 604 may be flushed with saline or heparinized saline to prevent needle clogging. While FIGS. 6A and 6B are shown with three needles positioned distal to the balloon, any number of needles may be used, for example, one, two, three, four, five, or six or more, and the needles may be positioned proximal to the balloon. The needle guide may be optionally flushed.

An embodiment of a rapid-exchange (RX) needle balloon catheter is shown in FIG. 7A and includes a rapid-exchange shaft. The rapid-exchange configuration allows for easier and faster catheter insertion after wire placement during a procedure. The guidewire lumen 709 has a wire entry or exit port 711 located near the center or distal end of the shaft 710. Optionally, a guide groove (not shown) is present on the distal head to facilitate wire feeding for the clinician during wire backfeeding at the distal port of the wire lumen. Except for the wire exchange method, the same needle and balloon manipulation procedures described in the paragraph above may be applied. Optionally, flushing and cleaning of the distal head and needle after a procedure may be performed by injecting saline or heparinized saline directly through the formulation lumen 704 at approximately 3 to 10 times the treatment volume.

The needle-type balloon infusion system may include a needle-type balloon catheter, a guidewire, an ablation agent, saline or heparinized saline or therapeutic agent, and a fluid container having a volume of 1 mL to 30 mL for medical fluid administration. Examples of the fluid container may include a syringe and an injection pump.

The needle-type balloon delivery catheter includes a distal head, at least one marker band, at least one needle, at least one needle exit hole, at least one flushing hole (which in some embodiments may be the same as the needle exit hole), a flushing lumen, a flushing port, a guidewire lumen, at least one balloon at approximately the distal end of the catheter, one inflation lumen, one inflation port, an ablation port, a needle movement shaft, and a needle movement controller. The balloon is inflated through the inflation port via the inflation lumen, the flushing port is in communication with the flushing hole through the flushing lumen, the guidewire lumen is connected to a groove in the distal head, the needle movement controller is in communication with the needle through the needle movement shaft, and the ablation port is in communication with the needle through the needle movement shaft. The needle is connected to the needle movement shaft, and needle movement is controlled by the needle movement controller through the needle movement controller. In some embodiments, the number of needles is 1, 2, 3, 4, or 5, and the number of needle exit holes is 1, 2, 3, 4, or 5. In other embodiments, the catheter size is 4F, 5F, 6F, 7F, 8F, 10F, 12F, 14F, 16F, 18F, 20F, 22F, 24F, or 26F. The balloon diameter may be in the range of 3mm to 40mm. The balloon length may be in the range of 3mm to 25mm. The needle size or needle outer diameter (OD) may be in the range of 0.3mm to 0.5mm, and the needle inner diameter (ID) may be in the range of 0.2mm to 0.35mm. When the catheter includes two or more needles, the needle span diameter may be in the range of 5mm to 80mm, or in the range of 5mm to 40mm, and is defined by the circumference of the needle tip when the needle is fully advanced. The catheter length may be in the range of 70cm to 260cm. The guidewire lumen may be compatible with 0.014 inch (0.36 mm), 0.018 inch (0.46 mm), or 0.035 inch (0.89 mm) guidewires. The needle span diameter may be fixed or adjustable, for example, the needle span diameter range may be adjustable between 5 mm to 80 mm, 5 mm to 30 mm, or 7 mm to 15 mm.

The needle may be visible under X-ray (fluoroscopy). The needle may be made of stainless steel, nitinol, cobalt-chromium, metal alloys, metal alloys, and shape memory metals and their alloys. The needle may be straight or curved. The radiopacity of the metal needle may be improved by surface modification with other metals, such as W, Au, Ta, Pt, Ir, or any combination of two metals, by physical vapor deposition (PVD) via sputtering.

The needle-type balloon delivery catheter may include a needle movement control and an ablative agent port. The ablative agent passes directly from the port to the needle.

Needle-type balloon delivery catheters may include a wire lumen for guiding a wire. The wire lumen may be provided as an over-the-wire (OTW) or rapid-exchange (RX) type. With an OTW shaft (catheter), the guidewire passes through the entire length of the catheter shaft. In contrast, with an RX shaft (catheter), the guidewire does not use a lumen passing through the catheter shaft. Typically, the RX wire lumen is located in the distal portion of the catheter and is shorter, approximately 10 inches (approximately 25 cm) in length. RX catheters can save time, especially during catheter exchanges during a procedure, compared to advancing a wire through the entire length of the guide.

The needle-type balloon delivery catheter may include at least one balloon. A short balloon length is desirable, and the balloon length may be in the range of 3 mm to 20 mm, preferably 5 mm to 10 mm. The balloon diameter may be 3 mm to 30 mm. The required balloon deformability depends largely on the application and may range from easy to difficult to deform. Balloon materials may be polyethylene, polyamide and its block copolymers, polyurethane, polyester and its block copolymers, nylon 12, Pebax, etc. Standard balloon inflation media may be used through the inflation lumen/port to inflate or deflate the balloon. The inflation device may be a syringe or a balloon inflation device; however, if the balloon is a low-pressure balloon that is easy to deform, an appropriate volume syringe is preferred depending on the balloon configuration.

A balloon on the catheter may be positioned behind the needle to serve to center the distal head of the needle and stop blood flow into the target treatment area.

Needle-type balloon delivery catheters may include markers to indicate balloon placement during the procedure. The markers may be the usual marker bands used on balloon catheters, or the radiopaque metal (distal) head of needle-type balloon catheters, etc. The balloon markers may be positioned distally, centrally, or proximally on the balloon, or a combination of these locations. The radiopaque marker bands may be made of platinum, platinum-iridium alloy, gold, or a composite polymer with a radiopaque filler.

The needle-type balloon delivery catheter may include a flushing lumen that is in direct communication with the needle exit hole for fluid outflow/passage. The flushing lumen may be connected through a flushing lumen port to a source of saline or heparinized saline for flushing and irrigation purposes, or to a source of therapeutic agent for inner surface treatment. The flushing lumen may be a channel with a coaxial structure (Figure 7B) or a separate tubing channel (not shown).

The needle-type balloon delivery catheter may include a balloon, three needles, a distal head and radiopaque marker in the needle chamber, a guidewire lumen, a balloon inflation lumen and port, an infusion lumen and port, and a flushing lumen and port.

An example of a rapid-exchange (RX) needle balloon delivery catheter is shown in FIG. 7B. The catheter shaft 720 includes a separate flushing lumen 715. The flushing lumen 715 is connected through the catheter shaft to the needle exit hole 716 and the flushing port 708, so that flushing medium flows out through the needle exit hole, as shown by the arrow. In this example, the flushing lumen is coaxially positioned above the infusion lumen 714. The infusion lumen 714 is directly connected to the needle tubing, which may be formed from polymer or metal tubing, preferably stainless steel hypotube. Three needles are bundled along a needle bundle tube 712. The needle bundle tube may have high strength and flexibility to hold the needles together and maintain a uniform spacing, and may be a polymer tube or a reinforced polymer tube, such as a braided polymer tube. The balloon 706, located behind the needle head, serves to center the needles within the vessel, ensuring that all three needles are equidistant to the vessel wall. The needle distal head 717 provides a needle retention chamber and a marker for needle placement during the procedure. The shape-memory needle returns to its preformed curve upon exiting the distal head. It has a beveled needle distal opening 713, with the bevel facing the intrados of the needle arch. The needle distal opening provides communication between the infusion lumen 714 and the infusion port 704.

Various cross sections of the needle balloon delivery catheter shown in Figure 7B are shown in Figures 7C through 7G, which are transverse cross sections of these cross sections. Figure 7C is a cross section of the catheter of Figure 7B at section 7C-7C, and includes the balloon body 706, guidewire lumen 709, braided outer shaft 721, three needle tubes 722 in direct communication with the distal head, and flushing lumen 715.

Figure 7D shows a cross-sectional view of section 7D-7D of the catheter of Figure 7B, including the balloon shaft 706, guidewire lumen 709, inflation lumen 707, flushing lumen 715, braided outer shaft 721, and needle tubing 722 with needle bundle tubing (braided tubing) 712 to hold the needles together and keep them evenly spaced apart. For three needles, the needle-to-needle spacing is 120°.

Figures 7E and 7F show cross-sectional views of sections 7E-7E and 7F-7F of the catheter of Figure 7B, respectively. Figure 7E includes a guidewire lumen 709 and an inflation lumen 707, both positioned in opposite directions on the braided outer shaft. Figure 7E also includes a flushing lumen 715, a braided outer shaft, and an infusion lumen 714. The infusion lumen may be formed of a polymer tube, a reinforced polymer tube, or a metal tube. For better pushability and dimensional stability, a stainless steel (SS) hypotube may be used as the infusion lumen 714. The infusion lumen 714 of the catheter connects to the infusion port 704 at the proximal end and to the needle tube at the distal end of the catheter. Alternatively, to save space or lower the overall catheter profile, the guidewire lumen 709 and inflation lumen 707 may be co-located on the same side of the shaft as shown in Figure 7F. The configuration of Figure 7F is not shown in the catheter of Figure 7B.

Figure 7G shows a cross-sectional view of section 7G-7G of the catheter in Figure 7B, including a braided outer shaft with an inflation lumen 707 connected to the outer wall, a flushing lumen, and an infusion lumen of the SS hypotube. The inflation lumen 707 is in communication with the inflation port 705 for inflation of the balloon. The infusion lumen 714 is in communication with the infusion port 705, the needle, and the needle distal opening 713. The flushing lumen 715 is in communication with the flushing port 708 and the flushing hole 716.

Rapid-exchange (RX) needle balloon delivery catheters may be used in ablation procedures through blood vessels. The infusion lumen and needle of the catheter may be prefilled with an ablation agent, such as ethanol, through port 704. The flushing lumen may be prefilled with a medium, such as saline or heparinized saline, through port 708. Prefilling the flushing liquid inside the distal head prevents the needle from directly contacting blood, thereby reducing the likelihood of needle clogging. Reduced clogging means a longer-lasting catheter that can be used for multiple treatments in a procedure, and fewer catheters are used, facilitating shorter procedure times and lower overall costs. The prepared catheter may be inserted into the blood vessel inside the guide catheter along a pre-placed guidewire to the treatment location. At the pre-identified treatment location, the balloon may first be inflated to the vessel diameter to center the needle heads. Then, the three needles may be advanced into or beyond the vessel wall, and the ablation agent may be infused through the needles to the intended area for denervation. Alternatively, for treatments other than ablation, a therapeutic agent may be used instead of an ablation agent. After treatment, the needle may be retracted inside the distal head, after which a flushing medium may be injected and expelled through the needle exit hole for flushing and irrigation, after which the balloon may be deflated and the catheter may be withdrawn or ready to move to the next treatment location for another ablation. The flushing medium may be a therapeutic agent if drug delivery is desired. Liquid drugs may be applied through the flushing hole to the location and its interior surface for treatment.

The flushing lumen on the catheter may be a safety feature for the patient, for example, to dilute excess or residual ablation solution inside the blood vessel to a non-functional level.

The needle-type balloon delivery catheter may be a three-needle balloon delivery catheter. The needle span diameter (calculated from the circumference formed by the needle tip-to-tip at the fully advanced stage) may be 5 mm to 30 mm, or 7 mm to 15 mm.

