Patent Application
20230404609
The present specification is related generally to resection of portions of the gastrointestinal tract to treat gastrointestinal conditions. More specifically, the present specification is related to devices and methods for resecting portions of the proximal foregut to treat diabetes, obesity, metabolic syndrome, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), or polycystic ovarian syndrome (PCOS).
Type 2 diabetes mellitus (T2D) is increasing at a disturbing rate throughout the world with an estimated global prevalence of 552 million by 2030. According to 2017 International Diabetes Federation (IDF) statistics, there are approximately 425 million people with diabetes worldwide. In the United States, there are an estimated 30.3 million adults living with diabetes, and its prevalence has been rising rapidly, with at least 1.5 million new diabetes cases diagnosed each year. Diabetes is a major public health epidemic despite recent advances in both pharmaceutical and technologic treatment options. The therapeutic goal of a glycated hemoglobin (HbA1c) level of ≤53 mmol/mol3 is achieved by less than half of the patients with T2D despite lifestyle interventions and an increasing number of medical treatment options. Bariatric surgery has proven to be successful in patients with class I, II and III obesity. In moderately obese patients with T2D, bariatric surgery is superior to intensive medical therapy alone. However, bariatric surgery is not a scalable solution for the growing T2D pandemic as most bariatric surgery procedures are invasive, irreversible and associated with some morbidity.
Fueled by increasing obesity rates, NAFLD has emerged as a leading global cause of chronic liver disease in the past few decades. The global prevalence of NAFLD among adults is estimated to be 23-25%. Up to 20% of people with NAFLD are affected by NASH. Despite growing prevalence, the factors influencing NAFLD development and subsequent progression to NASH, liver fibrosis, cirrhosis and hepatocellular carcinoma are poorly understood. In the vast majority of patients, NAFLD emerges in the context of metabolic syndrome, with insulin resistance an important pathophysiological mechanism. Liver cancer is now the second leading cause of years of life lost among all cancers globally.
Polycystic ovary syndrome (PCOS) is a hormonal disorder common among women of reproductive age. PCOS is now recognized as an important metabolic as well as reproductive disorder conferring substantially increased risk for type 2 diabetes. Affected women have marked insulin resistance, independent of obesity. Obese women with PCOS are insulin resistant. Early diagnosis and treatment along with weight loss may reduce the risk of long-term complications such as type 2 diabetes and heart disease.
The duodenum has become increasingly recognized as a metabolic signaling center that seems to play a role in regulating insulin action and, therefore, insulin resistance states. Hence, the duodenum has become a metabolic treatment target through bariatric surgery leanings and the specific observation that bypassing, excluding or altering duodenal nutrient exposure elicits favorable metabolic changes including immediate improvements in glycemic regulation after bariatric surgery, which do not appear to be due to malabsorption or the substantial weight loss often observed later post-surgery. Studies suggest a critical physiological and pathophysiological role of the small bowel in metabolic homeostasis. The easy endoscopic accessibility of the duodenum makes it a potential target for disease-modifying intervention for diseases associated with insulin resistance.
Two major mechanisms have been hypothesized to explain the rapid improvement of T2DM. Firstly, the foregut hypothesis suggests that improved glycemia after proximal intestinal exclusion results from reduced secretion of diabetogenic hormones/anti-incretin factors in response to the absence of nutrition in the proximal small intestine. For example, intestinal glucagon synthesis has been suggested to decrease after exclusion of the proximal intestine. Secondly, the hindgut hypothesis attributes improved glycemic control to enhanced secretion of incretins, like glucagon-like peptide-1 (GLP-1), in response to undigested nutrients in the distal small intestine. These theories are not mutually exclusive and additional factors likely play a role in the rapid glycemic improvement after bariatric surgery. Particularly, glucose dependent insulinotropic polypeptide (GIP), a gut hormone which stimulates glucagon secretion in response to a meal, may also be involved. Furthermore, caloric intake is of importance in improvement of T2DM.
The duodenum plays an important role in the control of glucose homeostasis through various mechanisms. A few key mechanisms include:
1. Enteroendocrine Hormone Release: The duodenum contains specialized cells called enteroendocrine cells, which secrete several hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). When glucose enters the duodenum from the stomach, these hormones are released into the bloodstream. GLP-1 stimulates insulin secretion from pancreatic beta cells in a glucose-dependent manner. It also inhibits glucagon secretion from pancreatic alpha cells, slows down gastric emptying, and promotes satiety. GIP also stimulates insulin release from pancreatic beta cells in response to elevated blood glucose levels. It enhances nutrient uptake and storage by promoting the release of insulin and inhibiting glucagon secretion.
2. Neural Signaling: The duodenum communicates with the brain via the vagus nerve, which plays a crucial role in regulating glucose homeostasis. Sensory signals from the duodenum, including the presence of glucose, activate the vagal afferent neurons, which transmit information to the brain. The brain, in turn, sends signals to regulate pancreatic hormone secretion, hepatic glucose production, and other metabolic processes.
3. Incretin Effect: The “incretin effect” refers to the enhanced insulin secretion observed when glucose is ingested orally compared to intravenously. This effect is attributed to the duodenal release of GLP-1 and GIP in response to oral glucose intake. These incretin hormones potentiate glucose-stimulated insulin secretion, leading to better glucose clearance.
4. Intestinal Gluconeogenesis: The duodenum, along with the jejunum, is capable of gluconeogenesis, the production of glucose from non-carbohydrate precursors. This process can contribute to glucose homeostasis by providing a source of glucose during fasting or periods of low blood glucose.
Overall, the duodenum exerts control over glucose homeostasis through the release of enteroendocrine hormones, neural signaling, the incretin effect, and intestinal gluconeogenesis. These mechanisms work together to regulate pancreatic hormone secretion, insulin sensitivity, and hepatic glucose production, helping to maintain glucose levels within a normal range.
The duodenum, as the first segment of the small intestine, can influence the development and progression of fatty liver disease through several mechanisms. Mechanisms underlying the relationship between the duodenum and fatty liver disease are complex and not fully elucidated. Various factors, including genetics, diet, lifestyle, and underlying metabolic conditions, can interact with the duodenal processes mentioned below to influence the development and progression of fatty liver disease. The key mechanisms explaining how duodenal influence NAFLD or fatty liver disease include:
Bile Acid Metabolism: The duodenum is responsible for receiving bile acids from the gallbladder, which are important for the digestion and absorption of dietary fats. Bile acids aid in the emulsification and absorption of dietary lipids in the small intestine. Disruption of bile acid metabolism or impaired bile acid flow from the duodenum can contribute to the development of fatty liver disease. Alterations in bile acid composition and availability can impact lipid metabolism in the liver and contribute to the accumulation of fat.
Gut Microbiota: The duodenum and the rest of the small intestine host a diverse population of microorganisms collectively known as the gut microbiota. The gut microbiota plays a crucial role in various metabolic processes, including lipid metabolism. Disturbances in the gut microbiota composition, often referred to as dysbiosis, can impact the metabolism of dietary fats and contribute to the development of fatty liver disease.
Intestinal Inflammation and Barrier Dysfunction: Chronic low-grade inflammation and increased intestinal permeability (leaky gut) are associated with the pathogenesis of fatty liver disease. The duodenum, being a critical site of nutrient absorption, can be influenced by various dietary and environmental factors, leading to intestinal inflammation and disruption of the intestinal barrier. Increased intestinal permeability can allow the translocation of bacterial products, such as lipopolysaccharides (LPS), into the bloodstream, triggering systemic inflammation and promoting the development of liver steatosis.
