Patent Application
20200253659
The small intestine is the body's largest hormone-producing organ, and hormones produced in the small intestine have long been known to play an important role in blood glucose regulation. Recent discoveries in metabolic science are now demonstrating that changes to the lining of the first segment of the small intestine—the duodenum—are associated with common metabolic disorders like type 2 diabetes mellitus, non-alcoholic steatohepatitis, as well as obesity.
After food passes through the stomach, it moves to the duodenum, which is the first part of the small intestine and the region where nutrient absorption begins in the gastrointestinal tract. The lining of the small intestine, or mucosa, is composed of several cell types, including hormone-producing cells (enteroendocrine cells). These hormone-producing cells (especially in the duodenum) sense the presence or absence of nutrients in the duodenum and send chemical signals to the body to help regulate insulin production and mediate glucose control.
Diets high in sugar and fat can cause significant changes in the duodenum over time, resulting in a thickened mucosa, abnormal nutrient absorption and alterations in the type and number of hormones released from the duodenum into the body, including hormones that help control insulin secretion and glucose homeostasis. This irregular chemical signaling is an important contributor to insulin resistance, which can develop into type 2 diabetes mellitus and other metabolic diseases such as non-alcoholic steatohepatitis.
Currently, there are varied treatment approaches to gastrointestinal related disorders. These approaches include devices that occupy space within the intestinal tract, such as intragastric balloons, transpyloric shuttles and devices that induce satiety; surgical interventions that include aspiration devices, gastric sleeves or pouches, gastrectomy, and Roux-en-Y bypass surgery; and implants, such as bypass sleeves. Each of these approaches have considerable drawbacks, including patient discomfort and nausea, erosion of the gastrointestinal tract, ulcers and bleeding, as well as implant migration and removal. In addition, conventional approaches have shown limited success with patient outcomes varying considerably across patient populations. There is a need for improved treatment devices and methods that can be effected in a minimally invasive procedure, that have minimal side effects, a shortened procedure and recovery time, and that are effective for longer durations of time, such as six months or more.
In recent years, small bowel interventional techniques have been developed that resurface the mucosal surface of the duodenum. Such techniques include ablation of the superficial duodenal mucosa after lifting of the surface by injection with a submucosal saline injection. While such techniques have shown promising patient outcomes, such procedures are painful, and require a series of time-consuming, complex steps, taking up to 40 minutes or more in performing such procedures. In addition, given the complexity of the procedure, inconsistencies in various steps can have adverse affects on patient outcomes. For example, if portions of the superficial duodenal mucosa are not lifted properly along the entire length of the treated portion of the duodenum, the treatment can result in incomplete resurfacing. Additionally, the surface of the lifted mucosa is highly irregular such that subsequent ablation still may not completely resurface the treated area, which can result in incomplete ablation resurfacing and repopulation of the treated area with errant mucosal cells. These drawbacks can result in inconsistent patient outcomes and require repeated procedures over time.
There is a need for improve devices and methods that allow for treatment of a portion of the gastroinstentinal tract in a minimally invasive manner with minimal pain and side effects for the patient and that can be effected by the clinician with greater use of use. There is further need for treatment methods that allow for shortened procedures, that can be performed more reliably and with greater consistency in patient outcomes, and that are effective long term.
This application generally relates generally to treatment devices and methods of treating disorders related to the gastrointestinal tract, in particular type 2 diabetes mellitus and non-alcoholic steatohepatitis.
In one aspect, the invention pertains to a method of treating a gastrointestinal disorder of a patient, such as type 2 diabetes mellitus. Such methods can include advancing a first catheter through a gastrointestinal tract of the patient to position a distal treatment region within a duodenum of the patient. In some embodiments, the distal treatment region includes a treatment delivery portion disposed between a proximal balloon and a distal balloon. The treatment delivery portion includes one or more delivery openings fluidly coupled with a delivery lumen extending to a proximal region of the first catheter. Next, the distal treatment region is positioned within a desired treatment region of the duodenum. The proximal and distal balloons are then inflated so as to sealingly engage an inside surface of the duodenum at opposite ends of the treatment region of the duodenum. Typically, the balloons are inflated by only a slight positive pressure. The treatment fluid is then delivered through the one or more openings while the proximal and distal balloons are sealingly engaged with the inside surface of the duodenum. Next, the treatment region of the duodenum between the inflated balloons is substantially filled with the treatment fluid. The treatment fluid is then maintained within the treatment region of the duodenum for a duration of time sufficient to treat the treatment region of the duodenum. It is appreciated that the treatment could be applied to other parts of the small intestine (e.g. jejunum) or other body lumens as well.