In some embodiments, a steerable single-needle catheter may be used to infuse a formulation, as shown in FIGS. 8A and 8B. As shown, the catheter has two-way steering, but one, two, three, four, or more directional capabilities may also be used. The steering mechanism may be, for example, a wire (not shown) connected to the distal end 801 of the catheter shaft 802 and having a handle (not shown) at the proximal end of the catheter. To steer the catheter, the user moves the handle proximally, causing the distal tip 801 to move away from the longitudinal axis of the catheter shaft 802. The needle tip is retracted inside the catheter during insertion and placement, which can be achieved with a guidewire. An off-center guidewire lumen design may be used to minimize the catheter profile for small vascular access. The overall catheter profile may be 3F to 10F, preferably 5F to 7F. Once at the treatment site, the catheter head 801, which may be radiopaque, is steered toward and preferably against the vessel wall. This may be visually guided using fluoroscopic observation. The needle (803 in FIG. 8B) is then advanced into or through the vessel wall and the formulation is infused. If desired, the needle may be retracted and the tip may be steered to a new direction for treatment in a new direction. After treatment, the needle is retracted and the catheter is withdrawn from the patient. Optionally, the steerable catheter may be used without a guidewire, as the catheter is visible under x-ray and has a steerable tip.

In another embodiment, as shown in Figures 9A, 9B, and 9C, a single-direction steerable catheter is used to infuse the formulation through the needle. This catheter 900 has a smaller profile than the two-way catheters described above, making it suitable for smaller diameter vessels. As described above, desirable and controlled perforation may involve achieving a needle orientation that is approximately perpendicular to the lumen wall (e.g., at or near 90° to the lumen wall), thereby providing a predictable infusion direction and depth. This may require a sharp bend at the distal end of the catheter 902, so that the tip 901 is positioned perpendicular to the vessel wall. This can be extremely difficult inside small lumens, as pushing the needle through small bends or curves can be nearly impossible. To overcome this problem, in some embodiments, the needle exit hole is located in the side wall of the tip head instead of the center of the tip 903 (see Figures 9B and 9C). Additionally, the exit hole is located on the side of the catheter shaft 902 in the same direction as the bend direction of the catheter tip (see Figure 9B). Once the catheter is positioned inside the small lumen at the target area, it only needs to be bent by a small angle (less than 90°) to align the hole approximately perpendicular to the vessel 5 (see FIG. 9C). Once alignment is achieved, the needle is advanced into the wall 5 as shown in FIG. 9C, and the system is ready for infusion therapy. After therapy, the needle is retracted inside the catheter, the catheter tip is returned to a straight configuration, and the catheter is ready to be withdrawn from the patient, rotated to a different orientation for therapy, or moved to a different position for other therapy. The distal tip may be plastic, metal, or a combination thereof, may be radiopaque, and may house the needle. The radiopaque tip 901 may serve as a marker band for needle placement during the procedure.

In some embodiments, the needle device can deliver extremely small and precise volumes of formulation, for example, in the range of 0.01 mL to 10.0 mL, preferably 0.05 mL to 5.0 mL, and most preferably 0.1 mL to 1.0 mL. Because of the small dose and precise control of treatment volume/dose, multiple treatments at the same location/region may be used to provide more optimal treatment results. As shown in FIG. 3 , a three-needle balloon catheter 108 is placed in the main renal artery 106 with the balloon and needle 110 deployed, and the perivascular infusion volume of formulation may be, for example, 0.6 mL. After needle retraction and balloon deflation, the catheter may be advanced to the lateral renal artery 502 (a branch of the renal artery), deploy the needle, and continue infusing another treatment volume, such as 0.3 mL, into the outer wall region (adventitia). Once both lateral renal arteries are accessible, both arteries may be treated with equal or different doses. To achieve similar doses per region in treatment, the dose for lateral renal artery treatment may be less than for main renal artery treatment, taking into account the difference in the surface area of the lateral artery wall and the closer proximity of the lateral renal artery to the renal organ than the main renal artery. The dose relationship between the dose for the main renal artery (DOSE _m ) and the lateral renal artery (branch) (DOSE _b ) is:
DOSE _b = DOSE _m *(D _b /D _m )
where _Dm is the diameter of the main artery and _Db is the diameter of the branching artery. For example, if the diameter of the main artery is 6 mm and the branching artery is 3 mm, then:
DOSE _b = DOSE _m * (D _b /D _m ) = DOSE _m * (1/2) or = 0.5 DOSE _m
If all three regions (one main and two branches) are treated, the total volume of arterial treatment may be 1.2 mL for one kidney.

In some cases, the length of the main renal artery is long enough to allow the device to treat it twice, for example, once in the middle and a second time near the bifurcated area of the artery (near the bifurcation). If the main renal artery is treated twice and the two branches of the artery are treated once, the total volume for one lateral renal artery treatment may be 1.8 mL.

In some embodiments, as shown in FIGS. 13 and 14, a spray catheter with a formulation outlet or spray hole at the distal end may be used for the delivery catheter to achieve a wider treatment area. The catheter 1300 shown in FIG. 13 has a coaxial design shaft 1309, with suction through an inner tube 1305 and spray through the space between the inner tube 1305 and outer tube 1304. The spray hole 1301 is located on the sidewall of the shaft 1309, allowing for direct delivery of the formulation to the vessel wall with good control over the spray direction and treatment area. The formulation is delivered to the spray hole 1301 through the spray lumen 1307. Any excess formulation remaining in the vessel after spray treatment may be removed/collected by the catheter's suction function. Removal may be achieved by applying a vacuum to the suction port 1308, resulting in the formulation being withdrawn through the suction location 1306. In this example, the suction opening 1306 is located distal to the spray opening 1301. The openings for suction and spray may be circular or any other geometric shape. There may be a single or multiple holes for the suction and spray functions, or any combination of hole numbers between the two functions. The number and size of holes are independent between suction and spray. Ideally, a fine mist is desired for spray, so the size of the spray holes is smaller than the size of the suction holes. Optionally, the suction line may be connected to a vacuum pump. The spray may contain two components: a liquid formulation and a compressed gas, such as air or oxygen. A specified volume of liquid formulation is delivered through the pressurized gas at a predetermined pressure. Under the pressure of the delivery gas, the delivered formulation is in the form of a fine mist that is applied to the target treatment area. The excess amount of formulation after each spray may be collected/removed at the treatment area by the suction function of the catheter, thereby allowing the formulation to be contained at the target area.

The exact spray location during the procedure may be visualized through a marker band under X-ray. The marker band 1303 may be located proximal to the spray hole 1309 at the distal end of the catheter 1309, or dual marker bands 1303 may be placed, for example, both distal and proximal to the spray hole 1301. Optionally, the distal marker band is sized to occupy the space between the inside and outside of the distal shaft, obstructing the fluid path and stopping the formulation at the location of the marker band. Thus, there is less priming volume in the catheter, which allows for more accurate spray volume.

In other embodiments, a two-position suction catheter may be used to ensure that the formulation does not leak in either direction (distal or proximal) to the spray orifice. An example is shown in FIG. 14, where suction orifice 1406A and suction orifice 1406B are located distally and proximally relative to the spray site on the catheter. Both the distal and proximal suction orifices may be connected through the same channel/lumen or may be independent of each other; for example, the distal and proximal suction orifices may be operated independently. Suction may occur at the distal position, the proximal position, or both positions simultaneously. The catheter may be operated as described above.

A multi-lumen shaft 1409 may be used to accommodate the features shown in FIG. 14, for example, a three-lumen shaft. Each suction location 1406 and 1406B has its own lumen, so distal and proximal suction may be performed independently. In one embodiment, a sleeve 1410 is placed over the spray outlet hole to achieve a uniform circumferential (e.g., 360°) spray. Two marker bands 1403 located at the distal and proximal ends of the sleeve 1410 assist in precise alignment at the treatment location or lesion. While FIG. 14 shows a sidewall spray outlet configuration, the spray outlet may alternatively or additionally be located at the distal tip. Depending on the design of the hole size 1401, the spray pattern may range in delivery effect (physical form) from a fine mist to coarse droplets to a jet.

15A and 15B show the various arteries surrounding the liver and stomach, as well as the various nerve systems innervating the liver, stomach, and surrounding organs and tissues. The arteries surrounding the liver and stomach include the abdominal aorta 305, the celiac artery 310, the common hepatic artery 315, the proper hepatic artery 320, the gastroduodenal artery 322, the right hepatic artery 325, the left hepatic artery 330, the splenic artery 335, and the esophageal bifurcation 361. The various nerves innervating the liver, stomach, and surrounding organs and tissues include the celiac plexus 340 and the hepatic plexus 345 (shown only in FIG. 15B). The blood supply to the liver is pumped from the heart into the aorta, down through the abdominal aorta 305, and into the celiac artery 310. From the celiac trunk 310, blood flows through the common hepatic artery 315 to the proper hepatic artery 320, and then through the right hepatic artery 325 and left hepatic artery 330 to the interior of the liver. The common hepatic artery 315 branches off from the celiac trunk to form the gastroduodenal artery. Nerves innervating the liver include the celiac plexus 340 and the hepatic plexus 345. The celiac plexus 340 wraps around the celiac trunk 310 and continues inside the hepatic plexus 345, which wraps around the common hepatic artery 320 and proper hepatic artery 315 and/or continues to the right hepatic artery 325 and left hepatic artery 330. In their anatomical structure, the celiac plexus 340 and the hepatic plexus 345 adhere tightly to the walls of the arteries supplying blood to the liver, thereby making medial-lateral vascular neuromodulation particularly advantageous. In some embodiments, the average thickness of a blood vessel (e.g., a hepatic artery) is in the range of about 0.1 cm to about 0.25 cm. In some embodiments, the formulation and/or energy may be delivered to the medial wall of the target blood vessel or nerve. Vascular delivery may be applied because nerves are tightly attached to the lateral wall of the artery and thus supply blood to the liver (e.g., in the case of a branch of the hepatic artery). In some embodiments, extraluminal/extravascular delivery is desired and may be achieved with any of the various needle catheters disclosed herein.

The arteries surrounding the stomach include the abdominal aorta 305, the celiac artery 310, the right gastric artery 355, the left gastric artery 360, and the esophageal bifurcation 361. The blood supply to the stomach is pumped from the heart into the aorta, down the abdominal aorta 305, and into the celiac artery 310. Blood travels from the celiac artery 310 through the right gastric artery 355, the left gastric artery 360, and the esophageal bifurcation 361 into the stomach. The left gastric artery 360 includes the left gastric artery plexus 362 (shown only in Figure 15A).

With continued reference to FIG. 15B, the hepatic plexus 345 is furthest offset from the celiac plexus 340. The hepatic plexus 345 is thought to primarily carry afferent and efferent sympathetic nerves, the stimulation of which may increase blood glucose levels through multiple mechanisms. For example, stimulation of sympathetic nerve fibers in the hepatic plexus 345 can increase blood glucose levels by improving hepatic glucose production or by decreasing hepatic glucose absorption. Impairment of sympathetic nerve signals in the hepatic plexus 345 therefore alters blood glucose levels.

The embodiment shown in FIG. 15B may be a balloon needle delivery catheter embodiment placed inside the hepatic artery for the treatment of diabetes. The embodiment shown in FIG. 15A may be a three-needle balloon delivery catheter placed in the left gastric artery for the treatment of obesity and/or diabetes. Access to these arteries is very similar to access to the renal arteries, and therefore the procedures described in the previous section are also applicable to these embodiments.

A safe and effective amount of the formulation may be applied to sufficiently and beneficially damage tissue, such as nerves. Generally, the amount of the dose is related to the degree of damage in the tissue. In some embodiments, effective formulation doses range from 0.2 microliters to 200 milliliters. These dose limits are not defined, and other delivery parameters (e.g., delivery rate, duration, etc.) may require different doses to achieve optimal damage benefit.

Treatment times may depend on the volume of the tissue mass to be treated and the intended degree of damage to the target tissue. Treatment times may vary from approximately 2 seconds to approximately 60 minutes. In some embodiments, safe and effective treatment times range from approximately 4 seconds to approximately 30 minutes to induce damage to alleviate symptoms.

The delivery rate can be set by controlling the delivery system. Once the user establishes the delivery rate, the formulation resource can specify the amount of pressure required to deliver vapor or liquid at the desired rate.