Incretin Hormones: As mentioned earlier, the duodenum releases incretin hormones, such as GLP-1 and GIP, in response to nutrient ingestion. These hormones not only regulate glucose homeostasis but also have effects on lipid metabolism. GLP-1 has been shown to reduce hepatic fat accumulation and improve insulin sensitivity, potentially protecting against fatty liver disease. GIP may also influence lipid metabolism and contribute to the development of hepatic steatosis.
Nutrient Sensing and Signaling: The duodenum is a critical site for nutrient sensing and signaling, relaying information about nutrient availability to other organs, including the liver. Changes in nutrient composition and absorption in the duodenum can impact signaling pathways involved in lipid metabolism and influence the development of fatty liver disease.
The duodenal submucosa, the layer beneath the mucosal lining of the duodenum, plays a role in glucose homeostasis through several mechanisms. Some of the key mechanisms of action related to the duodenal submucosa include:
Enteroendocrine Hormone Secretion: The duodenal submucosa contains specialized enteroendocrine cells that secrete various hormones involved in glucose regulation. These include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). When nutrients, especially glucose, encounter the duodenal submucosa, it triggers the release of these hormones into the bloodstream. GLP-1 promotes glucose-dependent insulin secretion from pancreatic beta cells. It also inhibits glucagon secretion from pancreatic alpha cells, slows down gastric emptying, and promotes satiety. GIP stimulates insulin release from pancreatic beta cells in response to elevated blood glucose levels. It enhances nutrient uptake and storage by promoting the release of insulin and inhibiting glucagon secretion.
Neural Signaling: The duodenal submucosa is innervated by a network of nerves, including the enteric nervous system (ENS) and autonomic nerves. These nerves sense and transmit signals related to glucose levels and participate in the regulation of glucose homeostasis. Sensory signals from the duodenal submucosa are transmitted via nerve pathways to the brain, which in turn modulates pancreatic hormone secretion, hepatic glucose production, and other metabolic processes.
Nutrient Sensing: The duodenal submucosa contains specialized nutrient-sensing cells, such as L-cells and K-cells. These cells can directly sense glucose and other nutrients in the intestinal lumen and respond by releasing hormones like GLP-1 and GIP, as mentioned earlier. This nutrient sensing helps regulate insulin secretion and other metabolic processes to maintain glucose homeostasis.
GLP-1 Receptor Signaling: GLP-1 released from the duodenal submucosa acts on target tissues throughout the body by binding to GLP-1 receptors. Activation of GLP-1 receptors has various effects that promote glucose homeostasis, such as stimulating insulin secretion, inhibiting glucagon secretion, enhancing glucose uptake by cells, and improving pancreatic beta cell function.
These mechanisms collectively contribute to the regulation of glucose homeostasis by the duodenal submucosa. By sensing glucose and other nutrients, releasing enteroendocrine hormones, and transmitting signals to the brain and other target tissues, the duodenal submucosa helps coordinate insulin and glucagon secretion, nutrient uptake and utilization, and other processes involved in maintaining stable blood glucose levels.
The submucosal tissue of the duodenum primarily contains blood vessels, nerves, and connective tissue, which provide structural and supportive functions. The submucosal nerves in the duodenum are part of the enteric nervous system and have an important role in the regulation of glucose homeostasis. Submucosal nerves contain sensory neurons that can detect changes in the luminal environment of the duodenum, including the presence of nutrients such as glucose and transmit signals to the central nervous system (CNS) and enteric nervous system (ENS) and with the autonomic nervous system (ANS). This allows for coordinated neural signaling that influences glucose metabolism, including insulin secretion, hepatic glucose production, and peripheral glucose uptake. Submucosal nerves also modulate the release of hormones involved in glucose homeostasis. For example, they can stimulate the secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) from the enteroendocrine cells in the duodenal mucosa. These hormones play a crucial role in insulin secretion and glucose regulation. The vagus nerve, a major component of the autonomic nervous system, innervates the submucosal layer of the duodenum and can influence glucose homeostasis by regulating insulin secretion, hepatic glucose metabolism, and gut motility. It helps maintain a balance in glucose levels through the interaction between the central and enteric nervous systems. The submucosal nerves participate in the bidirectional communication between the gut and the brain, known as the gut-brain axis. This communication pathway allows for the integration of signals from the gastrointestinal tract, including glucose-related information, with the CNS. The submucosal nerves play a role in transmitting these signals and influencing central control of glucose homeostasis. It is clear that the submucosal nerves, along with other components of the enteric nervous system, play a significant role in the neural regulation of glucose metabolism.
Several devices and methods have been developed to bypass or remove a portion of the duodenum in attempts to treat diabetes. A non-surgical duodenal-jejunal bypass liner (DJBL) has been developed to mimic Roux-en-Y Gastric Bypass (RYGB)-related proximal small intestinal exclusion. The DJBL is a 60-cm-long impermeable liner which is delivered and retrieved endoscopically. Similar to RYGB, the DJBL causes significant weight loss and improvement of glycemic control. Unlike RYGB, the anatomy of the stomach and small intestine is not affected by DJBL treatment, enabling mechanistic studies focusing exclusively on the role of the proximal intestine in T2DM.
Serious adverse events related to DJBL use have been reported, such as, gastrointestinal bleeding, device migration, obstruction, and the development of liver abscesses. Liver abscesses pose the most serious complication associated with the DJBS. The Food and Drug Administration (FDA) halted the US-FDA trial due to the development of 7 liver abscesses (3.5%), which was much higher than anticipated. The cause for these liver abscesses is unclear, but the theory is that the DJBS anchors in the duodenum creates a nidus of infection, which may spread to the liver bed.
A procedure known as duodenal mucosal resurfacing (DMR) is performed using specially designed catheters which are advanced over a guidewire next to the endoscope.
In one procedure, as shown in
The methods listed above mainly target the intestinal mucosa and do not significantly affect the glucose homeostasis mechanisms that are related to the intestinal submucosa and hence have suboptimal clinical outcomes.
Bariatric surgery has long been recognized as a potential treatment for both morbid obesity and the metabolic processes that accompany it, specifically T2D. The most performed bariatric surgeries in the United States include laparoscopic and robotic Roux-en-Y Gastric Bypass (RYGB) or Sleeve Gastrectomy (SG). While surgical treatment is based on the principles of restriction and intestinal malabsorption, evidence suggests that there are more complex mechanisms at play. Bariatric surgery has consistently been shown to improve blood glucose while allowing decreased oral hypoglycemic medications and insulin use dramatically and rapidly, effectively reversing diabetes in up to 80% of patients. In addition to early post-operative improvement in blood glucose and insulin sensitivity, bariatric surgery has also been shown to cause alterations in GI hormone release, including ghrelin, leptin, cholecystokinin (CCK), peptide-tyrosine-tyrosine (PYY), and glucagon-like peptide 1 (GLP-1), that may impact feeding behavior via the gut-brain axis, in addition to modulating euglycemia. Increases in insulin-like growth factor 1 levels (IGF-1) and decreases of plasma leptin levels have been seen in diabetic and non-diabetic morbidly obese patients. Furthermore, microbial changes in the human gut have been linked to obesity, and surgical alterations to gastrointestinal anatomy have been associated with dramatic changes in gut microbiota populations, with reversion from an “obesogenic” to a lean bacterial population.
It is speculated that T2D might be the result of an imbalance in the equilibrium between anti-incretin factors and incretins, which eventually leads to delayed insulin response and impaired insulin action.