In some embodiments, the treatment fluid is maintained at a suitable temperature for thermally treating the treatment region of the duodenum. This can be accomplished by delivering the treatment fluid at a temperature elevated above the lowest suitable temperature or by monitoring the temperature of the treatment fluid and adjusting the temperature as needed.
The treatment fluid can be any suitable liquid (e.g. water, saline, alcohol, acetic acid or combinations) that is heated to a temperature within a range between 40 degrees Celsius and 100 degrees Celsius so as to thermally ablate a superficial lining of the treatment region of the duodenum. In some embodiments, the temperature range is between 50-100 degrees Celsius, 60-100 degrees Celsius, 70-100 degrees Celsius, or 70-95 degrees Celsius. Typically, the duration of time for such a heated fluid is at least thirty seconds. In some embodiments, the duration of time is at least one minute, two minutes, three minutes, or any duration up to 10 minutes or more. It is appreciated that, in some embodiments, the duration may vary based on the temperature of the treatment fluid, see for example the contours in
In one aspect, the treatment fluid is delivered into the treatment region of the duodenum between the inflated balloons so as to substantially fill the treatment fluid without regard to a pressure within the proximal and distal balloons. In some embodiments, filling of the treatment region between the inflated balloons is performed by delivering the treatment fluid until a pre-determined pressure increment (e.g. 0.5 atm) from a baseline of the delivery pressure or pressure within the duodenum is observed. In some embodiments, the treatment fluid is delivered until a pre-determined volume of fluid is delivered.
In another aspect, endoluminal devices that facilitate treating a gastrointestinal disorder of a patient with a treatment fluid provided herein. Such devices can include a first catheter extending from a proximal end to a distal treatment delivery region thereof. The distal treatment delivery region can include a treatment delivery portion disposed between a proximal balloon and a distal balloon. The treatment delivery portion can include one or more delivery openings in fluid communication with a delivery lumen extending to the proximal end of the first catheter. The proximal and distal balloons are fluidly coupled with one or more inflation lumens extending to the proximal end of the first catheter. Typically, the proximal and distal balloons are spaced apart by a fixed distance suitable for treatment of a desired treatment region of a duodenum of the patient. In some embodiments, the fixed distance is between 5 and 15 cm in length so as to allow concurrent treatment of a portion of the duodenum suitable for treatment of type 2 diabetes mellitus or non-alcoholic steatohepatitis. In some embodiments, each of the proximal and distal balloons is between 1.5 and 4 cm in diameter to facilitate sealing engagement with the inside surface of the duodenum. Typically, the proximal and distal balloons are formed of a semi-compliant material. In some embodiments, the device can include a temperature sensor disposed along the treatment delivery portion. Such devices can further include a heater configured for heating the treatment fluid and a controller configured to adjust heating of the treatment fluid with the heater based on an output from the temperature according to a control loop. In some embodiments, the device further includes one or more aspiration ports to aspirate or circulate the treatment fluid within the treatment region or a circulator configured for circulating the treatment fluid.
In yet another aspect, endoluminal devices that facilitate treatment of a gastrointestinal disorder of a patient with various other means are provided herein. Such various other means include plasma ablation, electrical ablation, chemical ablation and treatment by a therapeutic from an implant, such as a stent. Some such devices include expandable structures or balloons that facilitate uniform release of a treatment gas, such as argon, to generate an ablating plasma along the entire treatment region. Other such devices include electrode balloons to ablate the superficial mucosa with electrical ablating energy. Still, other such device can include expandable structures, such as a stent, that gradually release a chemical or therapeutic to chemically ablate or treat the treatment region of the duodenum. In some embodiments, the above expandable structures are configured to treat the entire treatment region without requiring movement of the device during treatment delivery. Methods of delivering treatment utilizing the devices described herein are also provided.