In some embodiments, a method for treating hypertension includes percutaneously inserting a delivery catheter into a renal artery adjacent to a nerve, using the catheter to infuse the aforementioned formulation and/or energy into tissue in a body lumen adjacent to the nerve, and withdrawing the delivery catheter from the body lumen when the amount of formulation and/or energy delivered is effective to beneficially injure or damage the nerve. Injury or damage to the tissue can alleviate disease symptoms, for example, by reducing blood pressure. The purpose of the heat/energy may be to enhance the injuring/damaging effect by accelerating the reaction rate between the formulation and the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, suspensions, and combinations thereof, each containing one or more materials. If the formulation contains a vapor of one or more materials, heat may be generated within the tissue by condensation of the vapor into a liquid. If the formulation contains a liquid or solution, heat may be transferred from the formulation at an elevated temperature above body temperature. The temperature of the formulation may be from −40 to 140° C., from −30 to 100° C., from −30 to 80° C., or below −40° C., or less than, equal to, or greater than −30° C., −20, −10, −5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140° C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the temperature of the formulation and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may be -40 to 100°C, -30 to 90°C, -20 to 80°C, or less than -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or greater than 100°C. The formulation infusion pressure may be 0.1 to 14 atm, preferably 3 to 10 atm, and most preferably 4 to 8 atm.

In some embodiments, a method for treating asthma includes inserting a delivery catheter into an airway adjacent to a nerve, using the catheter to infuse the aforementioned formulation and/or energy into tissue of the airway adjacent to the nerve, and withdrawing the delivery catheter from the body lumen when the amount of formulation and/or energy delivered is effective to beneficially injure or damage the nerve. Injury or damage to the nerve can alleviate symptoms of the disease, for example, by reducing shortness of breath. The purpose of the heat/energy may be to enhance the injuring/damaging effect by accelerating the reaction rate between the formulation and the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, suspensions, and combinations thereof, each containing one or more materials. If the formulation contains a vapor of one or more materials, heat may be generated within the tissue by condensation of the vapor into a liquid. If the formulation contains a liquid or solution, heat may be transferred from the formulation at a temperature above body temperature. The temperature of the liquid formulation may be from −40 to 140° C., from −30 to 100° C., from −30 to 80° C., or below −40° C., or less than, equal to, or greater than −30° C., −20, −10, −5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140° C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the temperature of the formulation and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may be -40 to 100°C, -30 to 90°C, -20 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or above 100°C. The formulation infusion pressure should be 0.1 to 14 atm, preferably 3 to 10 atm, and most preferably 4 to 8 atm.

Alternatively, asthma may be treated using a balloon-less spray catheter. In some embodiments, a method of treating asthma includes inserting a delivery catheter into an airway adjacent to a nerve, using the catheter to infuse the formulation and/or energy described above into the tissue of the airway adjacent to the nerve, and withdrawing the delivery catheter from the body lumen when the amount of delivered formulation and/or energy is effective to beneficially injure or damage the nerve. Injury or damage to the nerve can alleviate symptoms of the disease, for example, by reducing shortness of breath. Advantages of this spray method include its simplicity, speed, and ability to treat airways with small diameters. Possible formulations include gases, vapors, liquids, solutions, emulsions, suspensions, and combinations thereof, each containing one or more ingredients. For vapor and liquid formulations, a fine mist may be desirable for delivery. The diameter of the formulation exiting the spray orifice may be 0.5 mm or less, more preferably 0.4 mm or less. It may be desirable for the delivery gas pressure to be less than 8 atm, more preferably 4 atm or less.

In some embodiments, a method for treating COPD and/or asthma includes inserting a delivery catheter into an airway adjacent to a nerve, using the catheter to infuse the aforementioned compound and/or heat into tissue in a body lumen adjacent to the nerve, and withdrawing the delivery catheter from the airway when the amount of compound and/or heat delivered is effective to beneficially damage or injure the nerve. Injury or damage to the nerve can alleviate symptoms of the disease, for example, by reducing the symptoms of COPD/asthma. The purpose of the heat/energy may be to enhance the damaging/injurious effect by accelerating the reaction rate between the compound and the nerve. Possible compounds include gases, vapors, liquids, solutions, emulsions, and suspensions containing one or more compounds. When the compound contains a vapor of one or more materials, heat may be generated by condensation of the vapor into a liquid. When the compound contains a liquid or solution, heat may be transferred from the compound at a temperature above body temperature. The temperature of the formulation may be from −40 to 140° C., from −30 to 100° C., from −30 to 80° C., or below −40° C., or less than, equal to, or greater than −30° C., −20, −10, −5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140° C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the temperature of the formulation and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may be from -40 to 140°C, from -30 to 100°C, from -30 to 80°C, or less than -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or greater than 140°C. The formulation infusion pressure may be 0.1 to 14 atm, preferably 3 to 10 atm, and most preferably 4 to 8 atm.

Alternatively, COPD can be treated with a spray catheter, and the same methods for treating asthma described herein may be used. The methods may include the combined use of a balloon catheter and a spray catheter in the same procedure to maximize denervation effects.

In certain embodiments, a method for treating severe emphysema accompanied by reduced lung volume includes inserting a delivery catheter into an airway adjacent to a target area, using the catheter to spray the formulation and/or energy described above to completely destroy the targeted lung tissue, and withdrawing the delivery catheter from the airway once the amount of formulation and/or energy delivered is effective to beneficially injure or damage the tissue. Damage to the tissue can alleviate symptoms of the disease, for example, by reducing the symptoms of emphysema. The formulation and/or energy may be delivered at a distal tip front, or a lateral wall location, or a combination of both.

In some embodiments, a method for treating diabetes and/or nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH) includes percutaneously inserting a delivery catheter into a hepatic artery adjacent to a nerve, particularly the celiac artery, common hepatic artery, proper hepatic artery, or left and right hepatic arteries; using any of the catheters described herein to infuse the aforementioned formulation and/or energy into tissue in a body lumen adjacent to the nerve or directly into the nerve; and withdrawing the delivery catheter from the body lumen once the amount of formulation and/or energy delivered is effective to beneficially injure or damage the nerve. The purpose of the heat/energy may be to enhance the injuring/damaging effect by accelerating the reaction rate between the formulation and the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, suspensions, and combinations thereof, each containing one or more materials. If the formulation contains a vapor of one or more materials, heat may be generated in the tissue by condensation of the vapor into a liquid. If the formulation contains a liquid or solution, heat may be transferred from the formulation at a temperature above body temperature. The temperature of the formulation may be from −40 to 140° C., from −30 to 100° C., from −30 to 80° C., or below −40° C., or less than, equal to, or greater than −30° C., −20, −10, −5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140° C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may be -40 to 100°C, -30 to 90°C, -20 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or above 100°C. The formulation infusion pressure may be 0.1 to 14 atm, preferably 3 to 10 atm, and most preferably 4 to 8 atm. For denervation, the formulation is delivered through a needle to the area surrounding the blood vessel, and the volume of the formulation may range from 0.1 mL to 1.0 mL, preferably 0.3 mL to 0.8 mL, and most preferably 0.4 mL to 0.7 mL.

In some embodiments, a method for reducing fasting blood glucose, HbA1c, glucagon, epinephrine, norepinephrine, cortisol, or growth hormone in diabetics includes percutaneously inserting a delivery catheter into a hepatic artery adjacent to a nerve, particularly the celiac artery, common hepatic artery, proper hepatic artery, or left and right hepatic arteries; using any of the catheters described herein to infuse the aforementioned formulation and/or energy into tissue in a body lumen adjacent to the nerve or directly into the nerve; and withdrawing the delivery catheter from the body lumen once the amount of delivered formulation and/or energy is effective to beneficially injure or damage the nerve. The purpose of the heat/energy may be to enhance the injuring/damaging effect by accelerating the reaction rate between the formulation and the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, suspensions, and combinations thereof, each containing one or more materials. If the formulation contains a vapor of one or more materials, heat may be generated in the tissue by condensation of the vapor into a liquid. If the formulation comprises a liquid or solution, heat may be transferred from the high temperature formulation above body temperature. The temperature of the formulation may be from -40 to 140°C, from -30 to 100°C, from -30 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140°C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the temperature of the formulation and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may be -40 to 140°C, -30 to 100°C, -30 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or greater than 140°C. For denervation, the formulation is delivered through a needle to the area surrounding the blood vessel, and the volume of the formulation may range from 0.1 mL to 1.0 mL, preferably 0.3 mL to 0.8 mL, and most preferably 0.4 mL to 0.7 mL.

In some embodiments, a method for treating obesity and/or diabetes includes inserting any of the delivery catheters described herein into the left and/or right gastric arteries adjacent to the gastric and esophageal nerves, using the catheter to infuse the formulation and/or energy described above into the tissue of the gastric artery or outside the artery adjacent to the nerve, and withdrawing the delivery catheter from the gastric artery once the amount of formulation and/or energy delivered is effective to beneficially injure or damage the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, suspensions, and combinations thereof, each containing one or more materials. If the formulation contains a vapor of one or more materials, heat may be generated within the tissue by condensation of the vapor into a liquid. If the formulation contains a liquid or solution, heat may be transferred from the formulation at elevated temperatures above body temperature. The temperature of the liquid formulation may be from −40 to 140° C., from −30 to 100° C., from −30 to 80° C., or below −40° C., or less than, equal to, or greater than −30° C., −20, −10, −5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140° C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may be -40 to 100°C, -30 to 90°C, -20 to 80°C, or less than -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or greater than 100°C. The formulation infusion pressure and/or balloon inflation pressure may be 0.1 to 14 atm, preferably 3 to 10 atm, and most preferably 4 to 8 atm.

In some embodiments, a method for treating obesity includes inserting a delivery catheter either inside or outside a lumen of the digestive system adjacent to a nerve, using the catheter to infuse the aforementioned formulation and/or energy into tissue in the digestive system lumen, and withdrawing the delivery catheter from the digestive system lumen after the amount of formulation and/or energy delivered is effective to beneficially injure or damage the tissue. Possible digestive system lumens in this embodiment include the esophagus, stomach, duodenum, jejunum, small and large intestines, and colon. The purpose of the heat/energy may be to enhance the injuring/damaging effect by accelerating the reaction rate between the formulation and the nerve. Possible formulations include gases, vapors, liquids, solutions, emulsions, suspensions, and combinations thereof, each containing one or more materials. If the formulation contains a vapor of one or more materials, heat may be generated by condensation of the vapor into a liquid. If the formulation contains a liquid or solution, heat may be transferred from the formulation at a temperature above body temperature. The temperature of the liquid formulation may be from −40 to 140° C., from −30 to 100° C., from −30 to 80° C., or below −40° C., or less than, equal to, or greater than −30° C., −20, −10, −5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140° C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the temperature of the formulation and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may be -40 to 100°C, -30 to 90°C, -20 to 80°C, or less than -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or greater than 100°C.

In some embodiments, a method for treating obesity and diabetes includes inserting any of the delivery catheters described herein into the left and/or right gastric arteries adjacent to the gastric and esophageal nerves, using the catheter to infuse the formulation and/or energy into tissue at or outside the gastric artery adjacent to the nerves, and withdrawing the delivery catheter from the gastric artery once the amount of formulation and/or energy delivered is effective to beneficially injure or damage the nerves. Possible formulations include gases, vapors, liquids, solutions, emulsions, suspensions, and combinations thereof, each containing one or more materials. If the formulation contains a vapor of one or more materials, heat may be generated within the tissue by condensation of the vapor into a liquid. If the formulation contains a liquid or solution, heat may be transferred from the formulation at elevated temperatures above body temperature. The temperature of the liquid formulation may be from −40 to 140° C., from −30 to 100° C., from −30 to 80° C., or below −40° C., or less than, equal to, or greater than −30° C., −20, −10, −5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140° C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the temperature of the formulation and higher than body temperature. The temperature of the treated tissue adjacent to the nerve may be -40 to 100°C, -30 to 90°C, -20 to 80°C, or less than -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or greater than 100°C.