Bariatric surgery, specifically procedures like Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, has been shown to have a profound impact on the improvement and even remission of type 2 diabetes. Some of the mechanisms that may explain how bariatric surgery improves diabetes:
Weight Loss and Caloric Restriction: Bariatric surgery leads to significant weight loss and caloric restriction, which can directly improve insulin sensitivity and glucose control. Reduction in adipose tissue, particularly visceral fat, is associated with improved insulin signaling and glucose metabolism.
Gut Hormone Changes: Bariatric surgery alters the gut hormone milieu, which can have significant effects on glucose homeostasis. Procedures like RYGB and sleeve gastrectomy result in the rearrangement of the gastrointestinal tract, leading to changes in the production and secretion of various gut hormones. These hormonal changes include increased secretion of glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and oxyntomodulin, which promote insulin secretion, enhance insulin sensitivity, suppress appetite, and regulate glucose metabolism.
Intestinal Nutrient Sensing: Bariatric surgery alters the nutrient flow and absorption patterns in the gastrointestinal tract. The rearrangement of the digestive system can result in accelerated nutrient delivery to the distal intestine, particularly the jejunum and ileum. This nutrient exposure in the lower intestine triggers specific nutrient-sensing mechanisms, leading to enhanced insulin secretion, improved glucose uptake, and regulation of hepatic glucose production.
Intestinal Microbiota Changes: Bariatric surgery has been shown to induce alterations in the gut microbiota composition, favoring a microbial profile associated with improved metabolic health. Changes in the gut microbiota after surgery can influence energy extraction from the diet, modulation of gut hormones, and inflammation, all of which impact glucose homeostasis.
Insulin-Independent Glucose-Lowering Effects: Bariatric surgery has been shown to have direct effects on glucose metabolism independent of insulin. This can include increased glucose uptake by peripheral tissues, enhanced hepatic glucose utilization, and improved insulin-independent pathways of glucose disposal.
The overall effects of bariatric surgery on diabetes are likely multifactorial and involve a combination of weight loss, hormonal changes, altered gut microbiota, and metabolic adaptations and most of these mechanisms are controlled by intestinal mucosa and submucosa.
Surgical procedures by resecting the complete intestine, target both the mucosal and submucosal mechanisms and have shown superior outcomes in improving type-2 diabetes, glucose intolerance, and related conditions. These procedures provide long-lasting and significant effects. However, it's important to note that these surgeries are highly invasive and expensive, and they carry a considerable risk of complications and mortality. Additionally, once the procedure is performed, it cannot be repeated if it fails to produce the desired outcomes. This lack of opportunity for repeat interventions is due to the accommodation or adaptation mechanisms that can occur in patients, is another significant negative with traditional surgeries.
Therefore, less invasive and more practical systems and methods that address the imbalance between anti-incretin factors and incretins by targeting both the intestinal mucosa and submucosa equally and not affecting the muscularis and serosa, and therefore treat diabetes, metabolic syndrome and various conditions associated with insulin resistance, are needed. Such systems and methods would be deployed less invasively, for example, using an endoscope, target the mucosa and submucosa and would not require the resection of a complete or full thickness organ or damage the full thickness of the intestine. Further, any foreign bodies introduced into the body during the procedure would be configured to exit the body naturally after the resection is completed, lowering the risk for complications, or requiring repeat procedures. Additionally, the procedure could be performed on an outpatient basis, lowering costs and complexity. Minimizing or eliminating use of thermal or other ablative energy required for mucosal ablation procedures will minimize or eliminate complications such as strictures, bleeding, perforation and pancreatitis.
The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods, which are meant to be exemplary and illustrative, and not limiting in scope. The present application discloses numerous embodiments.
The present specification discloses a device for resecting a body tissue, comprising: a cap configured to attach to a distal end of an endoscope wherein the cap comprises a central lumen; a suction source configured to apply a negative pressure through the central lumen of the cap; and at least one resection component positioned around an outer surface of the cap, wherein the at least one resection component has an inner surface comprising at least one anchor, wherein the at least one resection component comprises a first material, the at least one anchor comprises a second material, and wherein the first material is different from the second material, wherein the at least one resection component is configured to change from a first configuration when positioned on the cap to a second configuration once deployed, wherein, in the second configuration, the at least one resection component is configured to encircle a portion of said body tissue with the at least one anchor contacting the tissue to secure the resection component to constrict the tissue and reduce blood flow to the tissue.
Optionally, the at least one resection component comprises a band, a loop, an O-ring, an elastic circle, or any other component adapted to have a first configuration with a circumference of M when subjected to a pressure and adapted to automatically transition to a second configuration with a circumference of N when the pressure is removed, where N is less than M.
Optionally, the anchor comprises a wire of the shape-memory material having at least one first portion extending into the at least one resection component and at least one second portion extending out of and toward a center of the at least one resection component. Optionally, the shape memory material comprises Nitinol. Optionally, in the second configuration, the at least one second portion of the wire is configured to anchor into the body tissue. Optionally, in the second configuration, the at least one second portion of the wire is in the shape of a spike and is configured to pierce the body tissue.
Optionally, the device comprises 1 to 10 resection components.
Optionally, the device further comprises a catheter extending between the cap and the suction source.
The present specification also discloses a method for resecting a body tissue in a patient, comprising: providing a device configured to pass through an endoscope comprising: a cap positioned on the distal end of the device, wherein the cap comprises a central lumen; and at least one resection component positioned around an outer surface of the cap, wherein the at least one resection component has an inner surface comprising at least one anchor, wherein the at least one resection component is configured to change from a first configuration when positioned on the cap to a second configuration once deployed off the cap, wherein, in the second configuration, the at least one resection component is configured to encircle a portion of said body tissue, anchor into the tissue using the anchor, and to constrict the tissue and reduce blood flow to the tissue; inserting the device through the endoscope into the patient and advancing the device such that a distal end of the device is positioned in a gastrointestinal tract of the patient; activating a suction source to apply a negative pressure through the central lumen of the cap; drawing a portion of body tissue into the central lumen of the cap, wherein the portion includes at least 1 square centimeters of body tissue; deploying at least one resection component from the device around a base of the body tissue; removing the device from the patient; permitting the at least one resection component to remain around the body tissue and to cut off blood flow to the body tissue.
Optionally, the at least one resection component comprises a band, a loop, an O-ring, an elastic circle, or any other component adapted to have a first configuration with a circumference of M when subjected to a pressure and adapted to automatically transition to a second configuration with a circumference of N when the pressure is removed, where N is less than M.
Optionally, the anchor comprises a wire of a shape-memory material having at least one first portion extending into the at least one resection component and at least one second portion extending out of and toward a center of the at least one resection component. Optionally, the shape memory material comprises Nitinol. Optionally, in the second configuration, the at least one second portion of the wire is configured to anchor into the body tissue. Optionally, in the second configuration, the at least one second portion of the wire is in the shape of a spike and is configured to pierce the body tissue.
Optionally, the device comprises 1 to 10 resection components.
Optionally, the device further comprises a catheter extending between the cap and the suction source.
Optionally, the method is used to treat at least one of excess weight, obesity, an eating disorder, metabolic syndrome, dyslipidemia, diabetes, polycystic ovarian disease, fatty liver disease, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis disease.
Optionally, the method further comprises determining a therapeutic endpoint after the resection.