The invention pertains to non-invasive endoluminal devices that are advanced along the gastrointestinal tract via natural orifices. Typically, as shown in
As can be seen in
In one aspect, the invention pertains to an endoluminal catheter device having a distal region having a treatment delivery portion disposed between proximal and distal balloons. The overall length of the device from a proximal hub to the distal tip is sufficiently long, for example about 130 cm, so that the distal treatment delivery portion can be positioned within the desired treatment region of the duodenum while the hub remains readily accessible by the clinician. The treatment delivery portion can include one or more openings in fluid communication with a delivery lumen to facilitate delivery of the treatment fluid into a region of the duodenum between inflated proximal and distal balloons sealingly engaged within the duodenum. The balloons are of a size, shape and material suitable for inflation within the duodenum and to facilitate sealing engagement within the inner wall of the duodenum. The balloons can be formed of a compliant, non-compliant, or semi-compliant material or combinations thereof. Typically, the balloons are formed of a semi-compliant material so as to assume a rounded shape while still providing some conformance with the inner wall of the duodenum, thereby allowing for improving sealing within the duodenum. In some embodiments, each of the balloons have a diameter within a range of 1.5 cm and 4 cm, such as between 2 cm and 4 cm, so as to substantially fill and seal within the duodenum. In some embodiments, the balloons are formed of a clear or translucent material so as to allow the treatment region to be viewed through the balloons with an endoscope. In some embodiments, the balloons include a radiopaque marker to allow the bounds of the treatment region defined by the balloons to be readily determined through standard X-ray visualization techniques. The treatment deliver portion can include multiple openings for delivery and/or aspiration of the treatment fluid, and can further include one or more sensors for detecting a temperature of the treatment fluid. In some embodiments, the treatment delivery portion includes a heating or cooling device for actively controlling a temperature of the treatment fluid and can further include a circulator device to circulate the treatment fluid within the treatment region to facilitate a more uniform temperature distribution during treatment.
In some such devices, each of the proximal and distal balloons is inflatable so as to sealingly engage the walls of the duodenum, which are typically 20-30 mm in diameter. The balloons are spaced apart by a fixed length to define a treatment area between the inflated balloons, typically a portion of the duodenum about 8 to 10 cm in length. In some embodiments, the balloons are inflated with only a slight positive pressure (e.g. 1 psi-14 psi above ambient pressure). In some embodiments, the balloons are positionable such that the desired treatment area can be adjusted to a desired length. Each of the proximal and distal balloons can be fed by a separate lumen that extends to a proximal end of the device so as to be independently inflatable, or can be fed from a common inflation lumen so as to facilitate concurrent inflation and equalize pressure.
In such devices, the treatment delivery portion can include one or more outlets for delivery of an ablation agent, such as a hot fluid (e.g. water or vapor), into the portion of the duodenum sealed between the proximal and distal balloons. The outlets are fed by a lumen that extends to the proximal end of the device into which a clinician delivers the heated treatment fluid. The temperature of the fluid can be determined/monitored externally, or can be monitored by a sensor disposed on a distal portion of the device between the proximal and distal balloons. In some embodiments, the treated area can include a thermocouple in the treatment area to monitor temperature and a circulation loop to control water temperature by two or multiple inflow and outlet channels. The device can also include a localized heating element (e.g. a localized heating apparatus at the distal tip of fluid outflow channel) within the treatment area to generate or maintain the heated water or vapor within the treatment area for the duration of the treatment. The heated treatment fluid can be delivered so as to substantially fill the entire treatment region of the duodenum between the proximal and distal inflated balloons. The heated fluid is maintained for a period of time sufficient to ablate the superficial duodenal mucosa along the treatment area, and stimulate the regeneration of normalized population of enteroendocrine cells (e.g. L-cells) that are related to poor blood sugar regulation (type 2 diabetes mellitus) and other metabolic diseases (non-alcoholic steatohepatitis). The outlets can also be used as inlets to aspirate the heated fluid/vapor after treatment. In some embodiments, the device can include a nosecone for release of contrast media to determine whether the balloons are sufficiently sealed against the vessel walls of the duodenum. Example embodiments of such devices are shown in