In some embodiments, a method for treating urological disorders and/or benign prostatic hyperplasia (BPH) includes inserting a delivery catheter into a urological lumen, using the catheter to infuse the aforementioned formulation and/or energy into or outside the lumen of a urological tissue, e.g., the prostate, urethra, ureter, etc., and withdrawing the delivery catheter from the urological lumen after the amount of formulation and/or energy delivered is effective to beneficially injure or damage the tissue. The purpose of the heat/energy may be to enhance the injuring/damaging effect by accelerating the reaction rate between the formulation and nerves. The formulation may include one of a gas, vapor, liquid, solution, emulsion, suspension, and combinations thereof, having one or more materials. If the formulation includes a vapor of one or more materials, heat may be generated by condensation of the vapor into a liquid. If the formulation includes a liquid or solution, heat may be transferred from the formulation at a temperature above body temperature. The temperature of the liquid formulation may be from −40 to 140° C., from −30 to 100° C., from −30 to 80° C., or below −40° C., or less than, equal to, or greater than −30° C., −20, −10, −5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or above 140° C. The temperature of the tissue to be treated adjacent to the nerve may be lower than the temperature of the formulation and higher than body temperature. The temperature of the tissue to be treated adjacent to the nerve may be -40 to 100°C, -30 to 90°C, -20 to 80°C, or less than -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or greater than 100°C. The formulation infusion pressure and/or balloon inflation pressure may be 0.1 to 14 atm, preferably 3 to 10 atm, and most preferably 4 to 8 atm.

In some embodiments, a method of treating cancer or tumors involves inserting a needle or needle-type catheter into the cancer or tumor percutaneously, orally, or through a lumen under imaging guidance; using the catheter to infuse the compound and/or energy described above into cancerous tissue in a human body; and withdrawing the delivery catheter from the body when the amount of compound and/or energy delivered is effective to beneficially injure, damage, or eliminate the cancerous tissue. Injury, damage, or elimination of the cancerous tissue can alleviate disease symptoms, such as shrinking or eliminating a tumor. Possible imaging guidance includes ultrasound, X-ray, CT scan, NMR imaging, and endoscopy. Relevant cancers include adrenal, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, and uterine cancers. The purpose of the heat/energy may be to accelerate the rate of reaction between the compound and the cancerous tissue, thereby enhancing the injuring/damaging/eliminating effect. The formulation may comprise one of a gas, vapor, liquid, solution, emulsion, suspension, and combinations thereof, comprising one or more materials. If the formulation comprises a vapor of one or more materials, heat may be generated within the tissue by condensation of the vapor into a liquid. If the formulation comprises a liquid or solution, heat may be transferred from the high-temperature formulation, which is above body temperature. The temperature of the liquid formulation may be from -40 to 140°C, from -30 to 100°C, from -30 to 80°C, or below -40°C, or less than, equal to, or greater than -30°C, -20°C, -10°C, -5°C, 0°C, 5°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, or above 140°C. The temperature of the tissue to be treated may be lower than the temperature of the formulation and higher than body temperature. The temperature of the tissue being treated may be -40 to 100°C, -30 to 90°C, -20 to 80°C, or less than -40°C, or less than, equal to, or greater than -30°C, -20, -10, -5, 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or greater than 100°C.

A method for treating myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), rheumatoid arthritis, or cancer due to an immune response to inflammatory conditions may include percutaneously inserting a delivery catheter into a splenic artery adjacent to a nerve, using any of the catheters described herein to infuse the formulation and/or energy described above into tissue in a body lumen adjacent to the nerve or directly into the nerve, and withdrawing the delivery catheter from the body lumen, where the amount of formulation and/or energy delivered is effective to beneficially injure or damage the nerve. For denervation, the formulation may be delivered through a needle into the area surrounding the blood vessel, with the volume of the formulation varying from 0.1 mL to 1.0 mL, 0.3 mL to 0.8 mL, or 0.4 mL to 0.7 mL per dose.

A method for treating myocardial infarction, atherosclerosis, coronary artery disease (CAD), or peripheral vascular disease (PAD) due to hypercholesterolemia may include percutaneously inserting a delivery catheter into a splenic artery adjacent to a nerve, using any of the catheters described herein to infuse the formulation and/or deliver energy to tissue in a body lumen adjacent to the nerve or directly to the nerve, and withdrawing the delivery catheter from the body lumen, where the amount of formulation and/or energy delivered is effective to beneficially injure or damage the nerve. For denervation, the formulation may be delivered through a needle to the area surrounding the blood vessel, with the volume of the formulation varying from 0.1 mL to 1.0 mL, 0.3 mL to 0.8 mL, or 0.4 mL to 0.7 mL per dose.

Although hypertension and hypercholesterolemia predispose to vascular diseases such as coronary heart disease, their combined effects are considered multiplicative, not additive, and therefore significantly modify risk. Individuals with a combination of risk factors are therefore at particularly high risk for coronary heart disease. Impaired endothelium-dependent vasorelaxation in patients with essential hypertension may be related to hypercholesterolemia, and increased sympathetic activity may be associated with hyperlipidemia in hypertension. For example, the positive association between serum triglyceride levels and blood pressure is significant, especially in individuals with a high body mass index (BMI > 24). Embodiments of the present invention can not only reduce blood pressure but also cholesterol levels. The biological correlations between blood pressure and atherogenic blood lipid fractions and the pathophysical factors underlying these correlations may influence the mechanisms by which hypertension is associated with an increased risk of coronary heart disease. Thus, various embodiments of the methods of treatment result in a reduction in either blood pressure or cholesterol levels, or in both blood pressure and cholesterol levels, which may be beneficial in reducing the risk of coronary artery disease (CAD) and peripheral vascular disease (PAD).

A method for treating a disease using a needle-type balloon infusion system, the needle-type balloon infusion system including a set of a needle-type balloon delivery catheter, a guidewire, an ablation agent, saline or heparinized saline or a therapeutic agent, and a fluid reservoir, the method comprising: 1) inserting the needle-type balloon delivery catheter into a body lumen, the needle-type balloon delivery catheter including a distal head, at least one marker band, at least one needle, at least one needle exit hole, at least one flushing hole, a flushing lumen, a flushing port, a guidewire lumen, at least one centrally positioned balloon at approximately the distal end of the catheter, one inflation lumen, one inflation port, one ablation port, a needle movement shaft, and a needle movement controller, the needle lumen being pre-filled with a removal agent and the flushing lumen being pre-filled with a flushing medium prior to insertion; 2) inserting the delivery catheter shaft into the body lumen. 3) disposing at least one needle inside, outside, or inside the wall of the body lumen; 4) infusing a formulation through the at least one needle, wherein the amount of formulation delivered is effective to injure or damage the target tissue to alleviate symptoms of the disease; 5) selectively removing the formulation from the tissue; 6) retracting the needle inside the delivery catheter and deflating the centrally-located balloon; 7) flushing the flushing lumen before deflating the balloon or before inserting into a next body lumen to prevent clogging of the needle lumen and clot formation; 8) inserting the needle-type balloon delivery catheter into the next body lumen; 9) repeating steps 2) through 8) until all targeted body lumens have been treated; and 10) withdrawing the delivery catheter from the body lumen. The disease may be hypertension, pulmonary hypertension, diabetes, obesity, metabolic syndrome, heart failure, myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), end-stage renal disease, inflammatory bowel disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), urological disease, cancer, tumor, pain, rheumatoid arthritis (RA), asthma, chronic obstructive pulmonary disease (COPD), or a combination thereof. The ablative agent may be one of ethanol, dehydrated ethanol, acetic acid, or diluted acetic acid. The flushing medium may include saline, heparinized saline, or an agent neutralized against the ablative agent. The body lumen may include a renal artery (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of left main renal artery, distal end of right main renal artery, distal end of left main renal artery bifurcation, or distal end of right main renal artery bifurcation), renal vein, gastric artery, gastric vein, hepatic artery, hepatic vein, pulmonary artery, pulmonary vein, celiac artery, celiac vein, gastroduodenal artery, gastroduodenal vein, splenic artery, splenic vein, adrenal artery, adrenal vein, phrenic artery, phrenic vein, mesenteric artery, mesenteric vein, airway, esophagus, stomach, duodenum, jejunum, urological lumen, or combinations thereof.

A method for using a needle-type balloon delivery catheter may include pre-filling the needle lumen with an ablation agent, pre-filling the flushing lumen with a flushing medium, and inserting the catheter into the guiding catheter over a guidewire. Upon reaching the treatment site, the balloon may be inflated to the size of the vessel to center the needle head, after which the needle may be advanced to the treatment location and an ablation agent may be infused. After infusion, the needle may be retracted and retracted into the distal head, and a flushing fluid may be injected to keep the needle chamber/hole and needle tip/opening of the distal head clean and avoid direct contact with blood. The balloon may be deflated, and the catheter may be retracted from the treatment location and/or moved to another treatment location.

In some embodiments, if the target vessel is long and needs to be treated in more than one session, a distance between treatment locations may be used to separate the infused ablation agent. The separation distance between treatment locations may be from 5 mm to 30 mm, e.g., from 5 mm to 15 mm.

The volume of ablation agent may be 0.1 mL, 0.2, 0.3, 0.4, 0.5, 0.6, 0.8, 1.0, or 1.2 mL for each administration/treatment into a major blood vessel, such as an artery. If more than one treatment is performed, the total dose (volume) in a particular major blood vessel (length) may be 0.3 mL, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, or 2.4 mL or up to 3.6 mL. In a branch of a blood vessel or artery, the volume of each administration may be 0.1 mL, 0.2, 0.3, 0.4, 0.5, or 0.6 mL. If the treatment is administered more than once, the total dose (volume) in this branch may be 0.2 mL, 0.4, 0.6, 0.8, 1.0, or 1.2 mL.

Various embodiments of the present invention provide a needle-type balloon delivery catheter for delivery of a substance to a target tissue in a lumen of a patient's body. The delivery catheter may include a catheter shaft having a proximal end and a distal end. The delivery catheter may include at least one marker band disposed near the distal end of the shaft. The delivery catheter may include at least one needle (e.g., three needles), each needle disposed in a needle lumen. The needle lumen may open to the exterior of the catheter shaft through at least one needle exit hole. The delivery catheter may include a flushing port at the proximal end of the shaft in fluid communication with a flushing lumen. The flushing lumen is in fluid communication with the distal end of the needle lumen. The flushing port may be in fluid communication with the needle exit hole through the flushing lumen. The delivery catheter may include a guidewire lumen extending through at least the distal end of the shaft. The delivery catheter may include at least one balloon adjacent the distal end of the catheter. The delivery catheter may include an inflation lumen. The delivery catheter may include an inflation port in fluid communication with the inflation lumen and thus in fluid communication with the interior of the balloon. The balloon is inflatable through the inflation lumen and inflation port, allowing the distal end of the catheter shaft to be generally centered in the body lumen during inflation. The delivery catheter may include an ablation or denervation port at the proximal end of the shaft. The ablation or denervation port is in fluid communication with at least one needle to supply ablation energy or a formulation to the at least one needle. The delivery catheter may include a needle movement controller in electrical or mechanical communication with the at least one needle. The needle movement controller can position the at least one needle in the body lumen, within the wall of the body lumen, or outside the body lumen. Positioning the needle through the needle exit opening allows the formulation to enter the wall of the body lumen at a pressure higher than that of the body lumen. The target tissue may be a target tissue of the renal artery (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of the left main renal artery, distal end of the right main renal artery, distal end of the left main renal artery bifurcation, or distal end of the right main renal artery bifurcation), renal vein, gastric artery, gastric vein, hepatic artery, hepatic vein, pulmonary artery, pulmonary vein, celiac artery, celiac vein, gastroduodenal artery, gastroduodenal vein, splenic artery, splenic vein, adrenal artery, adrenal vein, phrenic artery, phrenic vein, mesenteric artery, mesenteric vein, airway, esophagus, stomach, duodenum, jejunum, urological lumen, or combinations thereof. The formulation pressure during infusion may be any suitable pressure, and the balloon inflation pressure may be any suitable pressure. For example, the formulation infusion pressure may range from 0.1 to 14 atm. The balloon inflation pressure may range from 0.1 to 14 atm.