Optionally, the therapeutic endpoint is at least one of a total body weight of the patient decreases by at least 1% relative to a total body weight of the patient before resection, an excess body weight of the patient decreases by at least 1% relative to an excess body weight of the patient before resection, a total body weight of the patient decreases by at least 1% relative to a total body weight of the patient before resection and a well-being level of the patient does not decrease more than 5% relative to a well-being level of the patient before resection, an excess body weight of the patient decreases by at least 1% relative to an excess body weight of the patient before resection and a well-being level of the patient does not decrease more than 5% relative to a well-being level of the patient before resection, a pre-prandial ghrelin level of the patient decreases by at least 1% relative to a pre-prandial ghrelin level of the patient before resection, a post-prandial ghrelin level of the patient decreases by at least 1% relative to a post-prandial ghrelin level of the patient before resection, or an exercise output of the patient increases by at least 1% relative to an exercise output of the patient before resection.
Optionally, the therapeutic endpoint is at least one of a glucagon-like peptide-1 level of the patient increases by at least 1% relative to a glucagon-like peptide-1 level of the patient before resection, a leptin level of the patient increases by at least 1% relative to a leptin level of the patient before resection, the patient's appetite decreases, over a predefined period of time, relative to the patient's appetite before resection, a peptide YY level of the patient increases by at least 1% relative to a peptide YY level of the patient before resection, a lipopolysaccharide level of the patient decreases by at least 1% relative to a lipopolysaccharide level of the patient before resection, a motilin-related peptide level of the patient decreases by at least 1% relative to a motilin-related peptide level of the patient before resection, a cholecystokinin level of the patient increases by at least 1% relative to a cholecystokinin level of the patient before resection, a resting metabolic rate of the patient increases by at least 1% relative to a resting metabolic rate of the patient before resection, a plasma-beta endorphin level of the patient increases by at least 1% relative to a plasma-beta endorphin level of the patient before resection, an HbA1c level of the patient decreases by at least 0.3% relative to an HbA1c level of the patient before resection, a triglyceride level of the patient decreases by at least 1% relative to a triglyceride level of the patient before resection, a total blood cholesterol level of the patient decreases by at least 1% relative to a total blood cholesterol level of the patient before resection, or a glycemia level of the patient decreases by at least 1% relative to a glycemia level of the patient before resection.
Optionally, the therapeutic endpoint is a cumulative daily dose of the patient's antidiabetic medications decreases by at least 10% relative to a cumulative daily dose of the patient's antidiabetic medications before resection or 10% of the patients eliminate the use of one or more of their antidiabetic medications being used before resection.
Optionally, the therapeutic endpoint is at least one of a 10% decrease in either ALT or AST levels relative to ALT or AST levels before resection, at least a 10% improvement in serum ferritin level or an absolute serum ferritin level of less than 1.5 ULN (upper limit normal) relative to serum ferritin levels before resection, at least a 5% improvement in hepatic steatosis (HS) or less than 5% HS relative to HS levels before resection, as measured on liver biopsy, at least a 5% improvement in HS or less than 5% HS relative to HS levels before resection, as measured by magnetic resonance (MR) imaging, either by spectroscopy or proton density fat fraction, at least a 5% improvement in an NAFLD Fibrosis Score (NFS) relative to an NFS before resection, at least a 5% improvement in an NAFLD Activity Score (NAS) relative to an NAS before resection, at least a 5% improvement in a Steatosis Activity Fibrosis (SAF) score relative to an SAF score before resection, or at least a 5% decrease in a mean annual fibrosis progression rate relative to a mean annual fibrosis progression rate before resection, as measured by histology.
The present specification also discloses a device for resecting a body tissue which include the gastric intestinal mucosa and submucosa without significantly affecting the muscularis or serosa, comprising: a cap configured to pass through a distal end of an endoscope wherein the cap comprises a central lumen; a suction source configured to apply a negative pressure through the central lumen of the cap; and at least one elastic ligation device such as a rubber band positioned around an outer surface of the cap, wherein the at least one band has an inner surface comprising at least one anchor, wherein the at least one band is configured to change from a first configuration when positioned on the cap to a second configuration once deployed, wherein, in the second configuration, the at least one band is configured to encircle a portion of said body tissue with the at least one anchor contacting the tissue to secure the band to constrict the tissue and reduce blood flow to the tissue. The device resects and/or affects the mucosa and submucosa in an equivalent amount to achieve the desired effect. Stated differently, the device resects and/or affects the functionality of the mucosa and the functionality of the submucosa in an equivalent amount, such as a decrease in functionality, including metabolic function, in a range of 10% to 90% and any increment therein, to achieve the desired effect.
Optionally, the anchor comprises a wire of the shape-memory material having at least one first portion extending into the at least one band and at least one second portion extending out of and toward a center of the at least one band. Optionally, the shape memory material comprises Nitinol. Optionally, in the second configuration, the at least one second portion of the wire is configured to anchor into the body tissue. Optionally, in the second configuration, the at least one second portion of the wire is in the shape of a spike and is configured to pierce the body tissue.
Optionally, the device comprises 1 to 100 bands or ligation devices.
Optionally, the device further comprises a wire or a catheter extending between the cap and the suction source to help deploy the bands.
The present specification also discloses a method for resecting a body tissue in a patient, comprising: providing a device configured to pass through an endoscope comprising: a cap positioned on the distal end of the device, wherein the cap comprises a central lumen; and at least one band or ligation device positioned around an outer surface of the cap, wherein the at least one band has an inner surface comprising at least one anchor, wherein the at least one band or ligation device is configured to change from a first configuration when positioned on the cap to a second configuration once deployed off the cap, wherein, in the second configuration, the at least one band is configured to encircle a portion of said body tissue, anchor into the tissue using the anchor, and to constrict the tissue and reduce blood flow to the tissue; inserting the device through the endoscope into the patient and advancing the device such that a distal end of the device is positioned in a duodenum of the patient; activating a suction source to apply a negative pressure through the central lumen of the cap; drawing a portion of body tissue into the central lumen of the cap, wherein the portion includes at least 5 square centimeters of body tissue; deploying at least one band from the device around a base of the body tissue; removing the device from the patient; permitting the at least one band to remain around the body tissue and to cut off blood flow to the body tissue. The portion of the body tissue constitute of at least a mucosal tissue and a submucosal tissue.
Optionally, the anchor comprises a wire of a shape-memory material having at least one first portion extending into the at least one band or ligation device and at least one second portion extending out of and toward a center of the at least one band or a ligation device. Optionally, the shape memory material comprises Nitinol. Optionally, in the second configuration, the at least one second portion of the wire is configured to anchor into the body tissue. Optionally, in the second configuration, the at least one second portion of the wire is in the shape of a spike and is configured to pierce the body tissue. Optionally, the devise comprises 1 to 100 bands. Optionally, the device further comprises a catheter extending between the cap and the suction source.
The method may be used to treat at least one of excess weight, obesity, an eating disorder, metabolic syndrome, dyslipidemia, diabetes, polycystic ovarian disease, fatty liver disease, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis disease or any other disease associated with insulin resistance.
Optionally, the method further comprises determining a therapeutic endpoint after the resection. The therapeutic endpoint may be at least one of a total body weight of the patient decreases by at least 1% relative to a total body weight of the patient before resection, an excess body weight of the patient decreases by at least 1% relative to an excess body weight of the patient before resection, a total body weight of the patient decreases by at least 1% relative to a total body weight of the patient before resection and a well-being level of the patient does not decrease more than 5% relative to a well-being level of the patient before resection, an excess body weight of the patient decreases by at least 1% relative to an excess body weight of the patient before resection and a well-being level of the patient does not decrease more than 5% relative to a well-being level of the patient before resection, a pre-prandial ghrelin level of the patient decreases by at least 1% relative to a pre-prandial ghrelin level of the patient before resection, a post-prandial ghrelin level of the patient decreases by at least 1% relative to a post-prandial ghrelin level of the patient before resection, or an exercise output of the patient increases by at least 1% relative to an exercise output of the patient before resection.