In some embodiments, the treatment fluid 340 is a fluid (e.g. water, saline) that is heated to a temperature sufficient to thermally ablate the superficial mucosa. Typically, the treatment fluid is a temperature within a range between 40 degrees and 100 degrees Celsius to facilitate thermal ablation of the superficial mucosa while avoiding unnecessary damage to underlying tissues. In some embodiments, the temperature range can be between 60 degrees and 100 degrees Celsius. Preliminary animal studies indicate a particularly therapeutic effect within a temperature range from 70 degrees and 100 degrees Celsius, preferably between 80 degrees and 95 degrees Celsius. Preferably, the superficial mucosa is maintained above 60 degrees Celsius for at least thirty seconds to ensure ablation of the superficial mucosa. In some embodiments, the duration can be one minute, two minutes, three minutes or any duration up to 10 minutes or more to ensure sufficient cell exposure. It is desirable to avoid ablating deeper tissues underlying the superficial mucosa as this can result in damages to nearby organs, such as the pancreas causing pancreatitis or damages to deeper intestinal tissues resulting in scarring and formation of stenosis with subsequent narrowing of the duodenum and stenosis complication. Since the temperature of the heated fluid tends to drop upon initial introduction into the treatment region, it is desirable for the treatment fluid to be maintained at a temperature above 60 degrees Celsius, for example between 80 degrees and 100 degrees Celsius. The heated treatment fluid is maintained for a period of time greater than 30 seconds, for example one or more minutes, typically about three minutes or more so as to ensure the expose superficial mucosa is sufficiently heated to ablate the errant cells. In some embodiments, the treatment can include a treatment fluid at a temperature within a range from 80 degrees to 95 degrees Celsius at a duration of at least 30 seconds or more, which thus far has demonstrated a robust and consistent therapeutic response, as demonstrated by
In some embodiments, the ports can be coupled with manually controlled pump or syringe to allow manual control of balloon inflation and introduction of treatment fluid. In some embodiments, the clinician introduces a pre-determine volume of the treatment fluid, which can be estimated by the morphology and length of the treated region of the duodenum or can be determined by pre-filling the treatment region before treatment.
In other embodiments, a pressure monitor can be used, for example, an external pressure sensor or gage fluidly coupled with the treatment fluid delivery path. A pressure sensor can be disposed within the treatment region or can be fluidly coupled with the flowpath or reservoir and disposed outside the patient's body. By monitoring the pressure during delivery of the treatment fluid, the clinician can determine when the treatment region is substantially filled with the treatment fluid, typically without any regard to an inflation pressure within the balloons. For example, when the treatment fluid entirely fills the treated region of the duodenum, there is an increase in pressure in the delivery pressure or the pressure within the duodenum since the filled space is confined by the proximal and distal balloons. It is desirable to observe this increase in pressure before it becomes substantial so as to prevent leakage of the treatment fluid beyond the inflated balloons. Thus, in some embodiments, delivery of the treatment fluid is terminated when the pressure increases by a relatively small margin of the average delivery pressure, for example about 25% or less, such as about 10% or less, or about 5%. In some embodiments, the delivery pressure and/or the pressure within the duodenum is monitored in conjunction with monitoring a volume of treatment fluid delivered to determine an approaching end point as the treatment region becomes filled.
In another aspect, the treatment device can include various other means of ablating or treating the superficial mucosa, including the use of plasma ablation (e.g. argon), electrical ablation (e.g. RF), chemical ablation, or therapeutic treatment (e.g. drug eluting implants).
While the exemplary embodiments have been described in some detail, by way of example and for clarity of understanding, those of skill in the art will recognize that a variety of modifications, adaptations, and changes may be employed. Hence, the scope of the present invention should be limited solely by the appending claims.
In the foregoing specification, the invention is described with reference to specific embodiments thereof, but those skilled in the art will recognize that the invention is not limited thereto. Various features, embodiments and aspects of the above-described invention can be used individually or jointly. Further, the invention can be utilized in any number of environments and applications beyond those described herein without departing from the broader spirit and scope of the specification. The specification and drawings are, accordingly, to be regarded as illustrative rather than restrictive. It will be recognized that the terms “comprising,” “including,” and “having,” as used herein, are specifically intended to be read as open-ended terms of art.
The present application is a Continuation of PCT/US2018/057842 filed Oct. 26, 2018; which claims the benefit of U.S. Provisional Appln No. 62/579,028 filed Oct. 30, 2017; the contents of which are incorporated herein by reference in their entirety for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 62579028 | Oct 2017 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2018/057842 | Oct 2018 | US |
| Child | 16861749 | US |