(Example)
Various embodiments of the invention may be better understood by reference to the following examples, which are provided by way of illustration.The invention is not limited to the examples set forth herein.

Example 1: Preclinical studies
A 47 kg animal, such as a pig, was anesthetized with isoflurane, and one side of the renal artery was transected with ethanol using a three-needle single-balloon catheter, while the contralateral renal artery served as a control. The catheter needle span diameter was approximately 10 mm. The catheter balloon was a low-pressure, flexible balloon with a diameter of 7 mm at 1 atm, which served to center the distal shaft without excessively stretching the artery. Optionally, the balloon may be inflated with a syringe without the use of an inflation device. Depending on the balloon's characteristics, the balloon may be used in arteries of any diameter (below or above the balloon diameter). Prior to insertion into the artery, the catheter was prefilled with a liquid formulation (with the needle out) until outflow occurred. The needle was then retracted, and a syringe needle with a predetermined treatment volume was connected to the catheter. Using standard renal access procedures, the three-needle balloon delivery catheter was placed over a guidewire into the target renal artery, one of the main and lateral renal arteries (branch), in order. Upon reaching the target ablation site, the balloon was inflated, followed by placement of the needle, and room-temperature absolute ethanol was infused into the adventitia and peri-adventitial space of the renal artery. The infusion volume was 0.6 mL in the main artery and 0.3 mL in the bifurcation, administered with a 1 mL syringe. The infusion time was within 5 seconds for both volumes. During balloon inflation, the balloon diameter was monitored by fluoroscopic imaging to ensure it had a ratio of approximately 1:1.1 (i.e., slightly larger) than the diameter of the surrounding artery. At the end of the treatment period, the needle was first retracted into the catheter, and then the balloon was deflated, ready for withdrawal or placement at another arterial location if necessary for the next treatment. In this example, four treatments were performed: two in the main artery and one in each bifurcation, using a total volume of 1.8 mL of formulation.

Post-resection renal angiograms were obtained to detect whether any spasms, stenosis, or other abnormalities occurred. There was no significant renal artery spasm during or after infusion therapy.

Two weeks after treatment, the animals were euthanized, and gross necropsy revealed normal tissue in all treatment-related organs. Renal tissue samples were obtained from the cranial (n=3), mid-section (n=3), and caudal (n=3) regions of the renal cortex to determine norepinephrine (NE) content in the renal tissue using a known HPLC method. Norepinephrine is a neurotransmitter used in the sympathetic nervous system, and its level serves as a standard indicator of renal denervation. Compared with the untreated side (control), NE levels were low or significantly lower in the treated side after denervation, as shown in Figure 10. Ethanol ablation of the renal artery resulted in a 94% reduction in renal NE levels (mean NE content: control: 87 ng/g vs. treatment: 4.9 ng/g). The percentage range of individual NE reduction calculated from similar tissue locations between control and treatment was 89% to 97.5%. Renal arteries and surrounding tissues were also collected for histopathological evaluation.

After ethanol ablation, not only was NE content reduced, but histopathological evaluation revealed renal nerve damage, with nerves (see arrows) surrounded by mild fibrosis at the outer edge of the adventitia, as shown in Figure 11.

Example 2: Preclinical studies
Two 46 kg piglets were treated with ethanol ablation of the hepatic artery using a three-needle single-balloon catheter similar to that used in Example 1, using a formulation containing room-temperature absolute ethanol. Prior to arterial insertion, the catheter was prefilled with the liquid formulation (with the needle extended) until outflow occurred. The needle was then retracted, and a syringe needle containing a predetermined treatment volume was connected to the catheter. Standard hepatic artery access procedures were performed. Each hepatic artery was treated twice, evenly spaced along the length of the artery. The infusion volume was 0.6 mL per administration using a 1 mL syringe, and the infusion time was less than 5 seconds. The inflated balloon diameter was monitored to have an inflation ratio of less than 1:1.1 relative to the artery, and inflation was performed using the syringe needle. Liver angiography showed no significant arterial spasm during or after infusion treatment in both piglets in this study. As controls, untreated piglets with similar body weights were used for NE reduction calculations and histopathological evaluation comparisons.

Two weeks after treatment, two animals were euthanized. Gross necropsy revealed normal tissue in all treatment-related organs. Liver tissue samples were obtained from the right lateral lobe (n=2), right median lobe (n=2), left lateral lobe (n=2), left median lobe (n=2), and caudal lobe (n=2) of the renal cortex to determine norepinephrine (NE) content in liver tissue using a known HPLC method. NE reduction was calculated based on data collected from similarly located tissues between treatment and control animals. As shown in Figure 12, the mean liver NE concentration reductions for the two animals were 85% and 94%. The individual calculated percentages ranged from 55% to 95% in one animal and 86% to 97.5% in the other. As with the kidney resection studies, arterial and surrounding tissues were collected for histopathological evaluation.

The results of the above preclinical studies indicate that ethanol treatment is effective and safe.

Example 3: Clinical Trial, Metabolic Syndrome
In one example, human male patient A was 53 years old and had metabolic syndrome, had hypertension for 10 years and was taking two antihypertensive medications, had type 2 diabetes for 2 years and was taking two T2DM medications, and had obesity for 8 years. Prior to treatment, his triglyceride level was 336 mg/dL. In his treatment, the target arteries were the renal artery, hepatic artery, splenic artery, and left gastric artery.

In line with institutional standard practice, modest sedation was used during the procedure; general anesthesia was not used. The arteries were accessed using a 7F guide catheter introduced through the femoral artery. Arterial angiography was performed prior to the intervention. All four arteries were treated with the same procedure. Treatment began in the upper body arteries, in the following order: splenic, hepatic, left gastric, left renal, and right renal arteries. After initial angiographic investigation of the hepatic, splenic, and left gastric arteries, a rapid-exchange, three-needle, single-balloon catheter was advanced through the guide catheter and into the artery over the guide catheter. Prior to insertion into the artery, the catheter was prefilled with a liquid ablation formulation (absolute ethanol) until flow occurred from the needle (with the needle out). The needle was then retracted, and a syringe needle containing a predetermined treatment volume was connected to the catheter.

The maximum catheter needle span diameter was approximately 12 mm, and the span diameter was adjustable for each arterial diameter. The catheter balloon was a low-pressure, deformable balloon with a diameter of 7 mm at approximately 1 atm. The function of this balloon was to center the distal head/shaft without overstretching the artery. The balloon was inflated (without the use of an inflation device) with a 30 cc syringe with a stopcock to gently control the balloon diameter.

A three-needle single-balloon delivery catheter was placed into the target splenic artery under fluoroscopic imaging guidance. Upon reaching the target ablation site, the balloon was inflated, the needle was placed, and room-temperature absolute ethanol was infused into the adventitia and periadventitial space of the splenic artery. The infusion volume was 0.6 mL per administration using a 1 mL syringe. The infusion time was within 10 seconds per administration. During balloon inflation, the balloon diameter was monitored by fluoroscopic imaging to have a ratio of approximately 1:1.1 (slightly larger) to the diameter of the surrounding artery. At the end of the treatment period, the needle was retracted inside the catheter, the balloon was deflated, and the catheter was moved to a second treatment location in the same splenic artery, approximately 15 mm away from the first treatment location. The treatment steps (balloon inflation, needle placement, infusion ablation, needle withdrawal, balloon deflation) were repeated for the second treatment. The total volume of alcohol used in the two treatments was 1.2 mL in the splenic artery.

The same treatment method and procedural steps as for the spleen treatment were also used for the common hepatic artery ablation. The catheter was replaced with a new catheter for the common hepatic artery ablation. There were a total of two treatments for the common hepatic artery, spaced 15 mm apart (between treatment locations), with the same ablation volume of 0.6 mL. The total volume of alcohol used for the hepatic artery ablation was 1.2 mL. After the liver treatment, the catheter was placed in the left gastric artery for the next ablation treatment. The same method and procedure were used for the left gastric artery, except that one ablation treatment of 0.6 mL of alcohol was also applied to the left gastric artery. After withdrawal of the three-needle single-balloon delivery catheter, an angiogram was performed.

After the above three arterial ablation treatments, a pre-interventional renal artery angiogram was performed. The appropriate branch and main arteries were analyzed and pre-identified for treatment. After analysis, a three-needle balloon delivery catheter was advanced over the guidewire through the guide catheter into the branch of the left renal artery and stopped just beyond the bifurcation area. Using the same catheter manipulation method and procedural steps, the branch artery was ablated once with 0.3 mL of alcohol. Upon completion of the bifurcation ablation, the catheter was withdrawn into the main artery to a position just short of the bifurcation area, and this position was treated with 0.6 mL of alcohol. The catheter was then withdrawn approximately 10 mm from the first treatment position in the main artery to a second ablation position, and a volume of 0.6 mL of alcohol was applied for the second ablation treatment. A total of three treatments were performed on the left renal artery: 2X on the main artery and 1X on the branch artery. The total volume of alcohol used was 1.5 mL.

The same method and procedural steps were repeated for the right renal artery. After initial angiography and analysis of the right renal artery, a three-needle balloon delivery catheter was advanced over the guidewire through the guide catheter into branch artery 1. Branch 1 was ablated twice at treatment locations approximately 10 mm apart, using 0.3 mL of alcohol for each treatment. The catheter was then placed into branch artery 2 and treated twice, using a 0.3 mL volume of alcohol for each treatment. After treatment of both branches, the catheter was withdrawn into the main artery until the needle was near the midpoint of the main artery, and the right main artery was ablated once with a 0.6 mL volume of alcohol. The total volume of alcohol used in the right renal artery treatment was also 1.8 mL.

Patient A was followed up at 2 weeks (2 wks), 1 month (1 mo), and 3 months (3 mo) after treatment, and his follow-up data are listed below, along with baseline data obtained before treatment for comparison. There were no changes in any medications during the follow-up period.

Body weight was 103 kg at baseline, 96.2 kg at 2 weeks, 95.6 kg at 1 month, and 96.2 kg at 3 months. The patient's weight loss was observed to be approximately 7% from the third week (2 weeks) after treatment, and the weight loss was maintained at three months of follow-up.

24-hour blood pressure, SBP/DBP: Base = 164/109 mmHg, 1 mos = 140/87 mmHg, 3 mos = 141/84 mmHg. Blood pressure data are 24-hour mean ambulatory blood pressure values. The reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline were significant, approximately 14% and 20%, respectively, and the reductions were maintained at 3-month follow-up.

Blood glucose levels and HbAlc were basal = 7.5% and 3mos = 6.6%. The patient's hemoglobin Ale (HbAlc) levels showed significant improvement. At the 3-month follow-up, the fluctuation in his HbAlc values compared to baseline was approximately -1%.

Triglycerides were basal = 336 mg/dL, 2wk = 160 mg/dL, 1mo = 139 mg/dL, and 3mos = 167 mg/dL. Triglycerides are a type of fat (lipid) found in the blood. High triglyceride levels may indicate that a person has fatty liver. Patient A's triglyceride levels improved at the two-week follow-up, with a reduction of approximately 50%. The reduced and improved triglyceride levels were maintained at the three-month follow-up. At the one-month follow-up, Patient A's TG levels were within the normal range.

High-density lipoprotein (HDL) levels were basal = 39 mg/dL, 2wk = 42 mg/dL, 1mo = 43 mg/dL, and 3mos = 40 mg/dL. Patient A's high-density lipoprotein (HDL) levels were just below the normal range. At follow-up, his HDL showed modest improvement, with all three values above 40. Patient A's TG/HDL ratio improved significantly from 8.6 (>5 is abnormal) at baseline to 4.2, which is within the normal range (≦5), at the 3-month follow-up. If the patient had NAFLD, Patient A's NASH status improved significantly.