The therapeutic endpoint may also be at least one of a glucagon-like peptide-1 level of the patient increases by at least 1% relative to a glucagon-like peptide-1 level of the patient before resection, a leptin level of the patient increases by at least 1% relative to a leptin level of the patient before resection, the patient's appetite decreases, over a predefined period of time, relative to the patient's appetite before resection, a peptide YY level of the patient increases by at least 1% relative to a peptide YY level of the patient before resection, a lipopolysaccharide level of the patient decreases by at least 1% relative to a lipopolysaccharide level of the patient before resection, a motilin-related peptide level of the patient decreases by at least 1% relative to a motilin-related peptide level of the patient before resection, a cholecystokinin level of the patient increases by at least 1% relative to a cholecystokinin level of the patient before resection, a resting metabolic rate of the patient increases by at least 1% relative to a resting metabolic rate of the patient before resection, a plasma-beta endorphin level of the patient increases by at least 1% relative to a plasma-beta endorphin level of the patient before resection, an HbA1c level of the patient decreases by at least 0.3% relative to an HbA1c level of the patient before resection, a triglyceride level of the patient decreases by at least 1% relative to a triglyceride level of the patient before resection, a total blood cholesterol level of the patient decreases by at least 1% relative to a total blood cholesterol level of the patient before resection, or a glycemia level of the patient decreases by at least 1% relative to a glycemia level of the patient before resection.
The therapeutic endpoint may also be at least one of a composition of the person's gut microbiota modulates from a first state before resection to a second state after resection, wherein the first state has a first level of bacteroidetes and a first level of firmicutes, wherein the second state has a second level of bacteroidetes and a second level of firmicutes, wherein the second level of bacteroidetes is greater than the first level of bacteroidetes by at least 3%, and wherein the second level of firmicutes is less than the first level of firmicutes by at least 3%, or a cumulative daily dose of the patient's antidiabetic medications decreases by at least 10% relative to a cumulative daily dose of the patient's antidiabetic medications before resection.
The therapeutic endpoint may also be at least one of a 10% decrease in either ALT or AST levels relative to ALT or AST levels before resection, at least a 10% improvement in serum ferritin level or an absolute serum ferritin level of less than 1.5 ULN (upper limit normal) relative to serum ferritin levels before resection, at least a 5% improvement in hepatic steatosis (HS) or less than 5% HS relative to HS levels before resection, as measured on liver biopsy, at least a 5% improvement in HS or less than 5% HS relative to HS levels before resection, as measured by magnetic resonance (MR) imaging, either by spectroscopy or proton density fat fraction, at least a 5% improvement in an NAFLD Fibrosis Score (NFS) relative to an NFS before resection, at least a 5% improvement in an NAFLD Activity Score (NAS) relative to an NAS before resection, at least a 5% improvement in a Steatosis Activity Fibrosis (SAF) score relative to an SAF score before resection, or at least a 5% decrease in a mean annual fibrosis progression rate relative to a mean annual fibrosis progression rate before resection, as measured by histology.
The therapeutic endpoint may also be at least one of a 20% decrease in the dose of oral antidiabetic drugs (OAD) or a reduction in the dose of OAD in at least 20% of the patients.
The therapeutic endpoint may also be at least one of a 20% decrease in the dose of insulin or a reduction in the dose of insulin in at least 20% of the patients or preventing at least 10% of patients from progressing from OAD to insulin therapy.
The therapeutic endpoint may also be at least one of decreasing the incidence of severe hypoglycemic events by 5% or decreasing the incidence of severe hyperglycemic events in at least 25% of the patients.
The aforementioned and other embodiments of the present specification shall be described in greater depth in the drawings and detailed description provided below.
The accompanying drawings illustrate various embodiments of systems, methods, and embodiments of various other aspects of the disclosure. Any person with ordinary skills in the art will appreciate that the illustrated element boundaries (e.g. boxes, groups of boxes, or other shapes) in the figures represent one example of the boundaries. It may be that in some examples one element may be designed as multiple elements or that multiple elements may be designed as one element. In some examples, an element shown as an internal component of one element may be implemented as an external component in another and vice versa. Furthermore, elements may not be drawn to scale. Non-limiting and non-exhaustive descriptions are described with reference to the following drawings. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating principles.
The present specification is directed towards methods and systems for proximal foregut mucosal and submucosal tissue removal or resection, and more specifically, duodenal mucosal and submucosal removal or resection. In embodiments, the imbalance in the equilibrium between anti-incretin factors and incretins because of overproduction of anti-incretins is addressed by the tissue removal or resection systems and methods of the present specification. Specifically, cells in the duodenum responsible to produce factors with anti-incretin effects are removed by the selective resection of mucosal and submucosal tissue in the duodenum without removing or resecting the muscularis or serosal tissue as done during a surgical procedure. The resection or tissue removal procedure is performed in the proximal foregut of diabetic patients. Resection is a medical procedure that is used to remove anatomical structures from the body. In embodiments of the present specification, portions of a mucosal and submucosal tissue of proximal foregut, or duodenum, are resected or removed. In some embodiments, mucosal and sub-mucosal tissue may be resected.
In some embodiments, resection of the foregut mucosa and/or submucosa is performed using one of the techniques of endoscopic band ligation, endoscopic mucosal resection, or endoscopic submucosal dissection. Elastic or rubber band ligation involves the deploying a constricting elastic resection component, device, member, material, or band about the mucosal tissue surface that is to be resected. Deploying the band around the tissue occludes distal blood supply to the tissue so that the affected portion slowly dies, sloughs off, and is passed out from the body. Endoscopic band ligation procedures involve use of a ligation device that is affixed to the distal end of an endoscope. One or more elastic bands are positioned at the distal end for this purpose. During deployment, the most distal band is stretched outwardly beyond its relaxed configuration, and placed upon a surface of the mucosa in the proximal foregut. In some embodiments, a shape-memory material, such as Nitinol, is positioned along with or within the loop of the band. The shape-memory material contracts upon deployment, along with constricting of the elastic band to its non-stretched configuration, and assists in keeping the band positioned about the target tissue until the ischemic necrosis and/or resection is complete, preventing premature dislodging of the bands or resection devices. In embodiments, the shape-memory material is configured in different forms to provide an anchor into the mucosal surface. The anchoring and constricting of the shape-memory material and the constricting action of the elastic band enables the loop of the elastic band to gather a portion of the encircled mucosal surface and submucosal tissue into a nodule. The continued constriction action of the anchor and the band apply pressure on the gathered target tissue surface, resulting in the cutting-off of blood supply to that portion of the tissue and eventual death and sloughing off of that tissue portion. Resecting and removing both the mucosal and submucosal tissue will target glucose homeostasis mechanisms that reside both the mucosal and submucosal layer, resulting in more profound synergistic effect on glucose metabolism.