Patient A's short-term results were significant and encouraging for this treatment and technique. Data showed that the patient's health improved, and his metabolic syndrome-related illnesses appeared to be in check at three-month follow-up.

Example 4: Clinical Trial, Hypertension
In another example, multiple arteries/tissues were treated for hypertension. Patient B, a 50-year-old male, had controlled blood pressure at a three-month follow-up after ablation treatment. Patient B had a five-year history of hypertension. Patient B underwent the same procedures and ablation treatment methods as Patient A in Example 3. The arteries treated and the ablation dose at each treatment location are summarized for Patient B in Table 1.

Table 1 shows the treated arteries for patient B and the ablation dose at each treatment location. Here, renal B refers to the renal branch artery, renal M refers to the main renal artery, R refers to the right, and L refers to the left.

Post-treatment mean 24-hour ambulatory blood pressure data were: baseline = 136/79 mmHg, 1 mo = 107/61 mmHg, 3 mo = 115/66 mmHg. The reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline at 1-month follow-up were significant, approximately 21% and 23%, respectively. His improved blood pressure was maintained at 3-month follow-up, with a reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline of approximately 15%.

Example 5: Clinical Trial, T2DM
In another example, multiple arteries/tissues were treated for diabetes. The same patient B described above had a one-year history of T2DM, and his hepatic, splenic, celiac, right renal, and left renal arteries were treated for diabetes. The treatment in Example 4 resulted in an improvement in patient B's fasting blood glucose and HbA1c levels.

Post-treatment fasting blood glucose data were: basal = 186 mg/dL, 2wk = 127 mg/dL, 1mo = 92 mg/dL, 3mo = 110 mg/dL. Tests were performed in the morning before the patient ate. A fasting blood glucose level of 100 to 125 mg/dL (5.6 to 9.6 mmol/L) is considered prediabetic. A fasting blood glucose level of 125 mg/dL or higher indicates the individual has diabetes. The data show that prior to treatment, Patient B had diabetes. His fasting blood glucose levels significantly improved from baseline after treatment, changing by -32% at the 2-week follow-up and -50% at the 1-month follow-up. At the 3-month follow-up, the reduced blood glucose levels were maintained at a low level of 110 mg/dL, a -41% decrease from baseline.

Blood glucose HbAlc data showed baseline = 8.1% and 3mos = 6.0%. The patient's HbAlc improved by an absolute value of -2.1% (approximately 26%) from baseline three months after treatment.

Example 6: Clinical Trial, Weight Loss
In another example, multiple arteries/tissues were treated to manage weight. Patient B, who had a 3-year history of obesity, had his weight improved after ablation treatment. The arteries treated were the hepatic, splenic, celiac, right renal, and left renal arteries. Treatment is described in Example 4.

Body weight was 83 kg at baseline, 79.3 kg at 2 weeks, 79.9 kg at 1 month, and 79.1 kg at 3 months. An initial weight loss of -4.5%, from a baseline of 83 kg to 79.3 kg, was observed at the 2-week follow-up. The improved body weight was maintained at the 3-month follow-up.

The terms and expressions employed are used as terms of description, not limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the shown and described features or portions thereof, and it is recognized that various modifications are possible within the scope of the embodiments of the present invention. Thus, while the present invention has been specifically disclosed with reference to specific embodiments, it will be understood that those skilled in the art may employ alternative features, modifications, and variations of the concepts disclosed herein, and that such modifications and variations are considered to be within the scope of the embodiments of the present invention.

Illustrative Embodiments
The following exemplary embodiments are provided, and the numbering of the embodiments should not be construed as designating a level of importance.

A first embodiment provides a method of treating at least one disease (e.g., one disease, two diseases, at least two diseases, three diseases, four diseases, or at least four diseases), the method including treating at least two different target tissues (e.g., at least three different target tissues, or at least four different target tissues) in at least two different body lumens (e.g., at least three different body lumens, or at least four different body lumens), the method including:
performing a therapeutic procedure on a body lumen, the body lumen being a first body lumen;
The treatment procedure is
inserting a delivery catheter into a body lumen;
wherein the delivery catheter has a catheter shaft, a balloon at a distal end of the shaft, and an inflation lumen in fluid communication with the interior of the balloon;
inflating the balloon to center the distal end of the shaft within the body lumen;
denervating or ablating target tissue in a body lumen with a delivery catheter;
wherein the method comprises delivering to the target tissue an amount of energy or agent effective to injure or damage the target tissue so as to alleviate symptoms of the disease;
Deflating the balloon;
removing the delivery catheter from the body lumen;
and
performing a therapeutic procedure on a lumen of a second body, the lumen being different from the lumen of the first body.

Embodiment 2 provides the method of embodiment 1, wherein performing the therapeutic procedure on the lumen of the second body includes reusing the same delivery catheter used to treat the lumen of the first body for the therapeutic procedure on the lumen of the second body.

Embodiment 3 provides a method according to any one of embodiments 1 and 2, wherein performing a therapeutic procedure on the lumen of the second body includes using a delivery catheter for the therapeutic procedure on the lumen of the second body that is different from the delivery catheter used for the therapeutic procedure on the lumen of the first body, the different delivery catheter having a catheter shaft, a balloon at the distal end of the shaft, and an inflation lumen that is in fluid communication with the interior of the balloon.

A fourth embodiment provides the method of any one of the first to third embodiments,
the target tissues of the lumen of the first body and the lumen of the second body are different and independently selected from target tissues of the renal artery, the pulmonary artery, the vascular lumen, the celiac artery, the common hepatic artery, the proper hepatic artery, the gastroduodenal artery, the right and left hepatic arteries, the splenic artery, the right and left gastric arteries, the adrenal artery, the phrenic artery, the mesenteric artery, the non-vascular arteries, the airway, the nasal cavity, the esophagus, the respiratory and digestive system lumens, the stomach, the duodenum, the jejunum, the prostate, the urethra, the ureter, and the urological lumens;
The first body lumen and the second body lumen belong to different classes of body lumens selected from a renal artery (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of left main renal artery, distal end of right main renal artery, distal end of left main renal artery bifurcation, distal end of right main renal artery bifurcation, or combinations thereof), a renal vein, a gastric artery, a gastric vein, a hepatic artery, a hepatic vein, a pulmonary artery, a pulmonary vein, a celiac artery, a celiac vein, a gastroduodenal artery, a gastroduodenal vein, a splenic artery, a splenic vein, an adrenal artery, an adrenal vein, a phrenic artery, a phrenic vein, a mesenteric artery, a mesenteric vein, an airway, an esophagus, a stomach, a duodenum, a jejunum, and a urological lumen, or combinations thereof.

Embodiment 5 provides the method of any one of embodiments 1-4, wherein the disease is selected from hypertension, pulmonary hypertension, diabetes, obesity, metabolic syndrome, heart failure, myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), end-stage renal disease, digestive disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), urological disease, cancer, tumor, pain, rheumatoid arthritis (RA), asthma, chronic obstructive pulmonary disease (COPD), or a combination thereof.

Embodiment 6 provides the method of any one of embodiments 1-5, wherein alleviating the symptoms of the disease includes alleviating the symptoms of hypertension, diabetes, obesity, coronary artery disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cancer, rheumatoid arthritis, or a combination thereof.

Embodiment 7 provides the method of any one of embodiments 1-6, wherein alleviating the symptoms of the disease includes reducing blood pressure, reducing blood glucose levels and AIC, reducing weight, reducing restenosis, reducing liver fat, and alleviating pain, or a combination thereof.

Embodiment 8 provides the method of any one of embodiments 1-7, wherein the delivery catheter further comprises a guidewire lumen extending through at least the distal end of the shaft, and the method further comprises advancing the delivery catheter over the guidewire.

Embodiment 9 provides a method according to any one of embodiments 1-8, wherein the delivery catheter further includes a marker band on or adjacent to the balloon, and the method further includes controlling the position of the marker band under fluoroscopic imaging.

Embodiment 10 provides the method of any one of embodiments 1-9, wherein the delivery catheter comprises a chemical infusion delivery catheter.

Embodiment 11 provides a method according to any one of embodiments 1-10, wherein the delivery catheter comprises a combination chemical infusion delivery catheter and an energy delivery catheter.

Embodiment 12 provides a method according to any one of embodiments 1-11, wherein the delivery catheter comprises an energy delivery catheter.

Embodiment 13 provides the method of any one of embodiments 1-12, wherein denervating or ablating the target tissue in the body lumen with the delivery catheter includes delivering an amount of energy from the delivery catheter to the target tissue using radiofrequency, cryoablation, microwave, laser, ultrasound, high-intensity focused ultrasound, vaporizing at least a portion of the formulation into a liquid, or a combination thereof.

Embodiment 14 provides the method of any one of embodiments 1-13, wherein the disease is:
Renal hypertension and diabetes, or
Renal hypertension and obesity, or
Diabetes and obesity, or
It has a combination of these.

Embodiment 15 provides the method of any one of embodiments 1-13, wherein the disease includes renal hypertension and diabetes.

Embodiment 16 provides the method of any one of embodiments 1-13, wherein the disease includes renal hypertension and obesity.

Embodiment 17 provides the method of any one of embodiments 1-13, wherein the disease includes diabetes and obesity.

Embodiment 18 provides the method of any one of embodiments 1-17, wherein the first or second body lumen comprises a splenic artery.

Embodiment 19 provides the method of any one of embodiments 1-18, wherein the first or second body lumen comprises a renal artery (e.g., a left main renal artery, a right main renal artery, a bifurcation of a renal artery, a bifurcation of a left renal artery, a bifurcation of a right renal artery, a distal end of a left main renal artery, a distal end of a bifurcation of a right main renal artery, a distal end of a bifurcation of a left main renal artery, a distal end of a bifurcation of a right main renal artery, or a combination thereof).

Embodiment 20 provides the method of any one of embodiments 1-19, wherein the first or second body lumen comprises the hepatic artery, a branch of the hepatic artery, the right hepatic artery, the left hepatic artery, the common hepatic artery, the proper hepatic artery, the celiac artery, or a combination thereof.

Embodiment 21 provides the method of any one of embodiments 1-20, wherein the first or second body lumen comprises a renal artery (e.g., a left main renal artery, a right main renal artery, a bifurcation of a renal artery, a bifurcation of a left renal artery, a bifurcation of a right renal artery, a distal end of a left main renal artery, a distal end of a bifurcation of a right main renal artery, a distal end of a bifurcation of a left main renal artery, a distal end of a bifurcation of a right main renal artery, or a combination thereof), and the method results in a reduction of renal norepinephrine by at least 40%.

Embodiment 22 provides a method for treating a disease, the method comprising:
inserting a delivery catheter into a body lumen;
wherein the delivery catheter has a catheter shaft, at least one spray hole, and at least one marker band;
spraying the formulation through at least one spray hole;
wherein the amount of the formulation delivered is effective to injure or damage the target tissue so as to alleviate symptoms of the disease;
Optionally, removing the formulation from the tissue;
withdrawing the delivery catheter from the body lumen;
It has.

Embodiment 23 provides the method of embodiment 22, wherein the delivery catheter has at least one centrally positioned balloon, and the method includes inflating the centrally positioned balloon to center the delivery catheter shaft in the body lumen, and deflating the centrally positioned balloon after spraying.

Example 24 provides the method of any one of Examples 22-23, wherein the delivery catheter has at least one injection needle and an infusion lumen in fluid communication with the at least one injection needle, and the method further comprises:
placing at least one injection needle within, outside, or inside the wall of a body lumen;
infusing the formulation through the infusion lumen and the at least one injection needle;
wherein the amount of the agent delivered is effective to injure or damage the target tissue so as to alleviate symptoms of the disease;
retracting the at least one needle within the delivery catheter after infusion;
It further has:

Embodiment 25 provides the method of any one of embodiments 1-24, wherein the at least one needle comprises at least two needles, the delivery catheter further comprises a needle lumen, a needle control mechanism, and a flushing lumen, the at least two needles are deployed from and retracted within the needle lumens by the needle control mechanism, the distal ends of the flushing lumen are in fluid communication with the needle lumens, and the method further comprises flushing the needles with a flushing fluid through the flushing lumen.

Embodiment 26 provides the method of any one of embodiments 1-25, wherein the at least two needles include three needles, the three needles being equally spaced around the circumference of the catheter shaft and positioned distal to the balloon.

[0013] Embodiment 27 provides a method for treating a disease, the method comprising:
inserting a centrally located balloon delivery catheter into a body lumen;
wherein the balloon delivery catheter has at least one centrally located balloon and catheter shaft, at least one injection needle, and at least one marker band;
inflating a centering balloon to center the delivery catheter shaft in the body lumen;
placing at least one injection needle within, outside, or inside the wall of a body lumen;
injecting the formulation through at least one needle;
wherein the amount of the formulation delivered is effective to injure or damage the target tissue so as to alleviate symptoms of the disease;
Optionally, removing the formulation from the tissue;
retracting the needle within the delivery catheter and deflating the centrally located balloon;
withdrawing the delivery catheter from the body lumen;
It has.

Embodiment 28 provides the method of any one of embodiments 1-27, wherein the disease is selected from hypertension, pulmonary hypertension, diabetes, obesity, metabolic syndrome, heart failure, myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), end-stage renal disease, digestive disorders, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), urological disorders, cancer, tumors, pain, rheumatoid arthritis (RA), asthma, chronic obstructive pulmonary disease (COPD), and combinations thereof.

Embodiment 29 provides the method of embodiment 28, wherein the cancer is selected from the group consisting of adrenal gland, bladder, cervix, colon, esophagus, gallbladder, kidney, liver, lung, ovary, pancreas, prostate, rectum, stomach, duodenum, jejunum, uterus, and combinations thereof.

Embodiment 30 provides the method of any one of embodiments 1-29, wherein the target tissue is tissue of a renal artery (e.g., left main renal artery, right main renal artery, renal artery bifurcation, left renal artery bifurcation, right renal artery bifurcation, distal end of left main renal artery, distal end of right main renal artery, distal end of left main renal artery bifurcation, distal end of right main renal artery bifurcation, or combinations thereof), renal vein, gastric artery, gastric vein, hepatic artery, hepatic vein, pulmonary artery, pulmonary vein, celiac artery, celiac vein, gastroduodenal artery, gastroduodenal vein, splenic artery, splenic vein, adrenal artery, adrenal vein, phrenic artery, phrenic vein, mesenteric artery, mesenteric vein, airway, esophagus, stomach, duodenum, jejunum, urological lumen, or combinations thereof.

Embodiment 31 provides the method of any one of embodiments 1-30, wherein the formulation comprises or consists essentially of ethanol.

Embodiment 32 provides the method of any one of embodiments 1-31, wherein the formulation comprises ethanol.

Embodiment 33 provides the method of any one of embodiments 1-32, wherein the formulation comprises a gas, vapor, liquid, solution, emulsion, suspension, or combination thereof of one or more materials.

Embodiment 34 provides the method of any one of embodiments 1-33, wherein the formulation comprises vapors of one or more materials, and heat is generated by condensation of the vapors into a liquid.

Embodiment 35 provides the method of any one of embodiments 1-34, wherein the formulation comprises a liquid or solution, and heat is transferred from the formulation to the tissue.

Embodiment 36 provides the method of any one of embodiments 1-35, wherein the formulation comprises an emulsion or suspension, and heat is transferred from the formulation to the tissue.

Embodiment 37 provides the method of any one of embodiments 1-36, wherein the temperature of the formulation ranges from 40 to 140°C.

Embodiment 38 provides the method of any one of embodiments 1-37, wherein the temperature of the formulation ranges from 0 to 140°C.

Embodiment 39 provides the method of any one of embodiments 1-38, wherein the temperature of the formulation ranges from -40 to 0°C.

Embodiment 40 provides the method of any one of embodiments 1-39, wherein the temperature of the formulation is room temperature.

Embodiment 41 provides a method of any one of embodiments 1-40, wherein the temperature of the target tissue is lower than the temperature of the formulation.

Embodiment 42 provides a method of any one of embodiments 1-41, wherein the temperature of the target tissue is higher than the temperature of the formulation.

Embodiment 43 provides a method according to any one of embodiments 1-42, wherein the formulation infusion pressure ranges from 0.1 to 14 atm.

Embodiment 44 provides a method according to any one of embodiments 1-43, wherein the temperature of the target tissue ranges from -40 to 100°C.

Embodiment 45 provides a method according to any one of embodiments 1-44, wherein the temperature of the target tissue ranges from -40 to 0°C.

Embodiment 46 provides a method according to any one of embodiments 1-45, wherein the temperature of the target tissue is equal to body temperature.

Embodiment 47 provides the method of any one of embodiments 1-46, wherein the pressure of the formulation is in the range of approximately 2 to 200 psi at a temperature range of approximately -40 to 150°C.

Embodiment 48 provides the method of any one of embodiments 1-47, wherein the volume of the formulation ranges from 0.2 microliters to 200 milliliters.

Embodiment 49 provides a method of any one of embodiments 1-48, the method including inflating the delivery catheter in the body lumen for an inflation period of approximately 2 seconds to approximately 60 minutes.

Embodiment 50 provides a method of any one of embodiments 1-49, wherein the method provides heat or energy to the target tissue from approximately 2 cal/g to approximately 150 cal/g.

Embodiment 51 provides a method of any one of embodiments 1-50, wherein the delivery catheter is a needle or needle-type delivery catheter, a single-balloon delivery catheter, a two-balloon delivery catheter, an energy delivery catheter, an infusion catheter, a balloon infusion catheter, a balloon catheter, a dumbbell balloon infusion catheter, or a combination thereof.

Embodiment 52 provides a method according to any one of embodiments 1-51, wherein the balloon inflation pressure ranges from 0.1 to 14 atm.

Embodiment 53 provides the method of any one of embodiments 1-52, wherein the formulation comprises one or more materials selected from water, saline, hypertonic saline, phenols, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, lipiodol, urea, derivatives thereof, and combinations thereof.

Embodiment 54 provides the method of any one of embodiments 1-53, wherein the formulation comprises a gas or vapor of oxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide, water, phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, or a combination thereof.

Embodiment 55 provides the method of any one of embodiments 1-54, wherein the formulation comprises a therapeutic agent for denervation, and the therapeutic agent comprises a sodium channel blocker, tetrodotoxin, saxitoxin, decarbamoylsaxitoxin, vanilloid, neosaxitoxin, lidocaine, conotoxin, cardiac glycoside, digoxin, glutamate, staurosporine, amlodipine, verapamil, cymarin, digitoxin, prosqualidine, quabain, veratridine, domoic acid, oleandrin, carbamazepine, aflatoxin, guanathidine, guanathidine sulfate, or a combination thereof.

Embodiment 56 provides the method of any one of embodiments 1-55, wherein the formulation comprises an imaging agent for imaging nerve denervation, and the imaging agent comprises one of iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan, iodoxanol, ioxaglate, derivatives thereof, or combinations thereof.

Embodiment 57 provides the method of any one of embodiments 1-56, wherein the formulation comprises an azeotrope.

Embodiment 58 provides the method of embodiment 57, wherein the azeotrope comprises ethanol/water, propanol/water, isopropanol/water, butanol/water, acetic acid/water, lactic acid/water, ethyl lactate/water, ethyl lactate/ethanol, lactic acid/ethanol/water, ethyl lactate/water/ethanol, ethyl acetate/ethanol, ethyl nitrate/ethanol, isopropyl acetate/ethanol, or a combination thereof.

Embodiment 59 provides the method of any one of embodiments 1-58, wherein the formulation comprises ethanol, ethanol/water, ethanol/water/oxygen, ethanol/water/air, ethanol/water/contrast agent, ethanol/water/surfactant, ethanol/water/contrast agent/surfactant, propanol/water, isopropanol/water, butanol/water, acetic acid/water, or a combination thereof.

[0023] Embodiment 60 provides a centrally placed balloon catheter for delivery of material to a target location in a lumen of a patient's body, the centrally placed balloon catheter comprising:
a proximal end;
a distal end; and
a wire lumen;
a balloon inflation lumen;
a formulation infusion lumen and/or a vacuum lumen;
an inflatable balloon portion;
at least one injection needle;
at least one marker band adjacent to the centrally located balloon;
at least one needle exit opening adjacent to the marker band for needle placement;
It has.

Embodiment 61 provides a centrally positioned balloon catheter similar to embodiment 60, but with three injection needles.

Embodiment 62 provides a centrally positioned balloon catheter according to any one of embodiments 60-61, wherein placement of a needle through the needle exit opening allows the formulation to enter the wall of the body lumen at a pressure higher than that of the body lumen.

Embodiment 63 provides a centrally positioned balloon catheter according to any one of embodiments 60-62, wherein the target tissue is a tissue of the renal artery, renal vein, gastric artery, gastric vein, hepatic artery, hepatic vein, pulmonary artery, pulmonary vein, celiac artery, celiac vein, gastroduodenal artery, gastroduodenal vein, splenic artery, splenic vein, adrenal artery, adrenal vein, phrenic artery, phrenic vein, mesenteric artery, mesenteric vein, airway, esophagus, stomach, duodenum, jejunum, urological lumen, or a combination thereof.

Embodiment 64 provides a centrally positioned balloon according to any one of embodiments 60-63, wherein the formulation infusion pressure is in the range of 0.1 to 14 atm and the balloon inflation pressure is in the range of 0.1 to 14 atm.

[0032] Embodiment 65 provides a needle-type delivery catheter for delivery of a substance to a target tissue in a body lumen of a patient, the delivery catheter comprising:
a catheter shaft having a proximal and a distal end;
at least one marker band disposed near the distal end of the shaft;
at least one needle disposed in the needle lumen;
wherein the needle lumen opens to the outside of the catheter shaft through at least one needle exit hole;
a flushing port at the proximal end of the shaft that is in fluid communication with the flushing lumen;
wherein the flushing lumen is in fluid communication with the distal end of the needle lumen, and the flushing port is in fluid communication with the needle exit hole through the flushing lumen;
a guidewire lumen extending through at least the distal end of the shaft;
at least one balloon adjacent the distal end of the catheter;
an inflation lumen;
an inflation port in fluid communication with the inflation lumen and in fluid communication with the interior of the balloon;
wherein the balloon is inflatable through an inflation port through the inflation lumen, and the distal end of the catheter shaft is positioned approximately in the center of the body lumen;
a resection or denervation port at the proximal end of the shaft;
wherein the ablation or denervation port is in fluid communication with at least one needle for providing ablation energy or a formulation to the at least one needle;
a needle movement controller for establishing electrical or mechanical communication with at least one needle;
and
Here, the needle movement controller positions at least one needle approximately in the center of the body lumen.

Embodiment 66 provides a delivery catheter similar to embodiment 65, but with three injection needles.

Embodiment 67 provides a delivery catheter according to embodiments 65-66, wherein placement of a needle through the needle exit opening allows the formulation to enter the wall of the body lumen at a pressure higher than the pressure of the body lumen.