Referring to
Foregut mucosal or submucosal resection and regeneration of normal/healthy foregut mucosa and or submucosa results in and increases the enteroglucagon and gastroinhibitory peptide response to oral glucose, increases insulin-like growth factor 1 levels (IGF-1), and lowers plasma leptin levels in diabetic and nondiabetic morbidly obese patients, similar to what is seen with gastric bypass surgery. Gastric bypass achieves normalization of plasma insulin and glucose by avoiding stimulation of cells producing the unknown factor with anti-incretin effect, in addition to earlier and/or increased GLP-1 production along with other hormones. Postprandial reduction of pancreatic polypeptide may also occur. Foregut mucosal/submucosal resection reduces leptin levels before weight loss occurs and increases the enteroglucagon response to a glucose test, similar to the results seen with biliopancreatic diversion. Embodiments of the present specification decrease plasma lipid levels similarly to that in biliopancreatic diversion in some patients. High levels of plasma glucagon-like peptide 1, reported after jejunoileal bypass, are also seen with foregut mucosal/submucosal resection using the devices and methods of the present specification. The high levels of plasma glucagon-like peptide 1 plays a role in the mechanism of diabetes control after bariatric surgeries and also results in improvement or resolution of many conditions associated with insulin resistance.
The present specification is directed towards multiple embodiments. The following disclosure is provided in order to enable a person having ordinary skill in the art to practice the invention. Language used in this specification should not be interpreted as a general disavowal of any one specific embodiment or used to limit the claims beyond the meaning of the terms used therein. The general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the invention. Also, the terminology and phraseology used is for the purpose of describing exemplary embodiments and should not be considered limiting. Thus, the present invention is to be accorded the widest scope encompassing numerous alternatives, modifications and equivalents consistent with the principles and features disclosed. For purpose of clarity, details relating to technical material that is known in the technical fields related to the invention have not been described in detail so as not to unnecessarily obscure the present invention.
In the description and claims of the application, each of the words “comprise”, “include”, “have”, “contain”, and forms thereof, are not necessarily limited to members in a list with which the words may be associated. Thus, they are intended to be equivalent in meaning and be open-ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items. It should be noted herein that any feature or component described in association with a specific embodiment may be used and implemented with any other embodiment unless clearly indicated otherwise.
It must also be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context dictates otherwise. Although any systems and methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present disclosure, the preferred, systems and methods are now described.
In the present specification, the term “resection component” is defined as any elastic resection component, device, member, or material that is configured to be positioned about a tissue surface, for example, via deployment from a deployment device, to encircle or wrap around a portion of that tissue which is to be resected. A resection component includes a band, a loop, an O-ring, an elastic circle, or any other component adapted to have a first configuration with a circumference of M when subjected to a pressure and adapted to automatically transition to a second configuration with a circumference of N when the pressure is removed, where N is less than M.
Insulin resistance can be assessed through various clinical and laboratory parameters. Some commonly used parameters to measure insulin resistance include:
Fasting Insulin: Fasting insulin levels are measured after an overnight fast and provide an indication of basal insulin secretion. Elevated fasting insulin levels are often associated with insulin resistance.
Fasting Glucose: Fasting blood glucose levels are measured to evaluate the fasting state of glucose metabolism. Insulin resistance can lead to impaired fasting glucose levels, indicating a reduced ability of insulin to promote glucose uptake.
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR): HOMA-IR is a mathematical formula that calculates insulin resistance using fasting glucose and fasting insulin levels. It provides an estimate of insulin sensitivity based on the assumption that the liver is the primary site of insulin resistance.
Oral Glucose Tolerance Test (OGTT): An OGTT involves measuring blood glucose and insulin levels before and after consuming a glucose solution. The response of blood glucose and insulin following glucose ingestion can help assess insulin resistance.
Insulin Sensitivity Index (ISI): ISI is a measure of whole-body insulin sensitivity and can be derived from either a hyperinsulinemic-euglycemic clamp technique or frequently sampled intravenous glucose tolerance test (FSIVGTT). It provides a quantitative assessment of insulin sensitivity.
Quantitative Insulin Sensitivity Check Index (QUICKI): QUICKI is a formula that uses fasting glucose and fasting insulin levels to estimate insulin sensitivity. It is based on the inverse relationship between insulin sensitivity and fasting insulin levels.
Matsuda Index: The Matsuda Index is calculated from glucose and insulin values obtained during an OGTT. It provides an estimate of insulin sensitivity by assessing the ability of insulin to facilitate glucose disposal.
Adipose Tissue Insulin Resistance (Adipo-IR): Adipo-IR is a measure of insulin resistance specific to adipose tissue. It is calculated using fasting plasma insulin and adiponectin levels, with lower adiponectin levels indicating higher adipose tissue insulin resistance.
Insulin Clamp Technique: The hyperinsulinemic-euglycemic clamp is considered the gold standard for measuring insulin sensitivity. It involves infusing insulin intravenously at a constant rate while maintaining blood glucose levels at a stable, predetermined level.
Lipid Profile: Insulin resistance is often associated with alterations in lipid metabolism. Assessing parameters such as triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol can provide insights into the metabolic abnormalities associated with insulin resistance.
Waist Circumference and Body Mass Index (BMI): Central obesity is strongly linked to insulin resistance. Waist circumference and BMI are simple anthropometric measures used to assess adiposity and estimate the risk of insulin resistance.
One of more of these parameters can be used to provide a comprehensive evaluation of insulin resistance. Different techniques and indices may be employed in research and clinical settings based on availability and specific research or diagnostic purposes. An improvement in insulin resistance of 10% or more measured using any of these parameters is concerned clinically significant and meaningful.
The severity of non-alcoholic fatty liver disease (NAFLD) is assessed using several clinical and laboratory tests. These tests help in evaluating the degree of liver damage, inflammation, fibrosis, and other related aspects. Commonly used tests used to measure NAFLD severity include:
Liver Function Tests: Elevated ALT levels are a marker of liver inflammation and injury. Higher ALT levels often indicate more severe liver damage in NAFLD.
Imaging Studies—Ultrasonography is a non-invasive imaging technique that can detect fat accumulation in the liver and is initial screening tool for NAFLD. Computed Tomography (CT) Scan provides detailed images of the liver and help evaluate the extent of fat deposition and fibrosis. Magnetic Resonance Imaging (MRI) can assess liver fat content, fibrosis, and inflammation, providing more precise information about the severity of NAFLD. Transient Elastography (FibroScan) measures liver stiffness, which is an indirect marker of fibrosis severity. Higher liver stiffness values indicate more advanced fibrosis.
Biomarkers of Fibrosis and Inflammation include Fibrosis-4 Index (FIB-4) is a simple calculation that combines age, AST (aspartate aminotransferase) levels, ALT levels, and platelet count to estimate the degree of liver fibrosis. Higher FIB-4 scores are associated with more severe fibrosis. The NAFLD Fibrosis Score uses several clinical parameters, including age, BMI, diabetes status, platelet count, albumin levels, and AST/ALT ratio, to predict the presence and severity of liver fibrosis. Enhanced Liver Fibrosis (ELF) Test measures three serum markers (hyaluronic acid, procollagen III N-terminal peptide, and tissue inhibitor of metalloproteinase 1) associated with liver fibrosis. It provides a numerical score indicating fibrosis severity.
Liver Biopsy is considered the gold standard for assessing NAFLD severity. A small sample of liver tissue is obtained and examined under a microscope to determine the degree of fat accumulation, inflammation, hepatocyte injury, and fibrosis.
The selection of tests depends on the clinical context, resources, and individual patient factors. Non-invasive methods are preferred whenever possible, but in some cases, a liver biopsy may be necessary to provide a definitive assessment of NAFLD severity.
One of more of these parameters can be used to provide a comprehensive evaluation of NAFLD. Different techniques and indices may be employed in research and clinical settings based on availability and specific research or diagnostic purposes. An improvement in insulin resistance of 10% or more measured using any of these parameters is concerned clinically significant and meaningful.
Foregut mucosa resection using a ligation or resection device such as elastic bands is depicted in
Referring simultaneously to
Referring to
A sequential progress of cap assisted foregut mucosa resection is illustrated in
A sequential progress of foregut mucosa resection using a band and a snare is illustrated in
In various embodiments of the present specification, the end cap positioned at a distal end of the endoscope may be made of one or more of: polycarbonate, PVC, silicone, or Teflon non-latex rubber material. The end-cap is preferably made of a transparent material to enable visibility of the procedure. In embodiments, the end cap has a diameter in the range of 5 mm to 25 mm. Additionally, in embodiments, the bands configured to be positioned on the end cap are made of one of silicone, Teflon rubber, or non-latex rubber.
In different embodiments, including those illustrated by
In general, it is preferred for the aforementioned resection components or bands to be made of a first material and the anchors to be made a second material where the first material is different from the second material. More preferably, the first material has a greater elasticity than the second material, and/or the first material has a shore durometer value that is less than the shore durometer value of the second material. More preferably, if the circular band is cut and laid out linearly, its entire length is equal to a first value and if the anchor is similarly cut and/or laid out linearly, its entire length is equal to a second value where the second value is greater than the first value. More preferably, a portion of the anchor is physically attached or embedded into the band, where that portion has a length that is equal to or less than 70%, preferably equal to or less than 50% and more preferably equal to or less than 25%, of the entire length of the anchor. More preferably, the unstretched band has a diameter equal to a first value and the anchor has one or more protrusions extending from the inner surface of the band, wherein each protrusion extends a distance into the area encircled by the band and wherein the distance is equal to at least 5% of the diameter, at least 10% of the diameter, at least 20% of the diameter, at least 30% of the diameter, at least 40% of the diameter, at least 50% of the diameter, at least 60% of the diameter, at least 70% of the diameter, at least 80% of the diameter, or at least 90% of the diameter. More preferably, the unstretched band has a diameter equal to a first value and the anchor has one or more protrusions extending from the inner surface of the band, wherein each protrusion extends a distance into the area encircled by the band and wherein the distance is equal to no more than 50% of the diameter, no more than 40% of the diameter, no more than 30% of the diameter, no more than 20% of the diameter, no more than 10% of the diameter, or no more than 5% of the diameter. The band may be divided into two equal halves, wherein the anchor comprises two protrusions where each of the two protrusions is positioned centrally within, and extends out from, each of the two halves. The band may be divided into three equal thirds, wherein the anchor comprises three protrusions where each of the three protrusions is positioned centrally within, and extends out from, each of the three thirds. The band may be divided into four equal fourths, wherein the anchor comprises four protrusions where each of the four protrusions is positioned centrally within, and extends out from, each of the four fourths. The band may be divided into five equal fifths, wherein the anchor comprises five protrusions where each of the five protrusions is positioned centrally within, and extends out from, each of the five fifths. The band may be divided into six equal sixths, wherein the anchor comprises six protrusions where each of the six protrusions is positioned centrally within, and extends out from, each of the six sixths. The band may be divided into seven equal sevenths, wherein the anchor comprises seven protrusions where each of the seven protrusions is positioned centrally within, and extends out from, each of the seven sevenths. The band may be divided into eight equal eighths, wherein the anchor comprises eight protrusions where each of the eight protrusions is positioned centrally within, and extends out from, each of the eight eighths. The band may be divided into nine equal ninths, wherein the anchor comprises nine protrusions where each of the nine protrusions is positioned centrally within, and extends out from, each of the nine ninths. The band may be divided into ten equal tenths, wherein the anchor comprises ten protrusions where each of the ten protrusions is positioned centrally within, and extends out from, each of the ten tenths.
In various embodiments, more than five discrete and less than 100 discrete resection components or elastic bands are applied to the foregut mucosa and left in place to resect the foregut mucosa or submucosa over a period of time using ischemic necrosis of the mucosa. In some embodiments, the bands are deployed and left in their position for approximately seven days. In some embodiments, the bands are deployed and left in their position for approximately one day. In another embodiment, the bands are deployed and left in their position for approximately 30 days. In most embodiments, the bands slough-off without the need for additional intervention after the ischemic necrosis process is completed and are naturally passed out of the human body.
In other embodiments, more than five discrete and less than 100 discrete resection components or bands are applied to the foregut mucosa and the foregut mucosa or submucosa is resected during the endoscopic procedure using hot or cold snare resection or band resection technique. In yet another embodiment, more than five discrete and less than 100 discrete areas of foregut mucosa and the foregut mucosa or submucosa are resected during the endoscopic procedure using cap assisted hot or cold snare resection technique.
In yet another embodiment, duodenal periampullary mucosa or submucosa are resected without resecting an ampullary mucosa during the procedure using cap assisted hot or cold snare or band resection technique.
In yet another embodiment, the foregut mucosa and/or submucosa is resected using endoscopic submucosal dissection technique where the foregut mucosa and/or submucosa is resected in one or more non-contiguous sections wherein the cumulative surface area of the resected mucosa is between 5 cm2 and 100 cm2.
In one embodiment, between 5 cm2 and 500 cm2 of proximal foregut mucosa is resected. In another embodiment, non-contiguous portions of the foregut mucosa are resected using multiple resection components or bands and corresponding anchor configurations. In cases of non-contiguous resection, a single mucosal resection area is less than 5 cm2 and the cumulative mucosal resection area may be greater than 10 cm2. In another embodiment, less than 50% of a contiguous circumferential mucosa is resected while greater than 50% non-contiguous circumferential mucosa is resected. In another embodiment, less than 5 cm of contiguous length of foregut mucosa is resected while greater than 5 cm of cumulative length of foregut mucosa is resected. In yet another embodiment, the resection is performed in two or more discrete sections of the foregut mucosa or submucosa, wherein the resected mucosa or submucosa is intervened by one or more sections of non-resected mucosa or submucosa. In some embodiments, the intervening non-ligated and/or resected mucosa can be treated with a different ablation or electroporation or morcellation technology to maximize the treated surface area.
Referring simultaneously to
At step 1554, and as illustrated by
At step 1556, and as illustrated by
Embodiments of the present specification can be used for treating at least one of excess weight, obesity, eating disorders, metabolic syndrome, dyslipidemia, diabetes, polycystic ovarian disease, fatty liver disease, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis disease by resecting foregut tissue using a foregut mucosal and/or submucosal resection and/or dissection system.