Embodiment 68 provides the method of any one of embodiments 65-67, wherein the target tissue is a tissue of a renal artery (e.g., a left main renal artery, a right main renal artery, a renal artery bifurcation, a left renal artery bifurcation, a right renal artery bifurcation, a distal end of the left main renal artery, a distal end of the right main renal artery, a distal end of a branch of the left main renal artery, a distal end of a branch of the right main renal artery, or a combination thereof), a renal vein, a gastric artery, a gastric vein, a hepatic artery, a hepatic vein, a pulmonary artery, a pulmonary vein, a celiac artery, a celiac vein, a gastroduodenal artery, a gastroduodenal vein, a splenic artery, a splenic vein, an adrenal artery, an adrenal vein, a phrenic artery, a phrenic vein, a mesenteric artery, a mesenteric vein, an airway, an esophagus, a stomach, a duodenum, a jejunum, a urological lumen, or a combination thereof.

Embodiment 69 provides a delivery catheter according to any one of embodiments 65-68, wherein the formulation infusion pressure ranges from 0.1 to 14 atm and the balloon inflation pressure ranges from 0.1 to 14 atm.

Embodiment 70 provides a delivery catheter, the delivery catheter comprising:
a shaft having a proximal and a distal end;
one or more needles for infusion therapy disposed around the distal end of the shaft;
an inflatable balloon disposed about the distal end of the catheter shaft such that when the delivery catheter is positioned in the lumen and the balloon is inflated, the distal end of the catheter shaft is centered in the lumen;
and a marker band at the distal end of the shaft.

Embodiment 71 provides a delivery catheter, the delivery catheter comprising:
a shaft having a proximal and a distal end;
one or more needles for infusion therapy disposed around the distal end of the shaft;
and a manipulation mechanism associated with the shaft by a distal end of the shaft that is manipulatable in a direction away from the longitudinal axis of the shaft.

Embodiment 72 provides a delivery catheter according to any one of embodiments 70-71, wherein the one or more needles include one needle.

Embodiment 73 provides a delivery catheter according to any one of embodiments 70-71, wherein the one or more needles have more than one needle.

Embodiment 74 provides a delivery catheter as in embodiment 73, wherein the one or more needles have a tip-to-tip needle span diameter of 5 mm to 80 mm, measured when the one or more needles are fully advanced from the delivery catheter.

Embodiment 75 provides a delivery catheter according to embodiments 73-74, wherein the delivery catheter has a constant tip-to-tip needle span diameter measured when the needle or needles are fully advanced from the delivery catheter.

Embodiment 76 provides a delivery catheter of any one of embodiments 73-75, wherein the delivery catheter has an adjustable end-to-tip needle span diameter as measured when one or more needles are fully advanced from the delivery catheter.

Embodiment 77 provides a delivery catheter according to any one of embodiments 70-71 and 73-76, wherein the one or more needles have three needles.

Embodiment 78 provides a delivery catheter of any one of embodiments 70-77, wherein one or more needles have a shape memory material.

Embodiment 79 provides a delivery catheter according to any one of embodiments 70-78, wherein one or more needles comprise nitinol.

Embodiment 80 provides a delivery catheter of any one of embodiments 70-79, wherein one or more needles have one or more radiopaque materials.

Embodiment 81 provides a delivery catheter according to any one of embodiments 70-80, wherein one or more needles have a thin membrane having one or more radiopaque materials.

Embodiment 82 provides a delivery catheter according to any one of embodiments 70-81, wherein the one or more needles have one or more radiopaque materials comprising tungsten (W), gold (Au), tantalum (Ta), platinum (Pt), iridium (Ir), compounds thereof, or combinations thereof.

Embodiment 83 provides a delivery catheter according to any one of embodiments 70-82, wherein the shaft has a wire lumen that is an over-the-wire (OTW) shaft.

Embodiment 84 provides a delivery catheter according to any one of embodiments 70-83, wherein the shaft has a wire lumen that is a rapid exchange (RX) shaft.

Embodiment 85 provides a delivery catheter according to any one of embodiments 70-84, wherein the shaft has one or more needle exit openings at the distal end of the shaft.

Embodiment 86 provides a delivery catheter according to any one of embodiments 71-85, in which the needle exit opening is located on the side of the shaft in the direction of movement of the operating mechanism.

Embodiment 87 provides a delivery catheter according to any one of embodiments 70-86, wherein the shaft has at least one spray hole.

Embodiment 88 provides a delivery catheter according to any one of embodiments 85-87, wherein the shaft has a flushing lumen connected to the needle exit opening.

Embodiment 89 provides a delivery catheter as in embodiment 88, wherein the flushing lumen is for carrying a flushing fluid, the flushing fluid being saline, heparinized saline, a therapeutic agent, or a combination thereof.

Embodiment 90 provides a delivery catheter according to any one of embodiments 87-89, further comprising a sleeve over at least some of the spray holes.

Embodiment 91 provides a delivery catheter of any one of embodiments 70-90, wherein the shaft has at least one vacuum hole.

Embodiment 92 provides a delivery catheter according to any one of embodiments 70-91, wherein the delivery catheter has an ablation or denervation port at the proximal end of the shaft, the ablation or denervation port being in fluid communication with at least one needle for delivering ablation energy or a formulation to the one or more needles.

Embodiment 64 provides a method, a centrally positioned balloon catheter, or a delivery catheter of any one or any combination of embodiments 1-63, optionally configured so that all described elements or options are available or selectable.

Claims (24)

A chemical ablation formulation having an alcohol ,
1. A method for treating at least one disease, comprising:
the method of treatment includes treating at least two different target tissues in at least two different body lumens;
the disease is selected from the group consisting of hypertension, pulmonary hypertension, diabetes, obesity, metabolic syndrome, heart failure, myocardial infarction, atherosclerosis, coronary artery disease (CAD), peripheral vascular disease (PAD), end-stage renal disease, digestive disorders, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), urological diseases, cancer, tumors, pain, rheumatoid arthritis (RA), asthma, chronic obstructive pulmonary disease (COPD), and combinations thereof;
The method of treatment comprises:
performing a therapeutic procedure on a body lumen, the body lumen being a first body lumen;
performing the treatment procedure on a lumen of a second body that is different from the lumen of the first body;
Including,
The therapeutic treatment comprises:
inserting a chemical infusion delivery catheter into a body lumen, the chemical infusion delivery catheter having a catheter shaft and a needle movement controller, the chemical infusion delivery catheter having at least one needle disposed in a needle lumen at a distal end of the catheter shaft, the needle lumen communicating with the outside of the catheter shaft through at least one needle exit hole in a side of the catheter shaft, the needle movement controller in electrical or mechanical communication with the at least one needle;
delivering to the target tissue an amount of a formulation effective to injure or damage the target tissue so as to alleviate symptoms of a disease, wherein the needle movement controller positions at least one needle from the needle lumen and the needle exit hole into a body lumen, a wall of the body lumen, or outside the body lumen, and denervates or ablates the target tissue in the body lumen with the delivery catheter;
removing the delivery catheter from the body lumen;
A chemical ablation preparation comprising: The chemical ablation formulation described in claim 1, wherein the formulation comprises ethanol. The chemical ablation formulation described in claim 1 or 2, wherein the formulation comprises an azeotrope. The chemical ablation formulation of claim 1, wherein the first body lumen and the second body lumen belong to different classes of body lumens selected from renal artery, renal vein, gastric artery, hepatic artery, pulmonary artery, celiac artery, gastroduodenal artery, splenic artery, adrenal artery, phrenic artery, mesenteric artery, airway, esophagus, stomach, duodenum, jejunum, and urological lumens. The at least one disease is
At least two diseases, or
At least three diseases, or
The chemoablation preparation of claim 1 or 2, wherein the chemoablation preparation is for treating at least four diseases. The at least one disease is
Renal hypertension and diabetes, or Renal hypertension and obesity, or
Obesity and diabetes, or
The chemoablation preparation according to any one of claims 1 to 3, wherein the chemoablation preparation is for treating at least two diseases, including a combination thereof. The chemical ablation preparation described in any one of claims 1 to 4, wherein alleviating the symptoms of the disease comprises reducing blood pressure, reducing blood sugar levels and A1C, reducing weight, reducing restenosis, reducing liver fat, and reducing pain, or a combination thereof. The chemical ablation formulation of any one of claims 1 to 4, wherein denervating or ablating target tissue in a body lumen using the delivery catheter further comprises delivering an amount of energy from the delivery catheter to the target tissue using radiofrequency, cryoablation, microwave, laser, ultrasound, high-intensity focused ultrasound energy, vapor coagulation of at least a portion of the formulation into a liquid, or a combination thereof. The chemical infusion delivery catheter comprises a needle-type balloon delivery catheter for delivery of a substance to a target tissue in a body lumen of a patient, the delivery catheter comprising:
the catheter shaft having a proximal and a distal end;
at least one marker band disposed about the distal end of the shaft;
a flushing port at the proximal end of the shaft in fluid communication with a flushing lumen that is in fluid communication with the distal end of the needle lumen, the flushing port being in fluid communication with the needle exit hole through the flushing lumen;
a guidewire lumen extending through at least the distal end of the shaft;
at least one balloon adjacent the distal end of the catheter and proximal to the at least one needle;
an inflation lumen;
an inflation port in fluid communication with an inflation lumen and in fluid communication with the interior of the balloon, the balloon being inflatable through the inflation port via the inflation lumen, and positioning the distal end of the catheter shaft substantially in the center of a body lumen;
10. The chemical ablation formulation of claim 1, further comprising an ablation or denervation port at a proximal end of the shaft, the ablation or denervation port being in fluid communication with at least one needle to provide ablation energy or formulation to the at least one needle. The chemical infusion delivery catheter comprises an infusion catheter, the infusion catheter comprising:
the catheter shaft having a proximal and a distal end;
one or more needles for infusion therapy disposed around the distal end of the shaft;
one or more needle lumens housing one or more needles, each having a needle exit hole in a side of the shaft;
a flushing port at the distal end of the shaft fluidly connected to one or more of the needle exit holes;
and
The infusion catheter comprises:
10. The chemical ablation formulation of claim 1, wherein the infusion catheter is positioned in a lumen and has an inflatable balloon positioned around the distal end of the catheter shaft proximal to one or more needles such that when the balloon is inflated, the distal end of the catheter shaft is centered in the lumen. The chemical ablation preparation of claim 10, wherein the one or more needles include more than one needle. The chemical ablation formulation of claim 11, wherein the needle has a tip-to-tip needle span diameter of 5 mm to 80 mm, measured when the needle is fully advanced from the infusion catheter. The chemical ablation preparation of claim 10, wherein the one or more needles comprise a shape memory material, nitinol, or one or more radiopaque materials. The chemical ablation preparation of claim 10, wherein the shaft has at least one vacuum hole. The chemical ablation preparation described in claim 10, wherein the one or more needles include three needles. the infusion catheter further comprising a steering mechanism associated with the shaft;
The chemical ablation formulation of claim 10 , wherein the distal end of the shaft is steerable away from the longitudinal axis of the shaft. The chemical ablation preparation described in claim 10, wherein the shaft has at least one spray hole. The chemical ablative formulation described in claim 17, further comprising a sleeve over at least a portion of the spray hole. the infusion catheter further comprising an ablation or denervation port at the proximal end of the shaft;
The chemical ablation formulation of claim 10 , wherein the ablation or denervation port is in fluid communication with at least one needle that delivers ablation energy or formulation to one or more needles. The chemical ablation preparation described in claim 10, wherein the distal end of the shaft has a marker band. The chemical ablation preparation described in claim 10, wherein one or more needles comprise nitinol. the chemical infusion delivery catheter further comprising a balloon at the distal end of the shaft and an inflation lumen in fluid communication with an interior of the balloon;
The method further comprises inflating the balloon to center the distal end of the shaft in a body lumen prior to denervation or ablation;
The chemical ablation formulation of claim 1 , wherein the method further comprises deflating the balloon after denervation or ablation. 10. The chemical ablation formulation of claim 1, wherein the alcohol is selected from methanol, ethanol, absolute alcohol, isopropanol, propanol, butanol, or isobutanol. 10. The chemical ablative formulation of claim 1, wherein the alcohol comprises ethanol.