In various embodiments, resection therapy is provided to achieve the following therapeutic goals or endpoints for patients with obesity, excess weight, eating disorders, dyslipidemia, or diabetes and a first phase of treatment is considered successful for these patients if any one or more of the following therapeutic goals or endpoints is reached: a total body weight of the patient decreases by at least 1% relative to a total body weight of the patient before resection; an excess body weight of the patient decreases by at least 1% relative to an excess body weight of the patient before resection; a total body weight of the patient decreases by at least 1% relative to a total body weight of the patient before resection and a well-being level of the patient does not decrease more than 5% relative to a well-being level of the patient before resection; an excess body weight of the patient decreases by at least 1% relative to an excess body weight of the patient before resection and a well-being level of the patient does not decrease more than 5% relative to a well-being level of the patient before resection; a pre-prandial ghrelin level of the patient decreases by at least 1% relative to a pre-prandial ghrelin level of the patient before resection; a post-prandial ghrelin level of the patient decreases by at least 1% relative to a post-prandial ghrelin level of the patient before resection; an exercise output of the patient increases by at least 1% relative to an exercise output of the patient before resection; a glucagon-like peptide-1 level of the patient increases by at least 1% relative to a glucagon-like peptide-1 level of the patient before resection; a leptin level of the patient increases by at least 1% relative to a leptin level of the patient before resection; the patient's appetite decreases, over a predefined period of time, relative to the patient's appetite before resection; a peptide YY level of the patient increases by at least 1% relative to a peptide YY level of the patient before resection; a lipopolysaccharide level of the patient decreases by at least 1% relative to a lipopolysaccharide level of the patient before resection; a motilin-related peptide level of the patient decreases by at least 1% relative to a motilin-related peptide level of the patient before resection; a cholecystokinin level of the patient increases by at least 1% relative to a cholecystokinin level of the patient before resection; a resting metabolic rate of the patient increases by at least 1% relative to a resting metabolic rate of the patient before resection; a plasma-beta endorphin level of the patient increases by at least 1% relative to a plasma-beta endorphin level of the patient before resection; an HbA1c level of the patient decreases by at least 0.3% relative to an HbA1c level of the patient before resection; a triglyceride level of the patient decreases by at least 1% relative to a triglyceride level of the patient before resection; a total blood cholesterol level of the patient decreases by at least 1% relative to a total blood cholesterol level of the patient before resection; a glycemia level of the patient decreases by at least 1% relative to a glycemia level of the patient before resection; a composition of the person's gut microbiota modulates from a first state before resection to a second state after resection, wherein the first state has a first level of bacteroidetes and a first level of firmicutes, wherein the second state has a second level of bacteroidetes and a second level of firmicutes, wherein the second level of bacteroidetes is greater than the first level of bacteroidetes by at least 3%, and wherein the second level of firmicutes is less than the first level of firmicutes by at least 3%; or, a cumulative daily dose of the patient's antidiabetic medications decreases by at least 10% relative to a cumulative daily dose of the patient's antidiabetic medications before resection. In most embodiments, the incidence of severe hypoglycemia is decreased to <1%.
In various embodiments, resection therapy is provided to achieve the following therapeutic goals or endpoints for patients with dyslipidemia and a first phase of treatment is considered successful for these patients if any one or more of the following therapeutic goals or endpoints is reached: a lipid profile of the patient improves by at least 10% relative a lipid profile of the patient before resection, wherein lipid profile is defined at least by a ratio of LDL cholesterol to HDL cholesterol, and improve is defined as a decrease in the ratio of LDL cholesterol to HDL cholesterol; an LDL-cholesterol level of the patient decreases by at least 10% relative to an LDL-cholesterol level of the patient before resection; or, a VLDL-cholesterol level of the patient decreases by at least 10% relative to a VLDL-cholesterol level of the patient before resection.
In various embodiments, resection therapy is provided to achieve the following therapeutic goals or endpoints for patients with non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD), and a first phase of treatment is considered successful for these patients if any one or more of the following therapeutic goals or endpoints is reached: at least a 10% decrease in either ALT or AST levels relative to ALT or AST levels before resection; at least a 10% improvement in serum ferritin level or an absolute serum ferritin level of less than 1.5 ULN (upper limit normal) relative to serum ferritin levels before resection; at least a 5% improvement in hepatic steatosis (HS) or less than 5% HS relative to HS levels before resection, as measured on liver biopsy; at least a 5% improvement in HS or less than 5% HS relative to HS levels before resection, as measured by magnetic resonance (MR) imaging, either by spectroscopy or proton density fat fraction; at least a 5% improvement in an NAFLD Fibrosis Score (NFS) relative to an NFS before resection; at least a 5% improvement in an NAFLD Activity Score (NAS) relative to an NAS before resection; at least a 5% improvement in a Steatosis Activity Fibrosis (SAF) score relative to an SAF score before resection; at least a 5% decrease in a mean annual fibrosis progression rate relative to a mean annual fibrosis progression rate before resection, as measured by histology, Fibrosis-4 (FIB-4) index, aspartate aminotransferase (AST) to platelet ratio index (APRI), serum biomarkers (Enhanced Liver Fibrosis (ELF) panel, Fibrometer, FibroTest, or Hepascore), or imaging (transient elastography (TE), MR elastography (MRE), acoustic radiation force impulse imaging, or supersonic shear wave elastography); at least a 5% decrease in circulating levels of cytokeratin-18 fragments relative to circulating levels of cytokeratin-18 fragments before resection; at least a 5% improvement in FIB-4 index, aspartate aminotransferase (AST]) to platelet ratio index (APRI), serum biomarkers (Enhanced Liver Fibrosis (ELF) panel, Fibrometer, FibroTest, or Hepascore), or imaging (transient elastography (TE), MR elastography (MRE), acoustic radiation force impulse imaging, or supersonic shear wave elastography) relative to FIB-4 index, aspartate aminotransferase (AST]) to platelet ratio index (APRI), serum biomarkers (Enhanced Liver Fibrosis (ELF) panel, Fibrometer, FibroTest, or Hepascore), or imaging (transient elastography (TE), MR elastography (MRE), acoustic radiation force impulse imaging, or supersonic shear wave elastography) before resection; at least a 5% decrease in liver stiffness relative to liver stiffness before resection, as measured by vibration controlled transient elastography (VCTE/FibroScan); an improvement in NAS by at least 2 points, with at least 1-point improvement in hepatocellular ballooning and at least 1-point improvement in either lobular inflammation or steatosis score, and no increase in the fibrosis score, relative to NAS, hepatocellular ballooning, lobular inflammation, steatosis, and fibrosis scores before resection; at least a 5% improvement in NFS scores relative to NFS scores before resection; or, at least a 5% improvement in any of the above listed NAFLD parameters as compared to a sham intervention or a placebo.
In various embodiments, resection therapy is provided to achieve the following therapeutic goals or endpoints for patients with diabetes and a first phase of treatment is considered successful for these patients if any one or more of the following therapeutic goals or endpoints is reached: at least one of a 20% decrease in the dose of oral antidiabetic drugs (OAD) or a reduction in the dose of OAD in at least 20% of the patients.
In various embodiments, resection therapy is provided to achieve the following therapeutic goals or endpoints for patients with diabetes and a first phase of treatment is considered successful for these patients if any one or more of the following therapeutic goals or endpoints is reached: at least one of a 20% decrease in the dose of insulin or a reduction in the dose of insulin in at least 20% of the patients or preventing at least 10% of patients from progressing from OAD to insulin therapy.
In various embodiments, resection therapy is provided to achieve the following therapeutic goals or endpoints for patients with diabetes and a first phase of treatment is considered successful for these patients if any one or more of the following therapeutic goals or endpoints is reached: at least one of decreasing the incidence of severe hypoglycemic events by 5% or decreasing the incidence of severe hyperglycemic events in at least 25% of the patients.
If any one of the above therapeutic goals or endpoints is met, therapy is completed, and no further resection is performed. If none of the above therapeutic goals or endpoints are met, then the entire resection procedure and evaluation, less the screening process, can be repeated for a second therapy phase, and subsequent therapy phases. If therapeutic goals or endpoints are still not met, the patient may wait for at least four weeks each time between each resection procedure and each evaluation.
The above examples are merely illustrative of the many applications of the system of present specification. Although only a few embodiments of the present invention have been described herein, it should be understood that the present invention might be embodied in many other specific forms without departing from the spirit or scope of the invention. Therefore, the present examples and embodiments are to be considered as illustrative and not restrictive, and the invention may be modified within the scope of the appended claims.
The present application relies upon U.S. Patent Provisional Application No. 63/365,079, titled “Systems and Methods for Duodenal Mucosal Resection”, and filed on May 20, 2022, for priority. The above-mentioned application is herein incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63365079 | May 2022 | US |
